Conditions: Hormone Receptor Positive Breast Cancer HER-2 Positive Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 237
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effectiveness of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus physicians choice standard of care chemotherapy in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) locally advanced or metastatic breast cancer after prior exposure to at least two HER2-directed therapies for advanced disease.

Detailed description:

Arms:
arm 1: 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter. arm 2: 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle. arm 3: 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician's choice administered according to product label

Interventions: intervention 1: Abemaciclib intervention 2: Trastuzumab intervention 3: Fulvestrant intervention 4: Standard of Care Single Agent Chemotherapy
Intervention descriptions: intervention 1: Administered Orally intervention 2: Administered IV intervention 3: Administered IM intervention 4: Standard-of-care single-agent chemotherapy of physician's choice administered according to product label

Protocol document:
Prot_002.pdf: 
Protocol  I3Y-MC-JPBZ(f)
A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of 
Abemaciclib plus Trastuzumab with or without Fulvestrant to Standard-of-Care 
Chemotherapy of Physician's Choice plus Trastuzumab in Women with HR+, HER2+ Locally 
Advanced or Metastatic Breast Cancer
NCT02675231
Approval date: 26-Feb-2021


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1.
Protocol I3Y-MC-JPBZ(f)
monarcHER:  A Phase 2, Randomized, Multicenter, 3-Arm, 
Open-Label Study to Compare the Efficacy of 
Abemaciclib plus Trastuzumab with or without 
Fulvestrant to Standard-of-Care Chemotherapy of 
Physician’s Choice plus Trastuzumab in Women with 
HR+, HER2+ Locally Advanced or Metastatic Breast 
Cancer
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
abemaciclib (LY2835219), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Abemaciclib (LY2835219)
This is a randomized, multicenter, 3-arm, open-label Phase 2 study to compare the efficacy 
of abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus trastuzumab to 
standard-of-care single-agent chemotherapy plus trastuzumab in women with HR+, HER2+ 
locally advanced or metastatic breast cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 05 October 2015
Amendment (a) Electronically Signed and Approved by Lilly on 22 December 2015
Amendment (b) Electronically Signed and Approved by Lilly on 23 May 2016
Amendment (c) Electronically Signed and Approved by Lilly on 23 January 2019.
Amendment (d) Electronically Signed and Approved by Lilly on 10 February 2020
Amendment (e) Electronically Signed and Approved by Lilly on 27 January 2021
Amendment (f) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 26-Feb-2021 GMT


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2.
Synopsis
Study Rationale
The overexpression of the human epidermal growth factor receptor 2 (HER2) is associated with a 
poor prognosis in hormone-receptor-positive (HR+) metastatic breast cancer (mBC) patients.  
Although HER2-targeted therapies such as trastuzumab have improved clinical outcomes in this 
patient population, resistance often emerges to these therapies, and HER2 positive (HER2+), 
HR+ mBC remains an incurable disease.  In preclinical models of resistance to a HER2-targeted 
agent, sustained cyclin D expression causes inappropriate activation of cyclin-dependent kinase 
(CDK) 4, which drives cancer cell growth.  Inhibition of cyclin D/CDK 4 was able to overcome 
this mechanism of resistance.  Abemaciclib (LY2835219) is a selective and potent small 
molecule inhibitor of CDK 4 and CDK 6 with antitumor activity in multiple preclinical 
pharmacology models and an acceptable toxicity profile in nonclinical species.  Cell-based 
studies across a diverse panel of cell lines representing the known molecular subgroups of breast 
cancer indicated that sensitivity to the antiproliferative activity of abemaciclib is greater in HR+ 
cell lines (including HER2+ and HER2 negative [HER2-] cell lines).  Clinically, abemaciclib has 
demonstrated evidence of single-agent activity in women with HR+ mBC (both HER2+ and 
HER2-) in the Phase 1 Study I3Y-MC-JPBA (JPBA).  In this same study, abemaciclib 
demonstrated a clinically manageable safety profile for women with HR+ mBC.  Preliminary 
safety data from Study I3Y-MC-JPBH of abemaciclib in combination with endocrine therapies in 
HR+ mBC patients are consistent with the safety profile from Study JPBA.
The evaluation of abemaciclib in combination with trastuzumab is of interest since CDK 4 
inhibition may enhance the response to HER2-targeted therapy and could delay or overcome 
resistance. Study I3Y-MC-JPBZ is a randomized, multicenter, 3-arm, open-label phase 2 study 
to compare the efficacy of abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus 
trastuzumab to standard-of-care single-agent chemotherapy plus trastuzumab in women with 
HR+, HER2+ locally advanced or metastatic breast cancer.


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Clinical Protocol Synopsis:  Study I3Y-MC-JPBZ
Name of Investigational Product:  Abemaciclib (LY2835219)
Title of Study:  monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the 
Efficacy of Abemaciclib plus Trastuzumab with or without Fulvestrant to Standard-of-Care Chemotherapy of 
Physician’s Choice plus Trastuzumab in Women with HR+, HER2+ Locally Advanced or Metastatic Breast 
Cancer
Number of Planned Patients:
Entered:  275
Enrolled/Randomized:  225
Completed:  225
Phase of Development:  2
Length of Study:  approximately 48 months
Planned first patient visit:  Apr 2016
Planned last patient visit:  Apr 2020
Objectives:  The primary objective of this study is to compare the efficacy of abemaciclib plus trastuzumab plus 
fulvestrant and abemaciclib plus trastuzumab to standard-of-care single-agent chemotherapy of physician’s choice 
plus trastuzumab with respect to progression free survival (PFS).
The secondary objectives of the study are to compare the 3 arms with respect to each of the following:

overall survival (OS) rate at 1, 2, and 3 years

objective response rate (ORR)

duration of response (DoR) (Complete response [CR] + partial response [PR])

disease control rate (DCR) (CR + PR + stable disease [SD])

clinical benefit rate (CBR) (CR + PR + SD ≥6 months)

safety and tolerability of abemaciclib in combination with trastuzumab and fulvestrant 

impact on pain, disease symptoms, and overall quality of life using the modified Brief Pain Inventory-Short 
Form (mBPI-sf), the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30), and the health status scores from the EuroQol 5-Dimension 5 
Level (EQ-5D 5L)

pharmacokinetics (PK) of abemaciclib and its metabolites, fulvestrant, and trastuzumab in the target patient 
population

relationship between abemaciclib, trastuzumab, and fulvestrant exposure and response for safety and efficacy 
endpoints 
The exploratory objectives of this study are:

to explore potential biomarkers related to the mechanism of action of abemaciclib, the cell cycle, and/or the 
pathogenesis of breast cancer and association with clinical outcome
Study Design:  Study I3Y-MC-JPBZ is a randomized, multicenter, 3-arm, open-label Phase 2 study to compare the 
efficacy of abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus trastuzumab to standard-of-care 
single-agent chemotherapy of physician’s choice plus trastuzumab in women with HR+, HER2+ locally advanced 
or metastatic breast cancer


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Diagnosis and Main Criteria for Inclusion and Exclusions:  Patients are eligible to be included in the study only 
if they meet all of the following criteria:  [1] have a diagnosis of HR+, HER2+ advanced breast cancer ; [2] have 
unresectable locally advanced recurrent breast cancer or metastatic breast cancer ; [3] have adequate tumor tissue 
(newly obtained biopsy; otherwise archived tissue) available prior to randomization; [4] have measurable and/or 
non-measurable disease according to RECIST version 1.1; [5] have previously received at least 2 HER2-directed 
therapies for advanced disease and must have received T-DM1 in any disease setting; [6] must have received a 
taxane in any disease setting; [7] may have received any endocrine therapy (excluding fulvestrant); [8] have 
postmenopausal status due to either surgical/natural menopause or induced by ovarian suppression; [9] have a 
performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) scale; [10] must have left 
ventricular ejection fraction (LVEF) of 50% or higher at baseline; [11] have adequate organ function; [12] have a 
negative serum pregnancy test at baseline and agree to use medically approved precautions to prevent pregnancy 
during the study and for 12 weeks following the last dose of abemaciclib if postmenopausal status is due to ovarian 
suppression; [13] 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; [14] have 
discontinued all previous therapies for cancer, except trastuzumab, for at least 21 days for myelosuppressive agents 
or 14 days for non-myelosuppressive agents prior to receiving study drug, and recovered from the acute effects of 
therapy except for residual alopecia and peripheral neuropathy; [15] are female and ≥18 years of age; [16] are 
reliable and willing to make themselves available for the duration of the study and are willing to follow study 
procedures; [17] have given written informed consent prior to any study-specific procedures; and [18] are able to 
swallow capsules.
Patients will be excluded from the study if they meet any of the following criteria:  [19] have visceral crisis; 
[20] have known central nervous system (CNS) metastases that are untreated, symptomatic, or require steroids to 
control symptoms; [21] have had major surgery within 14 days prior to randomization to allow for post-operative 
healing of the surgical wound and site(s); [22] have received prior treatment with any CDK 4 and CDK 6 inhibitor; 
[23] have received treatment with a drug that has not received regulatory approval for any indication within 14 or 
21 days of randomization for a non-myelosuppressive or myelosuppressive agent, respectively; [24] have serious 
preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study; 
[25] have a history within the last 6 months of symptomatic congestive heart failure, myocardial infarction, or 
unstable angina; [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; [27] have a 
history of any other cancer, unless in complete remission with no therapy for a minimum of 3 years.  For patients 
with history of other cancers within 3 years and considered of very low risk of recurrence per investigator’s 
judgment, eligibility is to be discussed with Lilly clinical research physician (CRP); [28] have active bacterial 
infection, fungal infection, or detectable viral infection; [29] have received any recent live virus vaccination; 
[30] are currently enrolled in a clinical trial involving an investigational product or non-approved use of a drug or, 
or concurrently enrolled in any other type of medical research judged not to be scientifically or medically 
compatible with this study; or [31] hypersensitivity to trastuzumab, murine proteins, fulvestrant, or to any of the 
excipients.
Test Product, Dosage, and Mode of Administration:  Abemaciclib will be supplied by the sponsor to be 
administered orally, 150 mg every 12 hours on Days 1 to 21 of a 21-day cycle.  Trastuzumab 8 mg/kg will be 
administered as an intravenous (IV) infusion on Day 1 of Cycle 1 (21 day cycle) then 6 mg/kg IV infusion on Day 
1 of each subsequent 21-day cycle. Fulvestrant 500 mg will be administered intramuscularly (IM) on Days 1, 15, 
and 29 (that is, Cycle 2 Day 8 [assuming no dose suspension for trastuzumab]), and once every 4 weeks thereafter.
Reference Therapy, Dose, and Mode of Administration:  Standard-of-care single-agent chemotherapy of 
physician’s choice will be administered according to product label.
Planned Duration of Treatment:  until disease progression or other discontinuation criteria are fulfilled
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  until death  


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Criteria for Evaluation:  
Efficacy:  

PFS

OS

ORR

DoR

DCR

CBR
Safety:  

Adverse events using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03
Health Outcomes:  

mBPI-sf, EORTC QLQ-C30:  assess impact on pain, disease symptoms, and overall quality of life  

EQ-5D 5L:  describe health status changes
Pharmacokinetics/Pharmacodynamics:

Population PK parameters for abemaciclib and its metabolites, fulvestrant, and trastuzumab

Relationship between exposure and response, PFS, and toxicity (for example, diarrhea, neutropenia)
Biomarkers:

Biomarkers related to the mechanism of action of abemaciclib, the cell cycle, and/or the pathogenesis of 
breast cancer and association with clinical outcome


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Statistical Methods:  
Statistical:  
The primary objective of this study is to compare abemaciclib plus trastuzumab plus fulvestrant and abemaciclib 
plus trastuzumab to standard-of-care single-agent chemotherapy of physician’s choice plus trastuzumab in terms of 
PFS in patients with advanced breast cancer.  The primary analysis will be performed after approximately 165 PFS 
events have occurred.  Assuming a hazard ratio of 0.667, this sample size yields at least 80% statistical power to 
detect superiority of the abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus trastuzumab arms over 
standard-of-care single-agent chemotherapy of physician’s choice plus trastuzumab arm with the use of an
experiment-wise 1-sided alpha level of .10.  An interim analysis of PFS for futility is planned by an assessment 
committee (AC) after 75 PFS events have been observed.  Overall survival, an important secondary endpoint for 
this study, will be tested only if the test of PFS is significant.  Up to a total of 2 interim analyses and a final 
analysis for OS may be performed, comparing the 2 pooled abemaciclib arms against the chemotherapy arm (at the 
time of PFS analysis, after approximately 105 deaths, and after approximately 158 deaths).  The type I experiment-
wise error rate will be controlled at 10% by using the Lan-Demets method with an O’Brien-Fleming like α-
spending function.
Efficacy:
The PFS and OS analyses to test the superiority of abemaciclib plus trastuzumab plus fulvestrant and abemaciclib 
plus trastuzumab to chemotherapy plus trastuzumab in improving PFS time will use the log-rank test stratified by 
the stratification variable.  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 confidence intervals.
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.  There are 
2 planned interim analyses to evaluate the safety and tolerability of the combination of abemaciclib plus 
trastuzumab plus fulvestrant in patients enrolled to the safety lead-in for Part A; these analyses will take place 
when data from the first 6 and 12 qualified patients who complete 1 cycle have been obtained.   For all treatment 
arms in Study JPBZ, additional interim safety analyses are planned by an AC after approximately 36, 75, and 150
patients overall (a minimum of 12, 25, and 50 patients in the abemaciclib plus trastuzumab plus fulvestrant and 
abemaciclib plus trastuzumab arms) have received 1 cycle of study treatment to determine whether there are 
sufficient safety concerns to justify the termination of study treatment and/or enrollment.
Health Outcomes:
Change in pain, symptom burden, and health status will be analyzed descriptively and treatment arms will be 
compared using a repeated measures model, where appropriate.
Pharmacokinetics/Pharmacodynamics:
Pharmacokinetic parameters for abemaciclib in plasma (clearance, exposure, volume of distribution, and half-lives) 
and inter-individual PK variability will be computed using nonlinear mixed effect modeling implemented in 
nonlinear mixed effects modelling (NONMEM).  If warranted by the data, PK parameters for abemaciclib
metabolites, fulvestrant, or trastuzumab in plasma and inter-individual variability estimates will also be computed 
using nonlinear mixed-effect modeling implemented in NONMEM.
Biomarkers:
Correlative analyses will be performed to investigate associations between biomarkers and clinical endpoints.  


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3.
Table of Contents
monarcHER:  A Phase 2, Randomized, Multicenter, 3-Arm, 
Open-Label Study to Compare the Efficacy of Abemaciclib 
plus Trastuzumab with or without Fulvestrant to Standard-of-
Care Chemotherapy of Physician’s Choice plus Trastuzumab 
in Women with HR+, HER2+ Locally Advanced or Metastatic 
Breast Cancer
Section
Page
1.
Protocol I3Y-MC-JPBZ(f)  monarcHER:  A Phase 2, Randomized, 
Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of 
Abemaciclib plus Trastuzumab with or without Fulvestrant to 
Standard-of-Care Chemotherapy of Physician’s Choice plus 
Trastuzumab in Women with HR+, HER2+ Locally Advanced or 
Metastatic Breast Cancer.....................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................14
5.
Introduction ......................................................................................................................19
5.1.
Rationale for Amendment (a).......................................................................................21
5.2.
Rationale for Amendment (b).......................................................................................21
5.3.
Rationale for Amendment (c).......................................................................................22
5.4.
Rationale for Amendment (d).......................................................................................22
5.5.
Rationale for Amendment (e).......................................................................................23
5.6.
Rationale for Amendment (f)........................................................................................23
6.
Objectives.........................................................................................................................24
6.1.
Primary Objective ........................................................................................................24
6.2.
Secondary Objectives...................................................................................................24
6.3.
Exploratory Objectives.................................................................................................24
7.
Study Population...............................................................................................................25
7.1.
Inclusion Criteria..........................................................................................................25
7.2.
Exclusion Criteria ........................................................................................................27
7.2.1.
Rescreening .........................................................................................................29
7.3.
Discontinuation............................................................................................................29
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................29
7.3.2.
Discontinuation from Study Treatment and/or from Study....................................30
7.3.3.
Discontinuation of Study Sites .............................................................................30


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7.3.4.
Discontinuation of the Study................................................................................30
8.
Investigational Plan...........................................................................................................31
8.1.
Summary of Study Design............................................................................................31
8.1.1.
Study Completion and End of Trial......................................................................32
8.1.2.
Continued Access Period......................................................................................33
8.2.
Discussion of Design and Control ................................................................................34
9.
Treatment..........................................................................................................................35
9.1.
Treatments Administered .............................................................................................35
9.1.1.
Treatment Administration Guidance.....................................................................37
9.1.1.1.
Abemaciclib (Arms A and B) .........................................................................37
9.1.1.2.
Trastuzumab (Arms A, B, and C)....................................................................37
9.1.1.3.
Fulvestrant (Arm A) .......................................................................................37
9.1.1.4.
Standard-of-Care Chemotherapy (Arm C).......................................................37
9.2.
Materials and Supplies .................................................................................................37
9.3.
Method of Assignment to Treatment ............................................................................38
9.4.
Selection and Timing of Doses.....................................................................................38
9.4.1.
Special Treatment Considerations ........................................................................40
9.4.1.1.
Dose Adjustments and Delays ........................................................................40
9.4.1.1.1.
Dose Adjustments.....................................................................................41
9.4.1.1.1.1.
Abemaciclib........................................................................................41
9.4.1.1.1.2.
Trastuzumab .......................................................................................42
9.4.1.1.1.3.
Fulvestrant ..........................................................................................43
9.4.1.1.2.
Dose Suspension (within a Cycle) and Cycle Delay ..................................43
9.4.1.1.2.1.
Abemaciclib........................................................................................44
9.4.1.1.2.2.
Trastuzumab .......................................................................................44
9.4.1.1.2.3.
Fulvestrant ..........................................................................................44
9.4.1.1.3.
Management of Patients Receiving Trastuzumab and 
Standard-of-Care Chemotherapy...............................................................44
9.5.
Blinding .......................................................................................................................44
9.6.
Concomitant Therapy...................................................................................................45
9.6.1.
Surgery and/or Radiotherapy for Locoregionally Recurrent 
Breast Cancer.......................................................................................................46
9.6.2.
Palliative Radiotherapy ........................................................................................46
9.6.3.
Supportive Care ...................................................................................................46
9.6.3.1.
Supportive Management for Diarrhea .............................................................46
9.6.3.2.
Therapy for Febrile Neutropenia.....................................................................47
9.6.3.3.
Growth Factors...............................................................................................47
9.7.
Treatment Compliance .................................................................................................47


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9.7.1.
Patient Diaries......................................................................................................47
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................49
10.1. Efficacy Measures........................................................................................................49
10.1.1.
Efficacy Assessments at Baseline and During Study 
Treatment.............................................................................................................49
10.1.2.
Efficacy Assessments during Postdiscontinuation Follow-Up...............................50
10.1.3.
Primary Efficacy Measure....................................................................................51
10.1.4.
Secondary Efficacy Measures...............................................................................52
10.2. Health Outcome/Quality of Life Measures ...................................................................53
10.2.1.
Patient-Reported Outcomes..................................................................................53
10.2.1.1.
Pain Intensity..................................................................................................53
10.2.1.2.
Health-Related Quality of Life........................................................................54
10.2.1.3.
Health Status ..................................................................................................54
10.2.2.
Resource Utilization.............................................................................................54
10.3. Safety Evaluations........................................................................................................55
10.3.1.
Adverse Events ....................................................................................................55
10.3.1.1.
Serious Adverse Events ..................................................................................57
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................58
10.3.2.
Other Safety Measures .........................................................................................58
10.3.2.1.
Electrocardiograms.........................................................................................58
10.3.2.2.
Assessment of LVEF by Echocardiography or 
Multigated Acquisition Scan...........................................................................59
10.3.3.
Safety Monitoring ................................................................................................59
10.3.3.1.
Special Hepatic Safety Data Collection...........................................................59
10.3.3.2.
Renal Function ...............................................................................................60
10.3.3.3.
Venous Thromboembolic Events....................................................................60
10.3.3.4.
Interstitial Lung Disease/Pneumonitis.............................................................61
10.3.4.
Complaint Handling.............................................................................................61
10.4. Sample Collection and Testing.....................................................................................61
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................62
10.4.2.
Samples for Pharmacogenetics and Biomarkers....................................................62
10.4.2.1.
Whole Blood Sample for Pharmacogenetic Research......................................63
10.4.2.2.
Biomarkers.....................................................................................................63
10.4.2.2.1.
Plasma ......................................................................................................63
10.4.2.2.2.
Tumor Tissue............................................................................................63
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................64


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10.5. Appropriateness of Measurements................................................................................65
11.
Data Quality Assurance.....................................................................................................66
11.1. Data Capture System....................................................................................................66
12.
Sample Size and Statistical Methods .................................................................................67
12.1. Determination of Sample Size ......................................................................................67
12.2. Statistical and Analytical Plans.....................................................................................67
12.2.1.
General Considerations ........................................................................................67
12.2.2.
Patient Disposition...............................................................................................68
12.2.3.
Patient Characteristics..........................................................................................68
12.2.4.
Concomitant Therapy...........................................................................................68
12.2.4.1.
Postdiscontinuation Therapy...........................................................................68
12.2.5.
Treatment Compliance .........................................................................................68
12.2.6.
Primary Outcome and Methodology.....................................................................68
12.2.7.
Other Analyses of Efficacy ..................................................................................70
12.2.7.1.
Overall Survival .............................................................................................70
12.2.7.2.
Other Analyses of Secondary Efficacy Endpoints ...........................................71
12.2.8.
Pharmacokinetic and/or Pharmacodynamic Analyses ...........................................71
12.2.9.
Biomarker Analyses.............................................................................................72
12.2.10. Health Outcome/Patient-Reported Outcome Analyses..........................................72
12.2.10.1. Pain Intensity and Assessment........................................................................73
12.2.10.2. Health-Related Quality of Life........................................................................73
12.2.10.3. Resource Utilization .......................................................................................73
12.2.10.4. Health State Utility.........................................................................................73
12.2.11. Safety Analyses....................................................................................................73
12.2.11.1. Dose-Limiting Toxicities for Arm A Safety Lead-In.......................................74
12.2.11.2. DLT-Equivalent Toxicity................................................................................75
12.2.12. Interim Analyses..................................................................................................75
12.2.13. Subgroup Analyses ..............................................................................................76
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................77
13.1. Informed Consent.........................................................................................................77
13.2. Ethical Review.............................................................................................................77
13.3. Regulatory Considerations ...........................................................................................77
13.3.1.
Investigator Information.......................................................................................78
13.3.2.
Protocol Signatures ..............................................................................................78
13.3.3.
Final Report Signature .........................................................................................78
14.
References ........................................................................................................................79


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List of Tables
Table
Page
Table JPBZ.9.1.
Treatment Regimens/Dosing Schedule ...................................................36
Table JPBZ.9.2.
Toxicity Dose Adjustments and Delays of Abemaciclib..........................40
Table JPBZ.9.3.
Dose Adjustments for Abemaciclib ........................................................42
Table JPBZ.10.1.
Secondary Efficacy Endpoints................................................................52
Table JPBZ.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........55
Table JPBZ.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival.......................................................................69


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List of Figures
Figure
Page
Figure JPBZ.8.1.
Illustration of study design......................................................................31
Figure JPBZ.8.2.
Study period and continued access diagram. ...........................................33
Figure JPBZ.9.1.
Algorithm for monitoring LVEF in Study JPBZ. ....................................43
Figure JPBZ.12.1.
Alpha spending for Study I3Y-MC-JPBZ. ..............................................70


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List of Attachments
Attachment
Page
Attachment 1.
Protocol JPBZ Study Schedule ...............................................................81
Attachment 2.
Protocol JPBZ Clinical Laboratory Tests................................................91
Attachment 3.
Protocol JPBZ Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................92
Attachment 4.
Protocol JPBZ ECOG Performance Status..............................................93
Attachment 5.
Protocol JPBZ RECIST Criteria 1.1........................................................94
Attachment 6.
Protocol JPBZ Pharmacokinetic Sampling Schedule.............................101
Attachment 7.
Protocol JPBZ Sampling Summary.......................................................104
Attachment 8.
Protocol JPBZ Dosing Schedule for Study Arm A................................105
Attachment 9.
Protocol JPBZ Inducers and Strong Inhibitors of CYP3A .....................106
Attachment 10.
Protocol JPBZ CTCAE 4.03  Definitions for Diarrhea and 
ILD/Pneumonitis ..................................................................................107
Attachment 11.
Protocol JPBZ Amendment (f) Summary monarcHER: A Phase 2, 
Randomized, Multicenter, 3-Arm, Open-Label Study to Compare 
the Efficacy of Abemaciclib plus Trastuzumab with or without 
Fulvestrant to Standard-of-Care Chemotherapy of Physician’s 
Choice plus Trastuzumab in Women with HR+, HER2+ Locally 
Advanced or Metastatic Breast Cancer .................................................109


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4.
Abbreviations and Definitions
Term
Definition
AC
Assessment Committee
AE
adverse event
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
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).
BPI-sf
Brief Pain Inventory-short form
CAP
chest/abdomen/pelvis
CDK
cyclin-dependent kinase
CI
confidence interval
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 
treatment who continue to experience clinical benefit and no undue risks may continue 
to receive study treatment until one of the criteria for discontinuation is met. 
CNS
central nervous system
CR
complete response


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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.
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
IDMC
independent data monitoring committee
DLT
dose-limiting toxicity
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
EQ-5D 5L
EuroQOL 5 Dimension 5 Level
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.
FSH
follicle-stimulating hormone
GCP
good clinical practice
GnRH
gonadotropin-releasing hormone
GPS
Global Patient Safety
HIV
human immunodeficiency virus


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HR
hormone receptor
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ILD
interstitial lung disease
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.  
INR
International Normalized Ratio
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 (IP)
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ITT
intention-to-treat
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IWRS
interactive web-response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LLT
Lower Level Term
MATE
multidrug and toxin extrusion protein
MedDRA
Medical Dictionary for Regulatory Activities
mBC
metastatic breast cancer
MRI
magnetic resonance imaging


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MUGA
multigated acquisition
NCI
National Cancer Institute
ORR
overall 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
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PS
performance status
PT
Preferred Term
QTc 
corrected QT interval
randomize
the process of assigning patients to an experimental group on a random basis
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
Statistical Analysis Plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws)].  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SOC
System Organ Class


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SPC
Summary of Product Characteristics
Study completion
This study will be considered complete after final evaluation of overall survival is 
performed.  
SUSARs
suspected unexpected serious adverse reactions 
TBL
total bilirubin
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
TPO
third-party organization
ULN
upper limits of normal
VAS
visual analog scale
VTE
venous thromboembolic event


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monarcHER:  A Phase 2, Randomized, Multicenter, 3-Arm, 
Open-Label Study to Compare the Efficacy of Abemaciclib 
plus Trastuzumab with or without Fulvestrant to Standard-of-
Care Chemotherapy of Physician’s Choice plus Trastuzumab 
in Women with HR+, HER2+ Locally Advanced or Metastatic 
Breast Cancer
5.
Introduction
Breast cancer is one of the most common cancers in women in the Unites States and Europe and 
is a leading cause of cancer death in women worldwide (Jemal et al. 2011).  Early stage disease 
is treatable, but metastatic breast cancer (mBC) has a median overall survival (OS) of only 2 to 3 
years (Cardoso et al. 2012).  Overexpression of human epidermal growth factor receptor 2 
(HER2) occurs in 20% to 25% of breast cancers with approximately half of these tumors also 
expressing hormone receptors (HR) (Konecny et al. 2003).  Clinical studies have demonstrated 
that cyclin D is overexpressed in more than 50% of breast cancers, the majority of which are also 
estrogen receptor positive (ER+) (Velasco-Velazeques et al. 2011).  While women who have 
been diagnosed with hormone receptor positive (HR+) mBC are typically treated with endocrine 
therapy, de novo or acquired resistance to endocrine therapy is a common clinical problem in this 
population. 
Patients with HER2 positive (HER2+) breast cancers have tumors with higher proliferation rates, 
their metastases show greater predilection to metastasize to the brain and internal organs, and 
their clinical outcomes are worse when treated without concomitant HER2-targeted therapy.
Fortunately, HER2 may be targeted therapeutically by the monoclonal antibody trastuzumab and 
the small molecule inhibitor lapatinib.  Recent advances have extended these treatment options to 
include the dimerization inhibitor pertuzumab and the antibody conjugate trastuzumab emtansine 
(T-DM1) (Kümler et al. 2014).  Unfortunately, multiple mechanisms of resistance are known to 
emerge to these HER2-targeted therapies, notably those mediated by effectors downstream of the 
HER2 receptor (Thery et al. 2014). Per international guidelines, patients whose tumors progress 
on an anti-HER2 therapy in combination with a cytotoxic or endocrine agent should be offered 
additional anti-HER2 therapy with subsequent treatment because it is beneficial to continue 
suppression of the HER2 pathway (Cardoso et al. 2014).
Mitogenic signaling by the HER family of receptors engages the cell cycle machinery to promote 
cell division via cyclin D/cyclin-dependent kinase (CDK) 4 complexes (Witkiewicz et al. 2014).  
In preclinical models, pharmacologic inhibition of CDK 4 has demonstrated efficacy in HER2+ 
breast cancer explants and enhances activity of HER2-targeted therapy (Witkiewicz et al. 2014).  
Abemaciclib (LY2835219) is a selective and potent small-molecule inhibitor of CDK 4 and 
CDK 6 with acceptable physical characteristics, pharmacokinetic (PK) properties, and safety 
profile in nonclinical species.  Cell-based studies in breast cancer models have confirmed and 
demonstrated that abemaciclib inhibits CDK 4 and CDK 6 to induce G1 arrest specifically in cell 


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lines with intact retinoblastoma (Rb) tumor suppressor function (Rb+) versus lines which lack 
functional Rb (Rb-).  These studies, which evaluated in vitro growth inhibition across a diverse 
panel of cell lines representing the known molecular subgroups of breast cancer, indicated that 
sensitivity to CDK 4 and CDK 6 inhibition was greater in hormone receptor positive (HR+) lines 
with luminal histology including a subset of those that are HER2+/ER+.  Abemaciclib also 
shows antitumor activity in additional nonclinical models of multiple human cancers including, 
but not limited to, colorectal cancer, glioblastoma multiforme, acute myeloid leukemia, non-
small cell lung cancer, and mantle cell lymphoma.  Preclinical data have demonstrated that 
abemaciclib crosses the blood brain barrier and inhibits glioblastoma intracranial-xenografts in a 
dose-dependent manner (Sanchez-Martinez et al. 2011). 
In the ongoing Phase 1 Study I3Y-MC-JPBA (JPBA), the maximum tolerated dose for single-
agent abemaciclib was established at 200 mg every 12 hours.  In Study JPBA, abemaciclib 
monotherapy has demonstrated a clinically manageable safety profile across 6 tumor-expansion 
cohorts, with the most common treatment-emergent adverse events (TEAEs) possibly related to 
study drug including diarrhea, nausea, fatigue, vomiting, and neutropenia.  The safety and 
tolerability of continual twice-daily oral dosing of abemaciclib in combination with trastuzumab 
administered as an intravenous (IV) infusion on Day 1 of a 21-day cycle is being evaluated in 
patients with HER2+ mBC in the ongoing Phase 1b study, I3Y-MC-JPBH (JPBH).  Preliminary 
safety data from Study JPBH have shown an adverse event (AE) profile for abemaciclib 
administered at 200 mg every 12 hours in combination with endocrine therapies that is consistent 
with the profile 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 in combination with 
endocrine therapies than when abemaciclib was administered alone (25.7% and 13.6%, 
respectively).  Clinical and PK findings from the single-agent Study JPBA and preliminary 
safety data from the abemaciclib/non-steroidal aromatase inhibitor (NSAI) combination in Study 
JPBH support 150 mg every 12 hours as the recommended dose for abemaciclib in combination 
with endocrine therapy in Study I3Y-MC-JPBZ (JPBZ). 
Importantly, abemaciclib has demonstrated evidence of clinical activity in women with HR+ 
mBC (both HER2+ and HER2 negative [HER2-]) at doses of both 150 mg and 200 mg every 12 
hours.  In the ongoing Study JPBA, 47 patients in a tumor-specific cohort of women with mBC 
with a median of 7 prior systemic regimens received abemaciclib monotherapy.  Among the 36 
patients with HR+ mBC, the median progression-free survival (PFS) was 8.8 months and there 
were 12 confirmed partial responses (PR) for an objective response rate of 33.3%.  The disease 
control rate (DCR) for patients with HR+ mBC was 80.6%.  Among responder patients, 4 had 
HR+, HER2+ disease (36%).  Collectively, these results support clinical development of 
abemaciclib in combination with HER2 targeted therapies for patients with HER2+ breast 
cancers.
More information about the known and expected benefits, risks and reasonably anticipated 
adverse events (AEs) of abemaciclib may be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to abemaciclib 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 


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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 trastuzumab,  
fulvestrant, and single-agent chemotherapy may be found in the following:  Patient Information 
Leaflet, Package Insert, or Summary of Product Characteristics (SPC).
5.1.
Rationale for Amendment (a)
The Study JPBZ protocol was amended to incorporate a safety lead-in for Arm A (abemaciclib, 
trastuzumab, and fulvestrant) to monitor the safety and tolerability of the 3-drug combination.  
Although the 3 drugs have been shown to be tolerated individually at the doses specified for 
Study JPBZ, and 150-mg abemaciclib has demonstrated tolerability when combined as a doublet 
with trastuzumab or fulvestrant, there is no experience with the combination of all 3 drugs in 
humans.  If the triplet combination is not tolerated, the starting dose of abemaciclib will be 
lowered to 100 mg.  If the 100-mg dose is not tolerated, Arm A will be stopped.
Further modifications along with minor typographical and formatting edits were made for clarity 
and consistency.
5.2.
Rationale for Amendment (b)
The Study JPBZ protocol has been amended to provide guidance on monitoring of renal function 
in patients receiving abemaciclib based on continued learning from the ongoing abemaciclib 
clinical program.  Testing for serum levels of cystatin C was added to the clinical laboratory tests 
required for the study to gain data regarding the impact of abemaciclib on cystatin C levels.
With amendment (b), an additional stratification factor has been added to the study, namely: 
status of disease (measurable vs. nonmeasurable).  While most patients in this disease setting are 
expected to present with visceral lesions that are measurable in a majority of cases, this 
additional stratification factor was necessary to ensure that randomization is balanced between 
treatment arms for the status of disease.
Abemaciclib suspension during the palliative radiotherapy period has been made mandatory 
regardless of the radiation target volume, in the absence of safety data for abemaciclib in 
concurrent combination with radiotherapy.
The protocol has also been amended to delete the analysis for time to worsening of pain, as this 
analysis should be considered exploratory and may be addressed in a separate Health Outcomes 
statistical analysis plan (SAP).
Consistent with requests from competent authorities in Europe (Agence Nationale de Sécurité du 
Médicament et des Produits de Santé and the Medicines and Healthcare Products Regulatory 
Agency), Exclusion Criterion [24] for preexisting conditions was updated to included severe 
dyspnea at rest or requiring oxygen therapy to align with the European trastuzumab label and to 
exclude patients with interstitial lung disease since prior exposure to taxanes is mandatory for all 
patients.  Exclusion Criterion [29] has been clarified further with regard to prior exposure to live 
virus vaccines, and Exclusion Criterion [31] has been added to align with both the trastuzumab 


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and fulvestrant labels.  In addition, the multigated acquisition (MUGA) scan and 
echocardiography schedule has been revised for consistency with the trastuzumab label.  The 
protocol was also amended to reference the product label for guidance regarding the 
management of patients receiving trastuzumab and standard-of-care chemotherapy.
A typographical error in instructions for fulvestrant administration during the second cycle has 
been corrected and clarification of the maximum time interval between randomization and 
Cycle 1 Day 1 has been added.  The protocol was also amended to clarify the tumor assessment 
guidance for patients with bone lesions.  Additional revisions were made to the hepatic 
monitoring criteria to align with current guidance from the Lilly Liver and Gastrointestinal (GI)
Safety Advisory Committee.  Changes were made to the specified confidence intervals in the 
statistical and analytical plans to align with standard reporting.
Minor typographical and formatting edits were made for clarity and consistency.
5.3.
Rationale for Amendment (c)
Study JPBZ protocol was amended to update the safety language regarding hepatic monitoring, 
assessment of renal function, and venous thromboembolic events (VTEs) for ongoing patients
and align with the updated label of abemaciclib.  Changes to the dose adjustment and delay 
section and Table JPBZ.9.2 were done to specify dose modifications in response to Grade 2 
diarrhea and increased alanine aminotransferase laboratory values. 
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.4.
Rationale for Amendment (d)
Study JPBZ protocol was amended to update the dose modification guidance and the safety 
language for interstitial lung disease (ILD)/pneumonitis.  Changes to the dose adjustment and 
delay section and to Table JPBZ.9.2 were made to include dose modifications in response to 
ILD/pneumonitis events. These updates are in alignment with changes made in the development 
core safety information of the IB. 
Section 9.6 (Concomitant Therapy) was updated to align with the current IB.  Additional 
language was added cautioning against concomitant use of abemaciclib and substrates of the 
following:

P-glycoprotein

breast cancer resistance protein

organic cation transporter 2

multidrug and toxin extrusion protein 1 (MATE1), and

MATE2-K
Substrates of these transporters, including metformin, digoxin, and dofetilide, should be 
substituted or avoided.


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The Concomitant Therapy (Section 9.6) was also updated to remove cautionary language 
regarding coadministration of narrow therapeutic index cytochrome P450 (CYP) substrate drugs. 
This is based on a clinical study (Study I3Y-MC-JPCB) which found no meaningful effect of 
abemaciclib on the PK of CYP substrates, namely 

caffeine (CYP1A2)

S-warfarin (CYP2C9)

midazolam (CYP3A), and 

dextromethorphan [CYP2D6]).  
The list of inducers and strong inhibitors of CYP3A (Attachment 9) was also modified to reflect 
updated guidance.
The protocol was updated to bring references to abemaciclib into alignment with the sponsor’s 
standard language.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.5.
Rationale for Amendment (e)
This amendment to the Study JPBZ protocol updates the dose adjustment guidance related to
nonhematologic toxicity, ALT/AST increased, and VTEs. Specifically, dose adjustment updates 
were made in Table JPBZ.9.2 to ensure alignment with the current IB. Additionally, the 
Concomitant Therapy (Section 9.6) information was updated for CYP3A modulators and 
transporter substrates. Finally, safety monitoring language in Special Hepatic Safety Data 
Collection (Section 10.3.3.1) and Venous Thromboembolic Events (Section 10.3.3.3) was
updated to align with current guidance and the IB, respectively.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.6.
Rationale for Amendment (f)
This amendment to the Study JPBZ protocol corrects an error in the table in Special Hepatic 
Safety Data Collection (Section 10.3.3.1) to align with current guidance.


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6.
Objectives
6.1.
Primary Objective
The primary objective of this study is to compare the efficacy of abemaciclib plus trastuzumab 
plus fulvestrant and abemaciclib plus trastuzumab to standard-of-care single-agent chemotherapy
of physician’s choice plus trastuzumab with respect to progression free survival (PFS).
6.2.
Secondary Objectives
The secondary objectives of the study are to compare the 3 arms with respect to each of the 
following:

overall survival (OS) rate at 1, 2, and 3 years

objective response rate (ORR)

duration of response (DoR) (Complete response [CR] + partial response [PR])

disease control rate (DCR) (CR + PR + stable disease [SD])

clinical benefit rate (CBR) (CR + PR + SD ≥6 months)

safety and tolerability of abemaciclib in combination with trastuzumab and fulvestrant 

impact on pain, disease symptoms, and overall quality of life using the modified Brief 
Pain Inventory-Short Form (mBPI-sf), the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the 
health status scores from the EuroQol 5-Dimension 5 Level (EQ-5D 5L)

PK of abemaciclib and its metabolites, fulvestrant, and trastuzumab in the target patient 
population

relationship between abemaciclib, trastuzumab, and fulvestrant exposure and response for 
safety and efficacy endpoints 
6.3.
Exploratory Objectives

to explore potential biomarkers related to the mechanism of action of abemaciclib, the 
cell cycle, and/or the pathogenesis of breast cancer and their association with clinical 
outcome


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7.
Study Population
Individuals who do not 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+ advanced breast cancer

To fulfill the requirement of HR+ disease, the primary tumor or metastatic 
lesion of the breast cancer must express at least one of the hormone 
receptors (estrogen receptor [ER] or progesterone receptor [PgR]) by 
immunohistochemistry (IHC). Estrogen receptor and PgR assays are 
considered positive if there are at least 1% positive tumor nuclei in the 
sample 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, the primary tumor or 
metastatic lesion of the breast cancer must demonstrate overexpression of 
HER2 by either IHC (3+) or gene amplification by positive in-situ 
hybridization (ISH) as defined in the relevant ASCO/CAP HER2 
guidelines (Wolff et al. 2013).
Although not required as a protocol procedure, a patient with a new metastatic 
lesion should be considered for fresh biopsy (whenever possible) to reassess 
HR and HER2 status prior to study entry if clinically indicated. The most 
recent receptor testing should be used to determine eligibility.
[2]
have unresectable locally advanced recurrent breast cancer or metastatic 
breast cancer (all termed advanced disease)
[3]
have adequate tumor tissue (newly obtained biopsy; otherwise archived tissue) 
available prior to randomization.
Note:  Sites should confirm the availability of adequate tumor tissue 
(Section 10.4.2.2.2) with the pathological laboratory prior to randomization.
[4]
have measurable and/or non-measurable disease according to RECIST 
version 1.1 (Eisenhauer et al. 2009)


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[5]
have previously received:

at least 2 HER2-directed therapies for advanced disease
o
prior HER2-directed therapies could be in combination with 
chemotherapy or endocrine therapy or as single agent
o
exposure to dual HER2 blockade (for example, combination 
trastuzumab and pertuzumab) is considered as 1 prior HER2-directed 
therapy

patient must have received T-DM1 in any disease setting

prior trastuzumab and/or pertuzumab and/or lapatinib are allowed in any 
disease setting
[6]
patient must have received a taxane in any disease setting
[7]
patients may have received any endocrine therapy (excluding fulvestrant)
[8]
have postmenopausal status due to either surgical/natural menopause or 
chemical ovarian suppression (initiated at least 28 days prior to Day 1 of 
Cycle 1) with a gonadotropin-releasing hormone (GnRH) agonist such as
goserelin or radiation-induced ovarian suppression

postmenopausal status due to surgical/natural menopause is defined as
meeting one of the following conditions:
o
prior bilateral oophorectomy
o
age ≥60 years
o
age <60 years and amenorrheic (in the absence of tamoxifen, 
toremifene, ovarian suppression, or chemotherapy) for at least 12 
months.  Follicle-stimulating hormone (FSH) and estradiol must be in 
the postmenopausal range.

Postmenopausal status due to radiation-induced ovarian suppression must 
be confirmed by FSH and estradiol level in the postmenopausal range
[9]
have a performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology 
Group (ECOG) scale (see Attachment 4)
[10] must have left ventricular ejection fraction (LVEF) of 50% or higher at 
baseline (determined by echocardiography or multiple-gated acquisition 
scanning)
[11] 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.  Initial treatment must not begin earlier than the day after the 
erythrocyte transfusion.


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
hepatic:  total bilirubin 1.5 × the upper limit of normal (ULN) (except in 
cases of known Gilbert’s syndrome where ≤ 2.0x ULN is allowed) and 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
3 × ULN.  If liver metastases are present, AST and ALT 5 × ULN are 
acceptable.

renal:  serum creatinine 1.5 × ULN
[12] have a negative serum pregnancy test at baseline (within 14 days prior to 
randomization) and agree to use medically approved precautions to prevent 
pregnancy during the study and for 12 weeks following the last dose of 
abemaciclib if postmenopausal status is due to ovarian suppression with a 
GnRH agonist or induced by radiation
[13] 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
[14] have discontinued all previous therapies for cancer (including chemotherapy, 
radiotherapy, immunotherapy, and endocrine therapy), except trastuzumab,
for at least 21 days for myelosuppressive agents or 14 days for non-
myelosuppressive agents prior to receiving study drug, and recovered from the 
acute effects of therapy (until the toxicity resolves to either baseline or at lease 
Grade 1) except for residual alopecia and peripheral neuropathy. See 
Table JPBZ.9.1 Footnote (a) for guidance regarding trastuzumab continuation
at the time of study entry.
[15] are female and ≥18 years of age
[16] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[17] have given written informed consent prior to any study-specific procedures
[18] are able to swallow capsules
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[19] have visceral crisis.  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.
[20] have known central nervous system (CNS) metastases that are untreated, 
symptomatic, or require steroids to control symptoms.  Note: patients with a 
history of treated brain- metastases are eligible.


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
treated brain-metastases are defined as those having no evidence of 
progression for ≥2 months and no ongoing requirement for corticosteroids, 
as ascertained by clinical examination and by brain imaging (magnetic 
resonance imaging [MRI] or computed tomography [CT]) during the 
screening period

any corticosteroid use for brain metastases must have been discontinued 
without the subsequent appearance of symptoms for ≥2 weeks before
randomization

treatment for brain metastases may include whole brain radiation
(WBRT), radiosurgery, or a combination as deemed appropriate by the 
treating physician.  Patients with CNS metastases treated by neurosurgical 
resection must be at least 8 weeks from surgery. A wash out period of at 
least 8 weeks is required after end of WBRT.
[21] have had major surgery within 14 days prior to randomization to allow for 
post-operative healing of the surgical wound and site(s).  Note:  A surgery is 
qualified as major per investigator/surgeon judgment based on the required 
recovery period, both from general patient status and post-operative healing 
perspectives.  
[22] have received prior treatment with any CDK 4 and CDK 6 inhibitor (or 
participated in any CDK 4 and CDK 6 inhibitor clinical trial for which 
treatment assignment is still blinded)
[23] have received treatment with a drug that has not received regulatory approval 
for any indication within 14 or 21 days of randomization for a non-
myelosuppressive or myelosuppressive agent, respectively  
[24] have serious preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study (for example,
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy,
history of major surgical resection involving the stomach or small bowel, or 
preexisting Crohn’s disease or ulcerative colitis)
[25] have a history within the last 6 months of symptomatic congestive heart 
failure, myocardial infarction, or unstable angina
[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
[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. For patients with history of other cancers within 3 
years and considered of very low risk of recurrence per investigator’s 
judgment (for example, papillary thyroid cancer treated with surgery), 
eligibility is to be discussed with Lilly clinical research physician (CRP)


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[28] have active bacterial infection (that is to say, requiring IV antibiotics at time 
of initiating study treatment), fungal infection, or detectable viral infection 
(for example, known human immunodeficiency virus [HIV] positivity or 
known active or inactive hepatitis carrier [for example, hepatitis B surface 
antigen (HBsAg) positive]).  Screening is not required for enrollment.
[29] have received any recent (within 28 days prior to randomization) live virus
vaccination
[30] are currently enrolled in a clinical trial involving investigational product (IP) 
or non-approved use of a drug or device (other than the IP/device used in this 
study), or concurrently enrolled in any other type of medical research judged 
not to be scientifically or medically compatible with this study
[31] hypersensitivity to trastuzumab, murine proteins, fulvestrant, or to any of the 
excipients
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.
Discontinuation
If a patient withdraws informed consent, she must not be contacted unless she has explicitly
provided permission and consent.  Lilly may continue to use previously collected medical 
research data prior to the withdrawal consistent with the original authorization.
7.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor CRP and the investigator to determine whether the patient may continue in the study, 
with or without study treatment.  Inadvertently enrolled patients may be maintained in the study 
and on study treatment when the Lilly CRP agrees with the investigator that it is medically 


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appropriate for that patient. The patient may not continue in the study with or without study 
treatment 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 treatment.
7.3.2. Discontinuation from Study Treatment and/or from Study
In addition, patients will be discontinued from the study drugs and/or from the study in the 
following circumstances:

progressive disease (PD) as defined by RECIST v1.1  

an unacceptable AE and/or toxicity occurs (for example, a persistent moderate toxicity 
that is intolerable to the patient)

enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

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

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)

patient is significantly non-compliant with study procedures and/or treatment
The reason and date of discontinuation will be collected for all patients.  All enrolled patients 
who discontinue regardless of whether or not they received study drug will have procedures 
performed as shown in the Study Schedule (Attachment 1).  
7.3.3. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.4. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.


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8.
Investigational Plan
8.1.
Summary of Study Design
Study I3Y-MC-JPBZ is a randomized, multicenter, 3-arm, open-label Phase 2 study to compare 
the efficacy of abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus trastuzumab 
to standard-of-care single-agent chemotherapy of physician’s choice plus trastuzumab in women 
with HR+, HER2+ locally advanced or metastatic breast cancer.
Figure JPBZ.8.1 illustrates the study design.
Abbreviations:  HER2+ = human epidermal growth factor receptor 2-positive; 
HR+ = hormone receptor-positive; n = number; PD = progressive disease; 
Q12H = every 12 hours; R = randomization.
a
If the dose of abemaciclib in Arm A is reduced to 100 mg, patients that initiated 
treatment at the 150-mg dose will be dose-reduced to 100 mg, and patients who 
started at the 150-mg abemaciclib dose will be replaced so that there are a total of 
75 patients in Arm A with a starting dose of 100-mg abemaciclib.
b
Standard-of-care single-agent chemotherapy should include approved drug in breast 
cancer.
Figure JPBZ.8.1.
Illustration of study design.
Approximately 225 patients will be randomized 1:1:1 between the 3 arms. Patients will be 
randomized using the following stratification factors:  the number of previous systemic regimens 
(excluding single-agent endocrine therapy) for advanced breast cancer (2 to 3 vs. more than 3)
and status of disease (measurable vs. nonmeasurable).
Patients with HR+, HER2+ 
advanced breast cancer with 
exposure to ~2 prior HER2-
directed therapies for 
advanced disease 
(n=225) 
R 
1 :1 :1 
Arm A• 
{n=75l 
Safety Lead-In 
n = up to 12 patients 
First cycle (21-day cycle) 
abemaciclib 
150 mg Q12H plus 
fulvestrant plus 
trastuzumab until PD 
Arm B {n=75l 
abemaciclib 150 mg 
Q12H plus trastuzumab 
until PD 
Arm C {n=75l 
trastuzumab plus 
physician's choice of 
standard-of-care single-
agent chemotherapy" 
until PD 
Abemaciclib at 
selected dose 
Q12H plus 
fulvestrant plus 
trastuzumab until 
PD 


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During enrollment into all 3 study arms, the first 12 patients enrolled to Arm A (abemaciclib plus 
trastuzumab plus fulvestrant) will be part of a safety lead-in.  If the triplet combination is not 
tolerated, the starting dose of abemaciclib will be lowered to 100 mg.  If the 100-mg dose is not 
tolerated, Arm A will be stopped. The interim analyses for the safety lead-in are described in 
detail in Section 12.2.12.
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 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 final evaluation of overall survival (refer to Figure JPBZ.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 any applicable continued access follow-up (refer to Figure JPBZ.8.2).


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Abbreviations:  OS = overall survival; PFS = progression-free survival
Figure JPBZ.8.2.
Study period and continued access diagram.
8.1.2. Continued Access Period
The continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs.
Patients receiving study treatment and experiencing ongoing clinical benefit and no undue risks 
may continue to receive study treatment in the continued access period until one of the criteria 
for discontinuation is met (Section 7.3).  During the continued access period, crossover into 
another treatment arm 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.
Continued Collection of OS Data
End of 
Trial
Study 
Completion
Patients 
on 
Treatment
Patient on Study Treatment
Study Period
Continued 
Access Perioda
Patient on 
Study 
Treatment
a Lilly will notify sites when this begins and ends.  
Short-Term 
Follow-Up 
Long-Term 
Follow-Up
Patient 
Discontinues 
Study 
Treatment
Continued 
Accesss 
Follow-Up
Primary 
Analysis of 
PFS
Final analysis 
of OS
Long-Term 
Follow-Up
Patient on 
Study 
Treatment
Short-Term 
Follow-Up 
Patient 
Discontinues 
Study 
Treatment
Last visit/
scheduled 
procedure for 
last patient
Patient 
Discontinues 
Study 
Treatment
\ __________ ,. ____ 
_____.~ 
y 
T 
y 
I 


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During the continued access period, all AEs, SAEs, and study treatment exposure will be 
reported on the eCRF.  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.
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 treatment 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 treatment 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.


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9.
Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study:

Experimental Arm A:  abemaciclib 150 mg orally Q12H on Days 1 to 21 of a 21-day 
cycle; plus trastuzumab 8 mg/kg IV infusion on Day 1 of Cycle 1 (21-day cycle) then 
6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent 21-day cycle; plus 
fulvestrant 500 mg intramuscularly (IM) on Days 1, 15, and 29 (that is, Cycle 2 Day 8
[assuming no dose suspension for trastuzumab]), and once every 4 weeks thereafter (see 
Attachment 8). If this combination is not tolerated during the safety lead-in period, the 
abemaciclib dose in this arm will be reduced to 100 mg.

Experimental Arm B:  abemaciclib 150 mg orally Q12H on Days 1 to 21 of a 21-day 
cycle plus trastuzumab 8 mg/kg IV infusion on Day 1 of Cycle 1 (21-day cycle) then 
6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent 21-day cycle

Control Arm C:  trastuzumab as 8 mg/kg IV infusion on Day 1 of Cycle 1 (21-day cycle) 
then 6 mg/kg IV infusion on Day 1 of each subsequent 21-day cycle plus standard-of-care 
single-agent chemotherapy of physician’s choice administered according to product label
Patients will receive study treatment in the assigned treatment arm until they meet any of the 
discontinuation criteria (see Section 7.3).
Table JPBZ.9.1 shows the treatment regimens.


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Table JPBZ.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Cycle Length
Drug
Dose
Experimental 
Arm A
21-day cycle
abemaciclib
The starting dose of abemaciclib will be determined based 
on the results of the safety lead-in; 150 mg PO Q12H dose
or 100 mg PO Q12H dose if the 150-mg dose is declared 
not tolerable.
trastuzumab
8 mg/kg loading dosea IV infusion over 90 min on Day 1 
of Cycle 1, then 6 mg/kg maintenance doseb on Day 1 of 
all subsequent cycles (see Section 9.1.1.2)
fulvestrantc
500 mg IM on Days 1, 15, and 29 (that is, Cycle 2 Day 8 
[assuming no dose suspension for trastuzumab]), and once 
every 4 weeks thereafter (see Attachment 8)
Experimental 
Arm B
21-day cycle
abemaciclib
150 mg PO Q12H dose 
trastuzumab
8 mg/kg loading dosea IV infusion over 90 min on Day 1 
of Cycle 1, then 6 mg/kg maintenance doseb on Day 1 of 
all subsequent cycles (see Section 9.1.1.2)
Control 
Arm C
21-day cycle
trastuzumab
8 mg/kg loading dosea IV infusion over 90 min on Day 1 of 
Cycle 1, then 6 mg/kg maintenance doseb on Day 1 of all 
subsequent cycles (see Section 9.1.1.2)
standard-of-care 
single-agent 
chemotherapyd
per label
Abbreviations:  IM = intramuscular; IV = intravenous; min = minute; PO = orally; Q12H = every 12 hours.
a
For patients already receiving trastuzumab at time of study entry (on a weekly or every-3-week basis), the 
trastuzumab dose on Cycle 1 Day 1 should be at least 21 days after the last dose administered.  No loading dose 
of trastuzumab is required if the last dose of trastuzumab was within 4 weeks of Day 1 of Cycle 1.  Loading dose 
of trastuzumab is required if the last dose of trastuzumab was administered more than 4 weeks prior to Day 1 of 
Cycle 1.
b
If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute infusion.
c
Fulvestrant should be administered IM into the buttocks slowly (1 to 2 minutes per injection) as two 250-mg 
injections, one in each buttock; however, for patients with moderate hepatic impairment (defined as Child Pugh 
Class B), including any patient who develops moderate hepatic impairment during study treatment, fulvestrant 
250 mg should be administered intramuscularly into the buttock slowly (1 to 2 minutes) as one 250-mg injection.  
It is recommended that fulvestrant be administered after trastuzumab for the comfort of the patient who must be 
seated during trastuzumab infusion.
d
Best supportive care alone, including palliative radiotherapy in the absence of chemotherapy, is not permitted.  
T-DM1 or pertuzumab are not considered a single-agent chemotherapy option.  Maintenance endocrine therapy 
(except fulvestrant) after single-agent chemotherapy, all concurrently with trastuzumab, is allowed.  Standard-of-
care single-agent chemotherapy should include approved drug in breast cancer.
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, 


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
maintaining accurate records of study treatment dispensing and collection, 

and returning all unused medication to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study treatment so that the situation can be assessed.
9.1.1. Treatment Administration Guidance
9.1.1.1.
Abemaciclib (Arms A and B)
Abemaciclib will be provided by the sponsor and dosed at 50 mg. Solid oral dosage units should 
be taken Q12H, at the same time each day with a glass of water. Swallow dosage units whole. 
Do not open, chew, or crush.
9.1.1.2.
Trastuzumab (Arms A, B, and C)
The investigator should refer to the trastuzumab label (Patient Information Leaflet, Package 
Insert, or SPC).  When locally sourced, it is important to check the vial labels to ensure that the 
drug being prepared and administered is Herceptin (trastuzumab) and not Kadcyla (trastuzumab 
emtansine) in order to prevent medication errors.  Trastuzumab loading dose should be 
administered as a 90-minute IV infusion. Do not administer as an IV push or bolus. If the initial 
loading dose was well tolerated, the subsequent doses can be administered as a 30-minute
infusion.
9.1.1.3.
Fulvestrant (Arm A)
The investigator should refer to the fulvestrant label (Patient Information Leaflet, Package Insert, 
or SPC).
Due to the intramuscular route of administration, fulvestrant should be used with caution if 
treating patients with bleeding diatheses, thrombocytopenia or those taking anticoagulant 
treatment.
9.1.1.4.
Standard-of-Care Chemotherapy (Arm C)
The investigator should refer to the product label for administration of standard-of-care single-
agent chemotherapy of choice.
9.2.
Materials and Supplies
Abemaciclib will be supplied by Lilly for oral administration.  Abemaciclib should be stored 
according to the temperature range listed on the product label, and should not be opened, 
crushed, or chewed.
Fulvestrant will be centrally sourced by Lilly.  Depending on country requirements, trastuzumab 
will be supplied by the site or centrally sourced by Lilly.  Sites should confirm trastuzumab 
source to ensure adequate supply.  Trastuzumab and fulvestrant should be stored according to the 


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instructions on the product label and administered according to the instructions in the protocol.  
Fulvestrant and trastuzumab, where supplied by Lilly, will be labeled according to the country’s 
regulatory requirements.
Investigators should instruct patients to store study drugs in the original package provided and in 
a location inaccessible to children.
9.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomly assigned to receive abemaciclib 
plus trastuzumab plus fulvestrant, abemaciclib plus trastuzumab, or standard-of-care single-agent 
chemotherapy of physician’s choice plus trastuzumab at Visit 1.  Randomization will be 
stratified by the number of previous systemic regimens (excluding single-agent endocrine 
therapy) for advanced breast cancer (2 to 3 vs. more than 3) and status of disease (measurable vs. 
nonmeasurable).
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).
The period between randomization to study drug and the first dose (Cycle 1, Day 1) should not 
exceed 7 days.
9.4.
Selection and Timing of Doses
A cycle is defined as an interval of 21 days. 
Abemaciclib will be taken orally Q12H (± approximately 2 hours) on Days 1 through 21 of a 
21-day cycle, for a total of 42 doses per cycle.  Abemaciclib may be taken without regard to 
meals.  During all cycles, abemaciclib should be taken at approximately the same times each day.  
If a patient misses (that is, dose is not taken within 2 hours of regularly scheduled dose) or 
vomits a dose, that dose should be omitted.
For patients already receiving trastuzumab at time of study entry, the trastuzumab dose on 
Cycle 1 Day 1 should be at least 21 days after the last dose administered prior to randomization.  
No loading dose of trastuzumab is required if the last dose of trastuzumab was within 4 weeks of 
Day 1 of Cycle 1.  Loading dose of trastuzumab is required if the last dose of trastuzumab was 
administered more than 4 weeks prior to Day 1 of Cycle 1.
The timing of drug doses for each treatment arm is as follows (arms are described in 
Section 9.1):


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
Arm A:  Abemaciclib morning dose should be administered any time prior to 
trastuzumab infusion on Cycle 1 Day 1.  After Cycle 1 Day 1, abemaciclib doses can be 
taken with no restriction relative to timing of trastuzumab infusion or fulvestrant dose.  
Fulvestrant is to be administered immediately after the end of trastuzumab infusion if 
trastuzumab is well tolerated.  

Arm B:  Abemaciclib morning dose should be administered any time prior to trastuzumab 
infusion on Cycle 1 Day 1.  After Cycle 1 Day 1, abemaciclib doses can be taken with no 
restriction relative to timing of trastuzumab infusion.

Arm C:  There are no restrictions relative to timing of trastuzumab and standard-of-care 
chemotherapy. Note that in trastuzumab clinical trials, chemotherapy is commonly 
administered immediately after trastuzumab infusion if trastuzumab was well tolerated.
In the event of a dose suspension of any study drug due to toxicity immediately prior to the
beginning of a cycle, the PK Sampling Schedule may require adjustment. In these exceptional
circumstances, the sponsor should be notified.
A patient may continue to receive study drug until she meets one or more of the specified 
reasons for discontinuation (as described in Section 7.3).


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9.4.1. Special Treatment Considerations
9.4.1.1.
Dose Adjustments and Delays
Table JPBZ.9.2 presents guidance for abemaciclib dose adjustments and delays due to toxicity.
Table JPBZ.9.2.
Toxicity Dose Adjustments and Delays of Abemaciclib
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion
Hematologic Toxicity
Recurrent Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2
Dose MUST be reduced 
by 1 dose level
Hematologic Toxicity
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2
Dose MUST be reduced 
by 1 dose level
Hematologic toxicity: If 
patient requires 
administration of blood cell 
growth factors
(Section 9.6.3.3)
Regardless of severity
(Use of growth factors according 
to ASCO Guidelines)
Dose MUST be suspended for 
at least 48 hours after the last 
dose of blood cell growth 
factors was administered and 
until toxicity resolves to at 
least Grade 2 
Dose MUST be reduced 
by 1 dose level unless 
already performed for 
incidence of toxicity that 
lead to the use of growth 
factor 
Nonhematologic Toxicityb 
(except diarrhea, ALT/AST
increased, ILD/pneumonitis, 
and VTEs)
Persistent or recurrent Grade 2 
that does not resolve with 
maximal supportive measures 
within 7 days to baseline or Grade 
1
Dose MUST be suspended 
until toxicity resolves to either 
baseline or Grade 1
Dose MUST be reduced 
by 1 dose level
Nonhematologic Toxicityb
(except diarrhea, ALT/AST 
increased, ILD/pneumonitis, 
and VTEs)
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to either 
baseline or Grade 1
Dose MUST be reduced 
by 1 dose level
Diarrhea
Section 9.6.3.1
Grade 2 that does not resolve 
within 24 hours to at least Grade 
1
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1
Dose reduction is NOT 
required
Diarrhea
Section 9.6.3.1
Persistent or recurrenta Grade 2 
that does not resolve with 
maximal supportive measures, or 
any Grade of diarrhea that 
requires hospitalization
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1
Dose MUST be reduced 
by 1 dose level


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Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Diarrhea
Section 9.6.3.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
ALT/AST Increased 
Section 10.3.3.1
Persistent or recurrent
a Grade
2 (>3.0-5.0×ULN)d, or
Grade 3 (>5.0-20.0×ULN)c
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
ALT/AST Increased
Section 10.3.3.1
Grade 4 (>20.0×ULN)
Abemaciclib therapy MUST
be discontinued.
Abemaciclib therapy  
MUST be discontinued.
ALT/AST Increased with 
increased total bilirubin, in 
the absence of cholestasis
≥Grade 2 increased ALT/AST
(˃3.0 x ULN) with total bilirubin 
>2 x ULN
Abemaciclib therapy MUST
be discontinued
Abemaciclib therapy 
MUST be discontinued
ILD/Pneumonitis
Section 10.3.3.4
Grade 2 that persists or recurs 
despite maximal supportive 
measures and does not return to 
baseline or Grade 1 within 7 days
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade ≤1
Dose MUST be reduced 
by 1 dose level.
ILD/Pneumonitis
Section 10.3.3.4
Grade 3 or 4
Abemaciclib therapy MUST
be discontinued
Abemaciclib therapy 
MUST be discontinued
VTEs
Section 10.3.3.3
Grade 3 or 4
Suspend dose and treat as 
clinically indicated. May 
resume study drug when 
participant is clinically stable
Suspend dose and treat 
as clinically indicated. 
May resume study drug 
when participant is 
clinically stable
Abbreviations:  ALT = alanine aminotransferase; ASCO = American Society of Clinical Oncology; AST = aspartate 
aminotransferase; ILD = interstitial lung disease; VTE = venous thromboembolic event.
Note:  MUST = mandatory.
a
Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 6 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 6 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:

shows stable hematological counts (Grade ≤2) during that timeframe

has the absence of any infectious sign or risk factor

is benefiting from study treatment
b
Additional guidance for renal and hepatic monitoring is in Sections 10.3.3.1 and 10.3.3.2.
c    Grade 3 ALT/AST increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section 
10.3.3.1 for additional guidance for hepatic monitoring.
d     The patient who presents with no liver metastases at baseline. 
9.4.1.1.1. Dose Adjustments
9.4.1.1.1.1.
Abemaciclib
Abemaciclib dose adjustments as outlined in Table JPBZ.9.3 are allowed both within a cycle and 
between cycles.  Abemaciclib must be reduced sequentially by 1 dose level.


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For patients requiring dose reduction(s), any re-escalation to a prior dose level is permitted only 
after consultation with the Lilly CRP.  After re-escalation, subsequent dose adjustments should 
be based on the dose of abemaciclib that the patient is currently receiving.
Table JPBZ.9.3.
Dose Adjustments for Abemaciclib
Dose Adjustment Level
Oral Dose
Frequency
0
150 mg
Every 12 hours
1
100 mg
Every 12 hours
2
50 mg
Every 12 hours
Abemaciclib must be discontinued if further dose reduction is required beyond 50 mg Q12H.  In 
the event that abemaciclib must be discontinued, a patient may continue to receive trastuzumab 
and/or fulvestrant per the investigator’s clinical judgment.
9.4.1.1.1.2.
Trastuzumab
Dose adjustment for trastuzumab will be determined by the investigator in accordance with the 
label. Per the trastuzumab SPC, no reductions in the dose of trastuzumab were made during 
clinical trials. Patients may continue therapy during periods of reversible, chemotherapy-
induced myelosuppression but they should be monitored carefully for complications of 
neutropenia during this time.
In the event that trastuzumab is discontinued, the patient may continue to receive abemaciclib or 
fulvestrant or standard-of-care single-agent chemotherapy.
For monitoring of LVEF, please refer to the algorithm in Figure JPBZ.9.1.


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Abbreviations:  CHF = congestive heart failure; EF = ejection fraction; LVEF = left 
ventricular ejection fraction.
Figure JPBZ.9.1.
Algorithm for monitoring LVEF in Study JPBZ.
9.4.1.1.1.3.
Fulvestrant
Dose adjustment for fulvestrant will be determined by the investigator in accordance with the 
label.  For patients with moderate hepatic impairment (defined as Child-Pugh Class B), including 
any patient who develops moderate hepatic impairment during study treatment, fulvestrant 
250 mg should be administered IM into the buttock slowly (1 to 2 minutes) as one 250-mg 
injection.  In the event that fulvestrant must be discontinued, a patient may continue to receive 
abemaciclib and/or trastuzumab.
9.4.1.1.2. Dose Suspension (within a Cycle) and Cycle Delay
Both dose suspension (within a cycle, when applicable) and cycle delay are permitted.  When a 
dose suspension or cycle delay occurs related to toxicity (defined as an AE possibly related to 
study treatment per investigator judgment), the relevant drug may be suspended or delayed as 
determined by the investigator’s judgment and the other drug(s) may be continued.
Regardless of dose delays for other study drugs, the date of trastuzumab administration shall 
constitute Day 1 of the next cycle.
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.
LVEF S44% 
Trastuzumab 
LVEF <50% 
LVEF .:50% 
LVEF 45%-49% 
Decrease of .:10 EF Points 
from Baseline 
Decrease of <10 EF Points 
from Baseline 
Hold Trastuzumab, 
Repeat LVEF in 3 Weeks 
Continue trastuzumab 
Repeat LVEF in 3 Weeks 
LVEF S44% or LVEF 45%-49% 
with a Decrease of .:10 EF 
Points from Baseline or 
Symptomatic CHF Has 
Developed 
Stop Trastuzumab 
LVEF 45% -49% with a Decrease 
of <10 EF Points from Baseline 
or LVEF >49% 
Resume Trastuzumab 
at the Same Dose 
Continue 
Trastuzumab 


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9.4.1.1.2.1.
Abemaciclib
Abemaciclib may be held up to 21 days to permit sufficient time for recovery from the toxicity.  
Patients not recovering from toxicity within 21 days should be considered for discontinuation of 
abemaciclib.  In exceptional circumstances, a delay >21 days is permitted upon agreement 
between the investigator and the Lilly CRP and abemaciclib 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.
9.4.1.1.2.2.
Trastuzumab
If a dose of trastuzumab is missed/omitted by 1 week or less, then the usual maintenance dose 
should be administered as soon as possible.  Then, subsequent maintenance doses should be
administered every 21 days.
If a dose is missed/omitted by more than 1 week, a re-loading dose of trastuzumab should be 
administered over approximately 90 minutes (8 mg/kg) as soon as possible.  Subsequent 
trastuzumab maintenance doses (6 mg/kg) should be administered 21 days later.
If the patient requires omission of more than 2 trastuzumab maintenance doses (2 cycles) for 
toxicity, the patient should be withdrawn from trastuzumab.
In exceptional circumstances, a longer delay may be permitted upon agreement between the 
investigator and the Lilly CRP.
9.4.1.1.2.3.
Fulvestrant
For fulvestrant (dosed every 4 weeks), a dose can be delayed up to 56 days from the last dose. If 
the patient requires more delay for toxicity, fulvestrant should be discontinued from study 
treatment.
In exceptional circumstances, a longer delay may be permitted upon agreement between the 
investigator and the Lilly CRP.
9.4.1.1.3. Management of Patients Receiving Trastuzumab and Standard-of-Care 
Chemotherapy
Investigators should refer to the product label (Patient Information Leaflet, Package Insert, or 
SPC) for trastuzumab and standard-of-care chemotherapy for guidance regarding contra-
indications, duration of the contraception, dose adjustments due to toxicity, patient monitoring,
and concomitant medications that are either prohibited or to be used with caution.
9.5.
Blinding
This is an open-label study.


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9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the 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.
Modulators of CYP3A
Abemaciclib is extensively metabolized through oxidation by CYP3A.  In clinical drug 
interaction studies, 

coadministration of clarithromycin, a strong CYP3A inhibitor, increased exposure (area 
under the concentration time curve) to abemaciclib by 3.4-fold (Study I3Y-MC-JPBE),
and 

coadministration of rifampin, a strong CYP3A inducer, decreased exposure to 
abemaciclib by 95% (Study I3Y-MC-JPBF).  
Strong inhibitors of CYP3A (given via non-topical routes of administration) should be 
substituted or avoided if possible (Attachment 9). This includes grapefruit or grapefruit juice. In 
particular, avoid oral administration of the very strong CYP3A inhibitor, ketoconazole.
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should reduce 
the dose of abemaciclib by 50 mg at the start of CYP3A inhibitor treatment. That is, for patients 
receiving 150 mg twice daily, reduce the dose to 100 mg twice daily. For patients who have 
already dose reduced to 100 mg twice daily for tolerability, reduce the dose further to 50 mg 
twice daily. Alternatively, the investigator may consider suspending abemaciclib for the duration 
of the CYP3A inhibitor medication. Dose suspensions ≥28 days must be discussed with Lilly 
CRP/CRS.
Upon discontinuation of the strong CYP3A inhibitor, the dose of abemaciclib may be re-
escalated to the dose that was used before starting the strong inhibitor after a sufficient washout 
period (3-5 half-lives of the strong inhibitor). Re-escalation of the abemaciclib dose requires 
review and approval from Lilly CRP/CRS.
Inducers of CYP3A should be substituted or avoided if possible (Attachment 9). 
Coadministration with a CYP3A inducer ≥28 days must be discussed with Lilly CRP/CRS.
Transporter Substrates
At clinically relevant concentrations, abemaciclib inhibits the transporters P-glycoprotein, breast 
cancer resistance protein, organic cation transporter 2 (OCT2), multidrug and toxin extrusion 
protein 1 (MATE1), and MATE2-K. The observed serum creatinine increase in clinical studies 
with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, 
and MATE2-K. In vivo interactions of abemaciclib with narrow therapeutic index substrates of 
these transporters, such as digoxin and dabigatran, may occur.


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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. Palliative Radiotherapy
Palliative radiotherapy in order to palliate to symptomatic bone metastases is allowed only if 
limited to non-target lesions.  Abemaciclib should be suspended during the palliative 
radiotherapy period and until complete recovery from acute reactions and potential GI toxicities,
if any.  Trastuzumab and or fulvestrant can be continued while on palliative radiotherapy at the
discretion of the investigator.  
9.6.3. Supportive Care
Patients should receive full supportive care to maximize quality of life (for example, anti-
emetics, approved bone-modifying agents).  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.
9.6.3.1.
Supportive Management for Diarrhea
At randomization, patient should receive instructions on the management of diarrhea.  In the 
event of diarrhea (see Attachment 10), 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 (for 
example, loperamide) and notify the investigator/site for further instructions and 
appropriate follow-up.

Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with anti-diarrheal therapy within 24 hours to either baseline 
or Grade 1, abemaciclib should be suspended until diarrhea is resolved to baseline or 
Grade 1.

When abemaciclib recommences dosing should be adjusted as outlined in
Section 9.4.1.1.1.


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In severe cases of diarrhea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed.
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given intravenous fluid (IV hydration) and electrolyte 
replacement.
9.6.3.2.
Therapy for Febrile Neutropenia
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation of 
intravenous antibiotic therapy.  Events that require a patient to be hospitalized are considered 
SAEs (see Section 10.3.1.1).
9.6.3.3.
Growth Factors
Growth factors should not be administered to enable a patient to satisfy study inclusion criteria.
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2015). 
Dosing of abemaciclib must be suspended if the administration of growth factors is required and 
must not be recommenced within 48 hours of the last dose of growth factors having been 
administered. The dose of abemaciclib must be reduced by 1 dose level on recommencement 
following the administration of growth factors.
9.7.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit.  
Abemaciclib compliance will be assessed by counting returned solid oral dosage units.  Study 
medication administration data will be recorded in the patient’s medical record and eCRF.
Patients who are significantly noncompliant will be discontinued from the study.  A patient will 
be considered significantly noncompliant if she misses 7 or more consecutive days of 
abemaciclib (full doses), or more than 25% cumulative days of abemaciclib (full doses) during 
the study.  Similarly, a patient will be considered significantly noncompliant if she is judged by 
the investigator to have intentionally or repeatedly taken more than the prescribed amount of 
medication.  Abemaciclib dose suspensions or delays related to toxicity may occur and will not 
result in a patient being considered as noncompliant.
Fulvestrant and trastuzumab will be administered only at the investigational sites by authorized 
study personnel.  As a result, treatment compliance is ensured.
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 


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to PK blood draws and electrocardiogram (ECG) collection. For patients randomized to either 
abemaciclib arm (Arm A or Arm B), diaries for Cycles 1 through 4 are mandatory. Diaries 
beyond Cycle 4 are optional.


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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 (bone scan) 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 randomization is also acceptable.  For patients 
with treated brain metastases, a gadolinium-enhanced magnetic resonance imaging scan will be 
performed at baseline.  Note:  progressive brain metastases will be considered PD, and patients 
will be discontinued from the study (Section 7.3.2). All tumor assessment images must be 
submitted for potential central review.
ONLY for patients with bone lesions identified on baseline bone scintigraphy, repeat bone 
scintigraphy every 24 weeks (that is, every 6 months [± 3 business days]) in order to detect new 
lesions.  Additional bone scintigraphy should be considered if there is clinical suspicion of 
disease progression in bone.  If a patient with bone lesions at baseline experiences a CR, bone 
scintigraphy should continue to be repeated every 24 weeks (± 3 business days) and until disease 
progression to detect new lesions.

Note: For patients with no bone lesions on baseline bone scintigraphy, bone 
scintigraphy should be performed ONLY if there is clinical suspicion of disease 
progression in bone, even if a CR is achieved.
For bone lesion measurements, if chest/abdomen/pelvis CT (CAP CT)/MRI does not capture 
bone lesions, perform specific bone-directed imaging (X-ray, CT scan with bone windows, or 
MRI) at baseline and repeatedly every 6 weeks (± 3 business days) for 36 weeks from first dose 
of study therapy, then every 9 weeks (± 3 business days), and within 14 days of clinical 
progression. EXCEPTION: For the following patients, NO specific bone-directed imaging is 
required: 

patients with no bone lesions at baseline 

patients with measurable visceral disease and nonmeasurable bone lesions 


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The same imaging method used at baseline for bone lesion measurement is to be used during 
treatment period and follow-up.
For all patients, imaging studies (CT, including spiral CT, or MRI scan of the chest, abdomen, 
and pelvis) will be performed locally at baseline and will be repeated every 6 weeks 
(± 3 business days) for 36 weeks from first dose of study therapy, then every 9 weeks 
(± 3 business days), 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 patients with ONLY locally advanced disease extension and NO measurable lesions out of 
the breast on CAP CT scan, MRI scan of the breast will be performed at baseline.  Breast MRI, if 
applicable, will be repeated every 6 weeks (± 3 business days) for 36 weeks from first dose of 
study therapy, then every 9 weeks (± 3 business days), and within 14 days of clinical 
progression.  
For patients with visible tumors (such as skin lesions), photography will be performed at baseline 
and every 6 weeks (± 3 business days) for 36 weeks from first dose of study therapy, then every 
9 weeks (± 3 business days), and within 14 days of clinical progression.  Each photographic 
image of the tumor should include a ruler.  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 are randomized and never receive study treatment or those who 
discontinue study treatment without objectively measured PD, the investigative sites will 
continue to monitor patients and periodically evaluate tumor response via measurement of visible 
tumors and radiological imaging approximately every 6 weeks for 36 weeks from first dose of 
study therapy and thereafter approximately every 9 weeks by the same method used at baseline 
and throughout the study until the patient has objective disease progression, or until primary 
analysis of PFS.  Bone scintigraphy, only for patients with bone lesions on baseline scintigraphy,
is to be performed approximately every 24 weeks until objective disease progression or primary 


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PFS analysis. 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 tests and photographic images are no longer required and the patient will continue 
with postdiscontinuation follow-up approximately every 9 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 investigator-assessed PFS as defined by RECIST 1.1 
(Eisenhauer et al. 2009) provided in Attachment 5.
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  Digital images are to be sent to a third-party organization (TPO) for 
storage.
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.  The censoring is taken in the following 
order:

if a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the enrollment date, regardless of whether or not objectively determined 
disease progression or death has been observed for the patient; otherwise,

if a patient is not known to have died or have objective progression as of the data 
inclusion cutoff date for the analysis, the PFS time will be censored at the last complete 
objective progression-free disease assessment date.
Detailed censoring rules are described in Table JPBZ.12.1.
The study will admit patients with both measurable and/or nonmeasurable disease.  For those 
patients with nonmeasurable, bone-only disease, objective progression will be established if at 
least 1 of the following criteria is met based on RECIST v1.1:

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 locally-advanced recurrent breast cancer 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


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
new development of metastatic disease.
For those patients with locally-advanced recurrent breast cancer for whom surgery is performed 
while on study with evidence of residual disease post-operatively, new baseline measurements 
should be taken and RECIST applied.  After surgery, restart tumor assessment according to the 
Study Schedule (Attachment 1) (that is, every 6 weeks for 36 weeks, then every 9 weeks).
10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures (Table JPBZ.10.1) will be collected at the times 
shown in the Study Schedule (Attachment 1).
Table JPBZ.10.1.
Secondary Efficacy Endpoints
Endpoint
Definition
Overall Survival
The time from the date of study enrollment to the date of death from any cause
Objective Response Rate 
The proportion of patients with CR or PR according to RECIST v1.1 
Duration of Response (DoR)
The time from the date of first evidence of CR or PR to the date of objective 
progression (according to RECIST v1.1) or death from any cause, whichever is 
earlier
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
Abbreviations:  CR = complete response; PR = partial response; PS = performance status; RECIST = Response 
Evaluation Criteria In Solid Tumors; SD = stable disease.
Overall Survival (OS):  Overall survival 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 is defined only for responders (patients with a CR or 
PR).  It is measured from the date of first evidence of a CR or PR to the date of objective 
progression or the date of death due to any cause, whichever is earlier.  If a responder is not 
known to have died or have objective progression as of the data inclusion cutoff date, DOR will 
be censored at the date of the last complete objective progression-free disease assessment.
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.


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10.2. Health Outcome/Quality of Life Measures
10.2.1. Patient-Reported Outcomes
The primary health outcomes research goal is to determine if abemaciclib combination therapy is 
able to palliate pain, as measured by the mBPI-sf (Cleeland 1991).  Additionally, the EORTC 
QLQ-C30 (Aaronson et al. 1993) will assess the broader impact of abemaciclib combination 
therapy on quality of life, 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 mBPI-sf, 
EORTC QLQ-C30, and EQ-5D 5L questionnaires should be administered to the patient prior to 
extensive interaction with site staff and study drug administration.
10.2.1.1. Pain Intensity
The mBPI-sf (Cleeland 1991) is an 11-item instrument used as a multiple-item measure of cancer 
pain intensity.  In addition to pain intensity (4 items), the mBPI-sf is designed for patients to 
record the presence of pain in general, pain relief, and pain interference with function (general 
activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, and 
enjoyment of life).
Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales 
anchored at 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can 
imagine or completely interferes).  The mBPI-sf recall period is 24 hours, and pain relief is 
assessed with a scale range from 0% (no relief) through 100% (complete relief).  Typical 
completion time for this instrument is less than 5 minutes.  Focused analysis will be on “worst 
pain”.
Use of pain medication will be assessed in conjunction with the mBPI-sf assessment.  Data on 
each individual prescription and over-the-counter analgesic medication will be recorded on the 
Concomitant Medications eCRF.  The use of pain medications should be reviewed with the 
patient at each subsequent visit.  Any changes to analgesic use (new or stopped analgesics) will 
be recorded on the eCRF.  Pain medication will be classified into 1 of 3 categories, using an 
analgesic ladder approach with medication category based on a World Health Organization
(WHO) pain relief ladder:  nonopioids (aspirin and paracetamol); then, as necessary, mild 
opioids (codeine); then strong opioids such as morphine (WHO cancer pain ladder page 
[WWW]).  A therapy category will be assigned according to the maximum category of therapy 
administered based on analgesic data for that cycle.  Category of pain medication for each cycle 
will be determined based on the data collected on analgesic use.
The BPI population will include all patients who completed at least 1 baseline followed by at 
least 1 BPI “worst pain” assessment after 1 cycle of study drug (Cycle 2 Day 1 or later).


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10.2.1.2. Health-Related Quality of Life
Broadly used in cancer trials, validated, and available in over 80 different languages, the EORTC 
QLQ-C30 (Aaronson et al. 1993) is a reliable and validated tool.  The EORTC QLQ-C30 self-
reported general cancer instrument (Aaronson et al. 1993) consists of 30 items covered by 1 of 3 
dimensions:

global health status/quality of life (2 items)

functional scales (15 total items addressing either physical, role, emotional, cognitive, or 
social functioning)

symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, or financial impact)
The EORTC QLQ-C30 questionnaire is administered per the Study Schedule (Attachment 1).  
The recall period is the past week, completion time is typically 5 to 7 minutes, and the 
questionnaire will be scored as described by the EORTC scoring manual (Fayers et al. 2001).  
The EORTC population will include all patients who completed at least 1 baseline followed by at 
least 1 EORTC assessment after 1 dose of study drug (Cycle 2 Day 1 or later).
10.2.1.3. Health Status
The EQ-5D 5L (Janssen et al. 2008) is a standardized instrument for use across diseases as a 
measure of self-reported health status.  Specifically, this questionnaire is included in this trial to 
evaluate health-state utilities associated with advanced breast cancer.  These utility measures are 
an important input for economic evaluations concerning the value of treatment interventions.
The EQ-5D 5L is designed to be used in conjunction with other patient-reported measures.  
Patients will complete the 5-dimension (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), 5-level (no problem, slight, moderate, severe, or extreme problem) 
assessment according to the Study Schedule (Attachment 1).  A visual analog scale (VAS) 
"thermometer" measures current health state.
Administration is preferably scheduled after the BPI and the EORTC, and before extensive 
contact with study personnel or clinicians, which could result in biased patient response.  The 
recall period is “today.”  The EQ-5D 5L is designed for self-completion by respondents and is 
cognitively simple, taking only a few minutes to complete.
The EQ-5D 5L population will include all patients who completed at least 1 baseline followed by 
at least 1 EQ-5D 5L assessment after 1 dose of study drug.
10.2.2. Resource Utilization
Investigators will be asked to document the use of all concomitant medications, transfusions, and 
treatment-related hospitalization days.  Such assessments are to be taken throughout the study up 
to the 30-day short-term postdiscontinuation follow-up visit.


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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 JPBZ.10.2 presents a summary of AE and SAE reporting guidelines.  Table JPBZ.10.2
also shows which database or system is used to store AE and SAE data.
Table JPBZ.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study drugs
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment 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.


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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.
Cases of pregnancy that occur during maternal exposures to study treatment should be reported.  
Data on fetal outcome and breast-feeding are collected for regulatory reporting and drug safety 
evaluation
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.
In addition, all AEs occurring after the patient receives the first dose of study treatment must be 
reported to Lilly or its designee via eCRF.
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 treatment 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 study treatment or study procedure, the following 
terminologies are defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study 
treatment
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study treatment/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)-Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.03 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 4.03 criteria, the investigator will be responsible for 
selecting the appropriate system organ class and assessing severity grade based on the intensity 
of the event. 


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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 adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed informed consent and has 
received study treatment.  If a patient experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will not be reported as serious unless the investigator 
feels the event may have been caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  If study site 
personnel contact Lilly or its designee by telephone regarding an SAE, study site personnel must 
also immediately provide official notification on study-specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.


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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 treatment.
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 
treatment, 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 Reference Safety Information (RSI) in the IB and that the investigator identifies as related 
to the study treatment or study procedure.  United States 21 CFR 312.32 and European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and associated detailed guidances.
10.3.2. Other Safety Measures
10.3.2.1. Electrocardiograms 
For each patient, 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, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/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.


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10.3.2.2. Assessment of LVEF by Echocardiography or Multigated Acquisition 
Scan
Since trastuzumab will be administered to all patients, an echocardiography or MUGA scan is 
required at baseline within 45 days of randomization. Only subjects with LVEF of 50% or 
higher should be enrolled in the study.  During study treatment period, echocardiography or 
MUGA scan is performed at Cycle 5 Day 1 (±7 days). Then, if LVEF is stable, 
echocardiography or MUGA is repeated every 12 weeks starting with Cycle 9 Day 1 (± 7 days) 
and then every 24 weeks following discontinuation of trastuzumab. If LVEF on trastuzumab 
therapy is <50%, refer to LVEF monitoring diagram in Figure JPBZ.9.1.
In addition, during the course of trastuzumab therapy, subjects should be monitored for signs and 
symptoms of congestive heart failure (dyspnea, tachycardia, new unexplained cough, neck vein 
distention, cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral 
edema, and rapid unexplained weight gain).  Any subject who develops clinical signs or 
symptoms of congestive heart failure should undergo an ECG and assessment of LVEF by either 
echocardiogram or MUGA scan.
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
10.3.3.1. Special Hepatic Safety Data Collection
Liver testing (Attachment 3), including ALT, AST, alkaline phosphatase, total bilirubin (TBL), 
direct bilirubin, gamma-glutamyl transferase, and creatine phosphokinase, should be repeated 
within 2 to 4 days to confirm the abnormality and to determine if it is increasing or decreasing, if 
one or more of these conditions occur:
If a participant with baseline results of…
develops the following elevations:
ALT or AST <1.5× ULN
ALT or AST ≥5× ULN or
ALT or AST ≥3× ULN concurrent with TBL ≥2× ULN
ALT or AST ≥1.5×ULN
ALT or AST ≥3× baseline or
ALT or AST ≥2× baseline concurrent with TBL ≥2× ULN
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ULN = 
upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 


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examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), history of concomitant medications 
(including over-the-counter, herbal and dietary supplements, history of alcohol drinking, and 
other substance abuse). In addition, the evaluation should include a blood test for prothrombin 
time international normalized ratio (PT-INR); serological tests for viral hepatitis A, B, C, E, 
autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan).
Additional Hepatic Safety Collection
Additional safety data should be collected via the case report form (CRF) if 1 or more of the 
following conditions occur:
In participants enrolled with baseline ALT or AST <1.5× ULN

Elevation of serum ALT or AST to ≥5× ULN on 2 or more consecutive blood tests

The combination of elevated ALT or AST ≥3× ULN and elevated TBL ≥2× ULN
In participants enrolled with baseline ALT or AST ≥1.5× ULN

Elevated ALT or AST ≥3× baseline on 2 or more consecutive tests

The combination of elevated ALT or AST ≥2× baseline and elevated TBL ≥2× ULN
In all study participants

Discontinuation from study treatment due to a hepatic event or abnormality of liver tests

Occurrence of a hepatic event considered to be an SAE
10.3.3.2. Renal Function 
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Table JPBZ.9.2).
A serum cystatin C will be collected with the central chemistry laboratory sample.
10.3.3.3. Venous Thromboembolic Events
VTE has been identified as an adverse drug reaction for abemaciclib in combination with 
endocrine therapy. In the randomized Phase 3 studies in patients with breast cancer treated with 
abemaciclib in combination with endocrine therapy (ET), a greater number of patients 


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experienced VTEs in the abemaciclib plus ET arm than in the placebo plus ET arm or ET alone 
arm. The majority of patients who experienced VTEs were treated with anticoagulants. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known. Monitor patients for signs and symptoms of deep vein thrombosis and 
pulmonary embolism and treat as medically appropriate.
10.3.3.4. Interstitial Lung Disease/Pneumonitis
Interstitial lung disease/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. The majority of events observed in clinical trials were Grade 1 or Grade 2, with 
serious cases and fatal events reported. Additional information is available in the IB.
Ask your patients to report any new or worsening pulmonary symptoms, such as dyspnea, cough, 
and fever, and investigate and treat as per your local clinical practice (including corticosteroids 
as appropriate). If ILD/pneumonitis is suspected, investigations may include imaging, such as 
high-resolution computed tomography, bronchoalveolar lavage, and biopsy as clinically 
indicated.
Refer to Table JPBZ.9.2 for guidance on dose adjustments of abemaciclib for patients with 
ILD/pneumonitis (see Attachment 10 for ILD/pneumonitis CTCAE grades). Discontinue 
abemaciclib in cases of severe (Grade 3 or 4) ILD/pneumonitis.
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.
Complaints related to comparator drugs or concomitant drugs are reported directly to the 
manufacturers of those drugs/devices in accordance with the package insert.
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 lists the schedule for PK sampling during the study.
Attachment 7 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.


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10.4.1. Samples for Study Qualification and Health Monitoring
Blood samples will be collected to determine whether patients meet inclusion/exclusion criteria 
and to monitor patient health. Enrollment and treatment decisions may be based upon results of 
tests performed locally.  If local laboratory tests are used for this purpose, then a duplicate 
specimen must be submitted to the central laboratory.  Discrepancies between local and central
laboratory results that may have an impact on eligibility or treatment decisions will not be 
considered protocol deviations.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Samples for Pharmacogenetics and Biomarkers
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.
Biomarker research is used to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety) and clinical outcome.  Specimen storage is incorporated in clinical trials to enable 
examination of these questions through measurement of biomolecules including DNA, RNA, 
proteins, lipids, other cellular elements.  
As part of Lilly’s ongoing efforts to understand the relationship between cancer, genetics, and 
response to therapy, this study will analyze biomarkers relevant to abemaciclib, trastuzumab,  
fulvestrant, the cell cycle, and/or breast cancer. The study will analyze the correlation between 
biomarkers and clinical outcome and may be used for related research methods or validation of 
diagnostic tools or assays.
Samples for biomarker research will be collected at times specified in Attachment 1.
Required samples for biomarker research to be collected from all patients in this study are the 
following:

Whole blood sample for genetic research (pharmacogenetic analysis)

Plasma for biomarkers

Tumor tissue (newly obtained; otherwise archived)


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10.4.2.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in Study
Schedule (Attachment 1).
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to study treatment.  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 treatment.
Molecular technologies are expected to improve during the 15 year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, candidate gene studies, and epigenetic analyses.  
Regardless of the technology utilized, genotyping data generated will be used only for the 
specific research scope described in this section.
10.4.2.2. Biomarkers
10.4.2.2.1.Plasma
Plasma samples for non-pharmacogenetic biomarker research will be collected at the times 
specified in the Study Schedule (Attachment 1) where local regulations allow.
Samples will be used for research on the cell cycle, breast cancer, mechanism of action 
associated with study treatment, and/or research method or in validating diagnostic tools or 
assay(s) related to breast cancer.
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 treatment.
10.4.2.2.2.Tumor Tissue
The availability of adequate tumor tissues is important to better characterize the relationship of 
tumor biology and response evaluation in this study.  As such, this study is requesting 
submission of tumor tissue (newly biopsied; otherwise archived) to support correlative studies.
Availability of either newly obtained biopsy OR archived tumor sample is mandatory at 
baseline; collection of fresh biopsy at baseline is preferred. If collection of fresh biopsy is not 
possible, submission of archived tumor specimen is mandatory, unless restricted by local 


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regulations. Sites should confirm the availability of adequate tumor tissue with the pathological 
laboratory prior to randomization.  Additionally, a biopsy will be requested during 
Postdiscontinuation Follow-Up from patients who discontinue due to PD; this 
postdiscontinuation biopsy is contingent upon patient consent, and the tumor tissue will 
potentially be used to explore mechanisms of resistance to abemaciclib.  
Formalin-fixed paraffin-embedded tumor tissue should be provided as a block or unstained 
slides. Sites should submit a minimum of 20 slides. Due diligence should be used to make sure 
that tumor specimen (not a normal adjacent or a tumor margin sample) is provided.  Pathology 
notes accompanying archival tissue may also be requested.  The report must be coded with the 
patient number.  Personal identifiers, including the patient’s name and initials must be removed 
from the institutional pathology report prior to submission.  Blocks will be sectioned and 
returned to the site.  Slides will not be returned.
Tumor tissue will be examined for biomarkers that may include, but are not limited to, those 
related to breast cancer, study treatment and/or cell cycle.  
In addition, centralized HER2 receptor testing will be conducted post-randomization and in an 
exploratory manner for all patients on the tumor tissue collected at baseline.  Testing will be 
performed according to ASCO/CAP HER2 guidelines (Wolff et al. 2013).  
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility 
selected by the sponsor.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in drug development or when the drug is commercially available.
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 treatment.
Technologies are expected to improve during the 15 year storage period and therefore cannot be 
specifically named.  However, existing approaches including mutation profiling, copy number 
variability, gene expression, and/or immunohistochemistry may be performed on these tissue 
samples to assess potential associations with these biomarkers and clinical outcomes.
10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics
Pharmacokinetic samples will be collected as specified in the Pharmacokinetic Sampling 
Schedule (Attachment 6). 
Blood samples will be used to determine the concentrations of abemaciclib and its metabolites, 
as well as trastuzumab and fulvestrant in patients enrolled on Arms A and B.
Bioanalytical samples collected to measure abemaciclib, fulvestrant, and trastuzumab 
concentrations will be retained for a maximum of 1 year following last patient visit for the study.


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10.5. Appropriateness of Measurements
Efficacy measurements by radiographic imaging are standard, widely used, generally recognized 
as reliable, accurate, and able to discriminate between effective and ineffective agents.
Safety measurements by laboratory monitoring are standard, widely used, 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.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
laboratory database.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome (PRO) measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary objective of this study is to compare abemaciclib plus trastuzumab plus fulvestrant 
and abemaciclib plus trastuzumab to standard-of-care single-agent chemotherapy of physician’s 
choice plus trastuzumab in terms of PFS in patients with locally advanced recurrent or metastatic
breast cancer.  The study will enroll approximately 225 patients in [1:1:1] randomization (75 
patients in abemaciclib plus trastuzumab plus fulvestrant; 75 patients in abemaciclib plus 
trastuzumab; and 75 patients in standard-of-care single-agent chemotherapy of physician’s 
choice plus trastuzumab).  The primary analysis will be performed after approximately 165 PFS 
events have occurred.  Assuming a hazard ratio of 0.667, this sample size yields at least 80% 
statistical power to detect superiority of the abemaciclib plus trastuzumab plus fulvestrant and 
abemaciclib plus trastuzumab arms over standard-of-care single-agent chemotherapy of 
physician’s choice plus trastuzumab arm with the use of an experiment-wise 1-sided alpha level 
of .10.
If the true median PFS for the standard-of-care single-agent chemotherapy of physician’s choice 
plus trastuzumab arm is 4 months, then the HR of 0.667 amounts to an approximately 2-month 
improvement in median PFS for the abemaciclib plus trastuzumab plus fulvestrant and 
abemaciclib plus trastuzumab arms under an additional assumption of exponential survival 
distribution.  Assuming a censoring rate of approximately 30%, the study will randomize
approximately 225 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 Safety Population, defined as all enrolled patients receiving 
at least 1 dose of any study drug.  Patients will be grouped according to treatment received in 
cycle 1.
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above populations from whom a valid assay result (according to laboratory guideline) 
has been obtained.  
All tests of treatment effects will be conducted at a 2-sided alpha, unless otherwise stated.  All 
confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise stated.  For 
regulatory purposes, tests may be performed at a 1-sided alpha level of 0.025, with 95% CIs.
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.


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Any other change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.  
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  A summary of all important protocol deviations will be provided.
12.2.3. Patient Characteristics
Patient characteristics will include a summary, by treatment arm, of the following:

patient demographics

baseline disease characteristics

preexisting conditions

historical illnesses

prior endocrine therapy

prior chemotherapy (including both cytotoxic and targeted agents)

prior HER2-directed therapy
Other patient characteristics will be summarized as deemed appropriate.
12.2.4. Concomitant Therapy
Concomitant medications will be summarized for the safety population. 
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 chemotherapy), 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.
Treatment compliance information for abemaciclib will be collected through pill counts at each 
visit and the number of tablets taken relative to the number expected to be taken will be 
summarized.  
12.2.6. Primary Outcome and Methodology
The primary endpoint of this study is PFS.  Progression-free survival time is measured from the 
date of randomization to the date of investigator-determined objective progression as defined by 


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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 JPBZ.12.1.
Table JPBZ.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Situation
Date of Event or Censor
Event / Censor
Tumor progression or death
Earliest date of PD or death
Event
No tumor progression and no death
Date of last adequate radiological assessment or 
date of randomization (whichever is later)
Censored
Unless
No baseline radiological tumor assessment 
available
Date of randomization
Censored
No adequate post baseline radiological 
tumor assessment available 
and death reported after 2 scan intervals 
following randomization
Date of randomization
Censored
New anticancer treatment started 
(excluding maintenance endocrine therapy 
following chemotherapy) and no tumor 
progression or death within 14 days
Date of adequate radiological assessment prior to 
(start of new therapy +14 days) or date of 
randomization (whichever is later)
Censored
Tumor progression or death
documented immediately after 2 or more 
scan intervals following last adequate 
radiological tumor assessment or 
randomization (whichever is later)
Date of last adequate radiological assessment or 
date of randomization (whichever is later)
Censored
Abbreviations:  PD = progressive disease.
The PFS analysis to test the superiority of abemaciclib plus trastuzumab plus fulvestrant and 
abemaciclib plus trastuzumab to chemotherapy plus trastuzumab in improving PFS time will be 
performed on the ITT population and will use the log-rank test stratified by number of previous 
regimens for advanced breast cancer and status of disease.  In addition, the Kaplan-Meier method 
(Kaplan and Meier 1958) will be used to estimate the PFS curves as well as PFS rates at every 3 
months for each treatment group.  These rates will be compared based on a normal 
approximation for the difference between the rates.
There is 1 planned primary analysis for PFS in this study, which will be performed after
approximately 165 events have been observed in the ITT population based on investigator 
assessment.  The primary PFS analysis will compare each arm against the control using a log 
rank test stratified by the randomization factors.  The primary objective of PFS will be tested at 
an experiment-wise 1-sided alpha level of .10.  The abemaciclib treatment arms will be tested 
sequentially against the trastuzumab plus chemotherapy arm, with the abemaciclib plus 
trastuzumab plus fulvestrant arm tested first.  A comparison of the 2 abemaciclib arms will be 
considered exploratory.  See Figure JPBZ.12.1 for a depiction of alpha spending.  A stratified 


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Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to estimate the 
HR and corresponding CI with Wald’s test p-value after adjusting for the same randomization 
variable specified for the primary analysis.  An additional unstratified Cox regression model will 
be employed to explore the effects of prognostic variables, such as of the stratification variables
and intrinsic/extrinsic factors, on treatment response.
Abbreviations:  OS = overall survival; PFS = progression-free survival; vs. = versus.
Figure JPBZ.12.1.
Alpha spending for Study I3Y-MC-JPBZ.
12.2.7. Other Analyses of Efficacy
12.2.7.1. Overall Survival
Overall survival is an important secondary endpoint for this study.  Overall survival will be 
tested only if PFS is significant for both abemaciclib arms.  Overall survival will be tested by 
pooling the 2 abemaciclib arms and comparing them against the chemotherapy arm.  Up to a 
total of 2 interim analyses and a final analysis for OS may be performed in this study.  The type I 
experiment-wise error rate will be controlled at 10% by using the Lan-Demets method with the 
following O’Brien-Fleming like α-spending function:





















k
k
t
t
2
/
1
1
2
1
*


.
Here, tk is the information fraction at time k, Φ is the standard normal cumulative distribution 
function, and Φ-1 is the standard normal quantile function.
PFS (test at 1-sided α=.10):
abemaciclib + trastuzumab + fulvestrant vs. 
single-agent chemotherapy + trastuzumab
PFS (test at 1-sided α=.10):
abemaciclib + trastuzumab vs.
single-agent chemotherapy + trastuzumab
OS (tests at cumulative 1-sided α=.10):   
pooled abemaciclib arms vs.
single-agent chemotherapy + trastuzumab
-11 
t 
I 
t 


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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).
To maintain the experiment-wise type I error rate, OS will be hierarchically tested in the 
following way:  only if the test of PFS is significant will OS also be tested inferentially for 
significance (Glimm et al. 2010); specifically:

The first potential time point for OS analysis will be at the time of the PFS analysis.  If 
PFS is significant at this stage, the first interim analysis of OS will also be performed.  If 
OS is not significant at this stage, the second interim analysis of OS will be performed 
after approximately 105 deaths have been observed in the ITT population (information 
fraction of 0.667).  If OS is not significant at this stage, a final analysis will be performed 
after approximately 158 deaths have been recorded in the ITT population.

If the primary analysis for PFS is not significant, OS will not be statistically evaluated.
The OS analysis to test the superiority of abemaciclib plus trastuzumab plus fulvestrant and 
abemaciclib plus trastuzumab to chemotherapy plus trastuzumab in improving OS time will use 
the log-rank test stratified by the number of previous systemic regimens for advanced breast 
cancer and disease status.
The following additional analyses will be conducted for OS:

Kaplan-Meier curves (Kaplan and Meier 1958) will be generated; medians, quartiles, and 
appropriate point probabilities with interval estimates will be calculated.

The Cox regression stratified by the randomization factors will be used to estimate the 
HR between the 2 treatment groups, along with CI.
In addition, OS rate at 1 year in each treatment arm will be calculated by determining OS time 
for each patient and using Kaplan-Meier techniques to assess OS time for each treatment arm.  
The Kaplan-Meier estimate of the OS rate at 1 year will be used to compare treatment arms using 
a standard normal test of the difference in OS rate at 1 year.  The same techniques will be used to 
calculate and compare OS rates at 2 years and 3 years between arms.
12.2.7.2. Other Analyses of Secondary Efficacy Endpoints 
Other secondary efficacy endpoints will be defined as shown in Table JPBZ.10.1.  Objective 
response rate, DCR, and CBR of each treatment arm will be calculated using the ITT population.  
All rates will be compared between the 3 treatment arms based on a normal approximation for 
the difference between the rates.  Duration of response time is defined only for responders 
(patients with a best response of CR or PR).  A Kaplan-Meier analysis of DoR will be performed 
to estimate the DoR curve for each arm.
12.2.8. Pharmacokinetic and/or Pharmacodynamic Analyses
Pharmacokinetic analyses will be conducted on all patients who have received at least one dose 
of abemaciclib and have had samples collected (see Attachment 6).


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Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and inter-individual PK variability will be computed using nonlinear 
mixed effects modelling (NONMEM).  The current PK model for abemaciclib, which has been 
developed using plasma concentration data available from the Phase 1 Study JPBA, will be 
updated using the plasma data collected in this study.  Covariate effects (such as age, weight, 
sex, and plasma protein levels) on the PK parameters of abemaciclib in plasma will also be 
investigated.
Likewise, and if warranted by the data, mean population PK parameters for fulvestrant and/or 
trastuzumab in plasma and inter-individual variability estimates will also be computed using 
nonlinear mixed-effect modelling implemented in NONMEM.
Pharmacodynamic and biomarker samples will be collected as specified in the Study Schedule 
(Attachment 1) and PK Sampling Schedule (Attachment 6).  Refer to these attachments 
(including footnotes) for important information about these samples and their collection.
Pharmacodynamic data (such as neutrophil, lymphocyte, or platelet counts in blood, PFS, OS) 
collected in this study may also be analyzed by means of NONMEM and connected to the 
population PK model in a PK/Pharmacodynamics model.
Pharmacodynamic data from all patients undergoing pharmacodynamic assessments will be 
analyzed.  The pharmacodynamic data will be combined and exploratory analyses will be 
conducted to determine if a relationship exists between plasma concentration and 
pharmacodynamic effect(s) in humans.  Interpatient variability in human pharmacodynamic 
response will also be assessed.
The version of software used for the analysis will be documented and will meet the Lilly 
requirements of software validation.
12.2.9. Biomarker Analyses
The distributions of biomarkers will be summarized.  Correlative analyses will be performed to 
investigate associations between biomarkers and clinical endpoints as deemed appropriate.
12.2.10.Health Outcome/Patient-Reported Outcome Analyses
Patient-reported outcomes are measured through paper versions of the following:

mBPI-sf (modified Brief Pain Inventory, Short Form)

EORTC QLQ-C30 (The European Organization for Research and Treatment of Cancer 
Quality of Life-Core 30)

EQ-5D 5L (EuroQol 5-Dimension 5 Level)
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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12.2.10.1.
Pain Intensity and Assessment
Individual pain items on the mBPI-sf (that is, worst, least, average, and current pain) will be 
described using descriptive statistics by treatment arm.  A mixed effects model, repeated 
measures model may be applied to compare between treatment arms, which will be adjusted for 
other covariates.  Corresponding analyses will also be conducted for the mean of 7 pain 
interference with function items.  If a patient does not complete Questions 5a through 5g on the 
BPI-sf, the mean score for the 7 pain interference items will be calculated based on those 
answered questions when at least 4 out of 7 questions were completed (that is, 50% of the 
questions were answered).
Pain analysis will be based on all randomized patients with at least 1 baseline BPI “worst pain” 
and one BPI “worst pain” score on Cycle 2 Day 1 or later.
The mBPI-sf will be administered at baseline prior to study drug dosing and the Cycle 1, Day 1 
score will be treated as a baseline observation and the Day 1 score of each subsequent cycle will 
be attributed to the previous cycle.  The mBPI-sf will be administered at treatment 
discontinuation and grouped with observations from the previous cycle.
12.2.10.2.
Health-Related Quality of Life
EORTC QLQ-C30 instrument data will be scored as described in the EORTC scoring manual 
(Fayers et al. 2001). Descriptive statistics for each EORTC QLQ-C30 scale will be calculated 
and compared between arms.
12.2.10.3.
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.  For categorical variables, frequency and the 
corresponding percentage will be derived and measures of central tendency and variability will 
be calculated for continuous variables by arm. Tests for differences in proportion between 
treatment groups and between response groups will be performed.
12.2.10.4.
Health State Utility
The EQ-5D 5L data will be scored as described 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 described in the SAP.  
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.
12.2.11.Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.1. 


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Overall exposure to study drugs, 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. 
Preexisting conditions are defined as AEs that begin prior to the first dose of study drug.
A TEAE is defined as an event that first occurred or worsened in severity after baseline. 
Comparisons of preexisting conditions to on-treatment events at the LLT level will be used in the 
treatment-emergent computation.
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to study treatment, and repeated for events regardless of study treatment causality.  
Incidence rates of these events will be compared between treatment arms using Fisher’s exact 
test.
The number of patients who experienced a TEAE, SAE, AE related to study treatment, died, or 
discontinued from the study due to an AE will be summarized by treatment.
Adverse events will be reported using the MedDRA dictionary.  Investigators will report a 
verbatim AE term and a CTCAE v4.03 term and severity for all AEs.  For analysis purposes, the 
following process will be used:

The CTCAE v4 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and System Organ Class (SOC) using the corresponding MedDRA 
Lower Level Term (LLT), unless the reported CTCAE term is ‘Other – specify.’

If the reported CTCAE term is ‘Other – specify,’ the MedDRA LLT, PT, and SOC 
centrally mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Laboratory and non-laboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grade, including the total for maximum Grade 3 and 4.  These summaries will be 
provided for events deemed by the investigator to be possibly related to study treatment and 
repeated for events regardless of causality.
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.
12.2.11.1.
Dose-Limiting Toxicities for Arm A Safety Lead-In
For analyzing the safety and tolerability of the triplet combination of abemaciclib plus 
trastuzumab plus fulvestrant during the safety lead-in, a dose-limiting toxicity (DLT) is defined 
as an AE during Cycle 1 that is possibly related to abemaciclib and fulfills any one of the 
following criterion using the NCI CTCAE v 4.03:


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
Grade 3 or 4 nonhematological toxicity except for nausea, vomiting, diarrhea, 
electrolyte disturbance, or alopecia

Grade 3 or 4 nausea, vomiting, or electrolyte disturbance that persists more than 
3 days despite maximal supportive intervention

Grade 3 or 4 diarrhea that does not resolve to at least Grade 2 after 3 days of 
maximal supportive intervention

Grade 4 hematological toxicity that persists more than 5 days

Grade 3 or 4 thrombocytopenia with bleeding

Febrile neutropenia

Death related to toxicity
The patient population used for determination of DLTs will consist of patients who have met the 
minimum safety evaluation requirements of the study and/or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of the safety lead-in, the patient 
receives at least 75% of the intended dose of study treatment and is observed for at least 28 days 
following the first dose of study drugs.  Any patients enrolled in the safety lead-in cohort that do 
not meet the dosing criteria defined above in order to be considered complete may be replaced.
12.2.11.2.
DLT-Equivalent Toxicity
A DLT-equivalent toxicity is defined as an AE that would have met the criteria for DLT in 
Section 12.2.11.1 if it had occurred during Cycle 1, but occurs in Cycle 2 or beyond during the 
monitoring for the safety lead-in period.
12.2.12.Interim Analyses
There are 2 planned interim analyses to evaluate the safety and tolerability of the combination of 
abemaciclib plus trastuzumab plus fulvestrant in patients enrolled to the safety lead-in for Part A; 
these analyses will take place when data from the first 6 and 12 qualified patients who complete 
1 cycle have been obtained.  These interim analyses will be performed by an assessment 
committee (AC) made up of Lilly members not involved in the day to day study conduct (the 
medical director, a Global Patient Safety [GPS] physician, and a statistician) plus the global
principal investigators.  In addition to the interim analyses for the safety lead-in, safety meetings
will be held every 3 weeks with sites that have recruited and enrolled patients to Arm A during 
the safety lead-in period.  These meetings will include the Lilly CRP, clinical trial manager, trial 
statistician, and GPS physician; additional personnel may participate as deemed appropriate.
If ≥2 of 6 patients or ≥4 of 12 patients in the safety lead-in experience a DLT or DLT-equivalent 
toxicity as defined in Sections 12.2.11.1 and 12.2.11.2, respectively, the dose of abemaciclib will 
be reduced to 100 mg for these patients and for all subsequent patients enrolled to Arm A.  Even 
if the AC does not observe the specified number of DLTs or DLT-equivalent toxicities that 
would lead to dose reduction, Lilly may elect to reduce the dose of abemaciclib in Arm A if 
warranted by safety concerns.  Safety data for Arm A will be continuously monitored during the 
safety lead-in period, and the decision to reduce the dose of abemaciclib may be made by Lilly at 


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any time.  No protocol amendment will be needed to proceed with a lower dose level of 
abemaciclib in Arm A.  If the dose of abemaciclib in Arm A is reduced to 100 mg, patients that 
initiated treatment at the 150-mg dose will be dose-reduced to 100 mg, and patients who started 
at the 150-mg abemaciclib dose will be replaced so that there are a total of 75 patients in Arm A 
with a starting dose of 100-mg abemaciclib.  If the 100-mg dose is found to be intolerable, 
enrollment into Arm A will be discontinued.
In addition to the safety lead-in interim analyses for Arm A, there are 3 planned interim analyses 
for safety and 1 planned interim analysis for futility for all treatment arms in Study JPBZ.  These 
interim analyses will be reviewed by the AC.
A safety interim analysis is planned after approximately 36 patients (a minimum of 12 patients in 
each of experimental arms A and B) have been treated for 1 cycle. There will be no prespecified 
rules for stopping the trial due to safety concerns.  The AC members will review safety data at 
the interim analysis to determine whether there are sufficient safety concerns to justify the 
termination of study treatment and/or enrollment.  Similar interim safety analyses will be 
performed after approximately 75 patients and after approximately 150 patients have been 
treated for 1 cycle (a minimum of 25 and 50 patients in experimental arms A and B).
The interim analysis for futility is planned after 75 PFS events have been observed.  Futility for 
the interim analysis will be determined in terms of PFS.  As guidance, an AC may recommend 
stopping the trial or closing an experimental arm for futility if the observed HR>1.3.  The 
stopping guidance should be viewed as only guidance, not an absolute rule.  The AC will 
consider all evidence, including safety and other efficacy parameters, in making this decision.
12.2.13.Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for each of following potential prognostic 
subgroup variables, including: 

Number of previous regimens (excluding single-agent endocrine therapy) for advanced 
breast cancer (2 to 3 versus more than 3)

Measurable disease at baseline (yes versus no)

Number of organs involved (1 versus 2 versus 3+)

PgR status (positive versus negative)

Baseline ECOG PS (0 versus 1)

Age (<65 years versus 65 years)

Region (North America, Europe, Asia, and Other)

Race (Caucasian, Asian, and Other)
If a level of a factor consists of fewer than 10% 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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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 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 treatment.
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 sites.  
All ICFs must be compliant with the ICH guideline on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site[s]. 
The study site’s ERB[s] should be provided with the following:

the current IB or package labeling (for example, Patient Information Leaflet, Package 
Insert, or SPC) and updates during the course of the study

the ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 

International Conference on Harmonisation (ICH) Good Clinical Practices (GCP) 
Guideline (E6)

applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of Lilly will be assigned to a TPO.


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An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
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 coordinating investigator will sign the final clinical study report 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. 
An investigator will be chosen by Lilly to serve as the clinical study report 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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14. References
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JCJM, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KCA, Sullivan M, Takeda F.The European Organisation for Research and Treatment 
of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst. 1993;85:365-376.
Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, Francis P, Gligorov J, 
Kyriakides S, Lin N, Pagani O, Senkus E, Thomssen C, Aapro M, Bergh J, Di Leo A, El 
Saghir N, Ganz PA, Gelmon K, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, 
Leadbeater M, Mayer M, Rodger A, Rugo H, Sacchini V, Sledge G, van't Veer L, Viale G, 
Krop I, Winer E. 1st International consensus guidelines for advanced breast cancer (ABC 1). 
Breast. 2012;21(3):242-252.
Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, 
Blackwell KL, Cardoso MJ, Cufer T, El Saghir N, Fallowfield L, Fenech D, Francis P, 
Gelmon K, Giordano SH, Gligorov J, Goldhirsch A, Harbeck N, Houssami N, Hudis C, 
Kaufman B, Krop I, Kyriakides S, Lin UN, Mayer M, Merjaver SD, Nordstrom EB, Pagani O, 
Partridge A, Penault-Llorca F, Piccart MJ, Rugo H, Sledge G, Thomssen C, Van't Veer L, 
Vorobiof D, Vrieling C, West N, Xu B, Winer E. ESO-ESMO 2nd international consensus 
guidelines for advanced breast cancer (ABC2). Breast. 2014;23(5):489-502.
Cleeland CS. Pain assessment in cancer. In: Osoba D(ed). Effect of Cancer on Quality of Life.
Chapter 21. Boca Raton (FL): CRC Press;1991.
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;74(2):187-220.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001.
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Stat Med. 2010;29(2):219-228.
Hammond 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.
Herceptin (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2016.
Herceptin (trastuzumab) [summary of product characteristics]. Welwyn Garden City, United 
Kingdom: Roche Registration Limited; 2016.


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Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value in Health. 2008;11(2):274-284.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer 
J Clin. 2011;61(2):69-90.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481.
Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong HM, 
Bauerfeind I, Felber M, Wang HJ, Beryt M, Seshadri R, Hepp H, Slamon DJ. Quantitative 
association between HER-2/neu and steroid hormone receptors in hormone receptor-positive 
primary breast cancer. J Natl Cancer Inst. 2003;95(2):142-153.
Kumler I, Tuxen MK, Nielsen DL. A systematic review of dual targeting in HER2-positive 
breast cancer. Cancer Treat Rev. 2014;40(2):259-270.
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.
Sanchez-Martinez C, Gelbert LM, Shannon H, De Dios A, Staton BA, Ajamie RT, Sawada G, 
Wishart GN, Raub TJ. LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 
and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against 
intracranial human brain tumor xenografts [abstract]. Mol Cancer Ther. 2011;Meeting 
Abstract Supplement:B234
Smith TJ, Bohlke K, Armitage JO. Recommendations for the use of white blood cell growth 
factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Oncol 
Pract. 2015.
Thery JC, Spano JP, Azria D, Raymond E, Penault Llorca F. Resistance to human epidermal 
growth factor receptor type 2-targeted therapies. Eur J Cancer. 2014;50(5):892-901.
van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value Health. 2012;15(5):708-715.
Velasco-Velazquez, M. A., Li, Z., Casimiro, M., Loro, E., Homsi, N., & Pestell, R. G. 
Examining the role of cyclin D1 in breast cancer. Future Oncol. 2011;7:753-765.
Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-
targeted therapies in preclinical breast cancer models. Genes Cancer. 2014;5(7-8):261-272.
[WHO] World Health Organization cancer pain ladder page. Available at: 
http://www.who.int/cancer/palliative/painladder/en/. Accessed September 10, 2015.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, 
Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, 
Press MF, Spears PA, Vance GH, Viale G, Hayes DF. Recommendations for human epidermal 
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Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol.
2013;31(31):3997-4013.


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Attachment 1.Protocol JPBZ Study Schedule


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Study Schedule, Protocol I3Y-MC-JPBZ
Perform procedure as indicated.
Baseline Schedule
Study Period
Baseline
Visit
0
Approximate Visit 
Duration (days)
Up to 28
Relative day to 
Randomization
8

Procedure 
Category
Procedure
Comments
Study Entry 
/Enrollment
Informed consent form signed
X
Prior to conducting any protocol-specific tests / 
procedures
Inclusion/exclusion evaluation
X
Collection of tumor tissue (newly obtained biopsy;
otherwise archived tissue) is required for ALL patients 
for eligibility.  Sites should confirm the availability of 
adequate tumor tissue with the pathological laboratory 
prior to randomization.
Medical 
History
Initial medical history/preexisting 
conditions
X
Historical illnesses
X
Including habits assessment of alcohol and tobacco use
Physical 
Examination 
Physical exam
X
Including but not limited to height and weight
Vital signs
X
Including blood pressure, pulse, respiratory rate, and 
temperature
ECOG performance status
X
Tumor 
Assessmenta
Tumor measurement (visible)
X
Photography of visible tumors (such as skin lesions)
with ruler required, if applicable
Radiologic imaging according to 
RECIST 1.1
X
Performed locally.  For patients with ONLY 
locoregional disease extension and NO measurable 
lesions on CAP CT scan, MRI scan of the breast is 
performed in addition to other scans.  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.  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.
Bone scintigraphy
X
Performed locally. For all patients, bone scintigraphy 
performed as part of routine clinical care within 45 days 
before randomization is also acceptable.
X-ray, CT scan with bone windows, or MRI
X
Performed locally. If CAP CT/MRI does not capture 
bone lesions, perform specific bone-directed imaging 
(X-ray, CT scan with bone windows, or MRI) at 
baseline. 
EXCEPTION: for the following patients, NO specific 
bone-directed imaging is required: 

patients with no bone lesions at baseline 

patients with measurable visceral disease and
nonmeasurable bone lesions


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Baseline Schedule
Study Period
Baseline
Visit
0
Approximate Visit 
Duration (days)
Up to 28
Relative day to 
Randomization
8

Procedure 
Category
Procedure
Comments
Tumor 
Assessmenta
Brain Gd-MRI
X
Required only for patients with treated brain metastases
Adverse Event Collection/CTCAE Grading
X
Concomitant Medication Notation
X
Health 
Outcomes
EORTC QLQ-C30
mBPI-SF
EQ-5D 5L
X
Patients complete during screening and prior to 
extensive interaction with site staff.  This is the first of 
two pre-abemaciclib collections (second is at Cycle 1 
Day 1 prior to abemaciclib dose).
Lab/ 
Diagnostic 
Tests
Central hematology
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
X
Cystatin C
X
Perform at central laboratory.
Serum pregnancy test
X
Required only if postmenopausal status is due to 
ovarian suppression with a GnRH agonist or induced by 
radiation
Local FSH and estradiol level
X
Required only for women <60 years with amenorrhea 
for at least 12 months and menopause due to radiation-
induced ovarian suppression in order to confirm post-
menopausal status
Local ECG
X
Patients must be supine for approximately 5 to 10 
minutes before ECG collection and remain supine but 
awake during ECG collection.
Echocardiography or multiple-gated 
acquisition scanning (MUGA scan)
X
LVEF of 50% or higher is required at baseline for 
eligibility.  Echocardiography or MUGA scan 
performed as part of routine clinical care within 45 days
before randomization is also acceptable
Abbreviations:  CAP = chest/abdomen/pelvis; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
FSH = follicle stimulating hormone; Gd-MRI = gadolinium-enhanced magnetic resonance imaging;
GnRH = gonadotropin-releasing hormone; IV = intravenous; MRI = magnetic resonance imaging; 
MUGA = multigated acquisition; RECIST = Response Evaluation Criteria in Solid Tumors.
a
If a patient requires palliative radiation at baseline, tumor assessments are to be conducted after end of 
radiotherapy and prior to randomization.


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During Treatment 
Study Schedule
Study Treatment Period
Cycle / Visit
1
2
3
4-X
Approximate Visit Duration 
(days)
21
21
21
21
Relative day within a cycle
1
1
1
1
Procedure Category
Procedure
Comments
Physical Examination
Physical exam
X
X
X
X
Including weight 
Vital signs
X
X
X
X
Including blood pressure, pulse, respiratory rate, and temperature
ECOG performance status
X
X
X
X
Archived Tumor Tissue
X
Block or 20 slides must be available prior to patient randomization.
Adverse Event Collection/CTCAE Grading
X
X
X
X
Concomitant Medication Notation
X
X
X
X
Lab/ Diagnostic Tests
Central hematology
X
X
X
X
For patients in the safety lead-in for Arm A, additional central hematology labs 
are required every week during Cycle 1.
For all patients, 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
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.
Cystatin C
X
X
X
X
Perform at central laboratory.
PK sampling
X
X
X
X
Refer to Attachment 6.
Pharmacogenetic blood sample
X
Draw sample before patient is dosed on Cycle 1 Day 1
Biomarker plasma sample
X
X
Draw sample before patient is dosed on Cycle 1 Day 1 and upon arrival at site 
on Cycle 2 Day 1
Local ECG
X
X
Xa
For patients in treatment Arms A and B, perform 2 to 4 hours after the 
abemaciclib dose on Cycle 1 Day 1, upon arrival at site on Cycle 2 Day 1, 2 to 
4 hours after the abemaciclib dose on Cycle 4 Day 1.  For patients in Arm C, 
perform at any time during visits.  Patients must be supine for approximately 5 
to 10 minutes before ECG collection and remain supine but awake during ECG 
collection.
Tumor Assessment
Echocardiography or multiple-gated 
acquisition scanning (MUGA scan)
X
Perform at Cycle 5 Day 1 (± 7 days).  If LVEF is stable, repeat every 12 weeks 
starting with Cycle 9 Day 1 (± 7 days) and then every 24 weeks following 
discontinuation of trastuzumab.  If LVEF on trastuzumab is <50%, refer to 
Section 10.3.2.2 for further monitoring guidance.


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Tumor measurement (visible)
X
Xb
Skin lesions identified at baseline require repeat photographic images every 
6 weeks (± 3 business days) for 36 weeks from first dose of study therapy, then 
every 9 weeks (± 3 business days), 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)
X
Xb
Performed locally.  For patients with ONLY locoregional disease extension and 
NO measurable lesions out of breast on CAP CT scan, MRI scan of the breast 
is performed in addition to other scans.  For all patients, imaging studies (CT 
scan or MRI of the chest, abdomen, and pelvis and breast MRI when 
applicable) will be repeated every 6 weeks (± 3 business days) for 36 weeks 
from first dose of study therapy, then every 9 weeks (± 3 business days), and 
within 14 days of clinical progression.  The same method of imaging used at 
baseline should be used for each subsequent assessment.
Bone scintigraphy
Xc
Performed locally. ONLY for patients with bone lesions identified on baseline 
bone scintigraphy, repeat bone scintigraphy every 24 weeks (± 3 business 
days).  Additional bone scintigraphy should be considered if there is clinical 
suspicion of disease progression in bone.  If a patient with bone lesions at 
baseline experiences a CR, bone scintigraphy should continue to be repeated 
every 24 weeks (± 3 business days) and until disease progression to detect new 
lesions.

Note: for patients with no bone lesions on baseline bone scintigraphy, 
bone scintigraphy should be performed ONLY if there is clinical suspicion 
of disease progression in bone, even if a CR is achieved.
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
X
Xb
Performed locally. If CAP CT/MRI does not capture bone lesions, repeat 
specific bone-directed imaging (X-ray, CT scan with bone windows, or MRI) 
every 6 weeks (± 3 business days) for 36 weeks from first dose of study 
therapy, then every 9 weeks (± 3 business days), and within 14 days of clinical 
progression.  EXCEPTION: for the following patients, NO specific bone-
directed imaging is required:

patients with no bone lesions at baseline 

patients with measurable visceral disease and nonmeasurable bone lesions
The same imaging method used at baseline for bone lesions measurement is to 
be used during treatment period and follow-up.
Health Outcomes
EORTC QLQ-C30
mBPI-sf
EQ-5D 5L
X
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 (this will be the second of two screening PROs collected).  
Cycle 2 and later questionnaires should be administered on Day 1 of each 
cycle.
Study Drugd
Abemaciclib (LY2835219)
Take 150 mg 
every 12 hours on Days 1 through 21 of every 
cycle.


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During Treatment Study Schedule (concluded)
Abbreviations:  CAP = chest/abdomen/pelvis; CR = complete response; 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; IM = intramuscular; LVEF = left ventricular ejection fraction; MRI = magnetic 
resonance imaging; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors.
a
ECG to be performed on Cycle 4 Day 1 but not in any subsequent cycle during Study Treatment Period.
b
Procedure will not be performed on Day 1 of all Cycles 4-X.  Rather, the procedure is to be performed every 6 weeks (± 3 business days) for 36 weeks from 
first dose of study therapy (regardless of treatment suspensions or delays), then every 9 weeks (± 3 business days), and within 14 days of clinical progression.
c
Procedure will not be performed on Day 1 of all Cycles 4-X.  Rather, the procedure is to be performed every 24 weeks (regardless of treatment suspensions or 
delays).
d
See Section 9 and Table JPBZ.9.1 for details on treatment administration.
Co-Administered 
Drugd
Trastuzumab
On label dosing:  8 mg/kg loading dose as a 90 
minute IV infusion on Day 1 of Cycle 1 (of a 21 
day cycle) then 6 mg/kg maintenance dose as a 
30 minute IV infusion on Day 1 of Cycle 2 and 
beyond.
For patients already receiving trastuzumab at time of study entry, the 
trastuzumab dose on Cycle 1 Day 1 should be at least 21 days after the last 
dose administered prior to randomization.  No loading dose of trastuzumab is 
required if the last dose of trastuzumab was within 4 weeks of Day 1 of 
Cycle 1.  Loading dose of trastuzumab is required if the last dose of 
trastuzumab was administered more than 4 weeks prior to Day 1 of Cycle 1.
Fulvestrant
On label dosing:  500 mg IM into buttocks 
slowly (1-2 minutes per injection) as two 5-mL
injections on Days 1 15, and 29 (that is, Cycle 2 
Day 8 [assuming no dose suspension for 
trastuzumab]), and every 4 weeks thereafter.
See Attachment 8 for more detail on the schedule for fulvestrant 
administration.
Single-agent chemotherapy
Standard of care per physician’s choice.  Dosing 
per label.
Best supportive care alone, including palliative radiotherapy in the absence of 
chemotherapy is not permitted.  T-DM1 or pertuzumab are not considered a 
single-agent chemotherapy option.  Maintenance endocrine therapy (except 
fulvestrant) after single-agent chemotherapy, all concurrently with 
trastuzumab, is allowed.


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Post-Treatment 
Discontinuation 
Study Schedule
Study Period
Postdiscontinuation 
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
Comments
Physical Examination
Physical exam
X
Including weight
Vital signs
X
Including blood pressure, pulse, respiratory rate, and temperature
ECOG performance status
X
Tumor Assessment
Tumor measurement (visible)
X
X
ONLY For patients who are randomized and never received study 
treatment or those who discontinue study treatment without 
objectively measured PD, continue to conduct tumor assessments 
approximately every 6 weeks for the first 36 weeks following 
randomization and thereafter approximately every 9 weeks until the patient 
has objective disease progression or until primary PFS analysis. After the 
patient has objective disease progression, photographic images are no 
longer required and the patient will continue with postdiscontinuation 
follow-up approximately every 9 weeks until the patient’s death or overall 
study completion.
Radiological imaging according to 
RECIST (CT scan/MRI)
X
X
The same method of imaging used at baseline should be used for each 
subsequent assessment.  ONLY For patients who are randomized and 
never received study treatment or those who discontinue study 
treatment without objectively measured PD, continue to conduct tumor 
assessment approximately every 6 weeks for the first 36 weeks following 
randomization and thereafter approximately every 9 weeks by the same 
method used at baseline and throughout the study until the patient has 
objective disease progression or until primary PFS analysis.  After the 
patient has objective disease progression, radiologic tests are no longer 
required and the patient will continue with postdiscontinuation follow-up 
approximately every 9 weeks until the patient’s death or overall study 
completion.
Bone scintigraphy
X
X
ONLY for patients with bone lesions on baseline scintigraphy who are 
randomized and never received study treatment or those who 
discontinue study treatment without objectively measured PD,
continue to evaluate bone scintigraphy approximately every 24 weeks until 
objective disease progression or primary PFS analysis. EXCEPTION: for 
patients with no bone lesions on baseline bone scintigraphy, bone 
scintigraphy should be performed ONLY if there is clinical suspicion of 
disease progression in bone, even if a CR is achieved.


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Post-Treatment 
Discontinuation 
Study Schedule
Study Period
Postdiscontinuation 
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
Comments
X-ray, CT scan with bone windows,
or MRI
X
X
ONLY For patients who are randomized and never received study 
treatment or those who discontinue study treatment without 
objectively measured PD, focused studies are performed (EXCEPT for 
patients with no bone lesions at baseline and patients with measurable 
visceral disease and nonmeasurable bone lesions).
To be repeated approximately every 6 weeks for the first 36 weeks
following randomization and thereafter approximately every 9 weeks by 
the same method used at baseline and throughout the study until the patient 
has objective disease progression or until primary PFS analysis.  After the 
patient has objective disease progression, radiologic tests are no longer 
required and the patient will continue with postdiscontinuation follow-up 
approximately every 9 weeks until the patient’s death or overall study 
completion.
Survival Information
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 postdiscontinuation 
anticancer therapies.
Adverse Events Collection/ CTCAE Grading
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 Medication Notation
X


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Post-Treatment 
Discontinuation 
Study Schedule
Study Period
Postdiscontinuation 
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
Comments
Lab/Diagnostic Tests
Central hematology
X
Central chemistry
X
Cystatin C
X
Perform at central laboratory.
Biomarker plasma sample
X
Draw sample for all patients
ECG
X
Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection
Biomarker Tests
Tumor tissue collection
X
Collect tumor tissue from new biopsy if feasible and ONLY for patients 
discontinuing due to PD
Health Outcomes
EORTC QLQ-C30
mBPI-sf
EQ-5D 5L
X
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; PD = progressive disease; PK = pharmacokinetics; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAEs = serious adverse events.


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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)
21
30
Relative day within a cycle
1
Procedure Category
Procedure
Comments
Adverse Event Collection/CTCAE Grading
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 Treatment
Abemaciclib
X
Only patients assigned to abemaciclib at randomization and receiving 
clinical benefit will continue to receive abemaciclib during the continued 
access period.  Abemaciclib is to be administered orally every 12 hours on 
Days 1 through 21 of each cycle.  Patients who were assigned to single-
agent chemotherapy plus trastuzumab cannot crossover to receive 
abemaciclib.
Trastuzumab
X
Patients receiving clinical benefit will continue to receive trastuzumab 
and/or fulvestrant during the continued access period.
Trastuzumab is to be administered as a 6 mg/kg 90 minute IV infusion on 
Day 1 of a 21 day cycle.  If the initial dose of trastuzumab was well 
tolerated, the subsequent doses can be administered as a 30-minute 
infusion.  For reloading of trastuzumab, take into account dose-adjustment 
guidanceb.
Fulvestrant is to be administered 500 mg IM into buttocks once monthly.  
Standard-of-care chemotherapy administered according to product label.
Fulvestrant
X
Single-agent standard-of-care 
chemotherapy
X
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; IM = intramuscular; IV = intravenous; OS = overall survival; SAEs = serious 
adverse events; SPC = Summary of Product Characteristics.
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).
b
See Section 2.2 (Important Dosing Considerations) of the United States package insert (Herceptin [trastuzumab] package insert 2016) or Section 4.2 
(Posology and Method of Administration) of the SPC (Herceptin [trastuzumab] SPC 2016).


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Attachment 2.Protocol JPBZ Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistrya:
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
Renal Panela
Cystatin-C
Follicle stimulating hormone (FSH) levelsb,c
Serum pregnancy testb,d
Estradiol levelb,c
Abbreviations:  GnRH = gonadotropin-releasing hormone; 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 amenorrheic for at 
least 12 months.
d To be performed at baseline to establish eligibility if postmenopausal status is due to ovarian suppression with a 
GnRH agonist or induced by radiation.


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Attachment 3.Protocol JPBZ 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
Anti-actin antibodya
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.


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


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Attachment 5.Protocol JPBZ 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 electronic case record form (eCRF) 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 
eCRF (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 scintigraphy 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 first dose.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study).


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


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Attachment 6.Protocol JPBZ Pharmacokinetic Sampling 
Schedule
Pre-abemaciclib dose samples are requested to be taken immediately before the dose. 
Aberrations to specified sampling times will not be considered protocol deviations as long as the 
samples are taken and the actual sampling time is recorded.  For abemaciclib, the date, time, and 
amount of each dose for 3 days prior to PK sampling and the day of PK sampling must be 
recorded on the appropriate form.  For trastuzumab, it is essential that the dose amount and exact 
infusion start and stop times (actual clock readings) are recorded.  For fulvestrant, record the 
dose amount and start time of the intramuscular injection.  The exact time of collection of each 
venous blood sample will be based on the clock used to record infusion times.  It is essential that 
the pharmacokinetic blood samples not be withdrawn from the same site as the drug infusion.
In the event of suspending dosing for any component of study treatment due to toxicity on a day 
when a PK sample is scheduled, the PK sample prior to when the dose would have normally 
occurred should still be taken. In these cases, the PK sample that was to be taken after drug 
administration should be omitted on that day.


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Arm A
Cycle (C)
and
Day (D)
Dose
Abemaciclib
Dose
Trastuzumab
Dose
Fulvestrant
Abemaciclib 
Plasma PK 
Sample Number
Trastuzumab 
Serum PK
Sample Number
Fulvestrant 
Plasma PK 
Sample Number
PK Sampling Timea
C1D1
X
X
X
1
1
1
Pre-abemaciclib dose (0 h)
C1D1
2
2
Immediately after end of 
trastuzumab infusionb
C1D15
X
X
3
2
Pre-fulvestrant dose (0 h)
C2D1
X
X
4
3
Pre-trastuzumab dose (0 h)
C2D1
5
4
Immediately after end of 
trastuzumab infusionb
C2D8
X
X
6
3
Pre-fulvestrant dose (0 h)
C3D1
X
X
7
5
Pre-trastuzumab dose (0 h)
C3D1
8
6
Immediately after end of 
trastuzumab infusionb
C3D15
X
X
9
4
Pre-fulvestrant dose (0 h)
C4D1
X
X
10
7
Pre-trastuzumab dose (0 h)
C4D1
11
8
Immediately after end of 
trastuzumab infusionb
C5D1
X
X
X
12
9
5
Pre-trastuzumab dose (0 h)
C5D1
13
10
Immediately after end of 
trastuzumab infusionb
Abbreviations:  h = hour; min = minute; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its metabolites concentrations in plasma.  A second set of 
samples of approximately 2 mL of whole blood will be drawn for measurement of trastuzumab concentrations in serum. A third set of samples of 
approximately 2 mL of venous blood will be drawn for measurement of fulvestrant concentrations in plasma.
b
These samples should be taken as soon as possible, up to 5 minutes, after the end of the infusion.


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Arm B
Cycle (C)
and
Day (D)
Dose
Abemaciclib
Dose
Trastuzumab
Abemaciclib 
Plasma PK 
Sample Number
Trastuzumab 
Serum PK
Sample Number
PK Sampling Timea
C1D1
X
X
1
1
Pre-abemaciclib dose (0 h)
C1D1
2
2
Immediately after end of 
trastuzumab infusionb
C2D1
X
X
3
3
Pre-trastuzumab dose (0 h)
C2D1
4
4
Immediately after end of 
trastuzumab infusionb
C3D1
X
X
5
5
Pre-trastuzumab dose (0 h)
C3D1
6
6
Immediately after end of 
trastuzumab infusionb
C4D1
X
X
7
7
Pre-trastuzumab dose (0 h)
C4D1
8
8
Immediately after end of 
trastuzumab infusionb
C5D1
X
X
9
9
Pre-trastuzumab dose (0 h)
C5D1
10
10
Immediately after end of 
trastuzumab infusionb
Abbreviations:  h = hour; min = minute; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its metabolites concentrations in plasma.  A second set of 
samples of approximately 2 mL of whole blood will be drawn for measurement of trastuzumab concentrations in serum.
b
These samples should be taken as soon as possible, up to 5 minutes, after the end of the infusion.


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Attachment 7.Protocol JPBZ Sampling Summary
This table provides estimates of the maximum number of samples, volumes for all sampling, and 
tests required for each patient during the study.  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, if the patient discontinues from the study early). 
Protocol I3Y-MC-JPBZ Sampling Summarya
Sample Type/Purpose
Maximum Amount per 
Sample 
Maximum 
Number Samples
Maximum Total 
Amount
Blood
Study qualification 
(Baseline)
Chemistry
2.5 mL
1
2.5 mL
Hematology
2.0 mL
1
2.0 mL
Health monitoring
Chemistry
2.5 mL
11
27.5 mL
Hematology
2.0 mL
11
22 mL
Drug concentration (Arm A)
2 mL
28
56 mL
Drug concentration (Arm B)
2 mL
20
40 mL
Tailoring biomarkers, pharmacogenetic
10 mL
1
10 mL
Tailoring biomarkers, serum and/or 
plasma
10 mL
3
30 mL
Hepatic monitoringb
3 - 30 mL
-
-
Total blood volume
-
-
190 mL
Tumor tissue
Tailoring biomarkers, tissue 
Refer to the study schedule (Attachment 1) for details and frequency 
of sampling.
a
Covers Cycles 1 through 10, and 801
b Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with the designated clinical research physician.


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Attachment 8.Protocol JPBZ Dosing Schedule for Study 
Arm A
The following dosing schedule assumes oral administration Q12H of abemaciclib on Days 1 
through 21 of each cycle and in the absence of treatment suspension or delay:
Cycle
Day 1
Day 8
Day 15
1
fulvestrant/trastuzumab
fulvestrant
2
trastuzumab
fulvestrant
3
trastuzumab
fulvestrant
4
trastuzumab
5
fulvestrant/trastuzumab
6
trastuzumab
fulvestrant
7
trastuzumab
fulvestrant
8
trastuzumab
9
fulvestrant/trastuzumab
10
trastuzumab
fulvestrant
11
trastuzumab
fulvestrant
12
trastuzumab
13
fulvestrant/trastuzumab
14
trastuzumab
fulvestrant
15
trastuzumab
fulvestrant
16
trastuzumab
17
fulvestrant/trastuzumab
18
trastuzumab
fulvestrant
19
trastuzumab
fulvestrant
20
trastuzumab
21
fulvestrant/trastuzumab
22
trastuzumab
fulvestrant
23
trastuzumab
fulvestrant
24
trastuzumab


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Attachment 9.Protocol JPBZ Inducers and Strong Inhibitors 
of CYP3A
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lesinurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if 
clinically indicated.


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Attachment 10.
Protocol JPBZ CTCAE 4.03 Definitions for Diarrhea and 
ILD/Pneumonitis
Diarrhea will be evaluated in this study using the criteria proposed by Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 revised:  CTCAE 4.03-June 14, 2010:  Gastrointestinal disorders. 
Gastrointestinal Disorders
Grade
Adverse Event
1
2
3
4
5
Diarrhea
Increase of <4 stools 
per day over baseline; 
mild increase in 
ostomy output 
compared to baseline.
Increase of 4-6 stools 
per day over baseline; 
moderate increase in 
ostomy output 
compared to baseline
Increase ≥7 stools per day 
over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self-care 
ADL
Life-threatening 
consequences; urgent 
intervention indicated
Death
Definition:  a disorder characterized by frequent and watery bowel movements
Abbreviation:  ADL = Activities of Daily Living.


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Interstitial lung disease/pneumonitis will be evaluated in this study using the criteria proposed by CTCAE v4.0 revised:  CTCAE 
4.03–June 14, 2010:  Respiratory, thoracic, and mediastinal disorders.
Respiratory, Thoracic, and Mediastinal Disorders
Grade
Adverse Event
1
2
3
4
5
ILD/Pneumonitis
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated
Symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL
Severe symptoms; limiting 
self-care ADL; oxygen 
indicated
Life-threatening 
respiratory compromise; 
urgent intervention 
indicated (e.g., 
tracheotomy or 
intubation)
Death
Definition: a disorder characterized by inflammation focally or diffusely affecting the lung parenchyma 
Abbreviations:  ADL = Activities of Daily Living; ILD = interstitial lung disease.


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Attachment 11.
Protocol JPBZ Amendment (f) Summary
monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, 
Open-Label Study to Compare the Efficacy of Abemaciclib 
plus Trastuzumab with or without Fulvestrant to Standard-
of-Care Chemotherapy of Physician’s Choice plus 
Trastuzumab in Women with HR+, HER2+ Locally 
Advanced or Metastatic Breast Cancer
Overview
Protocol I3Y-MC-JPBZ has been amended.  The new protocol is indicated by amendment (f) and 
will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The Rationale for Amendment (f) was added as Section 5.6.

An error was corrected in the table in Special Hepatic Safety Data Collection (Section 
10.3.3.1) to align with current guidance.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.


Leo Document ID = f16109d5-4281-4cee-879e-53e989226424
Approver: 
Approval Date & Time: 26-Feb-2021 01:55:46 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 26-Feb-2021 13:51:03 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan Version 3 I3Y-MC-JPBZ 
A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of 
Abemaciclib plus Trastuzumab with or without Fulvestrant to Standard-of-Care 
Chemotherapy of Physician's Choice plus Trastuzumab in Women with HR+, HER2+ Locally 
Advanced or Metastatic Breast Cancer 
NCT02675231 
Approval Date: 8-Feb-2019 


I3Y-MC-JPBZ Statistical Analysis Plan Version 3
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1.
Statistical Analysis Plan:
I3Y-MC-JPBZ (monarcHER): A Phase 2, Randomized, 
Multicenter, 3-Arm, Open-Label Study to Compare the 
Efficacy of Abemaciclib plus Trastuzumab with or without 
Fulvestrant to Standard-of-Care Chemotherapy of 
Physician’s Choice plus Trastuzumab in Women with 
HR+, HER2+ Locally Advanced or Metastatic Breast 
Cancer
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Abemaciclib (LY2835219) Breast cancer
This is a randomized, multicenter, 3-arm, open-label Phase 2 study to compare the efficacy 
of abemacicl b plus trastuzumab plus fulvestrant and abemaciclib plus trastuzumab to 
standard-of-care single-agent chemotherapy plus trastuzumab in women with HR+, HER2+ 
locally advanced or metastatic breast cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I3Y-MC-JPBZ
Phase 2
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 08-Feb-2019 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  I3Y-MC-JPBZ (monarcHER):  A Phase 2, 
Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the 
Efficacy of Abemaciclib plus Trastuzumab with or without 
Fulvestrant to Standard-of-Care Chemotherapy of Physician’s Choice 
plus Trastuzumab in Women with HR+, HER2+ Locally Advanced 
or Metastatic Breast Cancer.................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
4.3.
Exploratory Objectives...................................................................................................7
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................9
5.3.
Method of Assignment to Treatment ............................................................................10
6.
A Priori Statistical Methods ..............................................................................................11
6.1.
General Considerations ................................................................................................11
6.1.1.
Populations ..........................................................................................................11
6.1.2.
Definitions and Conventions ................................................................................11
6.2.
Handling of Dropouts or Missing Data.........................................................................12
6.3.
Multiple Comparisons/Multiplicity...............................................................................12
6.4.
Patient Disposition .......................................................................................................12
6.5.
Patient Characteristics ..................................................................................................13
6.5.1.
Demographics and Performance Status.................................................................13
6.5.2.
Baseline Disease Characteristics ..........................................................................13
6.5.3.
Historical Illnesses ...............................................................................................13
6.5.4.
Prior Therapies.....................................................................................................13
6.5.5.
Post-Study Treatment Discontinuation Therapies .................................................14
6.6.
Treatment Compliance .................................................................................................14
6.7.
Concomitant Therapy...................................................................................................14
6.8.
Efficacy Analyses ........................................................................................................14
6.8.1.
Primary Outcome:  Progression-Free Survival......................................................14
6.8.1.1.
Definition .......................................................................................................14
6.8.1.2.
Primary Analysis ............................................................................................15


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6.8.1.3.
Other PFS Analyses........................................................................................16
6.8.1.3.1.
Progression-Free Survival Curves and Hazard Ratio .................................16
6.8.1.3.2.
Restricted Mean Difference ......................................................................16
6.8.2.
Gated Secondary Efficacy Endpoint:  Overall Survival.........................................17
6.8.3.
Other Secondary Efficacy Analyses .....................................................................18
6.8.3.1.
Objective Response Rate, Disease Control Rate, and 
Clinical Benefit Rate ......................................................................................18
6.8.3.2.
Duration of Response .....................................................................................19
6.8.4.
Sensitivity Analyses.............................................................................................19
6.8.4.1.
Overall Survival .............................................................................................19
6.9.
Health Outcomes/Quality-of-Life Analyses..................................................................19
6.9.1.
Instruments ..........................................................................................................19
6.9.2.
Pain Intensity and Pain Assessment......................................................................20
6.9.3.
Quality of Life .....................................................................................................20
6.9.4.
Health State Utility...............................................................................................20
6.9.5.
Exploratory Analyses of Health Outcomes/Quality-of-Life ..................................20
6.9.6.
Utilization............................................................................................................21
6.10. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................21
6.11. Safety Analyses............................................................................................................22
6.11.1.
Extent of Exposure...............................................................................................22
6.11.2.
Adverse Events ....................................................................................................22
6.11.3.
Deaths, Other Serious Adverse Events .................................................................23
6.11.4.
Clinical Laboratory Evaluation.............................................................................24
6.11.5.
Vital Signs and Other Physical Findings...............................................................24
6.11.6.
Electrocardiograms ..............................................................................................24
6.12. Subgroup Analyses.......................................................................................................24
6.13. Protocol Violations.......................................................................................................25
6.14. Interim Analyses and Data Monitoring.........................................................................25
6.14.1.
Safety Interim Analyses .......................................................................................25
6.14.2.
Efficacy Interim Analyses....................................................................................26
6.15. Annual Report Analyses...............................................................................................26
6.16. Clinical Trial Registry Analyses...................................................................................26
7.
References ........................................................................................................................28


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Table of Contents
Table
Page
Table JPBZ.6.1. Rules for Determining Date of Progression or Censor for Progression-
Free Survival .................................................................................................15


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Table of Contents
Figure
Page
Figure JPBZ.5.1. Illustration of study design...............................................................................8
Figure JPBZ.6.1 Alpha spending for Study I3Y-MC-JPBZ. .....................................................16


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3.
Revision History
Statistical analysis plan (SAP) Version 1 was approved prior to the first visit when a subject 
received study drug or any other protocol intervention.
In SAP Version 2, SAP Version 1 was amended to update the SAP due to protocol amendment 
JPBZ(b).
SAP was amended to Version 3 due to protocol amendment JPBZ(c). Clarification was added to 
the censoring rules for new anticancer treatment.


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to compare the efficacy of abemaciclib plus trastuzumab 
plus fulvestrant and abemaciclib plus trastuzumab to standard-of-care (SOC) single-agent 
chemotherapy of physician’s choice plus trastuzumab with respect to progression-free survival 
(PFS).
4.2.
Secondary Objectives
The secondary objectives of the study are to compare the 3 arms with respect to each of the 
following:

overall survival (OS) rate at 1, 2, and 3 years

objective response rate (ORR)

duration of response (DoR) (complete response [CR] + partial response [PR])

disease control rate (DCR) (CR + PR + stable disease [SD])

clinical benefit rate (CBR) (CR + PR + SD ≥6 months)

safety and tolerability of abemaciclib in combination with trastuzumab and fulvestrant

impact on pain, disease symptoms, and overall quality of life using the modified Brief 
Pain Inventory-Short Form (mBPI-sf), the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the 
health status scores from the EuroQol 5-Dimension 5 Level (EQ-5D 5L)

pharmacokinetics (PK) of abemaciclib and its metabolites, fulvestrant, and trastuzumab 
in the target patient population

relationship between abemaciclib, trastuzumab, and fulvestrant exposure and response for 
safety and efficacy endpoints
4.3.
Exploratory Objectives

to explore potential biomarkers related to the mechanism of action of abemaciclib, the 
cell cycle, and/or the pathogenesis of breast cancer and their association with clinical 
outcome


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5.
Study Design
5.1.
Summary of Study Design
Study I3Y-MC-JPBZ (JPBZ) is a randomized, multicenter, 3-arm, open-label Phase 2 study to 
compare the efficacy of abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus 
trastuzumab to SOC single-agent chemotherapy of physician’s choice plus trastuzumab in 
women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-
positive (HER2+) locally advanced or metastatic breast cancer.
Figure JPBZ.5.1 illustrates the study design.
Abbreviations:  HER2+ = human epidermal growth factor receptor 2-positive; 
HER2- = human epidermal growth factor receptor 2-negative; HR+ = hormone 
receptor-positive; n = number; PD = progressive disease; Q12H = every 12 hours; 
R = randomization.
a
If the dose of abemaciclib in Arm A is reduced to 100 mg, patients that initiated 
treatment at the 150-mg dose will be dose-reduced to 100 mg, and patients who 
started at the 150-mg abemaciclib dose will be replaced so that there are a total of 
75 patients in Arm A with a starting dose of 100-mg abemaciclib.
b
Standard-of-care single-agent chemotherapy should include an approved drug in 
breast cancer.
Figure JPBZ.5.1.
Illustration of study design.
Approximately 225 patients will be randomized 1:1:1 across the 3 arms:

Arm A:  Abemaciclib + trastuzumab + fulvestrant

Arm B:  Abemaciclib + trastuzumab


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
Arm C:  Standard-of-care single-agent chemotherapy + trastuzumab
Patients will be randomized using the following stratification factors:  number of previous 
systemic regimens (excluding single-agent endocrine therapy) for advanced breast cancer 
(2 to 3 vs. more than 3) and the status of disease (measurable vs. nonmeasurable).
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the informed consent form 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 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.
5.2.
Determination of Sample Size
The study will enroll approximately 225 patients in [1:1:1] randomization (75 patients in 
abemaciclib plus trastuzumab plus fulvestrant; 75 patients in abemaciclib plus trastuzumab; and 
75 patients in SOC single-agent chemotherapy of physician’s choice plus trastuzumab).  The 
primary analysis will be performed after approximately 165 PFS events have occurred.  
Assuming a hazard ratio (HR) of 0.667, this sample size yields at least 80% statistical power to 
detect superiority of the abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus 
trastuzumab arms over SOC single-agent chemotherapy of physician’s choice plus trastuzumab
arm with the use of an experiment-wise 1-sided alpha level of 0.10.


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If the true median PFS for the SOC single-agent chemotherapy of physician’s choice plus 
trastuzumab arm is 4 months, then the HR of 0.667 amounts to an approximately 2-month 
improvement in median PFS for the abemaciclib plus trastuzumab plus fulvestrant and 
abemaciclib plus trastuzumab arms under an additional assumption of exponential survival 
distribution.  Assuming a censoring rate of approximately 30%, the study will randomize 
approximately 225 patients.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomly assigned to receive abemaciclib 
plus trastuzumab plus fulvestrant, abemaciclib plus trastuzumab, or SOC single-agent 
chemotherapy of physician’s choice plus trastuzumab at Visit 1.  Randomization will be 
stratified by the number of previous systemic regimens (excluding single-agent endocrine 
therapy) for advanced breast cancer (2 to 3 vs. more than 3) and status of disease (measurable vs.
nonmeasurable).
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).


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6.
A Priori Statistical Methods
6.1.
General Considerations
6.1.1. Populations
Statistical analysis of this study will be the responsibility of Lilly.
Disposition summaries will be performed on the entered population, defined as all patients who 
sign the informed consent document.
Efficacy analyses and patient characteristic summaries will be based on the enrolled or 
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 and exposure summaries will be based on the safety population, defined as all 
enrolled patients receiving at least 1 dose of any study drug.  Patients will be grouped according 
to treatment received in Cycle 1.
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above populations from whom a valid assay result (according to laboratory guideline) 
has been obtained.
6.1.2. Definitions and Conventions
Study drug refers to abemaciclib (LY2835219).
Study treatment refers to abemaciclib plus trastuzumab plus fulvestrant or abemaciclib plus
trastuzumab or SOC single-agent chemotherapy of physician’s choice plus trastuzumab.
The date of randomization is the date the patient was randomly assigned to study treatment
using the IWRS.
The date of first dose is the date of the first dose of study drug, trastuzumab, fulvestrant, or 
single-agent chemotherapy.
The baseline value of a safety assessment is the last value observed prior to the first dose of 
study drug, trastuzumab, fulvestrant, or single-agent chemotherapy.
The baseline value of an efficacy assessment is the last value observed prior to the date of 
randomization.  If a patient’s first assessment occurs after randomization but prior to the first 
dose, this assessment will be used as the baseline.
The study day of a safety event or assessment will be calculated as:

the difference between the date of the event or assessment and the date of first 
dose plus 1 for all events or assessments occurring on or after the day of first 
dose.  For example, if an event occurs on 08MAR2016 and the date of first 
dose was 06MAR2016, the study day of the event is 3.


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
the difference between the date of the event or assessment and the date of first 
dose for all events or assessments occurring before the day of first dose.  For 
example, if an event occurs on 05MAR2016 and the date of first dose was 
06MAR2016, the study day of the event is -1.
The study day of an efficacy event or assessment will be calculated as:

the difference between the date of the event or assessment and the date of 
randomization plus 1 for all events or assessments occurring on or after the 
date of randomization.

the difference between the date of the event or assessment and the date of 
randomization for all events or assessments occurring before the date of 
randomization.
One month is defined as 365/12 days.
Unless otherwise noted, summaries of continuous variables will include a mean, median, 
standard deviation, minimum, and maximum.
Unless otherwise noted, summaries of categorical variables will include the frequency and 
percentage (relative to the population being analyzed) of each category.
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
6.2.
Handling of Dropouts or Missing Data
With the exception of dates, missing data will not be imputed.  The method of imputation for any 
dates that are imputed is described in the relevant section.  Rules for determining date of 
progression or censor for PFS are defined in Table JPBZ.6.1.
6.3.
Multiple Comparisons/Multiplicity
Type I error for PFS will be controlled by testing the treatment arms sequentially.  The 
abemaciclib triplet arm will be compared to the single-agent chemotherapy plus trastuzumab arm 
first, and the abemaciclib doublet arm will be compared to the single-agent chemotherapy plus
trastuzumab arm only if the test for the triplet is significant.  OS will be tested only if both tests 
of PFS are significant.
6.4.
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, rescreened after screen failure, enrolled 
in the study, and treated in the study, reasons for discontinuation from study treatment (safety
population only), and reasons for discontinuation from study (ITT population only).  Reason for 
discontinuation from both study treatment and the study will be summarized by pre-determined 
categories.


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6.5.
Patient Characteristics
6.5.1. Demographics and Performance Status
Patient demographics will be summarized.  Patient demographics will include age, race, 
ethnicity, country, height, weight, and body mass index.
6.5.2. Baseline Disease Characteristics
Disease characteristics will be summarized.  Disease characteristics will include the following:

study entry diagnosis

disease extent at study entry (metastatic disease versus locally advanced 
recurrent disease)

nature of disease (visceral metastases or other)

measurable disease (yes versus no)

number of organs involved (1, 2, or 3+)

metastatic site(s)

estrogen receptor status

progesterone receptor status

baseline Eastern Cooperative Oncology Group (ECOG) performance status 
(PS)
Nature of disease will be reported directly from the ‘Nature of Disease’ eCRF.  Disease 
measurability and number of organs involved will be derived from the ‘Target Tumor 
Identification and Results’ and ‘Non-Target Tumor Identification and Results’ eCRFs at 
baseline.  All patients with at least 1 lesion on the target lesion form will be counted as having 
measurable disease.  The number of organs involved will be derived from the location codes of 
the target and non-target lesions.
6.5.3. Historical Illnesses
Historical illnesses are clinically relevant events in the past that ended before the screening visit.  
Historical illnesses (using Preferred Term(s) [PTs] from the most current version of the Medical 
Dictionary for Regulatory Activities [MedDRA®]) will be summarized.
6.5.4. Prior Therapies
Prior radiotherapy, surgery, and systemic therapy will be summarized.  Prior radiotherapy and 
surgery will be categorized by reason for regimen.  Prior systemic therapies will be categorized 
by type of regimen (endocrine therapy, chemotherapy, HER2 directed therapy, or other) and 
specific therapy within reason for regimen (neoadjuvant, adjuvant, locally advanced/metastatic, 
or any).  Frequency of each specific therapy will be tabulated within each type of therapy and per 
treatment setting (neoadjuvant, adjuvant, locally advanced/metastatic, or any).  Percentage of 


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patients with prior taxane use and percentage of patients with prior anthracycline use will be 
summarized. Time to progression on prior-anti HER2 therapies (that is, duration between 
progression and the start of prior anti-HER2 therapies) will also be summarized for the patients 
in advanced disease.
6.5.5. Post-Study Treatment Discontinuation Therapies
Therapies received following study treatment discontinuation will be summarized by arm.  
Therapies will be summarized overall and by category: endocrine therapy or 
targeted/chemotherapy.
6.6.
Treatment Compliance
Treatment compliance information for abemaciclib will be collected through pill counts at each 
cycle.  Compliance will be calculated as the ratio of total dose taken to the total assigned dose 
(minus any dose adjustments and doses omitted/withheld for medical or logistical reasons).  
Dosing information for trastuzumab, fulvestrant, and single-agent chemotherapy of physician’s 
choice will be collected at each cycle/visit.
6.7.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization drug dictionary.  All concomitant medications will be summarized by 
number and percentage of patients for the safety population using the base name (without esters 
or salts).
6.8.
Efficacy Analyses
Unless otherwise noted, all efficacy analyses will be performed on the ITT population.
The stratification factors for the analysis of primary and secondary analyses are the number of 
previous regimens for advanced breast cancer (2 to 3 vs. more than 3) and status of disease 
(measurable vs. nonmeasurable).  The stratification factors will be derived based on CRF data.  
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.20, unless otherwise 
stated.  All confidence intervals (CIs) will be given at a 2-sided 95% level, unless otherwise 
stated.  For regulatory purposes, tests may be performed at a 1-sided alpha level of 0.025.
6.8.1. Primary Outcome:  Progression-Free Survival
6.8.1.1.
Definition
The primary endpoint of this study is PFS.  PFS time is measured from the date of randomization 
to the date of investigator-determined objective progression as defined by Response Evaluation 
Criteria In Solid Tumors Version 1.1 (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 JPBZ.6.1.


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Table JPBZ.6.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Situation
Date of Event or Censor
Event / Censor
Tumor progression or death
Earliest date of PD or death
Event
No tumor progression and no death
Date of last adequate radiological assessment 
or date of randomization (whichever is later)
Censored
Unless
No baseline radiological tumor assessment 
available
Date of randomization
Censored
No adequate postbaseline radiological 
tumor assessment available
and death reported after 2 scan intervals 
following randomization
Date of randomization
Censored
New anticancer treatment started 
(excluding maintenance endocrine therapy 
following chemotherapy) and no tumor 
progression or death within 14 days
Date of adequate radiological assessment 
prior to start of new therapy +14 days or date 
of randomization (whichever is later)
Censored
Tumor progression or death
documented immediately after 2 or more 
scan intervals following last adequate 
radiological tumor assessment or 
randomization (whichever is later)
Date of last adequate radiological assessment 
or date of randomization (whichever is later)
Censored
Abbreviation:  PD = progressive disease.
Note:  Progression-free survival and associated outcome is determined by the earliest of the dates above, if more 
than 1 situation applies.
6.8.1.2.
Primary Analysis
The PFS analysis to test the superiority of abemaciclib plus trastuzumab and abemaciclib plus 
trastuzumab plus fulvestrant to chemotherapy plus trastuzumab in improving PFS time will be 
performed on the ITT population and will use the log-rank test stratified by number of previous 
regimens (excluding single-agent endocrine therapy) for advanced breast cancer and the status of 
disease (measurable vs. nonmeasurable).
There is 1 planned primary analysis for PFS in this study, which will be performed after 
approximately 165 events have been observed in the ITT population based on investigator 
assessment.  The primary PFS analysis will compare each arm against the control using a log-
rank test stratified by the randomization factors.  The primary objective of PFS will be tested at 
an experiment-wise 1-sided alpha level of 0.10.  The abemaciclib treatment arms will be tested 
sequentially against the trastuzumab plus chemotherapy arm, with the abemaciclib plus 
trastuzumab plus fulvestrant arm tested first.  A comparison of the 2 abemaciclib arms will be 
considered exploratory.  See Figure JPBZ.6.1 for a depiction of alpha spending.




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To estimate an improvement in PFS with abemaciclib, we will follow the method of Irwin (1949) 
detailed in Karrison (1997) and Meier (2004) for estimating the ‘difference in average PFS’, 
which we will refer to more formally as the restricted mean difference in PFS.
The area under each KM curve will be calculated using numerical integration (trapezium rule) 
per Karrison and implemented in SAS using PROC LIFETEST.  The difference between 
treatment arms and a 95% CI for the difference will be formed.
Since the KM curve may be ill-determined beyond a certain range, or even undefined (if the 
longest observation is censored), for evaluation and comparison of means, the area under each 
KM curve will be calculated between time 0 and restriction time T, which is why this is referred 
to as a "restricted mean".  Following the suggestion of Karrison, the restriction time T will be 
chosen as largest time point t such that the standard error (SE) of the survival estimate at time t 
in each treatment group is no more than 0.075.  For this purpose, we will use the simple, albeit 
conservative, formula proposed by Peto et al. (1977) for calculating the SE of S(t) as 




)
(
/
)
(
1
)
(
)
(
t
n
t
S
t
S
t
S
SE


, where n(t) is the number of patients still at risk at time t.
6.8.2. Gated Secondary Efficacy Endpoint:  Overall Survival
Overall survival (OS) is an important secondary endpoint for this study.  The OS time is 
measured from the date of randomization to the date of death from any cause.
OS will be tested only if PFS is significant for both abemaciclib arms.  OS will be tested by 
pooling the 2 abemaciclib arms and comparing them against the SOC systemic therapy arm.  Up 
to a total of 2 interim analyses and a final analysis for OS may be performed in this study.  The 
type I experiment-wise error rate will be controlled at 10% by using the Lan-Demets method 
with the following O’Brien-Fleming like alpha-spending function:





















k
k
t
t
2
/
1
1
2
1
*


Here, tk is the information fraction at time k, Φ is the standard normal cumulative distribution 
function, and Φ-1 is the standard normal quantile function.
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).
To maintain the experiment-wise type I error rate, OS will be hierarchically tested in the 
following way:  only if the test of PFS is significant will OS also be tested inferentially for 
significance (Glimm et al. 2010); specifically:

The first potential time point for OS analysis will be at the time of the primary PFS 
analysis.  If PFS is significant at this stage, the first interim analysis of OS will also be 
performed.  If OS is not significant at this stage, the second interim analysis of OS will be 
performed after approximately 105 deaths have been observed in the ITT population 


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(information fraction of 0.667).  If OS is not significant at this stage, a final analysis will 
be performed after approximately 158 deaths have been recorded in the ITT population.

If the primary analysis for PFS is not significant, OS will not be statistically evaluated.
The OS analysis to test the superiority of abemaciclib plus trastuzumab and abemaciclib plus 
trastuzumab plus fulvestrant to chemotherapy plus trastuzumab in improving OS time will use 
the log-rank test stratified by the number of previous regimens (excluding single-agent endocrine 
therapy) for advanced breast cancer and the status of disease (measurable vs. nonmeasurable).
The following additional analyses will be conducted for OS:

Kaplan-Meier curves (Kaplan and Meier 1958) will be generated; medians, quartiles, and 
appropriate point probabilities will be calculated.  Interval estimates will be calculated.

The Cox regression stratified by the randomization factors will be used to estimate the 
HR between the 2 treatment groups, along with CI.
In addition, OS rate at 1 year in each treatment arm will be calculated by determining OS time 
for each patient and using KM techniques to assess OS time for each treatment arm.  The KM 
estimate of the OS rate at 1 year will be used to compare treatment arms using a standard normal 
test of the difference in OS rate at 1 year.  The same techniques will be used to calculate and 
compare OS rates at 2 years and 3 years between arms.
6.8.3. Other Secondary Efficacy Analyses
6.8.3.1.
Objective Response Rate, Disease Control Rate, and Clinical Benefit 
Rate
Objective response rate, DCR, and CBR are summary measures of best overall response (BOR) 
as defined by RECIST v1.1.  BOR is derived from time point responses.  All time point 
responses observed while on study treatment and during the short-term follow-up period (but 
before the initiation of postdiscontinuation therapy) will be included in the derivation.  The one 
exception includes patients who receive surgery and/or radiotherapy for locally advanced breast 
cancer.  For these patients, only those time point responses occurring prior to 
surgery/radiotherapy will be included in the derivation.  The same rule will be applied to 
palliative radiation and palliative surgery.
Each patient’s BOR will be categorized as CR, PR, SD, progressive disease (PD), or not 
evaluable (NE).  For patients with bone-only nonmeasurable disease (see Section 6.5.2), BOR 
will be limited to CR, SD, PD, and NE.  Patients with SD will be further classified as SD 
≥6 months or SD <6 months.  Stable disease ≥6 months includes all patients with a best response 
of SD and a PFS time of ≥6 months.  A BOR of CR or PR will not require confirmation.
Objective response rate is the proportion of patients with a BOR of CR or PR.  Clinical benefit 
rate is the proportion of patients with a BOR of CR or PR, or SD ≥6 months.  Disease control 
rate is the proportion of patients with a BOR of CR, PR, or SD.  Patients with bone-only 


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nonmeasurable disease cannot have a best response of PR, thus ORR will be reported for both 
the ITT population and the subset of patients with measurable disease.
For each of these rates, point estimates and CIs (using the normal approximation to the binomial) 
will be calculated by treatment arm.  Stratified tests comparing these rates between treatment 
arms will be conducted using a Cochran-Mantel-Haenszel test using randomization factors as 
strata.
6.8.3.2.
Duration of Response
The DoR time is defined only for responders (patients with a BOR of CR or PR).  It is measured 
from the date of first evidence of CR or PR to the date of objective progression or the date of 
death due to any cause, whichever is earlier.  It is calculated as date of progression or death –
date of first response evaluation of CR or PR + 1.  The DoR will be censored according to the 
same rules as PFS.
A KM analysis of DoR will be performed to estimate the DoR curve for each arm.  Point 
estimates and CIs for DoR quartiles and DoR rates will be calculated every 3 months for the first 
12 months.
6.8.4. Sensitivity Analyses
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 (patients with centrally confirmed HER2+ 
disease):  Progression-free survival will be analyzed including only patients with centrally 
confirmed HER2+ disease.
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.
6.8.4.1.
Overall Survival
One sensitivity analysis on OS is planned.  Overall survival time for this analysis is defined as 
the time from the date of study enrollment to the date of death due to study 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 related to disease, survival time 
will be censored at the date of death.
6.9.
Health Outcomes/Quality-of-Life Analyses
6.9.1. Instruments
Patient-reported outcomes are measured through paper versions of the following:

mBPI-sf


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
EORTC QLQ-C30

EQ 5D 5L
6.9.2. Pain Intensity and Pain Assessment
Pain as assessed with the mBPI-sf questionnaire (that is, worst, least, average, and current pain 
over the last 24 hours) will be characterized with descriptive non-inferential statistics. Treatment 
arm comparisons will be conducted through use of mixed model repeated measures (MMRM) 
specified with an unstructured covariance matrix and estimated with restricted maximum 
likelihood (REML) to address the small sample negative bias in the variance component when 
using the maximum likelihood (ML) estimator (that is, the ML estimator usually has lower 
mean-squared error [MSE] than the REML estimator).
Corresponding analyses will be conducted for each of the 7 individual pain interference with 
function items (mBPI-sf items 5a-5g). Additionally, a composite score will be calculated if a 
majority of items are completed (that is, at least 4 out of 7 pain interference with function items 
must have a valid recorded response).
6.9.3. Quality of Life
Data from the EORTC QLQ-C30 instrument will be scored as described by Aaronson and 
colleagues (Aaronson et al. 1993).
Treatment arm comparisons will be conducted through use of MMRM specified with an 
unstructured covariance matrix and estimated with REML to address the small sample negative 
bias in the variance component when using the ML estimator (that is, the ML estimator usually 
has lower MSE than the REML estimator).
6.9.4. Health State Utility
The EQ-5D 5L data will be scored as described 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 Visual Analog Scale (VAS) is scored from 0 (worst imaginable health 
state) through 100 (best imaginable health state) to represent the patient’s self-reported health 
state “today”.  The 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 by 
arm.
For both the index score and VAS, treatment arm comparisons will be conducted through use of 
MMRM specified with an unstructured covariance matrix and estimated with REML to address 
the small sample negative bias in the variance component when using the ML estimator (that is, 
the ML estimator usually has lower MSE than the REML estimator).
6.9.5. Exploratory Analyses of Health Outcomes/Quality-of-Life
Following exploratory analyses will be done for each of the 3 scales, mBPI-sf, EORTC 
QLQ-C30, and EQ 5D 5L.


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For each of these 3 scales, summaries of patient-reported outcomes will also be calculated as part 
of a strategy to demonstrate postdiscontinuation treatment effect —an issue that continues to be 
discussed in both clinical and health technology assessment evaluations and which has a 
demonstrable impact on the results derived from the economic model. To deliver this 
information, we will conduct the following:
1.a.
For each patient with a baseline and at least 1 on-therapy observation, we will calculate 
the difference between the baseline assessment and the last on-study assessment.
1.b.
For each patient with a baseline and an 801 visit, we will also calculate the difference 
between the baseline assessment and the 801 assessment.
1.c.
Difference scores will be calculated between 1.a. and 1.b. mean difference scores (that is, 
differences between baselinelast on-study vs. baseline801 assessments) for patients 
with data from those assessments.
Mean differences will be calculated and treatment difference will be compared using a 
t-test, and effect sizes will be produced to aid interpretation.
2.a.
The duration in days from the last on-study assessment and the 801 assessment will be 
summarized.
6.9.6. Utilization
Utilization data will be summarized by category by arm.  The following categories will be 
described:

analgesics (at baseline, on study treatment, and during short-term follow-up)

anti-diarrheal therapy (at baseline, on study treatment, and during short-term 
follow-up)

transfusions (on study treatment and during short-term follow-up)

surgery (on study treatment and during short-term follow-up)

hospitalizations (on study treatment and during short-term follow-up)

postdiscontinuation radiotherapy and systemic therapy
For categorical variables, frequency and the corresponding proportions will be calculated and 
tests for differences in proportion between groups will be performed using a Fisher’s Exact test.  
Continuous variables will be described by the mean, median, and standard deviation. A t-test 
will be used to compare mean utilization.
6.10. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Pharmacokinetic and pharmacodynamic analyses will be performed according to a separate PK 
analysis plan.


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6.11. Safety Analyses
6.11.1. Extent of Exposure
Drug exposure, dose intensity, and drug adjustment (dose omissions, reductions, and delays) for 
abemaciclib, trastuzumab, fulvestrant, and SOC single-agent systemic therapy of physician’s 
choice will be summarized for all treated patients per treatment arm.  Drug exposure will include 
summaries of cycles received per patient, duration on therapy, and cumulative dose.  Dose 
intensity will be calculated as the actual cumulative amount of drug taken divided by the 
duration of treatment.  Relative dose intensity will be calculated as the actual amount of drug 
taken divided by the amount of drug prescribed times 100% (expressed as a percentage).  The 
summary of dose adjustments, omissions (oral drugs), and delays (intravenously or 
intramuscularly administered drugs) will include the reason for adjustment, omission, or delay.
For abemaciclib, extent of exposure will be measured by pill counts.  Dose intensity will be 
expressed in mg/day.  The assigned cumulative dose while on study is 2 × 150 mg × number of 
days on treatment.
For trastuzumab, extent of exposure and assigned cumulative dose while on study will be 
measured based on data reported on the infused drug form.
For fulvestrant, extent of exposure will be measuring using the fulvestrant administration eCRF.  
The assigned cumulative dose while on study is 500 mg + [500 mg × ceiling (number of days on 
treatment/28)].
For SOC single-agent systemic therapy of physician’s choice, extent of exposure and assigned 
cumulative dose while on study will be measured based on data reported on the eCRF 
appropriate for the route of administration.
For Arm C, SOC physician choice will be summarized by drug. The number of patients treated 
with maintenance endocrine therapy will be summarized as well.
6.11.2. Adverse Events
Adverse event (AE) terms and severity grades will be assigned by the investigator using 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.  In addition, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within MedDRA.  Adverse events will be reported using the following reporting process:

In CTCAE Version 4, each CTCAE term is a MedDRA lower level term (LLT), 
except in the case where the CTCAE term is a MedDRA system organ class (SOC) 
followed by ‘Other – specify’.

The CTCAE Version 4 term reported by the investigator will be mapped to 
the MedDRA PT and SOC of the corresponding MedDRA LLT, unless the 
reported CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’, the MedDRA LLT, PT, and 
SOC mapped from the verbatim AE term will be used.


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
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 any AE that begins on or after the day 
of first dose or any preexisting condition that increases in CTCAE grade on or after the day of 
first dose.  Comparisons of preexisting conditions to on-treatment events at the LLT level will be 
used in the treatment-emergent computation.
A serious adverse event (SAE) is any AE during this study that results in one of the following 
outcomes:

death

initial or prolonged inpatient hospitalization 

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

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 SAEs when, based on 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.
The following summaries and listings will be produced:

Overview of adverse events

Summary of TEAEs by PT (any grade and Grade ≥ 3)

Summary of TEAEs by SOC and PT (any grade and Grade ≥ 3)

Summary of TEAEs by SOC and PT and maximum grade (1-5)

Summary of SAEs by SOC and PT (any grade and Grade ≥ 3)

Summary of AEs as reason for study treatment discontinuation by SOC and PT

Listing of SAEs
The TEAE and SAE summaries will be produced for all TEAEs/SAEs and repeated for 
TEAEs/SAEs related to study treatment, where relationship of the AE to the study treatment will 
be assessed by the investigator (yes or no). Fisher’s Exact test may be used for comparing AEs
between treatment arms.
6.11.3. Deaths, Other Serious Adverse Events
A summary of all deaths, including reasons for deaths, will be provided.  All deaths, deaths on 
therapy, deaths within 30 days of discontinuation of study therapy, deaths on therapy or within 


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30 days of discontinuation of study therapy, and deaths after 30 days of discontinuation of study 
therapy will be summarized by reason for death.  For deaths due to AE, the preferred term will 
be provided.  In addition to the tabular summary, a by-patient listing of all deaths on study not 
attributed to study disease by the investigator will be provided.
6.11.4. Clinical Laboratory Evaluation
All relevant hematology and chemistry laboratory values will be graded according to CTCAE 
Version 4.  These calculated grades will be summarized by cycle and maximum postbaseline 
grade over the entire study for each treatment arm.  Treatment-emergent changes will be 
summarized by the maximum postbaseline grade, and a shift table of baseline grade by 
maximum postbaseline grade will be produced.
6.11.5. Vital Signs and Other Physical Findings
Temperature, blood pressure, pulse rate, respiration rate, weight, and ECOG PS will be 
summarized by cycle.
6.11.6. Electrocardiograms
Local electrocardiograms (ECGs) will be summarized by planned cycle and overall.  The 
summary by cycle will classify patients as having normal or abnormal ECG and summarize AEs 
identified by ECG within each cycle.  The overall summary will classify patients as having an 
abnormal ECG at any point and summarize all AEs identified by ECG.
Left ventricular ejection fraction percentage as recorded on the eCRF (based on echocardiogram 
or multiple gated acquisition scan) will be summarized by planned cycle for each treatment arm.
6.12. Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for each of following potential prognostic 
subgroup variables:

number of previous regimens for advanced breast cancer (2 to 3 vs. more than 3)

status of disease (measurable vs. nonmeasurable)

disease setting (metastatic versus locally advanced recurrent)

nature of disease (visceral or other)

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)

progesterone receptor status (positive versus negative)

baseline ECOG PS (0 versus 1)


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
number of prior HER2 directed therapy in advanced disease setting (2 to 3, 4 to 5, 
and more than 5)
If a level of a factor consists of fewer than 10% of randomized patients, analysis within that level 
will be omitted.
Analyses will be done within subgroup and, separately, across subgroups with a test of 
interactions of subgroups with treatment performed.  Estimated HRs and CIs for the 
within-subgroup analyses will be presented as a Forest plot along with p-values for tests of 
interactions between subgroup variables and treatment.
Other subgroup analyses may be performed as deemed appropriate.  If any safety analyses 
identify important imbalances between arms, subgroup analyses of these endpoints may be 
performed.
6.13. Protocol Violations
Significant protocol violations that potentially compromise the data integrity and patients’ safety 
will be summarized by treatment group for all randomized patients.  These violations will 
include deviations that can be identified programmatically and those which can only be 
identified by the clinical research associate during monitoring.  Significant protocol deviations 
are described in another document within the study Trial Master File.
6.14. Interim Analyses and Data Monitoring
6.14.1. Safety Interim Analyses
There are 2 planned interim analyses to evaluate the safety and tolerability of the combination of 
abemaciclib plus trastuzumab plus fulvestrant in patients enrolled to the safety lead-in for Part A; 
these analyses will take place when data from the first 6 and 12 qualified patients who complete 
1 cycle have been obtained.  These interim analyses will be performed by an assessment 
committee (AC) made up of Lilly members not involved in the day to day study conduct (the 
medical director, a Global Patient Safety physician, and a statistician) plus the global principal 
investigators.  If ≥2 of 6 patients or ≥4 of 12 patients in the safety lead-in experience a dose-
limiting toxicity (DLT) or DLT-equivalent toxicity as defined in the protocol, the dose of 
abemaciclib will be reduced to 100 mg for these patients and for all subsequent patients enrolled 
to Arm A.  Even if the AC does not observe the specified number of DLTs or DLT-equivalent 
toxicities that would lead to dose reduction, Lilly may elect to reduce the dose of abemaciclib in 
Arm A if warranted by safety concerns. No protocol amendment will be needed to proceed with 
a lower dose level of abemaciclib in Arm A.  If the dose of abemaciclib in Arm A is reduced to 
100 mg, patients that initiated treatment at the 150-mg dose will be dose-reduced to 100 mg, and 
patients who started at the 150-mg abemaciclib dose will be replaced so that there are a total of 
75 patients in Arm A with a starting dose of 100-mg abemaciclib.  If the 100-mg dose is found to 
be intolerable, enrollment into Arm A will be discontinued.
In addition to the safety lead-in interim analyses for Arm A, there are 3 planned interim analyses 
for safety for all treatment arms in Study JPBZ.  A safety interim analysis is planned after 


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approximately 36 patients (a minimum of 12 patients in experimental arms A and B) have been 
treated for 1 cycle.  There will be no prespecified rules for stopping the trial due to safety 
concerns.  The AC members will review safety data at the interim analysis to determine whether 
there are sufficient safety concerns to justify the termination of study treatment and/or 
enrollment.  Similar interim safety analyses will be performed after approximately 75 patients 
and after approximately 150 patients have been treated for 1 cycle (a minimum of 25 and 50 
patients in experimental arms A and B).
Each safety evaluation will be based, at least, on the following data reports:

summary of treatment discontinuations and reasons for discontinuation

summary of SAEs

summary of TEAEs

summary of CTCAE-graded central laboratory results

summary of drug exposure and dose adjustments (including delays and 
reductions) and reasons for adjustment

listing of treatment discontinuations due to AE or death

Lilly Safety System reports for all patients with SAEs (as requested).
6.14.2. Efficacy Interim Analyses
An interim analysis for futility is planned after 75 PFS events have been observed.  Futility for 
the interim analysis will be determined in terms of PFS.  As guidance, an AC may recommend 
stopping the trial or closing an experimental arm for futility if the observed HR>1.3.  The 
stopping guidance should be viewed as only guidance, not an absolute rule.  The AC will 
consider all evidence, including safety and other efficacy parameters, in making this decision.
6.15. Annual Report Analyses
Annual report analyses, including Developmental Safety Update Report and Investigator’s
Brochure analyses, are described in the LY2835219 Program SAP.
6.16. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset that will be converted to an XML file. Both 
SAEs and ‘Other’ AEs are summarized by treatment group and by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided:


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o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the clinical 
study report, manuscripts, and so forth.


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7.
References
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JC, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KC, Sullivan M, Takeda F. The European Organisation for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst. 1993;85(5):365-376.
Agresti A. Categorical Data Analysis. 2nd ed. New York: Wiley, 2002.
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;74(2):187-220.
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Stat Med. 2010;29(2):219-228.
Irwin JO. The standard error of an estimate of expectation of life, with special reference to 
expectation of tumourless life in experiments with mice. J Hyg (Lond). 1949;47(2);188.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53(282):457-481.
Karrison TG. Use of Irwin’s restricted mean as an index for comparing survival in different 
treatment groups-- interpretation and power considerations. Control Clin Trials. 
1977;18(2);151-167.
Meier P, Karrison T, Chappell R, Xie H. The price of Kaplan-Meier. J Am Stat Assoc. 
2004;99(467):890-896.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, 
Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged 
observation of each patient, II. analysis and examples. Br J Cancer. 1977;35(1):1-39.
van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value Health. 2012;15(5):708-715.


Leo Document ID = 6a13a30e-1be5-472d-99cb-ca1a50c621f4
Approver: 
Approval Date & Time: 07-Feb-2019 15:33:51 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Feb-2019 16:54:24 GMT
Signature meaning: Approved
PPD
PPD