A Randomized, Open-Label, Phase 2 Study of Abemaciclib Plus Tamoxifen or Abemaciclib Alone, in Women With Previously Treated Hormone Receptor-Positive, HER2-Negative, Metastatic Breast Cancer
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Sponsor: Eli Lilly and Company

 
I3Y-MC-JPCG(b) Clinical Protocol 
 
 
A Randomized, Open-Label, Phase 2 Study of Abemaciclib plus Tamoxifen or Abemaciclib 
Alone, in Women with Previously Treated Hormone Receptor-Positive, HER2-Negative, 
Metastatic Breast Cancer. 
 
NCT02747004 
 
Approval Date: 29-Jan-2019 
 
 

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Protocol I3Y-MC-JPCG(b)
A Randomized, Open-Label, Phase 2 Study of Abemaciclib 
plus Tamoxifen or Abemaciclib Alone, in Women with 
Previously Treated Hormone Receptor-Positive, 
HER2-Negative, 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)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Approved by Lilly: 11 April 2016
Amendment (a) Approved on date:  24 August 2016
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 29-Jan-2019 GMT

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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................23
5.
Study Design.....................................................................................................................24
5.1.
Overall Design .............................................................................................................24
5.2.
Number of Patients.......................................................................................................24
5.3.
End of Study Definition ...............................................................................................24
5.4.
Scientific Rationale for Study Design...........................................................................25
5.5.
Justification for Dose ...................................................................................................25
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................29
6.3.
Lifestyle Restrictions....................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatments........................................................................................................................32
7.1.
Treatments Administered .............................................................................................32
7.1.1.
Packaging and Labelling ......................................................................................33
7.2.
Method of Treatment Assignment ................................................................................33
7.2.1.
Selection and Timing of Doses.............................................................................33
7.3.
Blinding .......................................................................................................................33
7.4.
Dosage Modification....................................................................................................33
7.4.1.
Special Treatment Considerations ........................................................................33
7.4.1.1.
Dose Adjustments and Delays ........................................................................33
7.4.1.1.1.
Dose Adjustments.....................................................................................35
7.4.1.1.1.1.
Abemaciclib........................................................................................35
7.4.1.1.1.2.
Tamoxifen (Arm A only) ....................................................................36
7.4.1.1.1.3.
Loperamide.........................................................................................36
7.4.1.1.2.
Dose Delays and Omission .......................................................................36
7.4.1.1.2.1.
Abemaciclib........................................................................................36
7.4.1.1.2.2.
Tamoxifen (Arm A only) ....................................................................37

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7.5.
Preparation/Handling/Storage/Accountability...............................................................38
7.6.
Treatment Compliance .................................................................................................38
7.7.
Concomitant Therapy...................................................................................................38
7.7.1.
Supportive Care ...................................................................................................39
7.7.1.1.
Supportive Management for Diarrhea .............................................................39
7.7.2.
Growth Factor Therapy........................................................................................40
7.8.
Treatment after the End of the Study............................................................................40
7.8.1.
Continued Access.................................................................................................40
8.
Discontinuation Criteria ....................................................................................................42
8.1.
Discontinuation from Study Treatment.........................................................................42
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................42
8.2.
Discontinuation from the Study....................................................................................43
8.3.
Lost to Follow-Up........................................................................................................43
9.
Study Assessments and Procedures ...................................................................................44
9.1.
Efficacy Assessments...................................................................................................44
9.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................44
9.1.2.
Efficacy Assessments during Postdiscontinuation Follow-up................................45
9.1.3.
Appropriateness of Assessments ..........................................................................45
9.2.
Adverse Events ............................................................................................................45
9.2.1.
Serious Adverse Events........................................................................................46
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................47
9.2.3.
Complaint Handling.............................................................................................47
9.3.
Treatment of Overdose.................................................................................................48
9.4.
Safety...........................................................................................................................48
9.4.1.
Other Safety Measures .........................................................................................48
9.4.2.
Safety Monitoring ................................................................................................48
9.4.2.1.
Special Hepatic Safety Data Collection...........................................................48
9.4.2.2.
Renal Function ...............................................................................................49
9.4.2.3.
Venous Thromboembolic Events....................................................................49
9.5.
Pharmacokinetics .........................................................................................................49
9.6.
Pharmacodynamics ......................................................................................................49
9.7.
Pharmacogenomics ......................................................................................................49
9.7.1.
Samples for Pharmacogenetic Research ...............................................................49
9.8.
Biomarkers...................................................................................................................50
9.8.1.
Samples for Nonpharmacogenetic Biomarker Research........................................50
9.8.2.
Tissue Samples for Research................................................................................51
9.9.
Health Outcomes/Quality of Life..................................................................................52

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9.9.1.
Pain Assessment...................................................................................................52
9.9.2.
Health-Related Quality of Life .............................................................................52
9.9.3.
Resource Utilization.............................................................................................53
10.
Statistical Considerations ..................................................................................................54
10.1. Sample Size Determination ..........................................................................................54
10.2. Populations for Analyses..............................................................................................54
10.3. Statistical Analyses ......................................................................................................54
10.3.1.
Efficacy Analyses ................................................................................................55
10.3.1.1.
Progression Free Survival...............................................................................55
10.3.1.2.
Objective Response Rate, DCR, CBR, and DoR.............................................56
10.3.1.3.
Overall Survival .............................................................................................56
10.3.2.
Safety Analyses....................................................................................................57
10.3.3.
Other Analyses.....................................................................................................58
10.3.3.1.
Patient Disposition..........................................................................................58
10.3.3.2.
Patient Characteristics ....................................................................................58
10.3.3.3.
Concomitant Therapy .....................................................................................58
10.3.3.4.
Poststudy-Treatment-Discontinuation Therapy ...............................................58
10.3.3.5.
Treatment Compliance....................................................................................58
10.3.3.6.
Pharmacokinetic/Pharmacodynamic Analyses ................................................59
10.3.3.7.
Biomarker Analyses .......................................................................................59
10.3.3.8.
Health Outcome/Quality of Life Analyses ......................................................59
10.3.3.9.
Healthcare Resource Utilization......................................................................60
10.3.4.
Subgroup Analyses ..............................................................................................60
10.3.5.
Interim Analyses..................................................................................................60
11.
References ........................................................................................................................61

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List of Tables
Table
Page
Table JPCG.1.
Baseline Schedule of Activities ..............................................................11
Table JPCG.2.
On-Study-Treatment Schedule of Activities............................................13
Table JPCG.3.
Post-Treatment Follow-Up Schedule of Activities ..................................17
Table JPCG.4.
Continued Access Schedule of Activities................................................19
Table JPCG.5.
Objectives and Endpoints .......................................................................23
Table JPCG.6.
Treatment Regimens...............................................................................32
Table JPCG.7.
Toxicity Dose Adjustments and Delays of Abemaciclib..........................34
Table JPCG.8.
Dose Adjustments of Abemaciclib..........................................................35
Table JPCG.9.
General Dose Delays of Abemaciclib .....................................................37
Table JPCG.10.
PFS Event/Censoring Scheme ................................................................55
Table JPCG.11.
Other Secondary Efficacy Endpoints ......................................................56

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List of Figures
Figure
Page
Figure JPCG.1.
Illustration of study design......................................................................24
Figure JPCG.2.
Continued access diagram.......................................................................41

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................64
Appendix 2.
Study Governance, Regulatory, and Ethical Considerations....................68
Appendix 3.
Clinical Laboratory Tests........................................................................71
Appendix 4.
Sampling Schedule for Genetics/ Biomarkers/ Pharmacokinetics/ 
Pharmacodynamics.................................................................................72
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............73
Appendix 6.
Protocol JPCG Inducers, Strong Inhibitors of CYP3A or Substrates 
of CYPS with Narrow Therapeutic Range ..............................................74
Appendix 7.
Protocol JPCG CTCAE 4.03 Diarrhea Definition ...................................75
Appendix 8.
Protocol JPCG RECIST Criteria 1.1 .......................................................76
Appendix 9.
Protocol JPCG:  ECOG Performance Status ...........................................82
Appendix 10.
Protocol Amendment I3Y-MC-JPCG(b) Summary 
A Randomized, Open-Label, Phase 2 Study of Abemaciclib plus 
Tamoxifen or Abemaciclib Alone, in Women with Previously 
Treated Hormone Receptor-Positive, HER2-Negative, Metastatic 
Breast Cancer .........................................................................................83

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1.
Synopsis
Protocol Title:  A Randomized, Open-Label, Phase 2 Study of Abemaciclib plus Tamoxifen or Abemaciclib Alone, 
in Women with Previously Treated Hormone Receptor-Positive, HER2-Negative, Metastatic Breast Cancer. 
Rationale:  This Phase 2 study is a multicenter, randomized, open-label study to evaluate the efficacy and 
tolerability of abemaciclib alone or in combination with endocrine therapy as a treatment for patients with hormone 
receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer 
(mBC) who have progressed on or after prior endocrine therapies.  Patients must have received prior treatment with 
at least 2 chemotherapy regimens, of which at least 1 but no more than 2 regimens have been administered in the 
metastatic setting. The currently approved standards of care offered to this population are predominantly 
chemotherapies associated with treatment-limiting toxicity. Abemaciclib monotherapy and in combination with 
endocrine therapy has demonstrated clinical activity and an acceptable tolerability profile in patients with mBC.
This Phase 2 study will evaluate and compare the efficacy and tolerability of abemaciclib monotherapy at 2 dose 
levels and abemaciclib in combination with endocrine therapy for patients with previously treated HR+, HER2-
mBC.

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Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the efficacy, in terms of PFS, in patients 
with metastatic breast cancer for:

Abemaciclib 150 mg Q12H plus tamoxifen

Abemaciclib 150 mg Q12H 

Abemaciclib 200 mg Q12H plus primary 
prophylactic loperamide 
PFS (objective progression or death), as determined by 
investigator assessment per RECIST v1.1
Secondary
To evaluate the efficacy of abemaciclib monotherapy 
and in combination with tamoxifen, in terms of ORR, 
DoR, and OS 
To assess the safety profile of abemaciclib monotherapy 
and in combination with tamoxifen
To characterize the PK of abemaciclib and its 
metabolites; in addition to tamoxifen and its active 
metabolite endoxifen
To compare self-reported pain, pain interference,
symptom burden, health status, and overall quality of 
life
Efficacy endpoints will include:

ORR (CR + PR)  based on tumor assessment 
using RECIST v1.1 

DoR (CR+ PR) per RECIST v1.1 

OS
Safety endpoints will include but are not limited to the 
following:

TEAEs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and physical
examinations
PK parameters for abemaciclib and tamoxifen
Compare self-reported pain, pain interference, symptom 
burden, health status, and quality of life using the 
mBPI-sf and EORTC QLQ-C30
Abbreviations:  CR = complete response; DoR = duration of response; EORTC QLQ-C30 = European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; mBPI-sf = modified Brief Pain 
Inventory-short form; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PK 
= pharmacokinetics; PR = partial response; Q12H = every 12 hours; RECIST v 1.1 = Response Evaluation 
Criteria in Solid Tumors Version 1.1; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

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Overall Design:  I3Y-MC-JPCG (JPCG) is a Phase 2, multicenter, randomized, open-label study of abemaciclib 
plus tamoxifen or abemaciclib alone, in women with previously treated HR+, HER2- mBC.
Number of Patients:  The study will screen approximately 270 patients, and approximately 225 patients with HR+, 
HER2- mBC will be enrolled in the study and randomized 1:1:1 to one of the three treatment arms. Treatment will 
be given in an outpatient setting and will continue until evidence of disease progression or other discontinuation 
criteria are met.
Treatment Arms and Duration:
Dose and Schedule (Q28 Days)
Arm
Abemaciclib Dose
Tamoxifen Dose (Arm A only)
A
150 mg Q12H
20 mg QD
B
150 mg Q12H
--
Ca
200 mg Q12H
--
Abbreviations:  Q = every; Q12H = every 12 hours; QD = every 24 hours.
a
Arm C only. During Cycle 1, loperamide 2 mg will be administered orally, prophylactically with the first dose of 
abemaciclib daily. During Cycle 2 and beyond, loperamide will be administered either as prophylaxis or
supportive care based on investigator’s discretion and/or if clinically indicated. 

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2.
Schedule of Activities
Table JPCG.1.
Baseline Schedule of Activities
Relative Day Prior to Day 1 of
Cycle 1 (Day -1)
28
14
7
Comments
Procedure
Informed consent
X
Informed consent form signed (prior to 
performance of any protocol-specific 
tests/procedures).
Serum pregnancy test
X
Women with childbearing potential must 
have a negative serum pregnancy test 
within 7 days of the first dose of study drug 
(i.e. Day -7 to Day -1).
Medical history
X
Including alcohol/tobacco use and other 
relevant habits assessments.  Includes prior 
anticancer therapy.
Physical exam, vital signs, height, and 
weight
X
Vital signs include blood pressure, pulse, 
respiratory rate, and temperature.
ECOG performance status
X
Concomitant medications
X
Any current medications.
CTCAE version 4.0 grading 
(preexisting conditions)
X
Tumor measurement (visible lesions)
X
Photography of visible lesions (such as skin 
lesions) with ruler required, if applicable.
Radiological tumor assessment
X
Imaging studies (CT scan or MRI) are
performed locally (Day -28 to Day -1) at
baseline. It is recommended that CT
imaging of the chest, 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
Gd-MRI of the abdomen/pelvis are
encouraged.
Bone scintigraphy (preferred) or PET 
scan or PET component of PET/CT 
scan
X
One of these studies (Bone scintigraphy 
[preferred], PET scan, or PET component 
of PET/CT scan) of the whole body is 
performed locally at baseline.  An available 
prior bone scintigraphy or PET scan 
performed as part of routine clinical care 
within 45 days before Cycle 1 Day 1 is 
acceptable.

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Baseline Schedule of Activities
Relative Day Prior to Day 1 of
Cycle 1
28
14
7
Comments
Procedure
X-ray or CT scan with bone windows 
or MRI
X
Required only for patients with 
nonmeasurable bone disease identified on 
the baseline bone scintigraphy, PET, or 
PET component of PET/CT.  One or more 
of these studies (X-ray, CT scan with bone 
windows, or MRI) is performed locally 
(Day -28 to Day -1) at baseline. All bone
lesions will be evaluated by focused studies 
to enable serial assessment. 
MRI of brain
X
Required for all patients.  Performed locally 
(Day -28 to Day -1) at baseline.
ECG
X
ECGs will be performed locally (Day -14 to 
Day -1). This baseline ECG (no replicates 
required) is required to establish eligibility 
for this study. 
mBPI-sf and EORTC QLQ-C30
X
Patient completes prior to extensive 
interaction at site.
Central hematology
X
Enrollment and treatment decisions may be 
based upon local laboratory results. If local 
laboratory results are used for this purpose, 
a duplicate specimen must be submitted to 
the central laboratory. Discrepancies 
between local and central laboratory results 
will not be considered protocol deviations.
Central chemistry
X
Enrollment and treatment decisions may be 
based upon local laboratory results. If local 
laboratory results are used for this purpose, 
a duplicate specimen must be submitted to 
the central laboratory. Discrepancies 
between local and central laboratory results 
will not be considered protocol deviations.
Abbreviations:  CT = computerized tomography; CTCAE = Common Terminology Criteria for Adverse Events 
(NCI 2009); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); 
EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30; Gd = gadolinium; IV = intravenous; mBPI-sf = modified Brief Pain Inventory-short form;
MRI = magnetic resonance imaging; PET = positron emission tomography.

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Table JPCG.2.
On-Study-Treatment Schedule of Activities
Cycle 1
Cycle 2
Cycle 3 and 
beyond 
(per 
instructions)
Day within cycle
(28 days = 1 cycle)
1
15
1
15
1
Procedure
Comments
Physical examination
X
X
X
X
Including weight and vital signs (temperature, blood pressure, 
pulse rate, respiration rate).  May be performed up to 3 days 
prior to Day 1 of each cycle, as well as up to 3 days prior to 
Day 15 of Cycle 1.
Concomitant medication
X
X
X
X
Including concomitant medication at study start and, 
throughout study as needed.
Adverse event collection
X
X
X
X
Adverse event grading using CTCAE Version 4.0 will be 
performed throughout the study. All drug- or procedure-related 
AEs and SAEs should be followed until they resolve, are no 
longer considered to be drug- or procedure-related, become 
stable or return to baseline, the patient starts a new therapy, the 
patient dies, or the patient becomes lost to follow-up.
ECOG performance status
X
X
X
X
May be performed up to 3 days prior to Day 1 of each cycle, as 
well as up to 3 days prior to Day 15 of Cycle 1.
Radiological tumor assessment
X
Performed locally. Imaging studies are performed every 8 
weeks (-7 days) from the first dose of study therapy and within 
14 days of clinical progression.  The same method of imaging 
used at baseline should be used for each subsequent 
assessment.
Bone scintigraphy (preferred) or 
PET scan or PET component of 
PET/CT scan
X
Required only for patients with nonmeasurable bone disease 
identified at baseline or if clinically indicated. Postbaseline 
bone scintigraphy or PET should be performed every 24 weeks 
(-7 days) from first dose of study therapy. 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.

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On-Study-Treatment Schedule of Activities
Cycle 1
Cycle 2
Cycle 3 and 
beyond 
(per 
instructions)
Day within cycle 
(28 days = 1 cycle)
1
15
1
15
1 
Procedure
Comments
X-ray or CT scan with bone 
windows or MRI
X
Required only for patients with nonmeasurable bone disease
identified at baseline. One or more of these studies (X-ray, CT 
scan with bone windows, or MRI), identical to the study 
obtained at baseline, is performed locally every 8 weeks (-7 
days) from first dose of study therapy and within 14 days of 
clinical progression. For patients with new lesions identified 
by postbaseline bone scintigraphy, targeted assessment by X-
ray, CT scan with bone windows, or MRI will be performed to 
confirm findings. 
Tumor measurement ( visible
lesions)
X
Skin lesions identified at baseline require repeat photographic 
images every 8 weeks (-7 days) from the first dose of study 
therapy 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 postbaseline.
Patient diary 
dispensing/collection
X
X
X
X
X
Patient diaries should be completed by the patient during cycles 
1, 2, and 3.
Administer mBPI-sf and EORTC 
QLQ-C30 questionnaires
X
X
X
X
To be administered prior to extensive interaction with site staff
at each visit when administered.  Continue administration at 
every cycle through Cycle 7 Day 1 and then administer at every 
other cycle starting with Cycle 9 and beyond.  
Administer abemaciclib
X
Administer prescribed dose orally every 12 hours on Days 1 
through 28 of every cycle.  Patients may take study drug with 
or without meals.

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On-Study-Treatment Schedule of Activities
Cycle 1
Cycle 2
Cycle 3 and 
beyond 
(per 
instructions)
Day within cycle 
(28 days = 1 cycle)
1
15
1
15
1 
Procedure
Comments
Administer tamoxifen 
X
Arm A patients only. Administer prescribed dose orally every 
24 hours on Days 1 through 28 of every cycle.
Administer loperamide
X
Only patients in Arm C should take loperamide 
prophylactically (daily during Cycle 1 with their first dose of 
abemaciclib). Patients in Arms A and B should only take 
loperamide if the patient experiences diarrhea and requires 
treatment. See Section 7.4.1.1.1.3 for additional information.
Sample collection
Central hematology 
X
X
X
X
X
Central hematology labs can be drawn up to 3 days prior to 
Day 1 of each cycle, as well as up to 3 days prior to Day 15 of 
Cycles 1 and 2.  Additional local hematology labs may be 
drawn for treatment adjustment and patient management 
purposes.  Duplicate central labs should be submitted for 
assessment. Discrepancies between local and central 
laboratory results will not be considered protocol deviations.
Central chemistry
X
X
X
X
X
Central chemistry labs can be drawn up to 3 days prior to Day 
1 of each cycle, as well as up to 3 days prior to Day 15 of 
Cycles 1 and 2.  Additional local chemistry labs may be drawn 
for treatment adjustment and patient management purposes.  
Duplicate central labs should be submitted for assessment.  
Discrepancies between local and central laboratory results will 
not be considered protocol deviations.
Serum pregnancytest
X
X
Required only for women of child bearing potential if mandated 
by local country regulations.  Additional serum pregnancy tests 
performed locally, on Day 1 (or up to 3 days before Day 1) of 
every cycle beginning with Cycle 2. 
Pharmacokinetics 
X
X
X
X
X
See Appendix 4 for details on sample collection
Pharmacogenetic blood sample
X

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On-Study-Treatment Schedule of Activities
Cycle 1
Cycle 2
Cycle 3 and 
beyond 
(per 
instructions)
Day within cycle 
(28 days = 1 cycle)
1
15
1
15
1 
Procedure
Comments
Biomarker plasma sample
X
X
X
Collect at Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 3 Day 1. 
See Appendix 4 for details on timing for sample collection
Archived tumor tissue
X
Formalin-fixed paraffin-embedded (FFPE) tumor sample must 
be requested after study eligibility is confirmed.
Abbreviations:  AE = adverse event; CT = computerized tomography; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); 
ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30; mBPI-sf = modified Brief Pain Inventory-short form; MRI = magnetic resonance imaging; PET = positron emission 
tomography; RECIST v 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SAE = serious adverse event.

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Table JPCG.3.
Post-Treatment Follow-Up Schedule of Activities
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Comments
Visit
801
802-8XX
Procedure
Physical examination
X
Including weight and vital signs (temperature, blood pressure, pulse rate, 
respiration rate).
Concomitant medication
X
Adverse event collection
X
CTCAE Version 4.0. After Visit 801, only study protocol or drug-related events 
are reported. If a patient has an ongoing AE or SAE possibly related to study 
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 ± 7 in duration.
ECOG performance status
X
Radiological tumor assessment
X
X
Not required if objective progressive disease is documented while on treatment.
Continue to conduct tumor assessment every 8 weeks (-7 days) until 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 for a minimum of every 
90 days until death or study completion.
Bone scintigraphy (preferred) or PET 
Scan or PET component of PET/CT Scan
X
X
Not required if objective progressive disease is documented while on treatment. 
Continue to evaluate repeat bone scans approximately every 24 weeks until 
objective disease progression or primary PFS analysis.
X-ray or CT scan with bone windows or 
MRI
X
X
Only for patients with nonmeasurable bone disease previously identified. Not
required if objective progressive disease is documented while on treatment.
Continue to conduct tumor assessment every 8 weeks (-7 days) until 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 for a minimum of every 
90 days until death or study completion.

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Post-Treatment Follow-Up Schedule of Activities
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Comments
Visit
801
802-8XX
Procedure
Tumor measurement (visible lesions)
X
X
Not required if objective progressive disease is documented while on treatment.
Continue to conduct tumor assessment every 8 weeks (-7 days) until patient has 
objective disease progression or until primary PFS analysis. After the patient has 
objective disease progression, tumor assessments are no longer required and the 
patient will continue with postdiscontinuation follow-up for a minimum of every 
90 days until death or study completion.
Survival information
X
X
Survival information may be collected by contacting the patient or family directly
(for example, via telephone) if no procedures are required. This should be
collected at minimum every 90 days if no other procedures are performed.
Collection of post-study-treatment 
anticancer therapy information
X
X
Perform for a minimum of every 90 days until death or study completion.
Central hematology 
X
For sample collection, see Appendix 3.
Central chemistry
X
Serum pregnancy test
X
Required only for women of child bearing potential if mandated by local country 
regulations. Serum pregnancy test performed locally at short-term follow up visit. 
Biomarker plasma sample
X
Collect at time of discontinuation.
Administer mBPI and EORTC QLQ-
C30 questionnaires
X
Collect prior to extensive site interaction.
Abbreviations:  AE = adverse event; CT = computerized tomography; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); 
ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30; mBPI-sf = modified Brief Pain Inventory-short form; MRI = magnetic resonance imaging; PET = positron emission 
tomography; SAE = serious adverse event.
a
Short-term follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts 
approximately 30 days (± 7 days).  No follow-up procedures will be performed for a patient who withdraws informed consent unless she has explicitly 
provided permission and consent.
b Long-term follow up begins the day after short-term follow up is completed and continues every 90 days until the patient’s death or overall study completion.

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Table JPCG.4.
Continued Access Schedule of Activities
Study 
Treatment
Follow-Upa
Visit
501-5XX
901
Procedureb
Comments
Adverse event collection
X
X
CTCAE Version 4.0. Assessments to be 
conducted with each collection and dispensing of 
study drug (every 28 days) from Visits 501-5XX.
Administer study drug
X
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.
a
Continued access follow-up begins 1 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 (± 7 days). No follow-
up will be performed for a patient who withdraws informed consent unless she has explicitly provided permission 
and consent.
b Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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3.
Introduction
3.1.
Study Rationale
Study I3Y-MC-JPCG (JPCG) is a Phase 2 study for patients with previously treated hormone 
receptor-positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) metastatic 
breast cancer (mBC) who have progressed on or after prior endocrine therapy and have 
previously received treatment with at least 2 chemotherapy regimens, of which at least 1 but no 
more than 2 regimens have been administered in the metastatic setting. The study will evaluate 
the potential to enhance the risk/benefit profile of abemaciclib monotherapy, either administered 
at the maximum recommended single-agent dose of 200 mg every 12 hours (Q12H) with primary 
prophylactic antidiarrheal medication, at a lower dose of abemaciclib monotherapy, or in 
combination with endocrine therapy in approximately 225 patients.
3.2.
Background
Breast cancer is the most commonly diagnosed malignancy in women, and the second leading 
cause of cancer deaths in women in the United States (US), with 231,840 new cases of breast 
cancer and 40,290 deaths estimated in 2015 (ACS 2015).  Worldwide, breast cancer is the most 
frequent cancer among women and is a major cause of cancer-related deaths. It is estimated that 
more than 1.67 million new cases of breast cancer occurred worldwide in women in 2012 (Ferlay 
et al. 2015).  According to the National Cancer Institute Surveillance, Epidemiology, and End 
Results database, the 5-year survival rate for women with Stage IV breast cancer is 26%
(Howlader et al. 2015). 
The HR+/HER2- subtype is the most prevalent of breast cancer subtypes and accounts for 
approximately 70% of all breast cancers (Howlader et al. 2014).  Despite the availability of 
endocrine therapies for the treatment of HR+ mBC, most patients ultimately relapse and develop 
acquired endocrine resistance. Patients are generally treated with multiple lines of endocrine 
therapy with the benefit progressively diminishing as resistance develops. When endocrine 
therapy is no longer an appropriate therapeutic option, sequential single-agent cytotoxic 
chemotherapy becomes the standard of care for these patients (Swallow et al 2014). Hormone 
receptor-positive mBC is incurable and therefore considered a serious and life-threatening 
disease, with a median overall survival (OS) of only 2 to 3 years (Cardoso et al. 2012). In 
addition, after progressing on 1 to 2 cytotoxic chemotherapy regimens in the metastatic setting, 
life expectancy is only 12 to 15 months (O’Shaughnessy et al. 2002; Cortes et al. 2011; Krop et 
al. 2014; Kaufman et al. 2015). There is a significant unmet medical need for the development 
of novel agents for the treatment of HR+ mBC in order to improve OS, delay disease 
progression, minimize breast cancer-related symptoms, and/or delay the need for additional 
chemotherapy.
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
proper regulation of cell proliferation (Sherr 1996; Ortega et al. 2002).  Cyclin-dependent kinase 
(CDK) 4 and CDK 6 participate in a complex with the D-type cyclins to initiate progression 
through the G1 restriction point. The CDK 4 and CDK 6 – cyclin D complex regulates the G1 

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restriction point through phosphorylation and inactivation of the retinoblastoma (Rb) tumor 
suppressor protein, thereby promoting S phase entry (Sherr 1996; Ortega et al. 2002).  
Alterations in this pathway occur frequently in human cancers and include 1) loss of functional 
CDK inhibitors through deletion or epigenetic silencing, 2) activating mutations and/or 
overexpression of CDK 4 and CDK 6 or the D-type cyclins, and 3) loss of functional Rb through 
mutation or deletion (Malumbres and Barbacid 2001). Except for tumors with functional loss of 
Rb, which functions downstream of the CDK 4 and CDK 6-cyclin D complex, most cancers are 
potentially sensitive to pharmacologic inhibition of CDK 4 and CDK 6. From a therapeutic 
standpoint, the goal of inhibiting CDK 4 and CDK 6 in HR+ breast cancers is to prevent cell 
cycle progression through the G1 restriction point, thus arresting tumor growth.
Many HR+ breast cancers demonstrate overexpression of cyclin D1, which interacts directly 
with the estrogen receptor (ER) to activate ER target genes (Neuman et al. 1997; Zwijsen et al. 
1997, 1998).  Cyclin D also interacts directly with CDK 4 and CDK 6 in an active protein 
complex that promotes cell proliferation.  Furthermore, endocrine resistance in HR+ breast 
cancer is associated with the deregulation of proliferation-associated genes that are regulated by 
CDK 4 and CDK 6 (Asghar et al. 2015). In addition, 4-hydroxytamoxifen significantly inhibited
cyclin D1-mediated activation of the estrogen receptor (Neuman et al. 1997). Consequently, 
CDK 4 and CDK 6 inhibition represents a potential therapeutic target for HR+ breast cancer and 
dual inhibition of cyclin D1 (by inhibition of CDK 4 and CDK 6) and ER may enhance the 
prevention of cell cycle progression and overcome resistance to endocrine therapy. 
Abemaciclib is a potent and selective small molecule inhibitor of cyclin D-dependent kinases 
CDK 4 and CDK 6, showing some preference for inhibiting cyclin D1/CDK 4 relative to CDK 6 
in enzymatic assays. Abemaciclib prevents Rb phosphorylation, blocking progression from G1 
into S phase of the cell cycle, leading to suppression of tumor growth in preclinical models.  
Abemaciclib demonstrates suitable physical and pharmacokinetic (PK) properties, an acceptable 
toxicity profile in nonclinical species, and antitumor activity in multiple mouse models of human 
cancer. Cell-based studies in breast cancer models have demonstrated that abemaciclib inhibits 
CDK 4 and CDK 6 to induce G1 arrest specifically in cell lines with functional Rb versus lines 
which lack functional Rb.  Additional cell-based studies, which evaluated in vitro growth 
inhibition across a diverse panel of 46 breast cell lines representing the known molecular 
subgroups of breast cancer, indicated that sensitivity to CDK 4 and CDK 6 inhibition was greater 
in ER+ lines with luminal histology.  In ER+ breast cancer cell lines, sustained target inhibition 
with single-agent abemaciclib produces a continuous cell cycle arrest which over time results in 
a loss of replicative potential by inducing senescence or death through apoptosis. In vivo, 
abemaciclib monotherapy dosed daily without interruption at clinically relevant concentrations in 
xenograft models resulted in reduction of tumor size.  Studies in mice bearing ER+ breast cancer 
xenografts with abemaciclib and 4-hydroxytamoxifen showed that the combination of the 2 
agents improved the durability of the antitumor responses when compared to either abemaciclib 
or 4- hydroxytamoxifen alone.
In clinical trials, abemaciclib has induced partial responses and prolonged stable disease for 
patients with HR+ breast cancer (Patnaik et al. 2014; Goetz et al. 2015; Tolaney et al. 2015). In 

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study I3Y-MC-JPBA (JPBA), clinical activity of abemaciclib monotherapy and in combination 
with endocrine therapy was observed in patients with pretreated HR+ breast cancer across dose 
levels. In a cohort of 36 HR+ patients in Study JPBA the overall response rate was 33%. The 
tumors in 26% (7/27) of patients receiving abemaciclib monotherapy responded and 56% (5/9) 
of patients who received concomitant endocrine therapy with abemaciclib experienced a tumor 
response. The impact of starting dose (150 mg [n=25] or 200 mg [n=22]) and continuation of 
previous endocrine therapy (9 of 36 patients) was unclear due to the small sample size and 
nonrandomized design.  However, similar response rates were observed at both doses and 
patients continuing endocrine therapy remained progression free longer than those receiving 
monotherapy (mPFS of 24 months vs mPFS of 5.2 months). Additionally, abemaciclib in 
combination with multiple endocrine therapies demonstrated early evidence of activity against 
HR+ mBC in the ongoing Phase 1b Study I3Y-MC-JPBH (Goetz et al. 2015). One of the 
combinations studied in Study JPBH was abemaciclib plus tamoxifen. Safety and tolerability for 
this combination are described in more detail in Section 5.5.
This Phase 2 study I3Y-MC-JPCG (JPCG) will evaluate the potential to enhance the risk/benefit 
profile of abemaciclib in women with previously treated HR+, HER2- mBC, either administered
in combination with endocrine therapy, at the recommended single-agent dose with primary 
prophylactic antidiarrheal medication, or at a lower starting single-agent dose.
3.3.
Benefit/Risk Assessment
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 [DCSI]) of the IB.  Information on serious adverse 
events (SAEs) expected in the study population independent of drug exposure and that will be 
assessed by the sponsor in aggregate periodically during the course of the study may be found in 
Section 6 (Effects in Humans) of the IB.
More detailed information about the known and expected benefits and risks of tamoxifen may be 
found in the following:  Patient Information Leaflet, Package Insert, or Summary of Product 
Characteristics.

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4.
Objectives and Endpoints
Table JPCG.5 shows the objectives and endpoints of the study.
Table JPCG.5.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the efficacy, in terms of PFS, in patients 
with metastatic breast cancer  for:

Abemaciclib 150 mg Q12H plus tamoxifen

Abemaciclib 150 mg Q12H 

Abemaciclib 200 mg Q12H plus primary 
prophylactic loperamide 
PFS (objective progression or death), as determined by 
investigator assessment per RECIST v1.1
Secondary
To evaluate the efficacy of abemaciclib, monotherapy 
and in combination with tamoxifen, in terms of ORR, 
DoR, and OS 
To assess the safety profile of abemaciclib monotherapy 
and in combination with tamoxifen
To characterize the PK of abemaciclib and its 
metabolites; in addition to tamoxifen and its active 
metabolite endoxifen
To compare self-reported pain, pain interference, 
symptom burden, health status, and overall quality of 
life
Efficacy endpoints will include:

ORR (CR + PR)  based on tumor assessment 
using RECIST v1.1 

DoR (CR+ PR) per RECIST v1.1 

OS
Safety endpoints will include but are not limited to the 
following:

TEAEs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and physical 
examinations
PK parameters for abemaciclib and tamoxifen
Compare self-reported pain, pain interference, symptom 
burden, health status, and quality of life using the mBPI-
sf and EORTC QLQ-C30
Tertiary/Exploratory
To evaluate the associations between biomarkers and 
clinical outcomes
To evaluate the relationship between abemaciclib and
tamoxifen exposure and response 
Efficacy outcomes such as ORR, PFS, and/or OS
Drug exposure and efficacy outcomes such as PFS, OS 
and safety outcomes such as neutropenia and diarrhea
Abbreviations:  CR = complete response; DoR = duration of response; EORTC QLQ-C30 = European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30;  mBPI-sf = modified Brief Pain 
Inventory-short form; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PK 
= pharmacokinetics; PR = partial response; Q12H = every 12 hours; RECIST v 1.1 = Response Evaluation 
Criteria in Solid Tumors Version 1.1; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

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*
5.
Study Design
5.1.
Overall Design
Study I3Y-MC-JPCG is a Phase 2 multicenter, randomized, open-label trial in patients with 
HR+, HER2- mBC who have progressed on or after prior endocrine therapy and have received 
prior treatment with at least 2 chemotherapy regimens, of which at least 1 but no more than 2  
regimens administered in the metastatic setting.
Figure JPCG.1 illustrates the study design.
Abbreviations:  HER2- = human epidermal growth factor receptor 2 negative; HR+ = 
hormone receptor positive; Q12H = every 12 hours; QD = every day.
* For Arm C only. During Cycle 1, prophylactic loperamide (2 mg) will be 
administered orally with the first dose of abemaciclib daily. During Cycle 2 and 
beyond, loperamide will be administered at investigator’s discretion and/or if clinically 
indicated. 
Figure JPCG.1.
Illustration of study design.
5.2.
Number of Patients
Approximately 225 patients will be randomized in a 1:1:1 ratio to abemaciclib 150 mg Q12H 
plus tamoxifen 20 mg every day (QD) or abemaciclib 150 mg Q12H monotherapy; or 
abemaciclib 200 mg Q12H monotherapy plus primary prophylactic loperamide. 
5.3.
End of Study Definition
The primary analysis of the primary endpoint, progression-free survival (PFS), will be performed 
after 110 events have been observed in Arms A and C of the intent to treat (ITT) population. 
This study will be considered complete (that is, the scientific evaluation will be complete [study
completion]) following the evaluation of OS as determined by Lilly.  The first OS analysis will 

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be at the time of PFS analysis. The final analysis of OS will occur 24 months after the last 
patient enters treatment.  Investigators will continue to follow the study schedule for all patients 
until notified by Lilly that study completion has occurred.  End of study refers to the date of the 
last visit or last scheduled procedure for the last patient.
5.4.
Scientific Rationale for Study Design
Study JPCG is a multicenter, randomized, open-label parallel design with 3 separate treatment 
arms. The primary endpoint is to evaluate the efficacy of abemaciclib administered in 
combination with endocrine therapy compared to the efficacy of abemaciclib monotherapy in 
patients with pretreated HR+, HER2- mBC.  The study uses standardized eligibility criteria and 
stratification to facilitate consistency of sample populations. The patients will be randomized 
1:1:1 such that patients in each of the 3 arms will be allocated to receive investigational 
treatment. 
5.5.
Justification for Dose
In Study JPCG, abemaciclib will be administered orally at either 150 mg every 12 hours (Q12H) 
(Arms A and B) or at 200 mg Q12H (Arm C only) on Days 1 through 28 of a 28-day cycle.
In Study JPBA, pRb and topo II α expression in skin biopsies decreased from baseline following 
two weeks of twice daily dosing with both 150 and 200 mg abemaciclib, indicating inhibition of 
CDK 4 and CDK 6 that results in cell cycle inhibition upstream of the G1 restriction point. The 
plasma concentrations achieved by a dose of 150 mg Q12H in Study JPBA were similar to those 
associated with pRb and topo II alpha inhibition and tumor growth inhibition in the Colo-205 
xenograft model (Tate et al. 2014). Study JPBA evaluated abemaciclib monotherapy at multiple 
dose levels in patients with advanced solid tumors. Abemaciclib was administered on a once-
daily treatment schedule at 4 dose levels (50, 100, 150, and 225 mg), and steady state exposures
were only marginally higher than those observed after a single dose. Therefore a twice-daily 
schedule at 75, 100, 150, 200, and 275 mg Q12H was evaluated. 
The maximum tolerated dose (MTD) of single-agent abemaciclib was defined as 200 mg Q12H, 
with the dose-limiting toxicity (DLT) of Grade 3 fatigue. The most common adverse events 
(AEs) experienced by patients receiving abemaciclib included diarrhea and neutropenia, 
predominantly of low grade severity.  However, the incidence and severity of these events 
appears to be dose-dependent.  Approximately 80% of patients who received abemaciclib at 150 
mg Q12H experienced treatment-emergent diarrhea, of which 16% was Grade 2 and 4% was 
Grade 3. Approximately 77% of patients who received abemaciclib at 200 mg Q12H 
experienced treatment-emergent diarrhea, of which 27% was Grade 2 and 18% was Grade 3. No 
Grade 4 diarrhea events were reported.  No patients discontinued study treatment at either 
assigned dose level due to diarrhea.  In Study I3Y-MC-JPBN, an ongoing Phase 2 study of 
single-agent abemaciclib at 200 mg Q12H, the initial onset of diarrhea was observed during the 
first cycle, with a median time to onset for diarrhea of approximately 7 days after initial dosing 
of abemaciclib.  Diarrhea was managed successfully with dose omissions/reductions and
antidiarrheal medication, however further reduction in the incidence and severity of treatment-
emergent diarrhea may be achieved by the administration of primary prophylactic antidiarrheal 

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medication.  Such intervention with concurrent loperamide may increase dose intensity and
further optimize the clinical benefit received by patients. 
Study JPBH is an ongoing Phase 1b dose escalation study of abemaciclib in combination with 
multiple single-agent endocrine therapy options for patients with HR+ mBC. In Study JPBH,
similar safety and tolerability as single-agent abemaciclib was observed for the combination with 
tamoxifen (Part C, N=16). The most common adverse events (AEs) experienced by patients 
receiving abemaciclib plus tamoxifen included diarrhea, leukopenia and neutropenia which are 
predominantly of low grade severity and appear dose-dependent. Approximately, 94% of 
patients who received abemaciclib 200 mg Q12H plus tamoxifen 20 mg QD experienced 
treatment-emergent diarrhea, of which 63% were Grades 1-2 and 31% were Grade 3 (Goetz et al. 
2015). There was no evidence of a PK drug interaction between abemaciclib and tamoxifen
(Goetz et al. 2015). Based on the safety, tolerability, and PK results, the recommended dose for 
further study of abemaciclib for women with breast cancer in clinical trials is 150 mg Q12H 
when administered in combination with endocrine therapy. Therefore, in Study JPCG, 
abemaciclib will be administered orally at 150 mg Q12H in combination with tamoxifen 20 mg 
QD on Days 1 through 28 of a 28-day cycle. 

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Have confirmed HR+, HER2-negative (HER2-) recurrent, locally advanced, 
unresectable, or metastatic breast cancer with evidence of relapse or disease 
progression on or following endocrine therapy.  

To fulfill the requirement for HR+ disease by local testing, a breast 
cancer must express, at least 1 of the hormone receptors (ER or 
progesterone receptor [PgR]).  For ER and PgR assays to be considered 
positive, ≥1% of tumor cell nuclei must be immunoreactive by 
immunohistochemistry (IHC) (Hammond et al. 2010).

To fulfill the requirement of HER2- disease by local testing on most 
recent biopsy, HER2- negative tumor is determined as 
immunohistochemistry score 0/1+ or negative by in situ hybridization 
(FISH/CISH/SISH), as defined in the relevant American Society of 
Clinical Oncology (ASCO)/College of American Pathologists (CAP) 
guidelines (Wolff et al. 2013). 
[2]
Must have received prior treatment with at least 2 chemotherapy regimens:
-
At least 1 of these regimens must have been administered in the 
metastatic setting.
-
The additional chemotherapy regimens could have included, but are 
not limited to any of the following:  capecitabine, eribulin, 
gemcitabine, an anthracycline, vinorelbine, or taxane.
No more than 2 prior chemotherapy regimens in the metastatic setting.
[3]
Have the presence of measureable disease as defined by the Response 
Evaluation Criteria in Solid Tumors (for RECIST 1.1 refer to Appendix 8).  

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[4]
Have adequate organ function for all of the following criteria, as defined 
below:
System
Laboratory Value
Hematologic
ANC
1.5 × 109/L
Platelets
100 × 109/L
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. 
Hepatic
Total bilirubin
1.5 × ULN
ALT and AST
3.0 × ULN 
OR
5 × ULN if liver metastases are present
Renal
Serum creatinine
1.5 × ULN
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; ULN = upper limit of normal.
[5]
Have a performance status ≤1 on the Eastern Cooperative Oncology Group 
(ECOG; Appendix 9) scale (Oken et al. 1982).
[6]
Have discontinued all previous treatments for cancer and recovered from the 
acute effects of therapy.  Patients must have discontinued from previous 
treatments, as shown below:
Previous Treatment
Length of Time Prior to First Dose of Study 
Treatment
Chemotherapy 
21 days for myelosuppressive agents or ≥14 
days for nonmyelosuppressive agents, and 
recovered from the acute effects of therapy 
(treatment-related toxicity resolved to baseline) 
except for residual alopecia or peripheral 
neuropathy.
Investigational therapy
Immunotherapy
Radiotherapy 
Endocrine therapy
14 days and recovered from adverse events 
related to treatment. 
Any number of lines of prior hormone therapy is 
permitted. Patients may have received prior 
tamoxifen in the advanced/metastatic setting. 
Patients receiving tamoxifen immediately 
preceding study entry must have demonstrated 
unequivocal radiological progression for 
eligibility. 
[7]
Are female and ≥18 years of age. 

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[8]
Women of childbearing potential must have a negative serum pregnancy test 
at baseline (within 7 days prior to Cycle 1 Day 1), and agree to use a highly 
effective non-hormonal contraceptive method during the treatment period and 
for 3 weeks following the last dose of abemaciclib. This amount of time may 
be longer depending on the other treatments received during this trial.
Highly effective methods of contraception include the following:

Intrauterine device (IUD)

Bilateral tubal occlusion

Vasectomized partner: Vasectomized partner is a highly effective birth 
control method provided that partner is the sole sexual partner of the woman 
of childbearing potential trial participant and that the vasectomized partner 
has received medical assessment of the surgical success.

Total sexual abstinence: In the context of this guidance, sexual abstinence is 
considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the 
study treatments.  The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject.
If the highly effective contraceptive methods are contraindicated or strictly declined 
by patients, acceptable birth control methods may be considered.  These may include 
the combination of both of the following methods:

Male or female condom with spermicide

Cap, diaphragm, or sponge with spermicide
[9]
Have an estimated life expectancy of ≥12 weeks.
[10] Are willing and able to make themselves available for the duration of the 
study and are willing and able to follow study procedures.
[11] Have given written informed consent prior to any study-specific procedures.  
Refer to Appendix 2 for study governance, regulatory, and ethical 
considerations.
[12] Are able to swallow oral medications.
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[13] Have a personal history of any of the following conditions:  syncope of either 
unexplained or cardiovascular etiology, ventricular arrhythmia (including but 
not limited to ventricular tachycardia and ventricular fibrillation), or sudden 
cardiac arrest.  Subjects with controlled atrial fibrillation for >30 days prior to 
study treatment are eligible. 

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[14] Have history or evidence of central nervous system (CNS) metastasis on the 
MRI of brain obtained at baseline.
[15] Have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in-situ of the cervix or breast), unless in complete remission with 
no therapy for a minimum of 3 years. 
[16] Are pregnant or lactating.
[17] Have active bacterial or fungal infection (that is, requiring IV [intravenous]
antibiotics at the time of initiating study treatment) and/or detectable viral 
infection (for example, human immunodeficiency virus [HIV] positivity or 
known active or inactive hepatitis carrier [for example, hepatitis B surface 
antigen [HBSAg], or hepatitis C antibodies [HCAb]).  Screening is not 
required for enrollment.
[18] Have received prior treatment with any CDK4 and CDK6 inhibitor.
[19] Known hypersensitivity to loperamide hydrochloride or tamoxifen or to any of 
the excipients of either product. 
[20] Have a preexisting chronic condition resulting in baseline Grade 2 or higher 
diarrhea.
[21] 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. 
[22] Are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study.
[23] History or evidence of thromboembolic disease including any of the 
following, history of stroke, deep vein thrombosis (DVT), or pulmonary 
embolism (PE). Patients with documented hypercoagulable state are not 
eligible. 
[24] Are receiving treatment with Warfarin or coumarins.
6.3.
Lifestyle Restrictions
Patients should refrain from drinking grapefruit juice while on study drug.
Patients should not donate blood while on study drug and for 3 months after discontinuing study 
treatment.
Patients must agree to use a highly effective non-hormonal contraceptive method while on study 
drug and for 3 months after discontinuing study treatment (see Section 6.2).
6.4.
Screen Failures
Re-screening of individuals who do not meet the criteria for participation in this study is not 
permitted.

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Repeating of laboratory tests during the 14-day screening period does not constitute re-screening.

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7.
Treatments
7.1.
Treatments Administered
Patients will be randomized to one of the following treatment arms.
Table JPCG.6 shows the treatment regimens.
Table JPCG.6.
Treatment Regimens
Arm
Abemaciclib  
Dose
Tamoxifen
Dose
Treatment
Schedule
Route of Administration
A
150 mg Q12H
20 mg QD
D1 to D28 of a 28-day cycle
Orally
B
150 mg Q12H
NA
D1 to D28 of a 28-day cycle
Orally
Ca
200 mg Q12H
NA
D1 to D28 of a 28-day cycle
Orally
Abbreviations:  Q = every; Q12H = every 12 hours; QD = every 24 hours.
a
Arm C patients only. Prophylactic loperamide 2 mg orally is administered with the first dose of abemaciclib
daily. 
Abemaciclib will be administered orally at the assigned dose level Q12H (± approximately 2 
hours) in each treatment arm, respectively. Abemaciclib capsules should be taken whole and not
opened, crushed, chewed, dissolved in water, or altered in any way and may be taken with or 
without food. If a patient misses a dose, the dose should be omitted. If a patient vomits after 
taking a dose, the dose should not be retaken. Patients will receive either 150 mg of abemaciclib 
orally Q12H in combination tamoxifen (Arm A), 150 mg Q12H of abemaciclib monotherapy
(Arm B), or abemaciclib 200 mg Q12H plus primary prophylactic loperamide (Arm C).
For Arm A, during Cycles 1 through 3, when abemaciclib is scheduled to be administered on the 
same day as tamoxifen and PK samples are drawn, abemaciclib should be given at the same time 
as tamoxifen. 
For Arm C, during Cycle 1, prophylactic loperamide, 2 mg orally, will be administered with the 
first dose of abemaciclib daily. If the daily dose of loperamide is forgotten with the first dose of 
abemaciclib, it should be taken with the second dose of abemaciclib that day or after the first 
loose stool.  Patients may take an additional 2 mg (1 capsule/tablet) dose of loperamide after 
each loose stool up to a maximum of 16 mg (8 capsules/tablets) per day (including doses taken 
with abemaciclib). In the event a patient experiences Grade 2 diarrhea (4 to 6 loose stools per 
day above baseline) despite loperamide prophylaxis, a dose reduction (-1 level ) of abemaciclib 
should be considered before additional doses of loperamide are taken. If diarrhea recurs within 
24 hours despite a dose reduction, additional doses (2 mg each) of loperamide may be taken at 
the investigator’s discretion. Loperamide may be discontinued 28 days after initiation of 
abemaciclib therapy at the investigator’s discretion. Loperamide dose should be omitted if the
abemaciclib dose is omitted for a reason other than diarrhea. Loperamide administration, 
including dose adjustments (increases and/or decreases) and changes for indicated use, will be 
captured on the electronic case report form (eCRF). Additional loperamide dose modifications
are described in Section 7.4.1.1.1.3. 

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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/study site personnel/legal representative

verifying that instructions are followed properly 

maintaining accurate records of study treatment dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless Lilly and the site have agreed all unused medication is to be destroyed by 
the site, as allowed by local law
7.1.1. Packaging and Labelling
Study treatment will be provided as outlined in Section 7.5.  Clinical trial materials will be 
labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomly assigned to either Arm A, Arm B,
or Arm C.
Approximately 225 patients will be randomized in a 1:1:1 ratio.  Randomization will be stratified 
by the presence of liver metastases (yes versus no) and prior tamoxifen therapy in the 
advanced/metastatic setting (yes versus no). 
The interactive web-response system (IWRS) will use randomization factors to assign study 
treatment to each patient.
7.2.1. Selection and Timing of Doses
Abemaciclib will be administered orally at 150 mg (Arms A and B) or 200 mg (Arm C) Q12H 
on Days 1 through 28 of a 28-day cycle (± 3 days).  Details on treatment administration are 
described in Section 7.1. 
Patients will continue to receive study treatment until evidence of disease progression or any 
discontinuation criteria are met (see Section 8).
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
7.4.1. Special Treatment Considerations
7.4.1.1.
Dose Adjustments and Delays

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Table JPCG.7.
Toxicity Dose Adjustments and Delays of Abemaciclib
Toxicity Type
Toxicity Profile and 
Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Section 7.4.1.1.2.1
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be 
reduced by 1 dose 
level - investigator’s 
discretion.
Hematologic Toxicity 
Section 7.4.1.1.2.1
Recurrent Grade 3 
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be 
reduced by 1 dose 
level. 
Hematologic Toxicity 
Section 7.4.1.1.2.1
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be 
reduced by 1 dose 
level.
Hematologic toxicity:  If 
patient requires 
administration of blood cell 
growth factors.
Sections 7.4.1.1.2.1 and 
7.7.2
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  led to the use of 
growth factor 
Nonhematologic Toxicityb
(except diarrhea and ALT 
increased)
Section 7.4.1.1.2.1
Persistent or recurrent Grade 
2 that does not resolve with 
maximal supportive measures 
within 7 days to baseline or 
Grade 1
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
Nonhematologic Toxicity 
Section 7.4.1.1.2.1
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 7.7.1.1  
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 7.7.1.1
Persistent or recurrent Grade 
2 that does not resolve with 
maximal supportive measures 
or any Grade of diarrhea that 
requires hospitalization
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
Diarrhea
Section 7.7.1.1
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 Increased 
Section 9.4.2.1
Persistent or recurrent
a Grade
2 (>3.0-5.0×ULN), or
Grade 3 (>5,0-20.0×ULN)c
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
ALT Increased
Section 9.4.2.1
Grade 4 (>20.0×ULN)
Abemaciclib therapy MUST
be discontinued.
Abemaciclib therapy
MUST be discontinued.
ALT Increased with increased 
total bilirubin, in the absence of 
cholestasis
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN
Abemaciclib therapy MUST 
be discontinued
Abemaciclib therapy
MUST be discontinued

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Abbreviation:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology.
Note:  MUST = mandatory.
a  Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).This does 
not include events in the same class (for example, neutropenia followed by anemia 1 month later).  As a general 
guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences a new 
episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose if the patient 
satisfies the following conditions:

shows stable hematological counts (≤Grade 2) during that timeframe

has absence of any infectious sign or risk factor

is getting benefit from study treatment 
b    Additional guidance for renal and hepatic monitoring is in Section 9.4.2.
c    Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section
9.4.2.1 for additional guidance for hepatic monitoring.
Any questions regarding the dose reduction decision should be discussed with the Lilly clinical 
research physician (CRP).
7.4.1.1.1. Dose Adjustments
7.4.1.1.1.1.
Abemaciclib
Dose adjustments as outlined in Table JPCG.8 are allowed both within a cycle and between 
cycles.  Abemaciclib must be reduced sequentially by one dose level.
For patients requiring dose reduction(s), any re-escalation to a prior dose level is permitted only 
after consultation with the Lilly clinical research physician (CRP).  After re-escalation, 
subsequent dose adjustments should be based on the dose of abemaciclib that the patient is 
currently receiving.
Table JPCG.8.
Dose Adjustments of Abemaciclib
Arm
Dose Adjustment
Oral Dose
Frequency
A and B
0
150 mg
Q12H
1
100 mg
Q12H
2
50 mg
Q12H
C
0
200 mg
Q12H
1
150 mg
Q12H
2
100 mg
Q12H
Abbreviation:  Q12H = every 12 hours.
For Arms A and B, if a patient receiving the 50 mg Q12H dose of abemaciclib requires further 
dose reduction, the patient should be discontinued from study treatment. For Arm C, if a patient 
receiving the 100 mg Q12H dose of abemaciclib requires a further dose reduction, the patient 
should be discontinued from study treatment.  Based on the judgment of the investigator, if a 
patient is receiving clinical benefit from study therapy and requires further dose reduction than

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what is outlined in Table JPCG.8, the investigator must discuss with Lilly CRP prior to further 
dose reduction. 
For Arm A, in the event that abemaciclib must be discontinued due to tolerability, a patient may 
continue to receive tamoxifen at the investigator’s discretion. 
7.4.1.1.1.2.
Tamoxifen (Arm A only)
Dose adjustments for tamoxifen are not planned. If a dose of tamoxifen is forgotten, tamoxifen 
dosing will be continued the following day without change (meaning missed doses will not be 
made up). See Section 7.4.1.1.2.2 for details on dose delays for tamoxifen.
In the event there is evidence of metrorrhagia, rapid gynecological examination should be 
performed according to local institutional standards.  Tamoxifen will be permanently 
discontinued in the event of a thromboembolic episode or atypical hyperplasia of the 
endometrium.
If tamoxifen is permanently discontinued due to tolerability, a patient may continue to receive 
abemaciclib at the investigator’s discretion.  
7.4.1.1.1.3.
Loperamide 
Loperamide will be dispensed via IWRS for all patients in all the arms; however, only patients in 
Arm C should take loperamide prophylactically. Patients in Arms A and B should only take 
loperamide once the patient experiences diarrhea and requires treatment.
For Arm C, during Cycle 1, prophylactic loperamide should be taken with the first dose of 
abemaciclib. Loperamide may be discontinued 28 days after the initiation of abemaciclib 
therapy at the investigator’s discretion. However, if the patient develops diarrhea after 
loperamide discontinuation, loperamide administration should be reinitiated at the investigator’s 
discretion. If abemaciclib dosing is suspended for a reason other than diarrhea, loperamide 
administration should also be suspended and reinitiated when abemaciclib dosing is reinitiated.
If a patient experiences constipation or other symptoms related to loperamide dosing (for 
example, abdominal cramping), the investigator may reduce/stop the patient’s dosing of 
loperamide. If a patient does not have a bowel movement for ≥36 hours, loperamide is to be 
suspended until bowel movements resume.  If loperamide administration resumes, the dose may 
be adjusted (e.g. once every other day) at the investigator’s discretion. Investigators should take 
into account patient’s history and/or risk of constipation when considering increases in
loperamide dosing, more than prophylactic doses taken with abemaciclib.
7.4.1.1.2. Dose Delays and Omission
7.4.1.1.2.1.
Abemaciclib
Table JPCG.9 provides general guidelines for dose delays of abemaciclib.

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Table JPCG.9.
General Dose Delays of Abemaciclib
General Dose Delays
Time Permitted for Delay
Delay of a cycle due to holidays, weekends, bad weather, or other 
unforeseen circumstances
7 days
Toxicity-time for recovery to baseline or at least Grade 1 for 
nonhematologic and at least Grade 2 for hematologic toxicity
Up to 14 days
Both dose suspension (within a cycle) and cycle delay are permitted.  When a dose suspension or 
cycle delay occurs related to toxicity (defined as an AE possibly related to study treatment per 
investigator judgment), abemaciclib and/or tamoxifen (Arm A only) may be suspended or 
delayed as determined by the investigator’s judgment, but only for a maximum of 14 days.
Study treatment may be held up to 14 days within a cycle or at start of next cycle to permit 
sufficient time for recovery from the toxicity.  If a dose suspension occurs within a cycle, the 
investigator may resume study drug dosing at the same dose level for the remainder of the cycle 
or, for abemaciclib only, at a reduced dose (assuming resolution to at least Grade 1 for 
nonhematological and at least Grade 2 for hematological toxicity).  If the patient experiences the 
same toxicity with the same or greater severity (Common Terminology Criteria for Adverse 
Events [CTCAE] grade) requiring a dose suspension within a cycle or at start of the next cycle, 
the patient must be dose reduced for abemaciclib and not re-challenged a second time at the prior 
dose level (see Table JPCG.7).
Patients not recovering from toxicity within 14 days should be considered for discontinuation of 
study treatment.  In exceptional circumstances, a delay >14 days is permitted upon agreement 
between the investigator and the Lilly CRP and abemaciclib dose adjustment is to be considered.
A delay of a cycle due to holiday, weekend, bad weather, or other unforeseen circumstances will 
be permitted for a maximum of 7 days and not counted as a protocol deviation.  In exceptional 
cases of planned delays (including but not limited to vacation or holidays), additional study 
treatment may be dispensed. 
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.
7.4.1.1.2.2.
Tamoxifen (Arm A only)
In the event of the occurrence of Grade 3-4 toxicity related to tamoxifen, tamoxifen dosing 
should be stopped for a maximum of 14 days. If the toxicity improves during this period, 
tamoxifen may be resumed, if possible. If the toxicity does not improve within 14 days or recurs 
upon resumption, tamoxifen should be permanently discontinued. If tamoxifen is permanently 

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discontinued due to tolerability, the patient may continue to receive abemaciclib at the 
investigator’s discretion.
7.5.
Preparation/Handling/Storage/Accountability
Abemaciclib, tamoxifen, and loperamide will be supplied by Lilly and labeled according to
country regulatory requirements. All capsules/tablets should be stored according to their 
associated product label and taken as indicated. Patients should store these agents in the original 
package provided and according to the product label (where applicable) and be instructed to keep 
all medications out of reach of children.
7.6.
Treatment Compliance
Patient compliance with abemaciclib will be assessed by reconciliation at qualified visits (e.g. 
Day 1 of each Cycle).  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 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 (>125%) 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.
Patients randomized to Arm A, will be assessed by authorized study personnel for 
noncompliance of tamoxifen.  All tamoxifen administration data will be recorded in the patient’s 
medical record and eCRF.
Patients randomized to Arm C will be assessed by authorized study personnel for noncompliance 
of prophylactic loperamide only during Cycle 1.  Prophylaxis during Cycle 2 and beyond is at 
the discretion of the investigator. All loperamide administration, including but not limited to
dose adjustments during Cycle 1, will be recorded in the patient’s medical record and eCRF.
7.7.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, concomitant 
medications, and supplements must be captured at each visit in the eCRF.  Concomitant 
medications and supportive care therapies must also be documented at the time of 
discontinuation and at the 30-day short-term follow-up visit.
With the exceptions listed in the sections below,  no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy (with the 
exception of patients randomized to Arm A and receiving combination therapy with tamoxifen), 
radiation, surgery for cancer, or experimental medications will be permitted while patients are on 
study treatment. Megestrol acetate as an appetite stimulant is not permitted.
Patients may remain on concomitant therapy with approved bisphosphonates or approved RANK 
ligand targeted agents (for example, denosumab).  Patients who remain on bone modifying 

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agents are permitted to switch after randomization as long as it is in the absence of disease 
progression, and due to reasons, including but not limited to tolerability. The investigator must 
discuss with Lilly CRP prior to the change.  Patients not currently receiving therapy with bone 
modifying agents are not permitted to start bisphosphonates or RANK ligand targeted agents 
after randomization. 
Abemaciclib is extensively metabolized through oxidation by CYP3A.  In clinical drug 
interaction studies, coadministration of clarithromycin, a strong CYP3A inhibitor, increased 
exposure (AUC) 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). Therefore, grapefruit juice as well as inducers and strong inhibitors of CYP3A should be 
substituted or avoided if possible (Appendix 6).  
The results from in vitro studies in cultured human hepatocytes indicate that abemaciclib and its 
major metabolites, LSN2839567 and LSN3106726, down regulate mRNA of CYPs, including 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A, at clinically relevant 
concentrations.  The mechanism of mRNA down regulation and its clinical relevance are not yet 
understood.  Therefore, care should be taken when coadministering substrate drugs of the above 
CYPs with narrow therapeutic margin (Appendix 6).
Reduced efficacy of tamoxifen has been reported with concomitant usage of some selective 
serotonin reuptake inhibitor antidepressants (for example, paroxetine) in some studies, and 
pharmacokinetic interactions of tamoxifen with CYP2D6 inhibitors have also been reported 
(Stearns et al. 2003; tamoxifen product information). As a reduced effect of tamoxifen cannot be 
excluded, coadministration with potent CYP2D6 inhibitors (for example, paroxetine, fluoxetine, 
quinidine, cinacalcet, or bupropion) should, whenever possible, be avoided.
7.7.1. Supportive Care
Patients should receive full supportive care to maximize quality of life.  Patients will receive 
supportive care based on the judgment of the 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 eCRF.
Guidelines regarding the use of other specific supportive care agents are presented below.
7.7.1.1.
Supportive Management for Diarrhea
At enrollment, patients should receive instructions on the management of diarrhea.  In the event 
of diarrhea, supportive measures should be initiated as early as possible.  These include the 
following:

At the first sign of loose stools, the patient should initiate antidiarrheal therapy, if not 
already receiving such 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. 

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
If diarrhea does not resolve with antidiarrheal therapy within 24 hours to either baseline 
or Grade 1, study drug should be suspended until diarrhea is resolved to baseline or 
Grade 1.

When study drug recommences, dosing should be adjusted as outlined in Table JPCG.7
and Section 7.4.1.1.1.1.
In cases of significant diarrhea, Grade 2 through 4 (Appendix 7), which has not responded to 
interventions as outlined above, if the investigators are considering the addition of steroids to 
treat potential colitis, the sponsor strongly recommends an endoscopic procedure to document 
colitis prior to initiating steroids.
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.
7.7.2. Growth Factor Therapy
Growth factors should not be administered to a patient to satisfy study inclusion criteria.
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2015).  
Dosing of 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.  Following the administration of growth factors, the dose of abemaciclib must be 
reduced by 1 dose level on recommencement, if a dose reduction for the specific event 
necessitating the use of the growth factors has not already occurred.
7.8.
Treatment after the End of the Study
Study completion will occur following the final analysis of overall survival, as determined by 
Lilly.  Investigators will continue to follow the Schedule of Activities (refer to Section 2) for all 
patients until notified by Lilly that study completion has occurred.
7.8.1. Continued Access
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks (Figure JPCG.2).  
Continued access period will apply to this study only if at least 1 patient is still on abemaciclib 
when study completion occurs.  Lilly will notify investigators when the continued access period 
begins.

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Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
During the continued access period, all AEs, SAEs, and abemaciclib exposure will be reported 
on the eCRF at least every 28 days when drug is returned and dispensed. SAEs should be
reported immediately and patients should not wait for a drug return/dispensing visit.  SAEs will 
also be reported to Lilly Global Patient Safety.  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 tests will be at the investigator’s discretion. Lilly 
will not routinely collect the results of these assessments. 
Follow-up procedures will be performed as shown in the Continued Access Schedule of 
Activities (Table JPCG.4).
Abbreviation:  CA = continued access.
Figure JPCG.2.
Continued access diagram.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment in the following circumstances:

the patient is enrolled in any other clinical trial involving an investigational product or 
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 drug
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 drug occurs prior to introduction of the new agent

patient decision
o
the patient requests to be withdrawn from the study or study drug
o
the patient’s designee (for example, parents, legal guardian, or caregiver) requests 
that the patient be discontinued from study treatment

sponsor decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP)

the patient becomes pregnant during the study.  See Section 9.2 regarding regulatory 
reporting requirements on fetal outcome and breastfeeding.

the patient is significantly noncompliant with study procedures and/or treatment

disease progression

unacceptable toxicity
Patients who are discontinued from study treatment will have follow-up procedures performed as 
shown in the Schedule of Activities (Table JPCG.3).
For patients who discontinue study treatment without objectively measured progressive disease, 
continue to evaluate tumor response according to planned tumor assessment schedule by the 
same method used at baseline and throughout the follow-up periods until patient has objective 
disease progression or until the study’s primary analysis of PFS.  After the patient has objective 
disease progression, radiologic tests are no longer required. 
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate 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.

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8.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP

the patient becomes pregnant during the study.  See Section 9.2 regarding regulatory 
reporting requirements on fetal outcome and breastfeeding.

the investigator decides that the patient should be discontinued from the study

the patient requests to be discontinued from the study

the patient’s designee (for example, parents, legal guardian, or caregiver) requests that 
the patient be discontinued from the study.
Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Table JPCG.3).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.
Study site personnel, or an independent third party, will attempt to collect the survival status for 
all randomized patients who are lost to follow-up, including randomized patients who do not 
receive study treatment, within legal and ethical boundaries.  Public sources may be searched for 
survival status information.  If the patient’s survival status is determined, the survival status will 
be documented, and the patient will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect survival status information.

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9.
Study Assessments and Procedures
Section 2 (Table JPCG.1, Table JPCG.2, and Table JPCG.3) provides the Schedule of Activities 
for this study.  
Appendix 3 provides a list of the laboratory tests that will be performed for this study.
Appendix 4 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Efficacy Assessments at Baseline and during Study Treatment
Tumor assessments will be performed at baseline (within 28 days from first dose of study 
therapy) and every 8 weeks (- 7 days) by investigator. The same method of assessment and 
technique used at baseline should be used for each subsequent assessment thereafter.  
Radiological scan of the chest, abdomen, and pelvis is required. See Section 10.3.1 for 
definitions of the efficacy endpoints. All tumor assessment images must be submitted for 
potential central review.
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, magnetic resonance 
imaging (MRI) is also acceptable in certain situations, such as when body scans are indicated or 
if there is a concern about radiation exposure associated with CT.  Intravenous and oral contrast 
is required unless medically contraindicated.
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with intravenous and oral contrast).  A PET scan alone or as part of a PET-CT 
may be performed for additional analyses but cannot be used to assess response according to 
RECIST v.1.1 (Eisenhauer et al. 2009).
For only those patients with bone lesions identified by bone scintigraphy at baseline, directed 
imaging using one of the following methods will be performed at baseline:  X-ray, CT scan with 
bone windows, or MRI.  Directed imaging using the same method as at the baseline bone lesion 
assessment should be repeated every 8 weeks (-7 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 8 weeks (-7 business days), and within 14 days of clinical progression.  Each 
photographic image of the tumor should include a ruler.  Photographic images may be taken 

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more frequently based upon the discretion of the investigator or following the identification of 
new skin lesions postbaseline.
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.
9.1.2. Efficacy Assessments during Postdiscontinuation Follow-up
Tumor assessments will be performed within 14 days of clinical progression and during 
postdiscontinuation follow-up as described in the Schedule of Activities (see Section 2). 
For those patients who discontinue study treatment without objectively measured PD, the 
investigative sites will continue to monitor patients and periodically evaluate tumor response via 
radiological imaging and measurement of visible tumors (if applicable) approximately every 8 
weeks from the first dose of study therapy by the same method used at baseline and throughout 
the study until the patient has objective disease progression or until primary analysis of PFS. In 
addition, anticancer therapies initiated after study treatment discontinuation will be collected 
during this follow-up period.  After the patient has objective disease progression, radiologic tests 
and tumor assessments are no longer required and the patient will continue with 
postdiscontinuation follow-up approximately every 90 days until the patient’s death or overall 
study completion. For patients with nonmeasurable bone lesions identified at baseline, bone 
scans are to be performed approximately every 24 weeks until objective disease progression or 
primary PFS analysis.
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 (see 
Section 7.8.1).
9.1.3. Appropriateness of Assessments
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials.
9.2.
Adverse Events
The investigator will use Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 (NCI 2009) to assign AE terms and severity grades.
Investigators are responsible for:

monitoring the safety of patients in 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 appropriate medical care of patients during the study

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study treatment or the study, or that caused 

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the patient to discontinue study treatment before completing the study.  The patient 
should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  Frequency of follow-up evaluation is left to the 
discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, study site personnel 
will record via eCRF any change in the preexisting conditions and any new conditions as AEs.  
Investigators should record their assessment of the potential relatedness of each AE to study 
procedure or study treatment via eCRF. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies. A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuations that result 
from AEs to Lilly or its designee via eCRF, clarifying, if possible, the circumstances leading to 
the dose modification or discontinuation of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from 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 serious, based upon appropriate medical judgment.
In addition to the above criteria, AEs meeting either of the below criteria, although not serious 
per International Conference on Harmonisation (ICH) definition, are reportable in the same 
timeframe as SAEs to meet certain local requirements.
Therefore, these events are considered serious for collection purposes:

is a new cancer (that is not a condition of the study);

is associated with an overdose.

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Although all AEs after signing the ICF are recorded in the eCRF, SAE reporting begins after the 
patient has signed the ICF and has received study treatment.  However, if an SAE occurs after 
signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedure.
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly approved method.  If alerts are issued via telephone, they are 
to be immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported.  However, to fulfill regulatory requirements any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of 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.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment.
9.2.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to 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.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if she has a complaint or 
problem with the investigational product so that the situation can be assessed.

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9.3.
Treatment of Overdose
Refer to the IB and/or Product Label (abemaciclib and/or tamoxifen [Arm A only]).
9.4.
Safety
9.4.1. Other Safety Measures
For each patient, electrocardiograms (ECGs), vital signs, laboratory tests, or other tests should be 
collected as shown in the Schedule of Activities (Section 2).  
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 
performed locally.  If local laboratory tests are used for this purpose, then a duplicate specimen 
must be submitted to the central laboratory.  Discrepancies between local and central laboratory 
that may have an impact on eligibility or treatment decisions will not be considered protocol 
deviations.
Investigators must document their review of each laboratory safety report.
Any clinically significant findings that result in a diagnosis and that occur after the patient signs
the informed consent form (ICF) should be reported to Lilly or its designee as an AE via eCRF.
9.4.2. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.2.1.
Special Hepatic Safety Data Collection
If a study patient experiences elevated alanine aminotransferase (ALT) 5-fold the upper limit of 
normal (ULN) and elevated total bilirubin (TBL) 2-fold ULN, or ALT >8x ULN for patients 
with underlying baseline hepatic metastases, liver tests (Appendix 5), including ALT, AST, TBL, 
direct bilirubin, gamma glutamyl transferase (GGT), and creatine phosphokinase (CPK), should 
be repeated within 3 to 5 days to confirm the abnormality and to determine if it is increasing or 
decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring should be 
initiated by the investigator, based on the hepatic monitoring tests (Appendix 5) and in 
consultation with the Lilly CRP.  Monitoring of ALT, AST, and TBL should continue until 
levels normalize or return to approximate baseline levels.  Additional diagnostic testing should 
be considered to rule out cause of increased liver enzymes per the investigator’s discretion.
Hepatic monitoring tests (Appendix 5) should be collected in the event that 1 or more of the 
following conditions is met for the patient during the course of the study:

ALT ≥5×ULN and TBL ≥2×ULN

ALT>8x ULN for patients with underlying hepatic metastasis

discontinuation from study treatment due to a hepatic event or an abnormality of liver 
tests.

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9.4.2.2.
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. See Appendix 3.
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 JPCG.7).
9.4.2.3.
Venous Thromboembolic Events
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
venous thromboembolic events (VTEs) in the abemaciclib plus endocrine therapy arm than in the 
placebo plus endocrine therapy arm. The majority of the events were non-serious and were 
treated with low-molecular-weight heparin.  Generally, these events did not result in 
discontinuation of the study treatment. At this time, the mechanism underlying the association 
between abemaciclib and the occurrence of VTEs is not known.  For suspected or confirmed 
VTE (eg. deep vein thrombosis or pulmonary embolism), treatment should occur according to 
usual clinical practice.
9.5.
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected as shown in Appendix 4.
Blood samples will be used to determine the concentrations of abemaciclib and its metabolites in 
addition to tamoxifen and its active metabolite endoxifen.
Bioanalytical samples collected to measure abemaciclib and its metabolites or tamoxifen and its 
metabolite endoxifen concentrations will be retained for a maximum of 1 year following the last 
patient visit for the study.
9.6.
Pharmacodynamics
See Section 9.8.
Samples collected will be identified by the patient number (coded) and retained at a facility 
selected by Lilly for a maximum of 15 years following the last patient visit for the study. 
9.7.
Pharmacogenomics
9.7.1. Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in Appendix 
4, where local regulations allow.

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Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to study treatment
and to investigate genetic variants thought to play a role in cancer.  Assessment of variable 
response may include evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  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 ethical review boards (ERBs)/institutional review boards (IRBs) impose 
shorter time limits, at a facility selected by Lilly or its designee.  This retention period enables 
use of new technologies, response to questions from regulatory agencies, and investigation of 
variable response that may not be observed until later in the development of abemaciclib or after 
abemaciclib becomes commercially available.
Molecular technologies are expected to improve during the 15 year storage period and therefore 
cannot be specifically named.  However, existing technologies include whole genome and exome 
sequencing, genome-wide association studies, multiplex assays, candidate gene studies, and 
epigenetic analyses.  Regardless of the technology utilized, data generated will be used only for 
the specific research scope described in this section.
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics (PD), mechanism of action, variability of patient response 
(including safety), and clinical outcome.  Sample collection is incorporated into clinical studies 
to enable examination of these questions through measurement of biomolecules including 
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and 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, cell cycle, 
immune response/functioning, and /or cancer, and/or for related research methods or validation 
of diagnostic tools or assays.
Samples for biomarker research will be collected as specified in Appendix 4, where local 
regulations allow. It is possible that biomarker data for patients in the study has already been 
generated from samples that were collected and analyzed prior to enrolling in this trial. This 
may include data generated from genetic analyses. If available, these data may be requested 
from medical records for use in the research described in Sections 9.8.1 and 9.8.2.
9.8.1. Samples for Nonpharmacogenetic Biomarker Research
Plasma samples for nonpharmacogenetic biomarker research will be collected as specified in 
Appendix 4 where local regulations allow.

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Samples will be examined for biomarkers related to cancer, variable response to abemaciclib or 
study treatment, the mechanism of action of abemaciclib, immune response/functioning, and/or 
for research-related methods, or validating diagnostic tools or assays.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.
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/IRBs impose shorter time limits, at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in the development of abemaciclib or after abemaciclib becomes 
commercially available.
9.8.2. Tissue Samples for Research
Tumor tissue will be examined for biomarkers related to cancer, abemaciclib, immune 
response/functioning, and/or cell cycle. 
Collection of the following tumor tissue sample is required for all patients in order to participate 
in this study:

an archived tumor sample, if available and not restricted by local regulations
The absence of available archived tumor specimen does not preclude a patient from study entry.
Formalin-fixed paraffin-embedded tumor tissue obtained from the primary tumor or metastatic 
site should be provided as a block or unstained slides.  Due diligence should be used to make 
sure that tumor sample (not a normal adjacent or a tumor margin sample) is provided.  Pathology 
report 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.  Archival blocks will be sectioned 
and returned to the study site, at the end of the study. Slides and tissue samples collected on-
study will not be returned.
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/IRBs impose shorter time limits, at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in the development of abemaciclib or after abemaciclib becomes 
commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  However, existing technologies, including mutation profiling, copy number 
variability, gene expression, multiplex assays, and/or immunohistochemistry may be performed 
on these tissue samples to assess potential associations with these biomarkers and clinical 
outcomes.

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9.9.
Health Outcomes/Quality of Life
Self-reported questionnaires will be administered as shown in the Schedule of Activities (Section 
2) in countries where the questionnaires have been translated into the native language of the 
region and are linguistically validated.
The primary health outcomes research goal is to determine if abemaciclib therapy is able to 
palliate pain, as measured by the modified Brief Pain Inventory-Short Form (mBPI-sf).  
Additionally, the EORTC Quality of Life Questionnaire Core-30 version 3 (EORTC QLQ-C30) 
will assess the broader impact of abemaciclib therapy on quality of life.
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 Schedule of Events (Section 2), a paper copy of each 
questionnaire should be administered to the patient prior to extensive interaction with site staff.  
The mBPI-sf should be collected first, followed by the EORTC QLQ-C30.
9.9.1. Pain Assessment
The mBPI-sf (Cleeland and Ryan 1994) 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, 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 10 (pain as bad as you can imagine or
completely interferes).  The mBPI-sf recall period is 24 hours and typical completion time for 
this instrument is less than 5 minutes.
Use of pain medication will be assessed in conjunction with the mBPI-sf assessment.  Data on 
each individual prescription and over-the-counter analgesic at the baseline visit will be recorded 
on the Concomitant Medication page.  The use of pain medications should be reviewed with the 
patient at each subsequent visit.  Any changes to analgesic use (new or stopped analgesics) 
compared to the preceding cycle should be recorded on Concomitant Medication page.  
9.9.2. Health-Related Quality of Life
Broadly used in cancer trials, validated, and available in over 80 different languages, the EORTC 
QLQ-C30 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)

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The EORTC QLQ-C30 questionnaire is administered per the Schedule of Events (Section 2).  
The recall period is the past week and completion time is typically 5 to 7 minutes.
9.9.3. Resource Utilization
Utilization data overall and by arm will be summarized descriptively by category (for example, 
transfusions, antidiarrheals, and hospitalization days) as appropriate.

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10. Statistical Considerations
10.1. Sample Size Determination
The primary objective of PFS will be tested at an experiment-wise one-sided alpha level of .10.  
Assuming a hazard ratio (HR) of .667 for Arm A compared to Arm C (corresponding to an 
increase in mPFS from approximately 6 months to 9 months), approximately 110 events across 
the two arms are required to achieve approximately 80% power.  Assuming 30% censoring, 75 
patients per arm will be enrolled (225 patients total).  
The informal non-inferiority rule for comparing Arm B to Arm C is as follows: if the observed 
PFS hazard ratio is less than 1.2, Arm B will be considered non-inferior to Arm C. Assuming 
110 events across the 2 arms, this design provides 80% probability to show the PFS HR is less 
than 1.2, assuming a true HR = 1. 
The study will enroll approximately 225 patients in a 1:1:1 randomization (approximately 75
patients per treatment arm for women with previously treated HR+, HER2- mBC).  
10.2. Populations for Analyses
The following populations will be defined for this study:
Intention-to-Treat (ITT) population: will include all randomized patients.  The ITT analysis 
of efficacy data will consider allocation of patients to treatment groups as randomized and not by 
actual treatment received.  This population will be used for all baseline, efficacy, and health 
economics analyses. 
Safety population:  will include all randomized patients who received any quantity of study 
treatment, regardless of their eligibility for the study.  The safety evaluation will be performed 
based on the first dose of study treatment a patient actually received, regardless of the arm to 
which she was randomized.  The safety population will be used for all dosing/exposure, safety, 
and resource utilization analyses.
Pharmacokinetic population:  will include all randomized patients who received at least 1 dose 
of study treatment and have at least 1 postbaseline evaluable PK sample.
Biomarker population:  will include all randomized patients with evaluable baseline blood, 
plasma, or tissue samples. Patients with postbaseline samples will be a subset of this defined 
biomarker population. 
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Unless otherwise stated, all tests of treatment effects will be conducted at a 1-sided alpha level of 
.025, and all confidence intervals (CIs) will be given at a 2-sided 95% level.  The primary 
objective of PFS and secondary objective of OS will be tested at an experiment-wise one-sided 
alpha level of .10.

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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.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report.  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
10.3.1. Efficacy Analyses
10.3.1.1. Progression Free Survival
The primary endpoint of this study is PFS.  PFS time is measured from the date of randomization 
to the date of investigator-determined objective progression as defined by RECIST v1.1, or death 
from any cause.  Patients who have neither progressed nor died will be censored at the day of 
their last radiographic tumor assessment (if available) or date of randomization if no post 
initiation (that is, postbaseline) radiographic assessment is available.  The detailed censoring 
rules are described in Table JPCG.10.
Table JPCG.10.
PFS Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate radiological assessment 
or date of randomization (whichever is later)b
Unless
No baseline radiological tumor assessment 
available
Censored
Date of randomization
No adequate postbaseline radiological 
tumor assessment available and death 
reported after 2 scan intervals following 
randomizationb,c
Censored
Date of randomization
New anticancer treatment started and no 
tumor progression or death within 14 days
Censored
Date of adequate radiological assessment 
prior to (start of new therapy +14 days) or 
date of randomization (whichever is later)
Tumor progression or death documented
after 2 or more scan intervals following last 
adequate radiological tumor assessment or 
randomization (whichever is later)b,c
Censored
Date of last adequate radiological assessment 
or date of randomization (whichever is later)b
Abbreviations:  CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; SD = stable disease.
a
Symptomatic deterioration (that is, symptomatic progression that is not radiologically confirmed) will not be 
considered as tumor progression.
b
Adequate radiological tumor assessment refers to an assessment with one of the following responses:  CR, PR, 
SD, or PD.
c
Refer to the statistical analysis plan for the definition of 2 scan intervals, including any adjustment for scan 
window.  
There is one planned primary analysis for PFS in this study, which will be performed after 110
events have been observed in Arms A and C of the ITT population based on investigator 

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assessment.  The PFS analysis to test the superiority of abemaciclib plus tamoxifen (Arm A) to 
abemaciclib plus prophylactic loperamide (Arm C) in improving PFS time will be performed on 
the ITT population at an experiment-wise one-sided alpha level of .10 and will use the log-rank 
test stratified by the randomization factors of presence of liver metastases and prior use of 
tamoxifen in the advanced/metastatic setting.  The corresponding hazard ratio (HR) between 
treatment arms will be estimated using a stratified Cox regression model (Cox 1972), stratified 
by the randomization strata.  An additional unstratified Cox regression model will be employed 
to explore the effects of the stratification variables on treatment response.  In addition, the 
Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the PFS curves as well 
as PFS rates at 3, 6, 9, and 12 months for each treatment group.  These rates will be compared 
based on a normal approximation for the difference between the rates.
Arm B (abemaciclib 150 mg) will be compared against Arm C (abemaciclib 200 mg + 
prophylactic loperamide) in an informal manner.  If the PFS HR is less than 1.2, Arm B will be 
considered non-inferior to Arm C (“informal Phase 2 non-inferiority”).  This comparison will use 
the same methodology described above. Arm A will not be compared against Arm B using a 
log-rank test or Cox HR model, but the Kaplan-Meier estimates for Arms A and B will be 
available from the previous analyses.
10.3.1.2. Objective Response Rate, DCR, CBR, and DoR
Other secondary efficacy endpoints will be defined as shown in Table JPCG.11.
Table JPCG.11.
Other Secondary Efficacy Endpoints
Endpoint
Definition
ORR
The proportion of patients with CR or PR according to RECIST v1.1
DCR
The proportion of patients with CR, PR, or SD according to RECIST v1.1
CBR
The proportion of patients with CR, PR, or SD ≥6 months according to RECIST v1.1
DoR
The time from the date of first evidence of a CR or PR to the date of objective progression or death 
from any cause, whichever is earlier
Abbreviations:  CBR = clinical benefit rate; CR = complete response; DCR = disease control rate; DoR = duration 
of response; ORR = objective response rate; PD = progressive disease; PR = partial response; RECIST v 1.1 
= Response Evaluation Criteria in Solid Tumors Version 1.1; SD = stable disease.
The objective response rate (ORR), disease control rate (DCR), and clinical benefit rate (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.
The duration of response (DoR) time is defined only for responders (patients with a best 
response of complete response [CR] or partial response [PR]).  A Kaplan-Meier analysis of DoR 
will be performed to estimate the DoR curve for each arm.
10.3.1.3. Overall Survival
Overall survival is defined as the time from randomization until death from any cause.  If the 
patient is alive or lost to follow-up at the time of data analysis, OS data will be censored on the 

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last date the patient is known to be alive.  The first OS analysis will be at the time of the PFS 
analysis.  The final analysis of OS will occur 24 months after the last patient enters treatment.
Overall survival will be compared between treatment arms using a stratified log-rank test, 
stratified by the randomization strata.  The corresponding hazard ratio (HR) between treatment 
arms will be estimated using a stratified Cox regression model (Cox 1972), stratified by the 
randomization strata. Overall survival curves, the median OS time, and survival rates at every 6
months up to 24 months for each treatment arm will be estimated using the Kaplan-Meier 
method (Kaplan and Meier 1958).
10.3.2. Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.0 will serve as the reference document for choosing appropriate terminology for, 
and grading the severity of, all AEs and other symptoms.  For AEs without matching 
terminology within the NCI -CTCAE v 4.0 criteria, the investigator will be responsible for 
selecting the appropriate system organ class and assessing severity grade based on the intensity 
of the event.
Both the CTCAE code and the AE verbatim text will be mapped by Lilly or its designee to 
corresponding terminology within the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 18.1 (or higher). Adverse events will be reported using a process which includes both 
CTCAE v4.0 and MedDRA:

In CTCAE version 4.0, 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 v4.0 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (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.

All listings and summaries will use the PT resulting from this process.  The LLT will be 
used in the treatment-emergent computation.

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The following safety analyses will be based on the safety population. Safety analyses will be 
conducted by treatment arm and will include summaries of the following:

AEs, including severity and possible relationship to study drug

SAEs, including possible relationship to study drug

AEs leading to dose adjustments

discontinuations from study treatment due to AEs or death

treatment-emergent abnormal changes in laboratory values

treatment-emergent abnormal changes in vital signs 

extent of exposure
10.3.3. Other Analyses
10.3.3.1. Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as reasons for discontinuation from study treatment and reasons for discontinuation from 
study.  A summary of all important protocol deviations will be provided.
10.3.3.2. Patient Characteristics
Patient characteristics at baseline will be summarized by treatment arm:

Patient demographics 

Baseline disease characteristics 

Historical illnesses 

Prior anticancer therapy 
Other patient characteristics will be summarized as deemed appropriate
10.3.3.3. Concomitant Therapy
A summary of prior and concomitant medications by treatment arm will be reported.
10.3.3.4. Poststudy-Treatment-Discontinuation Therapy
The numbers and percentages of patients receiving poststudy-treatment-discontinuation 
anticancer therapies will be provided by type of therapy (surgery, radiotherapy, or systemic 
therapy), and by drug class and/or name, overall and by line of therapy.
10.3.3.5. Treatment Compliance
The number of cycles received, dose omissions, dose reductions, dose intensity, and treatment 
compliance will be summarized for all treated patients by treatment arm.
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed.  The 
expected cumulative dose to be taken will be determined based on the assigned dose and taking 
into account any dose reductions or omissions.  Treatment compliance will be measured as a 
percentage of the actual cumulative dose divided by the expected cumulative dose.

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10.3.3.6. Pharmacokinetic/Pharmacodynamic Analyses
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib 
and have evaluable PK samples and sufficient dosing information.
Mean population PK parameters for abemaciclib in plasma (for example, clearance, exposure, 
volume of distribution,) and inter-individual PK variability will be computed using nonlinear 
mixed effect modelling (NONMEM).  
Likewise, and if warranted by the data, mean population PK parameters for tamoxifen and 
endoxifen  in plasma and interindividual variability estimates will also be computed using 
nonlinear mixed-effect modelling implemented in NONMEM.
The observed concentrations of abemaciclib, tamoxifen, and their respective metabolites may be 
summarized by time and dose.
PD samples will be collected as specified in the Study Schedule and PK and PD Sampling 
Schedule (cross reference).  Refer to these attachments (including footnotes) for important 
information about these samples and their collection.  
Furthermore, PD data (such as neutrophil, lymphocyte, or platelet counts in blood) collected in 
this study may also be analyzed by means of NONMEM and connected to the population PK 
model in a PK/PD model.
PD data from all patients undergoing PD assessments will be analyzed.  The PD data will be 
combined and exploratory analyses will be conducted to determine if a relationship exists 
between plasma concentration and PD effect(s) in humans.  Interpatient variability in human PD 
response may also be assessed.
10.3.3.7. Biomarker Analyses
Biomarker analyses will be based on the subset of patients from the above cohorts from whom a 
valid assay result (according to laboratory guideline) has been obtained. Exploratory correlative 
analyses will be performed to investigate associations between biomarkers and clinical endpoints 
as deemed appropriate.
10.3.3.8. Health Outcome/Quality of Life Analyses
Patient-reported outcomes are measured through paper versions of the following: 

mBPI-sf (modified Brief Pain Inventory, Short Form)

EORTC QLQ-C30 (The European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30)
Descriptive statistics will be calculated for patient-reported data for each instrument.  
Comparisons between arms will be made for pain, pain interference, functional scales (physical, 
role, emotional, cognitive, and social), other disease symptoms, health status, and overall quality 
of life. The number of missing and incomplete questionnaires/assessments by visit will be 
summarized for each instrument, including the reason not completed.

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Exploratory analysis may be performed to investigate associations between patient-reported data 
(mBPI-sf and EORTC QLQ-C30) and additional clinical efficacy and/or utilization measures as 
appropriate.
Further analysis details will be described in the SAP.
10.3.3.9. Healthcare Resource Utilization
Utilization data overall and by study treatment arm will be summarized descriptively by category 
(for example, transfusions and hospitalization days) as appropriate.
Exploratory analyses may be performed to investigate associations between the utilization data 
and the clinical endpoints.
10.3.4. Subgroup Analyses
A prespecified list of subgroups will be identified in the SAP.  The treatment effect within each 
subgroup will be summarized. Other subgroup analyses not specified in the SAP may be 
performed as deemed appropriate.  These subgroups will be based on important characteristics, 
for example, prognostic significance. 
10.3.5. Interim Analyses
There are no planned interim analyses.

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11. References
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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 
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Krop I, Winer E. 1st International consensus guidelines for advanced breast cancer (ABC 1). 
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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. 
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F. Cancer incidence and mortality worldwide: sources, methods and major patterns in 
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Edenfield WJ, Richards DA, Turner PK, Cai N, Chan EM, Pant S, Becerra CH, Kalinsky K, 
Puhalla SL, Rexer BN, Burris HA, Tolaney SM. Abemaciclib, an inhibitor of CDK4 and 
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Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, 
Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, 
Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, 
Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff 
JL, Wolff AC. American Society of Clinical Oncology/College of American Pathologists 
guideline recommendations for immunohistochemical testing of estrogen and progesterone 
receptors in breast cancer. J Clin Oncol. 2010;28(16):2784-2795.
Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, Cronin KA. US incidence of 
breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 
2014;106(5). 
Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, 
Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER 
Cancer Statistics Review, 1975-2012. Bethesda, MD:  National Cancer Institute. Available at: 
http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, 
posted to the SEER web site, April 2015.  Accessed on February 1, 2016.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481.
Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus 
CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine 
in patients with locally advanced or metastatic breast cancer previously treated with an 
anthracycline and a taxane. J Clin Oncol. 2015;33(6):594-601. 
Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, 
Wildiers H; TH3RESA study collaborators. Trastuzumab emtansine versus treatment of 
physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a 
randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(7):689-699. 
Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev 
Cancer. 2001;1(3):222-231.
Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy 
SF, Brown M, Ewen ME. Cyclin D1 stimulation of estrogen receptor transcriptional activity 
independent of cdk4. Mol Cell Biol. 1997;17(9):5338-5347.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 
1982;5:649-655.
Ortega S, Malumbres M, Barbacid M. Cyclin-D dependent kinases, INK4 inhibitors and cancer. 
Biochim Biophys Acta. 2002;1602:73-87.
O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, 
Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior 
survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated 
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Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, 
Beeram M, Rasco DW, Myrand SP, Kulanthaivel P, Andrews JM, Frenzel M, Cronier D, Chan 
EM, Flaherty K, Wen PY, Shapiro G. LY2835219, a novel cell cycle inhibitor selective for 
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Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. 
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http://jco.ascopubs.org/content/early/2015/07/08/JCO.2015.62.3488.full.  Accessed 
October 01, 2015.
Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, 
Flockhart DA. Active tamoxifen metabolite plasma concentrations after coadministration of 
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Swallow E, Zhang J, Thomason D, Tan RD, Kageleiry A, Signorovitch J. Real-world patterns of 
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Curr Med Res Opin. 2014;30(8):1537-1545. 
Tate SC, Cai S, Ajamie RT, Burke T, Beckmann RP, Chan EM, De Dios A, Wishart GN, Gelbert 
LM, Cronier DM. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the 
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Puhalla SL, Rexer BN, Burris HA, Goetz MP.  A phase Ib study of abemaciclib with therapies 
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Appendix 1. Abbreviations and Definitions
Term
Definition
AE
Adverse event:  any untoward medical occurrence in a patient or clinical investigation 
patient 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
blinding
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment.  
CAP
College of American Pathologists
CBR
clinical benefit rate
CDK
cyclin-dependent kinase
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
collection database
a computer database where clinical trial data are entered and validated.
CR
complete response
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
DCR
disease control rate
DoR
duration of response
ECG
electrocardiogram
eCRF
electronic case report form
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.

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EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
ER
estrogen receptor
ERB/IRB
ethical review board/institutional review board
GCP
good clinical practice
HER2-
human epidermal growth factor receptor 2 negative
HIV
human immunodeficiency virus
HR
hazard ratio
HR+
hormone receptor positive
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
Interim analysis
An interim analysis is an analysis of clinical trial data conducted before the final 
reporting database is created/locked.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
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.
IVRS/IWRS
interactive voice-response system/interactive web-response system
LLT
lower level term
mBC
metastatic breast cancer
mBPI-sf
modified Brief Pain Inventory-short form

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MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PT
Preferred Term
Q12H
every 12 hours
QD
every day 
randomize
the process of assigning patients to an experimental group on a random basis
RANK-L
receptor activator of nuclear factor kappa-B ligand
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SOC
System Organ Class
SUSARs
suspected unexpected serious adverse reactions 
TEAE
Treatment-emergent adverse event:  an untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.

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TBL
total bilirubin
ULN
upper limit of normal
VTE
venous thromboembolic event
women of child 
bearing potential 
(WOCBP)
Fertile, following menarche and until becoming postmenopausal, unless permanently 
sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy.

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Appendix 2. Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any study procedures and prior to the administration of study treatment.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial.
Ethical Review
Documentation of ERB/IRB approval of the protocol and the ICF must be provided to Lilly
before the study may begin at the investigative site(s).  Lilly or its representatives must approve 
the ICF, including any changes made by the ERBs/IRBs, before it is used at the investigative 
site(s).  All ICFs must be compliant with the ICH guideline on GCP.
The study site’s ERBs/IRBs should be provided with the following:

the current IB and updates during the course of the study

the ICF

relevant curricula vitae
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 

applicable ICH GCP Guidelines

applicable laws and regulations.
Some obligations of Lilly may be assigned to a third-party organization.
Investigator Information
Licensed physicians specializing in oncology will participate as investigators in this clinical trial.
Protocol Signatures
Lilly’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.

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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.
Final Report Signature
The investigator will sign the final clinical study report for this study, indicating agreement, to 
the best of his or her knowledge, with the analyses, results, and conclusions of the report.
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.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the clinical study report coordinating investigator.
The Lilly responsible medical officer and statistician will 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.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide Lilly, 
applicable regulatory agencies, and applicable ERBs/IRBs with direct access to original source 
documents.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into Lilly provided electronic data capture system.

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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 data 
warehouse.
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, MDASI) or a participant diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the 
ERB/IRB of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 3. Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology - central laboratory a
Leukocytes (WBC)
Erythrocytes (RBC)
Neutrophilsb
Hemoglobin (HGB)
Lymphocytes
Hematocrit (HCT)
Monocytes
Mean corpuscular volume (MCV)
Eosinophils
Mean corpuscular hemoglobin concentration (MCHC)
Basophils
Platelets (PLT)
Chemistry - central laboratory (except as indicated) a
Serum Concentrations of:
Alanine aminotransferase (ALT)
Calcium
Albumin
Chloride
Alkaline phosphatase
Creatinine
Aspartate aminotransferase (AST)
Potassium
Bilirubin, direct
Protein, total
Bilirubin, total (TBL)
Sodium
Blood urea nitrogen (BUN) or blood urea
Triglycerides (Arm A only)c
Renal panel - central laboratory
Cystatin-C
Pregnancy Test (for female patients of childbearing potential) - local laboratory
Serum pregnancy test d
Abbreviations:  CRF = case report form; RBC = red blood cells; WBC = white blood cells.
a
Treatment decisions may be based on local laboratory results.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. When a manual differential is needed to report the neutrophils, the segmented and band forms should 
reported together.
c
Arm A only. Triglycerides will be evaluated every other cycle starting with Cycle 2 until Cycle 6, and then 
every third cycle thereafter until treatment discontinuation.  
d
Additional serum pregnancy tests may be performed locally, on Day 1 (or up to 3 days before Day 1) of every 
cycle beginning with Cycle 2 and at short term follow up for women of child bearing potential if mandated by 
local country regulations.

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Appendix 4. Sampling Schedule for Genetics/ 
Biomarkers/ Pharmacokinetics/ Pharmacodynamics
It is essential that the exact time of dose administration is recorded.  The exact time of collection 
of each venous blood sample will be based on the time of study drug administration.  
Pharmacokinetic sampling windows are provided as guidance.  Due to practical and logistical 
concerns, some deviation from the specified sampling time is normal and expected.  Sites should 
keep in mind that drawing the sample and recording the actual time on the appropriate form is of 
primary importance.  Differences from the time specified in the protocol are not considered 
protocol deviations as long as samples are collected and accurate dates and times are recorded in 
a timely manner on the appropriate forms.
Sampling Schedule for Genetics/Biomarkers/ Pharmacokinetics/Pharmacodynamics
Procedure
Baseline/Cycle 1
Cycle 2
Cycle 3
Short-Term 
Follow up 
Pharmacokineticsa
C1D1: any time after 
abemaciclib dosing
C1D15: any time after  
abemaciclib dosing
C2D1: any time after  
abemaciclib dosing
C2D15: any time after  
abemaciclib dosing
C3D1: any time after  
abemaciclib dosing
Archived Tumor 
tissueb
Obtain archived tumor 
block or cut unstained 
positively charged slides 
after eligibility is 
confirmed. 
Plasma (Biomarker)
C1D1:  before dosing of 
abemaciclib 
C2D1:  any time
before dosing of 
abemaciclib
C3D1:  any time
before dosing of 
abemaciclib
Collect at time 
of 
discontinuation 
Whole blood 
(Pharmacogenetics)c
C1D1:  any time before 
or after abemaciclib 
dosing
Abbreviations:  C1D1 = Cycle 1 Day 1; C1D15 = Cycle 1 Day 15; C2D1 = Cycle 2 Day 1; C2D15 = Cycle 2 Day 
15; C3D 1 = Cycle 3 Day 1; h = hour.
a
Whole blood (2 mL) will be collected to determine concentrations of abemaciclib and its metabolites. A separate 
2 mL whole blood will be collected to determine concentrations of tamoxifen and its metabolite endoxifen. All 
PK samples should be taken anytime after the AM dose.
b Collection of archived tumor tissue is required if available.  Previously archived formalin-fixed paraffin-
embedded tumor tissue obtained from the primary tumor or metastatic site should be provided as a whole block 
or unstained slides.
c
A pretreatment blood sample is preferred; however, the whole blood sample for genetic analysis may be 
collected at a later time point if necessary.

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Appendix 5. 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 (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time (PT)
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin (TBL)
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Recommended Autoimmune Serology:
Aspartate aminotransferase (AST)
Anti-nuclear antibodya
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibodya
Creatine phosphokinase (CPK) 
Anti actin antibodya
Abbreviations:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 6. Protocol JPCG Inducers, Strong Inhibitors 
of CYP3A or Substrates of CYPS with Narrow 
Therapeutic Range 
The information in this attachment is provided for guidance to investigators and 
does not preclude the use of these medications if clinically indicated.
Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St. John’s wort
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 
days, if clinically indicated.
Strong inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenadine

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Appendix 7. Protocol JPCG CTCAE 4.03 Diarrhea 
Definition
Diarrhea will be evaluated in this study using the criteria proposed by Common Terminology 
Criteria for Adverse Events (CTCAE) v4.0 revised:  CTCAE 4.03–June 14, 2010: 
Gastrointestinal disorders.
Gastrointestinal Disorders
Grade
Adverse Event
1
2
3
4
5
Diarrhea
Increase of <4 
stools per day 
over baseline; 
mild increase in 
ostomy output 
compared to 
baseline
Increase of 4-6 
stools per day 
over baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline
Increase of >= 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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Appendix 8. Protocol JPCG 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.
Cystic Lesions:  

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

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

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lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease (PD).
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment.  If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan.
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected.
Response Criteria
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of 1 or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response.
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10 mm 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. 
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment.  Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6-8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.

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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).
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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Appendix 9. Protocol JPCG: ECOG Performance 
Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to 
carry out any work activities.  Up and about more than 
50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours
4
Completely disabled.  Cannot carry on any selfcare.  
Totally confined to bed or chair
5
Dead.
Abbreviation:  ECOG = Eastern Cooperative Oncology Group.

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Appendix 10. Protocol Amendment I3Y-MC-JPCG(b) 
Summary 
A Randomized, Open-Label, Phase 2 Study of 
Abemaciclib plus Tamoxifen or Abemaciclib Alone, in 
Women with Previously Treated Hormone Receptor-
Positive, HER2-Negative, Metastatic Breast Cancer
Overview
Protocol I3Y-MC-JPCG (A Randomized, Open-Label, Phase 2 Study of Abemaciclib plus 
Tamoxifen or Abemaciclib Alone, in Women with Previously Treated Hormone 
Receptor-Positive, HER2-Negative, Metastatic Breast Cancer) has been amended.  The new 
protocol is indicated by amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes for the changes made to this protocol are as follows:

Section 6.1 modified inclusion criterion [8] contraceptive method period

Section 7.4.1.1, Table JPCG.7. modified along with Sections 9.4.2.1, 9.4.2.2 and 9.4.2.3 for 
alignment with safety monitoring information for hepatic conditions, renal function and 
VTEs.

Appendix 1 included TBL and VTE in abbreviations 

Appendix 6 CYPs text updated to align with abemaciclib program information.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Section 6.1 Inclusion Criteria
[8]
Women of childbearing potential must have a negative serum pregnancy test at baseline 
(within 7 days prior to Cycle 1 Day 1), and agree to use a highly effective non-hormonal 
contraceptive method during the treatment period and for 3 months weeks following the 
last dose of abemaciclibthe study drug. This amount of time may be longer depending on 
the other treatments received during this trial.
Section 7.4.1 Special Treatment Considerations
Table JPCG.7.
Toxicity Dose Adjustments and Delays of Abemaciclib
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Section 7.4.1.1.2.1
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be 
reduced by 1 dose 
level - investigator’s 
discretion.
Hematologic Toxicity 
Section 7.4.1.1.2.1
Recurrent Grade 3 
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be 
reduced by 1 dose 
level. 
Hematologic Toxicity 
Section 7.4.1.1.2.1
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be 
reduced by 1 dose 
level.
Hematologic toxicity:  PatientIf 
patient requires administration 
of blood cell growth factors.
Section 7.4.1.1.2.1 and 7.7.2
Regardless of severity. 
(Growth factors uUse 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  led to the use of 
growth factor 
Nonhematologic Toxicityb
(except diarrhea and ALT 
increased)
Section 7.4.1.1.2.1
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 7 days 
to baseline or Grade 1
Dose MAY MUST be 
suspended until toxicity 
resolves to either baseline or 
Grade 1.
Dose MAY MUST be 
reduced by 1 dose 
levelinvestigator's 
discretion.
Nonhematologic Toxicity 
Section 7.4.1.1.2.1
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 7.7.1.1
Grade 2 that does not resolve within 
24 hours to at least Grade 1Requires 
hospitalization or Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose reduction is 
NOT required.MUST
be reduced by 1 dose 
level
Diarrhea
Section 7.7.1.1
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures or any Grade of 
diarrhea that requires 
hospitalizationwithin 24 hours to at 
least Grade 1
Dose SHOULD MUST be 
suspended until toxicity 
resolves to at least Grade 1.
Dose MAY MUST be 
reduced by 1 dose 
level investigator's 
discretion.
Diarrhea
Section 7.7.1.1
Grade 3 or 4Diarrhea recurs despite 
maximal supportive measures after 
resuming same dose level after 
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be 
reduced by 1 dose 
level.

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initial Grade 2 diarrhea
ALT Increased 
Section 9.4.2.1
Persistent or recurrent
a Grade
2 (>3.0-5.0×ULN), or
Grade 3 (>5,0-20.0×ULN)c
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
ALT Increased 
Section 9.4.2.1
Grade 4 (>20.0×ULN)
Abemaciclib therapy MUST
be discontinued.
Abemaciclib therapy
MUST be 
discontinued.
ALT Increased with increased 
total bilirubin, in the absence of 
cholestasis
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x ULN
Abemaciclib therapy MUST 
be discontinued
Abemaciclib therapy
MUST be 
discontinued
Abbreviation:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology.
Note:  MAY = per the investigator’s clinical judgment; SHOULD = not mandatory but highly 
recommended;MUST = mandatory.
a  Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).Recurrent 
in the context of dose interruptions and delays refers to the same event occurring within the next 8 weeks (as 
measured from the stop date of the first event).  This does not include events in the same class (for example, 
neutropenia followed by anemia 1 month later).As a general approachguidance, based on the risk/benefit balance 
assessment per the investigator:  F, for a patient who experiences a new episode of Grade 3 hematological 
toxicity after more than 8 weeks following the last episode of same Grade 3 hematological toxicity, the 
investigator may consider resuming the patient on the same drug dose if the patient satisfies the following 
conditions:

The patient showedshows stable hematological counts (≤Grade 2) during that timeframe

In thehas absence of any infectious sign or risk factor

The patient is getting benefit from study treatment 
b    Additional guidance for renal and hepatic monitoring is in Section 9.4.2.
c    Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section 
9.4.2.1 for additional guidance for hepatic monitoring
Section 9.4.2.1
Special Hepatic Safety Data Collection
If a study patient experiences elevated alanine aminotransferase (ALT) 5-fold the upper limit of 
normal (ULN) and elevated total bilirubin (TBL) 2-fold ULN, or ALT >8x ULN for patients 
with underlying baseline hepatic metastases, liver tests (Appendix 5), including ALT, AST, TBL, 
direct bilirubin, gamma glutamyl transferase (GGT), and creatine phosphokinase (CPK), should 
be repeated within 3 to 5 days to confirm the abnormality and to determine if it is increasing or 
decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring should be 
initiated by the investigator, based on the hepatic monitoring tests (Appendix 5) and in 
consultation with the Lilly CRP.  Monitoring of ALT, AST, and TBL should continue until 
levels normalize or return to approximate baseline levels.  Additional diagnostic testing should 
be considered to rule out cause of increased liver enzymes per the investigator’s discretion.
Hepatic monitoring tests (Appendix 5) should be collected in the event that 1 or more of the 
following conditions is met for the patient during the course of the study:

ALT ≥5×ULN and TBL ≥2×ULN

ALT>8x ULN for patients with underlying hepatic metastasis

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
discontinuation from study treatment due to a hepatic event or an abnormality of liver 
tests
clinical and laboratory monitoring should be initiated by the investigator.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP regarding collection of specific recommended 
clinical information and follow-up laboratory tests.  See Appendix 5.
Section 9.4.2.2. 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.  See Appendix 3.  Dose alterations (omission, reduction, 
and discontinuation) should not solely be based on interpretations of serum creatinine values 
because they may not reflect 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 JPCG.7).
Section 9.4.2.3.  Venous Thromboembolic Events
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
venous thromboembolic events (VTEs) in the abemaciclib plus endocrine therapy arm than in the 
placebo plus endocrine therapy arm. The majority of the events were non-serious and were 
treated with low-molecular-weight heparin.  Generally, these events did not result in 
discontinuation of the study treatment. At this time, the mechanism underlying the association 
between abemaciclib and the occurrence of VTEs is not known.  For suspected or confirmed 
VTE (eg. deep vein thrombosis or pulmonary embolism), treatment should occur according to 
usual clinical practice.
Appendix 1.  Abbreviations and Definitions…
TBL
total bilirubin
…
VTE
venous thromboembolic event
…

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Appendix 6.  Protocol JPCG Inducers, Strong Inhibitors of CYP3A or Substrates of CYPS with Narrow 
Therapeutic Range…
Strong inhibitors of CYP3A
All HIV protease inhibitors
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel
…

Leo Document ID = 3c0a3ac1-bdbd-4b7a-994d-9b5f967a5b04
Approver: 
Approval Date & Time: 29-Jan-2019 19:11:10 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 29-Jan-2019 19:14:41 GMT
Signature meaning: Approved
PPD
PPD