Clinical trial NCT04031885
Conditions: Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Start date: 2019-08-14; Completion date: 2020-08-11
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The reason for this study is to compare the efficacy of abemaciclib, in combination with fulvestrant, to that of physician's choice of chemotherapy in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer that has spread to internal organs. Your participation in this trial could last up to 31 months, depending on your cancer type and how you and your tumor respond.

Detailed description:

Arms: arm 1: 150 milligram (mg) Abemaciclib given orally twice a day (BID) with 500 mg fulvestrant given by intramuscular (IM) injection on Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15), then Day 1 of each subsequent cycle. arm 2: Standard chemotherapy of physician's choice (capecitabine, docetaxel, nab paclitaxel, or paclitaxel), administered according to product label.
Interventions: intervention 1: Abemaciclib intervention 2: Fulvestrant intervention 3: Standard Chemotherapy
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered IM intervention 3: Standard chemotherapy of physician's choice administered according to product label.

Protocol documents:
Prot_000.pdf: 
I3Y-MC-JPCU Protocol (b) 
 
A Multicenter, Open-Label, Randomized-Controlled Study of Abemaciclib, a CDK4 and 6 
Inhibitor, in Combination with Fulvestrant Compared to Chemotherapy in Women with HR 
Positive, HER2 Negative Metastatic Breast Cancer with Visceral Metastases 
 
NCT04031885 
 
Approval Date: 20-Feb-2020 


C O N FI D E N TI A L
Pr ot oc ol  I 3 Y-M C -J P C U( b)
L Y 2 8 3 5 2 1 9
1
Title P a ge
C o nfi de nti al I nf or m ati o n
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is c o nfi de ntial a n d is i nte n de d f or t he use of cli nical i n vesti gat ors.  It is t he pr o pert y of Eli Lill y a n d 
C o m pa n y or its s u bsi diaries a n d s h o ul d n ot be c o pie d b y or distri b ute d t o pers o ns n ot i n v ol ve d i n t he cli nical i n vesti gati o n of a be macicli b
(L Y 2 8 3 5 2 1 9 ), u nless s uc h pers o ns are b o u n d b y a c o nfi de ntialit y a gree me nt wit h Eli Lill y a n d C o m pa n y or its s u bsi diaries.  
N ote t o Re g ul at or y A ut h orities:   T his d oc u me nt ma y c o ntai n pr otecte d pers o nal data a n d/ or c o m mer ciall y c o nfi de ntial i nf or mati o n e xe m pt 
fr o m p u blic discl os ure.  Eli Lill y a n d C o m pa n y re q uests c o ns ultati o n re gar di n g release/re dacti o n pri or t o a n y p u blic release.  I n t he U nite d 
States, t his d oc u me nt is s u bject t o Free d o m of I nf or mati o n Act ( F OI A) E xe m pt i o n 4 a n d ma y n ot be re pr o d uce d or ot her wise disse mi nate d 
wit h o ut t he writte n a p pr o val of Eli Lill y a n d C o m pa n y or its s u bsi diaries.
Pr ot oc ol Title:
A M ult ice nter, O pe n-La bel, Ra n d o mize d -C o ntr olle d St u d y  of A be macicli b, a 
C D K 4 a n d 6 I n hi bit or, i n C o m bi nat i on wi t h F ul vestra nt C o m pare d t o C he mot h era p y in W o me n 
wi t h H R P ositive, H E R 2 Ne gati ve Metastati c Breast Ca ncer wit h Visceral Metastases
Pr ot oc ol N u m ber: I 3 Y-M C -J P C U
A me n d me nt N u m ber: ( b)
C o m p o u n d N u m ber: L Y 2 8 3 5 2 1 9
St u d y P h ase: 4
S h ort Title: A St u d y  of A be macicli b i n C o m bi nati o n wi t h F ul vestra nt C o m pare d t o
C he m ot h era p y in W o m e n wit h H R+, H E R 2 - Metastatic
Breast Ca ncer wi t h Visceral Metastases
S p o ns or N a me:  El i Lill y a n d C o m pa n y
Le g al Re gistere d A d dress:  I n dia na p olis, I n dia na U S A 4 6 2 8 5 
A p pr o v al D ate:
Pr ot oc ol A me n d me nt ( b ) Electr o nicall y Sig ne d a n d A p pr o ve d b y  Lill y o n date 
pr o vi de d bel o w.
A p pr o v al D at e: 2 0- F e b- 2 0 2 0 G M T


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Protocol I3Y-MC-JPCU(b)
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Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment a
21-Jun-2019
Protocol I3Y-MC-JPCU
15-Apr-2019
Amendment b
Overall Rationale for the Amendment:
This amendment incorporates updates made in the development core safety information of the 
Investigator’s Brochure. Additional protocol changes and rationale are provided below.  
Section # and Name
Description of Change
Brief Rationale
6.6.1 Abemaciclib
Updated and added new 
abemaciclib dose modification 
and management tables and 
language.
Alignment with Investigator’s 
Brochure update.
8.2.1.4 Interstitial 
Lung Disease 
(ILD)/Pneumonitis
Revised language.
Alignment with Investigator’s 
Brochure update.
8.2.1.1 Hepatic 
Safety Monitoring
Deleted and replaced with new 
hepatic safety monitoring 
language. 
Changes to the Special Hepatic 
Safety Data Collection were done to 
ensure a comprehensive evaluation 
of patients with treatment-emergent 
abnormal liver tests and to align with 
current guidance from the Lilly Liver 
and Gastrointestinal (GI) Safety 
Advisory Committee.


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Section # and Name
Description of Change
Brief Rationale
Appendix 4: Liver 
Safety: Suggested 
Actions and Follow-
up Assessments
Deleted and replaced with new 
hepatic safety monitoring 
language. Added: Cell 
morphology (RBC and WBC), 
HBV DNA, HCV RNA, HDV 
antibody, HEV RNA, blood 
culture, urine culture, 
Acetaminophen, 
Acetaminophen Protein 
Adducts, Alkaline 
Phosphatase Isoenzymes, 
Ceruloplasmin, Copper, Ethyl 
Alcohol (EtOH), 
Immunoglobulin IgA 
(Quantitative), 
Immunoglobulin IgG 
(Quantitative), 
Immunoglobulin IgM 
(Quantitative), 
Phosphatidylethanol (PEth), 
Drug Screen, Ethyl 
glucuronide (EtG), EBV 
antibody, EBV DNA, CMV 
antibody, CMV DNA, HSV 
(Type 1 and 2) antibody, HSV 
(Type 1 and 2) DNA, and 
Liver Kidney Microsomal 
Type 1 (LKM-1) Antibody.
Changes to the Special Hepatic 
Safety Data Collection were done to 
ensure a comprehensive evaluation 
of patients with treatment-emergent 
abnormal liver tests and to align with 
current guidance from the Lilly Liver 
and Gastrointestinal (GI) Safety 
Advisory Committee.
Throughout
Added “at least 6 hours apart” 
to describe BID dosing.
Clarification.
1.3 Schedule of 
Activities
Removed grouping of Cycle 1 
and 2 and added column for 
Cycle 2. 
No new procedures were added. 
Revised for readability.
1.3 Schedule of 
Activities
Changed visit window for 
Cycle 1 Day 1 to minus 7 
days.
Revised for flexibility. 
1.3 Schedule of 
Activities
Clarified clinical tumor 
measurement assessment 
timing and added window.
Revised for flexibility and 
clarificiation.
1.3 Schedule of 
Activities
Clarified radiologic tumor 
measurement instructions.
Clarification.


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Protocol I3Y-MC-JPCU(b)
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Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities
Clarified x-ray, or CT scan 
with bone windows, or MRI 
assessment instructions.
Clarification.
1.3 Schedule of 
Activities
Merged Worst pain NRS, 
Bowel movement diary, 
Bristol stool scale, and 
loperamide doses into one row 
and added new instructions.
Revised for readability and added 
instructions for clarity.
1.3 Schedule of 
Activities
Merged FACT GP5, PRO 
CTCAE, and EORTC IL36 
into one row and added new 
instructions.
Revised for readability and added 
instructions for clarity.
1.3 Schedule of 
Activities; 6.3 
Measures to 
Minimize Bias: 
Randomization and 
Blinding
Added abemaciclib, 
fulvestrant, and chemotherapy 
administration window from 
randomization to C1D1. 
Revised to allow flexibility. 
5.1 Inclusion Criteria
Added omentum as an 
example in Inclusion Criterion
8.
Revised to add an example.
5.2 Exclusion 
Criteria
Merged Exclusion Criterion
26 into Exclusion Criterion 23.
Revised for readability.
5.2 Exclusion 
Criteria
Changed “randomization” to 
“C1D1” in Exclusion Criterion
28.
Clarified timing of biophosphonates 
initiation.
6.5 Concomitant 
Therapy
Removed cautionary language 
regarding coadministration of 
narrow therapeutic index CYP 
substrate drugs
Alignment with Investigator’s 
Brochure update.
8.1 Efficacy 
Assessments
Changed “bone scans” to 
“bone scintigraphy”
Clarification and alignment with 
Schedule of Activities.
9.4.4.1 Patient-
Reported Outcome 
(PRO)
Changed PRO summary to 
visit and treatment arm, 
overall treatment arm, and 
overall for the trial. 
Alignment with Schedule of 
Activities.
10.6 Appendix 6: 
CTCAE 5.0 
Diarrhea/Pneumonitis 
Definition
Added pneumonitis CTCAE 
definition.
Reference for investigators.


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Protocol I3Y-MC-JPCU(b)
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Section # and Name
Description of Change
Brief Rationale
Throughout
Minor editorial and formatting 
changes
Minor and therefore not summarized.


CONFIDENTIAL
Protocol I3Y-MC-JPCU(b)
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Table of Contents
1.
Protocol Summary ..............................................................................................................9
1.1.
Synopsis.........................................................................................................................9
1.2.
Schema ........................................................................................................................11
1.3.
Schedule of Activities (SoA)........................................................................................12
2.
Introduction ......................................................................................................................20
2.1.
Study Rationale............................................................................................................20
2.2.
Background..................................................................................................................20
2.3.
Benefit/Risk Assessment..............................................................................................21
3.
Objectives and Endpoints..................................................................................................22
4.
Study Design.....................................................................................................................23
4.1.
Overall Design .............................................................................................................23
4.2.
Scientific Rationale for Study Design...........................................................................23
4.3.
Justification for Dose ...................................................................................................24
4.4.
End of Study Definition ...............................................................................................24
5.
Study Population...............................................................................................................25
5.1.
Inclusion Criteria..........................................................................................................25
5.2.
Exclusion Criteria ........................................................................................................27
5.3.
Lifestyle Considerations...............................................................................................28
5.4.
Screen Failures.............................................................................................................28
6.
Study Intervention.............................................................................................................30
6.1.
Study Intervention(s) Administered..............................................................................30
6.2.
Preparation/Handling/Storage/Accountability...............................................................30
6.3.
Measures to Minimize Bias:  Randomization and Blinding...........................................30
6.4.
Study Intervention Compliance ....................................................................................31
6.5.
Concomitant Therapy...................................................................................................31
6.5.1.
Palliative Medicine and Supportive Care..............................................................32
6.5.2.
Supportive Management for Diarrhea in Patients Receiving 
Abemaciclib.........................................................................................................32
6.5.3.
Bisphosphonates and Receptor Activator of Nuclear Factor 
Kappa-Β Ligand (RANK-L) Targeted Agents ......................................................33
6.6.
Dose Modification........................................................................................................33
6.6.1.
Abemaciclib.........................................................................................................33
6.6.2. 
Dose Suspension and Cycle Delay .......................................................................36
6.6.3
Fulvestrant and Chemotherapeutic Agents............................................................36
6.7.
Intervention after the End of the Study.........................................................................37
6.7.1.
Treatment after Study Completion........................................................................37


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7.
Discontinuation of Study Intervention and Patient 
Discontinuation/Withdrawal..............................................................................................38
7.1.
Discontinuation of Study Intervention..........................................................................38
7.2.
Patient Discontinuation/Withdrawal from the Study.....................................................38
7.2.1.
Discontinuation of Inadvertently Enrolled Patients...............................................39
7.3.
Lost to Follow-Up........................................................................................................39
8.
Study Assessments and Procedures ...................................................................................40
8.1.
Efficacy Assessments...................................................................................................40
8.2.
Safety Assessments ......................................................................................................41
8.2.1.
Clinical Safety Laboratory Assessments...............................................................41
8.3.
Adverse Events and Serious Adverse Events................................................................44
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information..........................................................................................................47
8.3.2.
Follow-Up of AEs and SAEs................................................................................47
8.3.3.
Regulatory Reporting Requirements for SAEs......................................................47
8.3.4.
Pregnancy ............................................................................................................48
8.3.5.
Cardiovascular and Death Events .........................................................................48
8.3.6.
Complaint Handling.............................................................................................48
8.4.
Treatment of Overdose.................................................................................................48
8.5.
Pharmacokinetics .........................................................................................................48
8.6.
Pharmacodynamics ......................................................................................................48
8.7.
Genetics .......................................................................................................................48
8.8.
Biomarkers...................................................................................................................49
8.9.
Medical Resource Utilization and Health Economics ...................................................49
8.9.1.
Patient-Reported Outcomes (PRO).......................................................................50
8.9.2.
Healthcare Resource Utilization ...........................................................................51
9.
Statistical Considerations ..................................................................................................52
9.1.
Statistical Hypotheses ..................................................................................................52
9.2.
Sample Size Determination ..........................................................................................52
9.3.
Populations for Analyses..............................................................................................55
9.4.
Statistical Analyses ......................................................................................................55
9.4.1.
General Statistical Considerations ........................................................................55
9.4.2.
Efficacy Analyses ................................................................................................56
9.4.3.
Safety Analyses....................................................................................................57
9.4.4.
Other Analyses.....................................................................................................58
9.5.
Interim Analyses ..........................................................................................................60
10.
Supporting Documentation and Operational Considerations..............................................61


CONFIDENTIAL
Protocol I3Y-MC-JPCU(b)
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10.1. Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations .............................................................................................................62
10.1.1.
Regulatory and Ethical Considerations.................................................................62
10.1.2.
Informed Consent Process....................................................................................62
10.1.3.
Data Protection ....................................................................................................63
10.1.4.
Dissemination of Clinical Study Data...................................................................63
10.1.5.
Data Quality Assurance........................................................................................63
10.1.6.
Source Documents ...............................................................................................64
10.1.7.
Study and Site Closure .........................................................................................65
10.2. Appendix 2:  Clinical Laboratory Tests ........................................................................66
10.3. Appendix 3:  Contraceptive Guidance and Collection of 
Pregnancy Information.................................................................................................68
10.4. Appendix 4:  Liver Safety:  Suggested Actions and Follow-up 
Assessments.................................................................................................................69
10.5. Appendix 5:  Creatinine Clearance Formula .................................................................71
10.6. Appendix 6:  CTCAE 5.0 Diarrhea/Pneumonitis Definition..........................................72
10.7. Appendix 7:  Inducers and Strong Inhibitors of CYP3A ...............................................73
10.8. Appendix 8:  Abbreviations..........................................................................................74
10.9. Appendix 9: Protocol Amendment History...................................................................79
11.
References ........................................................................................................................82


CONFIDENTIAL
Protocol I3Y-MC-JPCU(b)
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title:
A Multicenter, Open-Label, Randomized-Controlled Study of Abemaciclib, a CDK4 and 6 
inhibitor, in Combination with Fulvestrant Compared to Chemotherapy in Women with HR 
Positive, HER2 Negative Metastatic Breast Cancer with Visceral Metastases
Short Title:
A Study of Abemaciclib in Combination with Fulvestrant Compared to Chemotherapy in 
Women with HR+, HER2- Metastatic Breast Cancer with Visceral Metastases
Rationale: 
The use of cytotoxic chemotherapy may be initiated earlier in the course of hormone receptor 
positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast 
cancer (MBC) than recommended by the American Society of Clinical Oncology (ASCO) and 
National Comprehensive Cancer Network (NCCN) guidelines, potentially denying patients an
effective and tolerable standard of care (SOC) regimen containing endocrine therapy (ET). 
The proposed Study I3Y-MC-JPCU (hereafter referred to as Study JPCU) will compare the 
efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, in combination with 
fulvestrant to that of physician’s choice of  chemotherapy (capecitabine, docetaxel, nab-
paclitaxel or paclitaxel) in patients with HR+, HER2- MBC with at least 1 site of visceral 
metastases and at least 1 line of prior ET.  Efficacy will be measured by the primary endpoint 
objective response rate (ORR).


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Protocol I3Y-MC-JPCU(b)
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Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of abemaciclib 
in combination with fulvestrant to 
chemotherapy 

ORR
Secondary

To further characterize the efficacy of 
abemaciclib in combination with 
fulvestrant compared to chemotherapy 

PFS 

TTR

DoR

PFS2

To compare the safety and tolerability 
of abemaciclib in combination with 
fulvestrant to chemotherapy

Safety:  including but not limited to TEAEs, SAEs, 
deaths, and clinical laboratory abnormalities per 
CTCAE version 5.0
Abbreviations:  CTCAE = Common Terminology Criteria in Adverse Events; DoR = duration of response; TTR = 
time to response; ORR = objective response rate; PFS = progression-free survival; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event.
Overall Design:
Study JPCU is a multicenter, open-label, randomized-controlled study of abemaciclib in 
combination with fulvestrant compared to physician’s choice of chemotherapy in women with 
HR+, HER2- locally advanced or metastatic breast cancer (hereafter referred to as “metastatic
breast cancer”) who have poor prognosis due to visceral metastases. 
Disclosure Statement: 
This is a parallel group treatment study with 2 arms and no masking.
Number of Patients:
Approximately 300 patients will be randomized in the study. 


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Protocol I3Y-MC-JPCU(b)
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Intervention Groups and Duration:
Arm
Arm A
Arm B
Intervention
Abemaciclib
Fulvestrant
Chemotherapy (capecitabine, docetaxel, nab-
paclitaxel, or paclitaxel)
Dose
150 mg
500mg
Refer to PI or per physician’s routine clinical 
practice
Schedule
BID
C1D1,C1D15, 
Day 1 of each 
subsequent cycle
Refer to PI or per physician’s routine clinical 
practice
Route
PO
IM
Refer to PI
Abbreviations: BID = twice a day, at least 6 hours apart; C = Cycle; D = Day; IM = intramuscular; PI = package 
insert; PO = by mouth.
Data Monitoring Committee:  No
1.2.
Schema
Abbreviations:  ET = endocrine therapy; GnRH = gonadotropin-releasing hormone;  HER2- = human epidermal 
growth factor receptor 2-negative; HR+ = hormone receptor positive; MBC = metastatic breast cancer; N = 
number of enrolled patients; ORR = objective response rate; R = randomization.


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Protocol I3Y-MC-JPCU(b)
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1.3.
Schedule of Activities (SoA)
This section includes the following SoAs:

Baseline, On-Study, and Post-Study Treatment Follow-Up SoA for all patients

Continued Access SoA for all patients


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Baseline, On-Study and Post-Study Treatment Follow-Up SoA for All Patients
Study Period
Baseline
Study treatment 
(Cycle = 21 or 28 days)
Post-discontinuation
Instructions
Cycle/Visit
Screening
Cycles 1
Cycle 2
Cycle 3
Cycle 4-n
Short-
Term 
Follow-upa
Long-
Term 
Follow-upb
Visit duration for Arm A 
(days)
Up to 28
28
28
28
28
30
90
Visit duration for Arm B 
(days)
Up to 28
21 or 28
21 or 28
21 or 28
21 or 28
30
90
Relative Day within 
Dosing Cycle & Visit 
Window
≤28
≤14
1
(-7d)
15 
(±3d)
1
(±3d)
15 
(±3d)
1 (+3d)
1 (+3d) 
V801
(±7d)
V802-8XX 
(±14d)
Procedure
Informed consent
X
ICF must be signed before any protocol-
specific procedures are performed. 
See Appendix 1.
Inclusion/exclusion criteria
X
See Section 5.
Medical history
X
Includes assessment of pre-existing 
conditions, historical illnesses, prior 
anticancer therapy and habits.
Concomitant medication
X
X
X
Record prior and concurrent medications 
at baseline. Record all premedication, 
supportive care, and concomitant 
medication continuously at every visit 
and throughout the study.
Clinically directed physical 
examination
X
X
X
X
X
X
Height, weight and vital 
signs
X
X
X
X
X
X
Includes height (only at baseline), weight 
(only at D1 of every cycle), BP, pulse, 
and temperature.
ECG
X
Collect locally.
ECOG performance status
X
X
X
X
X
X
During study treatment, perform ≤3 days 
prior to treatment.
AE collection
X
X
X
Collect continuously at every visit and 
throughout the study. Use CTCAE v 5.0
Tumor Assessments


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Study Period
Baseline
Study treatment 
(Cycle = 21 or 28 days)
Post-discontinuation
Instructions
Cycle/Visit
Screening
Cycles 1
Cycle 2
Cycle 3
Cycle 4-n
Short-
Term 
Follow-upa
Long-
Term 
Follow-upb
Visit duration for Arm A 
(days)
Up to 28
28
28
28
28
30
90
Visit duration for Arm B 
(days)
Up to 28
21 or 28
21 or 28
21 or 28
21 or 28
30
90
Relative Day within 
Dosing Cycle & Visit 
Window
≤28
≤14
1
(-7d)
15 
(±3d)
1
(±3d)
15 
(±3d)
1 (+3d)
1 (+3d) 
V801
(±7d)
V802-8XX 
(±14d)
Procedure
Clinical Tumor 
Measurement 
(lesions that are palpable or 
visible on exam)
X
See 
Instructio
ns
See instructions
Assessments should be performed at 
baseline and Q12W (±7d) from 
randomization of study therapy.  See 
Section 8.1 for additional guidance.
Radiologic Tumor 
Measurement
(e.g.; CT, MRI)
X
See Instructions
See instructions

Perform a CT or MRI scan of the 
chest, abdomen, pelvis and any 
clinically indicated sites of disease at 
baseline and every Q12W (±7 days) 
after randomization until documented 
disease progression per the RECIST 
v1.1 criteria, initiation of new 
anticancer therapy, death, patient 
withdrawal, or study completion, 
whichever occurs first.  

See Section 8.1 for additional 
guidance.
Bone 
scintigraphy
X
See Instructions
See 
instructions
Required for all patients at baseline 
and 
post-baseline every Q24W (±7 days), or 
to confirm complete response, or when 
progression in bone is suspected until 
documented disease progression per the 
RECIST v1.1 criteria, initiation of new 
anticancer therapy, death, patient 
withdrawal, or study completion, 
whichever occurs first
See Section 8.1 for additional guidance.


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Study Period
Baseline
Study treatment 
(Cycle = 21 or 28 days)
Post-discontinuation
Instructions
Cycle/Visit
Screening
Cycles 1
Cycle 2
Cycle 3
Cycle 4-n
Short-
Term 
Follow-upa
Long-
Term 
Follow-upb
Visit duration for Arm A 
(days)
Up to 28
28
28
28
28
30
90
Visit duration for Arm B 
(days)
Up to 28
21 or 28
21 or 28
21 or 28
21 or 28
30
90
Relative Day within 
Dosing Cycle & Visit 
Window
≤28
≤14
1
(-7d)
15 
(±3d)
1
(±3d)
15 
(±3d)
1 (+3d)
1 (+3d) 
V801
(±7d)
V802-8XX 
(±14d)
Procedure
X-ray, or CT scan with 
bone windows, or MRI
X
See Instructions
See 
instructions
Required only for patients with bone 
disease identified at baseline
Assessment should be performed at 
baseline and every Q12W (±7 days) after 
randomization until documented disease 
progression per the RECIST v1.1 criteria, 
initiation of new anticancer therapy,
death, patient withdrawal, or study 
completion, whichever occurs first. See 
Section 8.1 for additional guidance
Clinical laboratory tests
Pregnancy Test
X
Only for postmenopausal women whose 
ovarian suppression is due to a GnRH 
agonist.  See Appendix 2.
Postmenopausal 
Confirmation Testing
X
Only for postmenopausal women <60 
years, and ammehoric for at least 12 
months (in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian 
suppression).  See Appendix 2.
Hematology
X
X
X
X
X
X
X
See Appendix 2.
Coagulation
X
See Appendix 2. For patients receiving 
oral coumarin-derivative anticoagulations
while on chemotherapy, coagulation 
should be collected locally at every visit.
Urinalysis
X
See Appendix 2. 
Clinical Chemistry
X
X
X
X
X
X
X
X
See Appendix 2. 
Post-study collection


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Study Period
Baseline
Study treatment 
(Cycle = 21 or 28 days)
Post-discontinuation
Instructions
Cycle/Visit
Screening
Cycles 1
Cycle 2
Cycle 3
Cycle 4-n
Short-
Term 
Follow-upa
Long-
Term 
Follow-upb
Visit duration for Arm A 
(days)
Up to 28
28
28
28
28
30
90
Visit duration for Arm B 
(days)
Up to 28
21 or 28
21 or 28
21 or 28
21 or 28
30
90
Relative Day within 
Dosing Cycle & Visit 
Window
≤28
≤14
1
(-7d)
15 
(±3d)
1
(±3d)
15 
(±3d)
1 (+3d)
1 (+3d) 
V801
(±7d)
V802-8XX 
(±14d)
Procedure
Survival Information
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 approximately every 90 days.
Collection of post-study-
treatment anticancer 
therapy information
X
Perform every 90 days for the first 2 
years after discontinuation from study 
treatment and every 6 months (±14 days)] 
thereafter until death or study 
completion.
Patient-reported Outcomes

Worst pain NRS

Bowel movement diary

Bristol stool scale 

Loperamide doses
X
X
X
X
X
X
X
X
Record daily for at least 3 days in the 
baseline screening period and continue 
daily following C1D1, and for the period 
between treatment discontinuation until 
the short-term follow-up visit (V801) is 
completed

FACT GP5

PRO CTCAE 

EORTC IL36
X
X
X
X
X
X
X
X
Record at least once weekly during 
screening period, weekly during study 
treatment and at least once weekly 
following discontinuation until the short-
term follow-up visit (V801) is completed
HCRU (Hosp, ER, 
analgesic, GF, transfusions)
X
X
X
X
X
X
X
X
Record weekly during screening, weekly 
during study treatment and at short-term 
follow-up
Genetic and biomarker collections
Whole blood 
(for genetic analysis)
X
See Section 8.7.
Collect sample for all participants, 
preferably at Cycle 1 Day 1 but can be 


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Study Period
Baseline
Study treatment 
(Cycle = 21 or 28 days)
Post-discontinuation
Instructions
Cycle/Visit
Screening
Cycles 1
Cycle 2
Cycle 3
Cycle 4-n
Short-
Term 
Follow-upa
Long-
Term 
Follow-upb
Visit duration for Arm A 
(days)
Up to 28
28
28
28
28
30
90
Visit duration for Arm B 
(days)
Up to 28
21 or 28
21 or 28
21 or 28
21 or 28
30
90
Relative Day within 
Dosing Cycle & Visit 
Window
≤28
≤14
1
(-7d)
15 
(±3d)
1
(±3d)
15 
(±3d)
1 (+3d)
1 (+3d) 
V801
(±7d)
V802-8XX 
(±14d)
Procedure
collected at any time throughout the 
study.
Plasma 
(for biomarker collection)
Pre-
dose 
Cycle 
1
X
See Section 8.8. Collect pre-dose sample 
at C1D1 for all participants. 
Collect short term follow-up sample for 
participants only on Arm A who have PD 
after they have been on treatment for at 
least 12 months.  Do not collect samples 
for participants on the chemotherapy arm 
at this visit.
Study Interventions
Administer abemaciclib
X
See Section 6.1.  C1D1 administration 
should occur within 7 days of 
randomization
Administer fulvestrant
X
See Section 6.1.  C1D1 administration 
should occur within 7 days of 
randomization
Administer chemotherapy
X
See Section 6.1.  C1D1 administration 
should occur within 7 days of 
randomization
Chemotherapy includes capecitabine, 
docetaxel, nab-paclitaxel or paclitaxel.


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Abbreviations:  AE = adverse event; BP = blood pressure; C = Cycle; CT = computer tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC IL36 = European Organisation for Research and Treatment of Cancer quality of 
life questionnaire (abridged); ER = emergency room; FACT-GP5 = Functional Assessment of Cancer Therapy- Side Effects; GF = growth factor; HCRU = healthcare resources 
used; Hosp = hospitalization; ICF = informed consent form; MRI = magnetic resonance imaging; PD = progressive disease; PRO CTCAE = patient reported outcome Common 
Terminology Criteria for Adverse Events; Q12W = every 12 weeks; Q24W = every 24 weeks; QoL = quality of life; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (Eisenhauer et al. 2009); V = Visit.
a
Short-term follow-up begins when the patient and investigator agree that the patient will no longer continue study treatment and lasts approximately 30 days.
b
Long-term follow-up begins when short-term follow-up period is completed and continues until death, study withdrawal, or the patient is lost to follow-up.  In all cases, no 
follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent.


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Continued Access Schedule of Activities
Visit
Study Treatment
30-Day Follow-Up
Instructions
501-5XX
901
Procedure
AE Collection
X
X
Per CTCAE v 5.0, for post follow-up, the investigator should only be made aware of 
collected SAEs related to study regimen or protocol procedures.
Collect continuously at every visit and throughout the study.
Administer study intervention
X
See Section 6.1 for Study Intervention administration details and guidelines..
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; SAE = serious adverse event.
a
Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued access period and lasts 
approximately 30 days. In all cases, no follow-up procedures will be performed for a patient who withdraws informed consent unless he or 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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2.
Introduction
2.1.
Study Rationale
Both the ASCO and NCCN guidelines recommend initial sequential use of ET-based treatment 
over cytotoxic chemotherapy in the treatment of HR+, HER2- MBC due to the superior benefit-
risk profile of the former therapeutic strategy (Rugo et al. 2016; NCCN 2018).  However, data 
from a survey of United States (US) oncologists suggests that cytotoxic chemotherapy may be 
initiated earlier in the course of MBC than recommended by consensus guidelines, potentially 
denying patients an effective and tolerable SOC ET-based therapy (Lin et al. 2016).  
Study JPCU aims to compare the efficacy of ET fulvestrant in combination with abemaciclib, a 
CDK 4 and 6 inhibitor, to that of physician’s choice of chemotherapy (capecitabine, docetaxel, 
nab-paclitaxel, or paclitaxel) in patients with HR+, HER2- MBC with at least 1 site of visceral 
metastases.  Efficacy will be measured by the primary endpoint ORR.
2.2.
Background
Breast cancer is the second most commonly diagnosed cancer and accounts for the second 
highest number of cancer deaths among women globally (CDC Breast Cancer).  While the 
prognosis for locally occurring disease is typically promising, the outlook for MBC (metastatic
breast cancer) is poor, with a median overall survival (OS) of 2 to 3 years and a 5-year survival 
rate of only ~25% (Harbeck and Gnant 2017; Cardoso et al. 2018). 
Clinical decision-making for the management of patients with MBC takes into account multiple 
clinical factors such as HR/HER2 status, age, comorbidities, and patient preference. More 
specifically, treatment options for women with breast cancer are largely determined by tumor HR 
and HER2 status. For patients with HR+ HER2- MBC, treatment includes ET (e.g., anastrazole, 
letrozole, fulvestrant) alone or in combination with the CDK 4 and 6 inhibitors (such as 
abemaciclib, palbociclib, or ribociclib), as well as standard chemotherapy (e.g. capecitabine, 
docetaxel, paclitaxel, nab-paclitaxel [NCCN 2018; Waks and Winer 2019]).  Growing evidence 
has suggested visceral metastasis and sites of metastases as potential prognostic factors for 
patients with HR+ MBC (Solomayer et al. 2000; Leone et al. 2017; Di Leo et al. 2018). 
Furthermore, possible improvements in treatment effect have been observed in patients with 
visceral metastases compared to non-visceral metastases (Di Leo et al. 2018).  
“Visceral crisis” is a well described clinical syndrome characterized by rapid cancer progression 
causing fulminant or impending organ dysfunction (Cardoso et al. 2018). Regardless of HR and 
HER2 status, there is uniform agreement on the initiation of cytotoxic chemotherapy for patients 
in visceral crisis (Cardoso et al. 2016; Rugo et al. 2016; NCCN 2018).  However, in the absence 
of visceral crisis, ASCO (Rugo et al. 2016) and NCCN 2019 guidelines recommend sequential 
use of ET-based treatment prior to the initiation of cytotoxic chemotherapy, due to the greater 
tolerability of the former class of agents (Cardoso et al. 2018).  Nevertheless, a real-world 
retrospective Flatiron Health database analysis of HR+ HER2- metastatic breast cancer (MBC)
patients, diagnosed and treated between 01 March 2017 to 28 February 2019 showed that of 


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2392 treated patients, 16.6% received chemotherapy as first line treatment while the most 
common first line treatments were CDK-based therapies (50% [Flatiron Health HER-derived 
database]). Of those receiving an ET as the first line therapy, 10.6% received chemotherapy as 
the second line of therapy.  The most frequently used mono chemotherapeutics were paclitaxel, 
capecitabine, and nab-paclitaxel. The factors influencing choice of chemotherapy include new 
mechanism of action, response to prior therapies and tolerability of the chemotherapy. In a 
survey of community-based US cancer specialists, approximately 30% of physicians reported the 
presence of organ threatening disease or ”visceral crisis” as the rationale for starting 
chemotherapy (Lin et al. 2016).  These data suggest discontinuation of ET occurs earlier than 
recommended in favor of chemotherapy in spite of the less favorable tolerability profile of 
chemotherapy.  
Abemaciclib, a potent inhibitor of the CDK 4 and 6 pathway, in combination with a non-
steroidal aromatase inhibitor when administered as first-line treatment (Study I3Y-MC-JPBM) 
and the addition of abemaciclib in combination with fulvestrant as second-line treatment 
following disease progression on ET (Study I3Y-MC-JPBL) significantly improved progression-
free survival (PFS) in patients with HR+ HER2- MBC (Goetz et al. 2017; Sledge et al. 2017). In 
addition, the combination treatment was generally well tolerated, with diarrhea and neutropenia 
being the only treatment emergent adverse events of Grade 3/4 severity occurring in more than 
10% of patients (diarrhea [%]:  13/0; neutropenia [%]:  24/3 in Study I3Y-MC-JPBL [Sledge et 
al. 2017)). The overall positive benefit risk profile of abemaciclib in combination with 
fulvestrant is consistent with the overarching goal of current guidelines offering sequential ET 
until ET options have exhausted with HR+, HER2- MBC (Verzenio package insert).  
Importantly, the benefit from abemaciclib was observed in all patient subgroups including 
patients with poor prognostic features such as visceral metastases (Di Leo et al. 2018). Study 
I3Y-MC-JPCU will assess if abemaciclib and fulvestrant in combination have comparable 
efficacy, as defined in Section 9.1, to physician’s choice of chemotherapy by measuring ORR in 
patients with HR+, HER2- MBC with the presence of visceral metastases.
2.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of abemaciclib are found in the Investigator’s 
Brochure (IB), Patient Information Leaflet, Package Insert (PI), or Summary of Product 
Characteristics.
More detailed information about the known and expected benefits and risks of fulvestrant and the 
chemotherapeutic agents may be found in the following: Patient Information Leaflet, PI, or
Summary of Product Characteristics.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare the efficacy of abemaciclib 
in combination with fulvestrant to 
chemotherapy 

ORR
Secondary

To further characterize the efficacy of 
abemaciclib in combination with 
fulvestrant compared to chemotherapy 

PFS

TTR

DoR

PFS2

To compare the safety and tolerability 
of abemaciclib in combination with 
fulvestrant to chemotherapy

Safety:  including but not limited to TEAEs, SAEs, 
deaths, and clinical laboratory abnormalities per 
CTCAE version 5.0
Exploratory/Tertiary

To evaluate PROs and HCRU for 
abemaciclib in combination with 
fulvestrant compared to chemotherapy

PROs
o
Worst-pain NRS
o
BM Frequency
o
Bristol Stool Form Scale
o
Loperamide doses
o
FACT-GP5
o
PRO-CTCAE
o
EORTC IL36

HCRU
o
Hospitalization (reason, duration)
o
Emergency room visits (reason)
o
Analgesic use
o
Growth factor use
o
Transfusions use and type

To assess the relationship between 
pharmacogenomics and clinical 
outcome

Results of genetics and clinical outcome assessments

To assess the relationship between 
biomarkers and clinical outcome

Results of biomarkers and clinical outcome 
assessments
Abbreviations: BM = bowel movement; CTCAE = Common Terminology Criteria in Adverse Events; DoR = 
duration of response; TTR = time to response; EORTC IL36= European Organisation for Research and 
Treatment of Cancer quality of life questionnaire (abridged); FACT-GP5 = Functional Assessment of Cancer 
Therapy- Side Effects; HCRU = healthcare resources used; NRS = numeric pain rating scale; ORR = objective 
response rate; PFS = progression-free survival; PRO = patient reported outcome; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event.


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4.
Study Design
4.1.
Overall Design
Study JPCU is a multicenter, open-label, randomized-controlled study of abemaciclib, a CDK 4 
and 6 inhibitor, in combination with fulvestrant compared to physician choice of standard 
chemotherapy in a patient population of post menopausal women with HR+, HER2- locally 
advanced or MBC who have poor prognosis due to visceral metastasis.
Patients will be randomized using the following stratification factors: the presence of liver 
metastases (Yes/No), sensitivity to prior ET (sensitive versus primary resistance versus 
secondary resistance), and postmenopausal status (natural/surgical/therapeutic radiation versus 
gonadotropin-releasing hormone [GnRH] agonist use).
Sensitivity to prior ET is defined as follows, and will be determined based on the patients’ most 
recent sensitivity status.  For example, if a patient met the definition of primary resistance on 
adjuvant ET and subsequently met the definition of secondary resistance on ET for MBC, the 
patient would be categorized as having secondary resistance.  
1. Primary resistance: a relapse while on the first 2 years of adjuvant ET, or progressive 
disease (PD) within first 6 months of first-line ET for MBC, while on ET
2. Secondary resistance: a relapse while on adjuvant ET but after the first 2 years, or a 
relapse within 12 months of completing adjuvant ET, or PD ≥6 months after initiating ET 
for MBC, while on ET
3. Sensitive: patients who do not meet the definition of primary resistance or secondary 
resistance will be considered to be sensitive
Patients who meet all criteria for enrollment will be randomly assigned 1:1 to:
1. Arm A: abemaciclib in combination with fulvestrant, or 
2. Arm B: physician choice of standard chemotherapy (capecitabine, docetaxel, nab-
paclitaxel, or paclitaxel). 
Cross over between study treatments is not allowed in this study.  Additionally, post-
discontinuation therapy is neither specified nor restricted. 
Taken together, these data will be used to characterize the efficacy, safety and tolerability of 
abemaciclib in combination with fulvestrant compared to chemotherapy.  Section 1.2 illustrates 
the study schema.
4.2.
Scientific Rationale for Study Design
Study JPCU is a study in women participants with HR+ HER2- MBC with visceral metastasis, a 
poor prognostic feature which prompts some cancer specialists to initiate cytotoxic 
chemotherapy earlier than recommended by consensus treatment guidelines (Cardoso et al. 2016; 
Rugo et al. 2017; NCCN 2018). Visceral metastases and prior ET may typically steer a 
physician towards considering chemotherapy as a therapeutic choice. Eligible JPCU patients 
with visceral metastasis must have received at least 1 line of prior ET. Endocrine therapy may 


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have occured in either (or both) the (neo)adjuvant or metastatic setting; however, it must be 
limited to no more than 1 ET in the metastatic setting.  
JPCU patients must be appropriate candidates for randomization to either abemaciclib-
fulvestrant treatment or physician’s choice of allowed chemotherapy agents (capecitabine, 
docetaxel, nab-paclitaxel or paclitaxel).  
Patients will be randomized by a number of stratification factors thought to be associated with 
clinical outcomes to further reduce the potential for bias and improve the power of the analyses:  
namely sensitivity to prior ET, liver metastases, and postmenopausal status. Our internal data 
indicate that postmenopausal status is an important prognostic factor:  in Study I3Y-MC-JPBL, 
the patients receiving GnRH agonist had a median PFS of 28.6 months versus 15.5 months for 
those patients who were naturally postmenopausal. As this study is assessing different methods 
of study intervention administrations, a Phase 4 open-label study is appropriate.  The primary
purpose of the study is to demonstrate that abemaciclib in combination with fulvestrant provides 
at least the same clinical benefit as chemotherapy to the patients, as defined by “comparability,”
and abemaciclib in combination with fulvestrant has a preferred safety profile over 
chemotherapy.  An interim analysis of futility for ORR is planned.
4.3.
Justification for Dose
Abemaciclib is Food and Drug Administration (FDA) and European Medicine Agency (EMA)-
approved for use in combination with fulvestrant for the treatment of women with HR+, HER2-
MBC with disease progression following ET.  Justification for dose may be found in the IB and 
PI.
Justification for chemotherapy dosing is per package insert guidelines in association with 
physician’s routine clinical practice for each agent.
4.4.
End of Study Definition
The end of study is defined as the date of the last visit of the last patient in the study or last 
scheduled procedure shown in the SoA (Section 1.3) for the last patient in the trial globally.
Study completion will occur following the final analysis of primary and secondary objectives, as 
determined by Lilly.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
5.1.
Inclusion Criteria
Patients are eligible to be included in the study only if all of the following criteria apply:
1. Must be able to provide informed consent, as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol, according to local regulations and are at 
least 18 years of age.
2. Must be patients who, in the opinion of the treating physician, are candidates 
suitable for randomization to single agent chemotherapy or abemaciclib/fulvestrant 
combination therapy 
3. Must be female.
4. Must be of postmenopausal status due to natural cessation of ovarian function, 
surgery, therapeutic radiation or ovarian suppression with a GnRH agonist such as 
goserelin (initiated at least 28 days prior to Cycle 1 Day 1).  Patients must meet at 
least 1 of the following criteria to document post-menopausal status:

prior bilateral oophorectomy

age ≥60 years, or

age <60 years, amenorrheic for at least 12 months (in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone 
(FSH) and estradiol levels in the postmenopausal range.
5. Must have a negative serum pregnancy test at baseline (within 14 days prior to 
randomization) and agree to use medically approved precautions to prevent pregnancy 
during the study and for 12 weeks following the last dose of abemaciclib if postmenopausal 
status is due to ovarian suppression with a GnRH agonist
6. Must have confirmed HR+, HER2- recurrent, locally advanced, unresectable, or MBC with 
evidence of relapse or disease progression on or following ET.

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 IHC score 0/1+ or negative by in situ 
hybridization (FISH/CISH/SISH), as defined in the relevant ASCO/College of American 
Pathologists guidelines (Wolff et al. 2013).
7. Must have disease progression following at least 1 line of ET.  ET may have been in the 
(neo)adjuvant or metastatic setting.


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8. Must have metastatic disease with at least one site of visceral metastasis (e.g., pleura, lung, 
liver, peritoneum, omentum, ovary, or adrenal gland).  Metastases to bone only is not 
permitted in this study.
9. Must have at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009).  If the patient has only 1 measurable 
lesion, and it has been previously radiated, then progressive disease must have occurred at 
least 28 days after completion of palliative radiotherapy.
10. Must be willing to participate for the duration of the study and to follow study 
procedures
11. Must be able to swallow tablets
12. Must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 
or 1 on the scale (Oken et al. 1982)
13. Must have discontinued all previous treatments for cancer and recovered from the acute 
effects of therapy.  All patients who have experienced diarrhea as a side effect of prior 
therapies must have recovered to Grade 1 or less.
Patients must have discontinued from previous treatments, as shown below:
Previous Treatment
Length of Time Prior to Study Entry
Endocrine therapies
≥14 days
Cytotoxic therapies or targeted agents that are small 
molecule inhibitors
≥21 days or ≥5 half-lives, whichever is longer
Biologic agents that are large molecules including 
immunotherapy
≥28 days
Major surgery, excluding biopsy
≥28 days
Radiotherapy
Limited-field radiotherapy with palliative intent
≥14 days
Other radiotherapy
≥28 days


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14. Must have adequate organ function, as defined below: 
System
Laboratory Value
Hematologic
Absolute neutrophil count
≥1.5×109/L
Platelets
≥100×109/L
Hemoglobin
≥9 g/dL
Note:  transfusions to increase a patient’s hemoglobin level or initiation of erythropoietin or granulocyte-colony 
stimulating factor therapy to meet enrollment criteria are not allowed in the 14 days preceding the first dose of 
study drug.  If a patient receives transfusions, erythropoietin, or granulocyte-colony stimulating factor therapy 
≥14 days prior to the first dose, the hematologic criteria listed above must be met following the 14 day window 
and prior to the first dose of study therapy.
Hepatic
Total bilirubin
≤1.5×ULN
Except patients with a documented history of 
Gilbert Syndrome who must have a total bilirubin 
level of <3.0×ULN
ALT and AST
≤3×ULN if there is no liver metastasis,  OR  
≤5×ULN if there are liver metastases
Renal
Serum creatinine OR
≤1.5×ULN OR
Measured creatinine clearance OR
≥30 mL/min/1.73 m2
Calculated creatinine clearance (Appendix 5)
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of 
normal. 
5.2.
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply:
15. Have received prior systemic therapy (e.g., cytoxic chemotherapy, targeted treatment such 
bevacizumab, immunotherapy) for metastatic disease except ET
16. Have received more than 1 prior ET for metastatic disease.
17. Have visceral crisis including, lymphangitic spread, or leptomeningeal carcinomatosis, as 
determined by the treating physician.  “Visceral crisis” is defined by the presence of visceral 
disease associated with impending or actual severe organ dysfunction due to rapid disease 
progression as assessed by clinically significant symptoms, signs and/or laboratory studies
(Cardoso et al. 2018).
18. Have clinical evidence of symptomatic untreated central nervous system (CNS) metastases 
that may impede participation in this study. Patients with active untreated CNS metastasis 
are eligible if the investigator/treating physician has determined that CNS specific treatment 
(e.g., radiation) is not warranted and is not required and is unlikely to be required due to 
clinical and radiologic stability for the last 28 days preceding study screening.  Screening 
for CNS metastases is not required for enrollment.
19. Have received prior treatment (for any duration) with fulvestrant or any CDK4/6 inhibitor.


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20. Have received live vaccination within 28 days prior to randomization.  Seasonal flu 
vaccinations that do not contain a live virus are permitted.
21. Have a personal history of any of the following conditions within the last 12 months: 

syncope of cardiovascular etiology 

ventricular tachycardia 

ventricular fibrillation, or 

sudden cardiac arrest
22. Have serious and/or uncontrolled preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study including interstitial lung disease, 
severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection 
involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or 
a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea  
23. Have any active and clinically relevant systemic bacterial, fungal or viral infection (for 
example, bacterial infection requiring intravenous [IV] antibiotics at time of initiating study 
treatment, fungal infection, human immunodeficiency virus or viral hepatitis, or detectable 
viral infection requiring systemic therapy). Screening is not required for enrollment.
24. Have inflammatory breast cancer or a history of any other cancer unless in complete 
remission with no therapy for a minimum of 3 years. Non-melanomatous skin cancer,
carcinoma in-situ of the cervix and carcinoma in-situ of the bladder are the only exceptions 
to this exclusion criterion.
25. Have received an autologous or allogeneic stem-cell transplant.
26. Deleted. 
27. Are breastfeeding.
28. Have initiated bisphosphonates or approved Receptor activator of nuclear factor kappa-Β
ligand targeted agents (for example, denosumab) <7 days prior to C1D1.
29. Are currently enrolled in any other type of medical research judged not to be scientifically 
or medically compatible with this study.
30. Have participated, within the last 30 days, in a clinical study involving an investigational 
product.  If the previous investigational product has a long half-life, 5 half-lives or 30 days
(whichever is longer) should have passed from the last dose.  Exceptions will be considered 
on a case by case basis by the Lilly clinical research physician (CRP)/clinical research 
scientist (CRS).
5.3.
Lifestyle Considerations
Patients should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study due to the effect on cytochrome P450 (CYP)3A4 .  Investigators are 
expected to review the appropriate product label for the standard chemotherapy treatment that 
he/she has proposed for the patient. 
5.4.
Screen Failures
Screen failures are defined as patients who consent to screening but do not meet 1 or more of the 
eligibility criteria. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure patients to meet the Consolidated Standards of Reporting Trials) 


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publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. The interval between rescreening should be weeks. Individuals may be 
rescreened a maximum of one time.  The individual must sign a new ICF and will be assigned a
new identification number. Repeating laboratory testing during the screening period or repeating 
screening tests to comply with the protocol designated screening period does not reconstitute
rescreening. Repeat of laboratory testing is allowed once within the designated screening period.


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6.
Study Intervention
Study intervention is defined as any investigational intervention or marketed product intended to 
be administered to a study patient according to the study protocol.
6.1.
Study Intervention(s) Administered
Arm
Arm A
Arm B
Intervention
Abemaciclib
Fulvestrant
Chemotherapy (capecitabine, docetaxel, nab-
paclitaxel, or paclitaxel)
Dose
150 mg
500mg
Refer to PI/routine clinical practice
Schedule
BID
C1D1, C1D15, 
Day 1 of each 
subsequent cycle
Refer to PI/routine clinical practice
Route
PO
IM
Refer to PI
Abbreviations:  BID = twice a day, at least 6 hours apart; C = Cycle; D = Day; IM = intramuscular; PI = package 
insert; PO = by mouth.
For the physician’s choice of the four chemotherapies, it is expected that the investigator review 
appropriate product label/institutional guidelines for confirmation dosing (i.e., need for pre-
medication, dose, schedule, toxicity management and dose modifications). 
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only patients enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.
Investigators should consult the study drug information provided in the Pharmacy Manual and on 
the Product Label for the specific administration information (including warnings, precautions, 
contraindications, adverse reactions, and dose modifications).
6.3.
Measures to Minimize Bias:  Randomization and Blinding
This is an open-label study. Patients will be randomized to 1 of 2 treatment arms, stratified by 
endocrine sensitivity status, presence of liver metastases and postmenopausal status. 
Stratification is intended to promote balance of known prognostic factors between treatment 
arms.


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Randomization can occur up to 7 days prior to C1D1. Before a patient is randomized, the 
chemotherapy choice that the patient would receive if she was randomized to Arm B will be 
recorded in the Interactive Web Response System.
6.4.
Study Intervention Compliance
Patient compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by direct questioning, counting returned tablets/capsules, etc. Deviation from the 
prescribed dosage regimen should be recorded in the electronic case report form (eCRF).
Some study intervention will be administered only at the investigational sites by the authorized 
study site personnel.  As a result, treatment compliance is ensured.
A patient will be considered noncompliant if he or she takes <75% of the planned doses for 
assigned study drug in a cycle.  A patient will also be considered noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken ≥125% of the planned doses 
of study drug in a cycle.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.
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 or grapefruit juice as well as inducers and inhibitors of CYP3A 
should be substituted or avoided if possible (Appendix 7). 
Abemaciclib can be coadministered with drugs which are substrates of CYP enzymes.
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should consult 
the study drug information provided on the Product Label for dose adjustment recommendations.
Specifically for coadministration with the strong CYP3A inhibitor ketoconazole, the abemaciclib 
dose should be reduced to 50 mg twice daily.
Abemaciclib and its major active metabolites inhibit the renal transporters organic cation 
transporter 2, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K.  In vivo 
interactions of abemaciclib with clinically relevant substrates of these transporters, such as 
creatinine, may occur.


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Based on the in vitro inhibition of P-glycoprotein and breast cancer resistance protein observed 
with abemaciclib, in vivo interactions of abemaciclib with narrow therapeutic index substrates of 
these transporters, such as digoxin, may occur.
In clinical studies in patients with breast cancer, no clinically relevant pharmacokinetic drug
interactions were observed between abemaciclib and anastrozole, exemestane, fulvestrant,
letrozole, or tamoxifen.
The Lilly CRP should be contacted if there are any questions regarding concomitant or prior 
therapy.  No other chemotherapy, immunotherapy, herbal supplements and/or herbal drugs 
intended to treat cancer, or experimental drugs will be permitted while the patients are on this 
study.
6.5.1.
Palliative Medicine and Supportive Care 
Palliative radiation therapy is permitted for irradiating small areas of painful metastases that 
cannot be managed adequately using systemic or local analgesics after discussion with and 
agreement of the Lilly CRP or designee.  Such areas must not be an identified target lesion and 
must not constitute progressive disease or meet RECIST criteria for progressive disease.  Any 
symptomatic deterioration or clinical disease progression requiring, in the opinion of the 
investigator, other forms of specific antitumor systemic therapy, will be cause for discontinuation 
of study therapy.
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study.  Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the case 
report form (CRF).  Replacement hormonal therapy (e.g., thyroid or adrenocorticoid 
supplementation) will be allowed.  Post-menopausal hormone replacement therapy (e.g., 
estrogen or progesterone agents) is not allowed.
Patients should receive full supportive care.  The use of granulocyte-colony stimulating factor is 
permitted at the discretion of the investigator based on ASCO (Smith et al. 2015) and European 
Society for Medical Oncology (Crawford et al. 2009) guidelines.  
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008).  Prophylactic 
antibiotic treatment should be consistent with ASCO guidelines (Flowers et al. 2013).
Megestrol acetate use is not permitted for this study.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
6.5.2.
Supportive Management for Diarrhea in Patients Receiving Abemaciclib
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:


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
At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (e.g., 
loperamide) and notify the investigator for further instructions and appropriate follow-up.

Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear liquids 
per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with anti-diarrheal therapy within 24 hours to at least Grade 1 
(per CTCAE v 5.0), study abemaciclib treatment should be suspended until diarrhea is 
resolved to at least Grade 1.

When abemaciclib treatment recommences, dosing should be adjusted as outlined in 
Section 6.6.1.  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 intravenous rehydration) and/or associated with fever or severe
neutropenia, broad-spectrum antibiotics such as fluoroquinolones should be considered.
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting should 
be carefully monitored and given intravenous fluid and electrolyte replacement as clinically 
indicated.
6.5.3.
Bisphosphonates and Receptor Activator of Nuclear Factor Kappa-Β Ligand 
(RANK-L) Targeted Agents
Patients with bone metastases present on baseline imaging should be appropriately treated with 
bisphosphonates or RANK-L targeted agents (for example, denosumab), per respective approved 
labels. Initiation of treatment with bone-modifying agents must begin at least 7 days prior to 
randomization.  Patients receiving bisphosphonates or RANK-L targeted agents should not 
switch treatments (for example, replace a bisphosphonate with denosumab) while on study 
treatment. However, exceptional cases without evidence of PD may be considered in 
consultation with the CRP.  These exceptional cases will not incur a protocol deviation.
6.6.
Dose Modification
6.6.1.
Abemaciclib
Please refer to the following tables for dose modifications for adverse reactions related to 
abemaciclib.  If dose reduction is necessary, decrease the dose by 50 mg at a time.  Discontinue 
abemaciclib for patients unable to tolerate 50 mg twice a day, at least 6 hours apart(BID).


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Abemaciclib dose modification for adverse reactions
Dose Level
Abemaciclib dose in combination with 
fulvestrant
Recommended starting dose
150 mg BID
First dose reduction
100 mg BID
Second dose reduction
50 mg BID
Third dose reduction
Not applicable
Abbreviation:  BID = twice a day, at least 6 hours apart.
Abemaciclib dose modification and management- hematologic toxicitiesa
CTCAE Grade
Abemaciclib dose modifications
Grade 1 or 2
No dose modification is required.
Grade 3
Suspend dose until toxicity resolves to ≤Grade 2. 
Dose reduction is not required.
Grade 3 recurrent or Grade 4
Suspend dose until toxicity resolves to ≤Grade 2. 
Resume at next lower dose.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.
a
If blood cell growth factors are required, suspend abemaciclib dose for at least 48 hours after the last dose of 
blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already 
performed for the toxicity that led to the use of the growth factor.  Growth factor use as per current treatment 
guidelines.


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Abemaciclib dose modification and management- diarrhea
At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral 
fluids.
CTCAE Grade
Abemaciclib dose modifications
Grade 1
No dose modification is required.
Grade 2
If toxicity does not resolve within 24 hours to 
<Grade 1, suspend dose until resolution. No dose 
reduction is required.
Grade 2 that persists or recurs after resuming the 
same dose despite maximal supportive measures
Suspend dose until toxicity resolves to ≤Grade 1. 
Resume at next lower dose.
Grade 3 or 4 or requires hospitalization 
Suspend dose until toxicity resolves to ≤Grade 1. 
Resume at next lower dose.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.
Abemaciclib dose modification and management - increased ALT/AST
CTCAE Grade for ALT and AST
Abemaciclib dose modifications
Grade 1 (>ULN-3.0 x ULN)
Grade 2 (>3.0-5.0 x ULN),
WITHOUT increase in total bilirubin above 2 x 
ULN
No dose modification is required.
Persistent or Recurrent Grade 2, or Grade 3 (>5.0-
20.0 x ULN), WITHOUT increase in total bilirubin 
above 2 x ULN
Suspend dose until toxicity resolves to baseline or 
Grade 1. Resume at next lower dose.
Elevation in AST and/or ALT >3 x ULN WITH 
total bilirubin >2 x ULN, in the absence of 
cholestasis
Discontinue abemaciclib.
Grade 4 (>20.0 x ULN)
Discontinue abemaciclib.
Abbreviations:  ALT = alanine aminotransferase, AST = aspartate aminotransferase, CTCAE = Common 
Terminology Criteria for Adverse Events, ULN = upper limit of normal.


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Abemaciclib dose modification and management - interstitial lung disease/pneumonitis
CTCAE Grade
Abemaciclib dose modifications
Grade 1 or 2
Grade 2 that persists or recurs despite maximal 
supportive measures and does not return to 
baseline or Grade 1 within 7 days
No dose modification is required.
Suspend dose until toxicity resolves to baseline or 
Grade ≤1. Resume at next lower dose.
Grade 3 or 4
Discontinue abemaciclib.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.
Abemaciclib dose modification and management - nonhematologic toxicities excluding 
diarrhea, increased ALT/AST, and ILD/pneumonitis
CTCAE Grade
Abemaciclib dose modifications
Grade 1 or 2
No dose modification is required.
Persistent or recurrent Grade 2 toxicity that does not 
resolve with maximal supportive measures (within 7 
days to baseline) or Grade 1
Suspend dose until toxicity resolves to baseline or 
Grade 1. Resume at next lower dose.
Grade 3 or 4
Suspend dose until toxicity resolves to baseline or 
Grade 1. Resume at next lower dose.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.
6.6.2. 
Dose Suspension and Cycle Delay
Both dose suspension (within a cycle) and cycle delay are permitted. 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. Patients not recovering from toxicity within 14 days should be considered for 
discontinuation. In exceptional circumstances, a delay >14 days is permitted upon agreement 
between the investigator and the Lilly CRP.
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 
circumstances, a delay >7 days is permitted upon agreement between the investigator and the 
Lilly CRP.
6.6.3
   Fulvestrant and Chemotherapeutic Agents
Refer to local PI and label for dose adjustments related to fulvestrant or any of the 
chemotherapeutic agents in the study. There is no cross-over between treatment arms in this 
study. In addition, patients in the abemaciclib plus fulvestrant arm who develop unacceptable 
toxicity owing to abemaciclib must discontinue abemaciclib and may remain on fulvestrant; 
patients who develop unacceptable toxicity due to fulvestrant must discontinue fulvestrant and 
may remain on abemaciclib.


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6.7.
Intervention after the End of the Study
The end of the study is defined as the date of the last visit of the last patient in the study or last 
scheduled procedure shown in the SoA (Section 1.3) for the last patient in the trial globally.
6.7.1.
Treatment after Study Completion 
Study completion will occur following the final analysis of primary and secondary objectives, as 
determined by Lilly.  Investigators will continue to follow the SoA (Section 1.3) for all patients 
until notified by Lilly that study completion has occurred.
6.7.1.1.
Continued Access
Patients who are still on study intervention (i.e., study treatment) at the time of study completion 
may continue to receive study intervention if they are experiencing clinical benefit and no undue 
risks. The continued access period will apply to this study only if at least 1 patient is still 
receiving study intervention when study completion occurs.  Lilly will notify investigators when 
the continued access period begins.  Lilly may allow patients to enroll in a “rollover” protocol to 
provide long-term continued access for patients enrolled in this study.
Patients are not required to sign a new ICF before treatment is provided during the continued 
access period; the initial ICF for this study includes continued access under this protocol.
The continued-access period will begin after study completion and ends at End of Study.  The 
patient’s continued access to study intervention will end when a criterion for discontinuation is 
met (Section 7).  Continued-access follow-up will begin when the patient and the investigator 
agree to discontinue study intervention and lasts approximately 30 days.  Follow-up procedures 
will be performed as shown in the SoA (Section 1.3).
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 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.


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7.
Discontinuation of Study Intervention and Patient
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention 
Patients will be discontinued from the study intervention in the following circumstances:

enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

patient decision
o
the patient or the patient’s designee (for example, parents or legal guardian) 
requests to discontinue study product

sponsor decision

investigator decision
In addition, patients will be discontinued from study treatment in the following circumstances:

The patient becomes pregnant during the study

The patient is significantly noncompliant with study procedures and/or treatment

Disease progression (as defined by RECIST v1.1). 

Unacceptable toxicity

The patient, for any reason, requires treatment from another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication.  Discontinuation 
from abemaciclib will occur prior to introduction of the new agent

If the investigator decides that the patient should be discontinued from study treatment 
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 1.3 (SoA), Section 8.3 (AEs and 
SAEs), and Section 8.2 (Safety Assessments) of the protocol.
7.2.
Patient Discontinuation/Withdrawal from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

subject decision
o
the patient or the patient’s designee, for example, parents or legal guardian
requests to be withdrawn from the study


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o
The patient becomes pregnant during the study. See Section 8.3 regarding 
regulatory reporting requirements on fetal outcome.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 1.3 (SoA), Section 8.3 (AE and SAE), and Section 8.2 (Safety 
Assessments) of this protocol.
7.2.1.
Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  
If the investigator and the sponsor CRP agree it is medically appropriate to continue, the 
investigator must obtain documented approval from the sponsor CRP to allow the inadvertently 
enrolled patient to continue in the study with or without treatment with investigational product.  
Safety follow up is as outlined in Section 1.3 (SoA), Section 8.3 (AEs and SAEs), and Section 
8.2 (Safety Assessments) of the protocol.
7.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the patient
within legal and ethical boundaries for all patients randomized, including those who did not get 
investigational product.  Public sources may be searched for vital status information.  If vital 
status is determined, this will be documented and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Section 
10.1.7.2.


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8.
Study Assessments and Procedures

Unless otherwise stated in the subsections below, all samples collected for specified 
laboratory tests will be destroyed within 60 days of 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.

Study procedures and their timing are summarized in the SoA (Section 1.3).  Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
intervention.

Adherence to the study design requirements, including those specified in the SoA
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the patient’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (Section 1.3).

Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1.
Efficacy Assessments
Tumor assessments will be performed for each patient as shown in the SoA (Section 1.3).  
RECIST v1.1 (Eisenhauer et al. 2009) will be applied as the primary criteria for assessment of 
tumor response and date of tumor progression.  Tumor assessment will be performed until 
documented PD as per the RECIST v1.1 criteria, initiation of new anticancer therapy, 
discontinuation of patient from overall study participation (eg, death, patient's request, lost to 
follow-up), or completion of the study, whichever occurs first.
The following general guidelines will apply:

A positron emission tomography (PET) scan alone or as part of a PET-computer 
tomography (CT) scan may be performed separately as part of routine clinical care but 
cannot be used for tumor assessment.

It’s recommended that the CT scans of the abdomen and pelvis be performed with IV 
contrast, whenever possible. For patients with known hypersensitivity to CT contrast 
material, a CT scan of the chest without contrast and gadolinium-enhanced MRI of the 
abdomen and pelvis are encouraged.


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
The CT portion of a PET-CT scan may be used as a method of response assessment if the 
site can document that the CT is of similar diagnostic quality to a diagnostic CT (i.e., 
with intravenous and oral contrast).

The same measuring modality must be used consistently throughout study for tumor 
assessment. 

Measurements should be performed on schedule even in the event of study treatment 
delay or omission.

Imaging delays due to patient deterioration will not be considered a protocol deviation.

Patients who discontinue study treatment without document progressive disease should 
continue to undergo clinical/radiologic tumor assessment until progressive disease is 
documented per RECIST 1.1 criteria, death, or study completion, whichever occurs first.
Bone scintigraphy and tumor assessment in patients with bone metastases 

Please refer to the SoA (Section 1.3) for assessment timelines.

Bone scintigraphy will be performed in all patients. Prior bone scintigraphy, obtained 
within 45 days of C1D1 as part of routine clinical care, may serve as the baseline bone 
scintigraphy.

Bone scintigraphy should be repeated to confirm complete response (CR) or performed as 
clinically indicated (e.g. new or worsening bone pain, or increasing alkaline phosphatase 
level, or other signs and symptoms of new/progressing bone metastases).

Bone scintigraphy should be repeated every 24 weeks after a CR is confirmed.

For patients with new lesions identified by post-baseline bone scintigraphy , targeted 
assessments by X-ray, CT scan with bone windows, or MRI will be performed to confirm 
findings.
Bone lesions identified at baseline will follow the same assessment schedule as for 
measurable lesions.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).  For each 
patient, vital signs, laboratory tests, and other tests should be collected as shown in the SoA 
(Section 1.3).
Results from any clinical laboratory test analyzed by a central laboratory (refer to Appendix 2) 
will be provided to investigative sites by Lilly or its designee.
Refer to Section 8.3 for details on the recording of AEs.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
8.2.1.
Clinical Safety Laboratory Assessments

Lilly or its designee will provide the investigator with the results of safety laboratory 
tests analyzed by a central vendor, if a central vendor is used for the clinical trial.  

See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency.


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
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the CRF. 
The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
patient's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or until the completion of V801 should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by 
the investigator or medical monitor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
o
If there is an abnormal laboratory value or abnormal value for any other diagnostic or 
screening test (for example, blood pressure increased, neutrophils decreased, etc.) and 
it is known to be related to a disease diagnosis (for example, hypertension, 
neutropenia, etc.), this should be entered into the CRF.  Do not enter the test 
abnormality, enter the disease diagnosis or categorical term. 
o
If laboratory values from non-protocol specified laboratory assessments require a 
change in patient management (e.g., dose modification) or are considered clinically 
significant by the investigator (e.g., AE or SAE), then the event(s) results must be 
recorded in the CRF.
8.2.1.1.
Hepatic Safety Monitoring
Liver testing (Section 10.4), including alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBL), direct bilirubin (D. 
Bil), gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 2 
to 4 days to confirm the abnormality and to determine if it is increasing or decreasing, if 1 or 
more of these conditions occur:
If a participant with baseline results 
of ... 
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥5x ULN or
ALT or AST ≥3x ULN concurrent with TBL ≥2x ULN
ALT or AST ≥1.5x ULN
ALT or AST ≥3x baseline or
ALT or AST ≥2x baseline concurrent with TBL ≥2x ULN


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If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), and history of concomitant 
medications (including over-the-counter, herbal and dietary supplements, history of alcohol 
drinking and other substance abuse).  In addition, the evaluation should include a blood test for 
prothrombin time (international normalization ratio); serological tests for viral hepatitis A, B, C, 
E, and autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT 
scan). 
Based on the patient’s history and initial evaluation results, further testing should be considered, 
in consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and serum phosphatidylethanol.  Based on the circumstances and the 
investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, and/or liver biopsy.  
Additional Hepatic Safety Data Collection
Additional safety data should be collected via the CRF if 1 or more of the following conditions 
occur: 
In participants enrolled with baseline ALT or AST <1.5x ULN

Elevation of serum ALT or AST to ≥5x ULN on 2 or more consecutive blood tests

The combination of elevated ALT or AST ≥3x ULN and elevated TBL ≥2x ULN
In participants enrolled with baseline ALT or AST ≥1.5x ULN

Elevated ALT or AST ≥3x baseline on 2 or more consecutive tests

The combination of elevated ALT or AST ≥2x baseline and elevated TBL ≥2x ULN
In all study participants 

Discontinuation from study treatment due to a hepatic event or abnormality of liver tests

Occurrence of a hepatic event considered to be an SAE
8.2.1.2.
Venous Thromboembolic Events (VTEs)
In the randomized Phase 3 studies in breast cancer participants (Studies JPBL and JPBM, 
abemaciclib in combination with ET), there was a greater number of participants who 
experienced VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus 
endocrine therapy arm.  The majority of the events were non-serious and were treated with 
low-molecular-weight heparin.  Generally, these events did not result in discontinuation of the 
study treatment.  In Study JPCG, a greater number of participants experienced VTE events in the 


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abemaciclib plus tamoxifen arm compared with the abemaciclib monotherapy arms.  No events 
of VTE resulted in death or discontinuation of the study treatment and most patients were treated 
with low-molecular-weight heparin.  In studies with single-agent abemaciclib use in the MBC 
population or other tumor types, including non-small cell lung cancer, no increased rates of 
VTEs were observed as compared to the incidence of VTEs for these particular patient 
populations who were treated with other anticancer agents.  At this time, the mechanism 
underlying the association between abemaciclib and the occurrence of VTEs is not known.  
VTEs have been reported with other CDK4 and 6 inhibitors and endocrine therapy is known to 
be associated with the occurrence of VTEs.  Participants should be monitored for signs 
and symptoms of deep vein thrombosis and pulmonary embolism and treated as medically 
appropriate.
8.2.1.3.
Serum Creatinine Increased
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting glomerular filtration rate (as measured by ioxhexol 
clearance).  In clinical studies, increases in serum creatinine occurred within the first month of 
abemaciclib dosing (remained elevated but stable through the treatment period) were reversible 
upon treatment discontinuation, and were not accompanied by changes in markers of renal 
function, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate
based on cystatin C.  
Dose adjustment (omission, reduction, or discontinuation) should not be based solely 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, a cystatin C 
measurement may be performed to confirm renal status. Dose alteration should follow the 
protocol guidance for non-hematological toxicities.
8.2.1.4.
Interstitial Lung Disease (ILD)/Pneumonitis
Interstitial lung disease/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. Additional information is available in the IB.
Ask your participants to report any new or worsening pulmonary symptoms such as dyspnea, 
cough, and fever, and investigate and treat as per your local clinical practice (including 
corticosteroids as appropriate). If ILD/pneumonitis is suspected, investigations may include 
imaging, such as high resolution CT, broncheoalveolar lavage, and biopsy as clinically indicated.
Refer to Section 6.6.1 for guidance on dose adjustments of abemaciclib for patients with 
ILD/pneumonitis (see Appendix 6 for ILD/pneumonitis Common Terminology Criteria for 
Adverse Events [CTCAE] grades). Discontinue abemaciclib in cases of severe 
ILD/pneumonitis.
8.3.
Adverse Events and Serious Adverse Events
The investigator should provide AE verbatim terms and then the terms will be mapped by Lilly 
or its designee to corresponding terminology within the Medical Dictionary for Regulatory 


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Activities (MedDRA) Lower Level term (LLT) dictionary. The investigator will use CTCAE v 
5.0 to assign AE severity grades.
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is otherwise explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
After the ICF is signed, study site personnel will record via CRF 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, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure, investigational product, via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via CRF, clarifying if possible, the circumstances leading 
to any dosage modifications, or discontinuations of treatment.
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


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
a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria.  
The SAE reporting to the sponsor begins after the patient has signed the ICF and has received 
investigational product.  However, if an SAE occurs after signing the ICF, but prior to receiving 
investigational product, the SAE should be reported to the sponsor as per SAE reporting 
requirements and timelines (see Section 8.3.1) if it is considered reasonably possibly related to 
study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Patients with a serious hepatic AE should have additional data collected using the 
CRF..
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  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 subjects once they have 
discontinued and/or completed the study (the patient disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject 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.
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.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information in the IB and that the investigator identifies as 
related to the study drug or study procedure.  United States 21 CFR 312.32 and European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs. Lilly has procedures 


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that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and associated detailed guidances.
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
Although all AEs, after signing the ICF, are recorded by the site in the CRF/electronic data entry, 
SAE reporting to Lilly begins after the patient has signed the ICF and has received study drug. 
However, if a SAE occurs after signing the ICF, but prior to receiving study drug, it needs to be 
reported ONLY if it is considered reasonably possibly related to study procedures.
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the AE section of the CRF.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of investigator awareness. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. SAEs, 
including death, caused by disease progression should not be reported unless the investigator 
deems them to be possibly related to study treatment.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about AE
occurrences.
8.3.2.
Follow-Up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 1.3). 
8.3.3.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
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8.3.4.
Pregnancy
This section is not applicable as the patient population being evaluated is post-menopausal 
women (refer to Section 5 for additional details).
8.3.5.
Cardiovascular and Death Events
Not applicable.
8.3.6.
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 patients, monitor quality, and to facilitate 
process and product improvements.Patients will be instructed to contact the investigator as soon 
as possible if he or she has a complaint or problem with the investigational product so that the 
situation can be assessed.
8.4.
Treatment of Overdose
Refer to the IB and/or Product Label for intervention or comparator for available information on 
the signs, symptoms, and treatment of overdose.
8.5.
Pharmacokinetics
Not applicable
8.6.
Pharmacodynamics
Not applicable
8.7.
Genetics
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA
(Section 1.3) where local regulations allow.  
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 breast 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 investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
ERBs/IRBs impose shorter time limits.  This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of study treatment.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome and exome 


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sequencing, genomewide association studies and candidate gene studies.  Regardless of 
technology utilized, data generated will be used only for the specific research scope described in 
this section.
8.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of participant 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, ribonucleic acid, proteins, lipids, and other cellular elements.
This study will analyze biomarkers relevant to abemaciclib, mechanism of action of study 
treatment, the variable response to study drug(s), immune function, tumor microenvironment, 
and pathways associated with cancer.  These samples may also be used to develop related 
research methods or to validate diagnostic tools or assays.
Plasma sample for biomarker research will be collected at the times specified in the Schedule of 
Activities (Section 1.3) where local regulations allow.  A maximum of 3 samples may be 
collected at additional time points during the study if warranted and agreed upon by the 
investigator and Lilly.
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 study.  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 Section 8.8.
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of study treatment.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  Existing approaches, including mutation profiling, copy number variability 
analysis, gene expression assays and protein measurements may be performed on these samples 
to assess potential associations between these biomarkers and clinical outcomes.
8.9.
Medical Resource Utilization and Health Economics
The self-reported questionnaires will be administered according to the SoA (Section 1.3) in 
countries where the questionnaires have been translated into the native language of the region 
and linguistically validated.  Patient-reported questionnaires should be completed by patients 
when a language translation is available in which the patient is fluent or literate.


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8.9.1.
Patient-Reported Outcomes (PRO)
The following PROs will be measured using an electronic device:

Worst-pain numeric pain rating scale (NRS)

Bowel movement (BM) frequency

Bristol Stool Form Scale

Loperamide doses

Functional Assessment of Cancer Therapy- Side Effects (FACT-GP5)

Patient reported outcome-Common Terminology Criteria in Adverse Events (PRO-
CTCAE)

European Organisation for Research and Treatment of Cancer quality of life 
questionnaire (abridged) (EORTC IL36)  
Worst-pain NRS is a single item that asks about worst pain in the past 24 hours.
Use of pain medication will be assessed in conjunction with the worst-pain assessment.  Data on 
each individual prescription and over-the-counter analgesic medication will be recorded on the 
Concomitant Medications eCRF.  The use of pain medications should be reviewed with the 
patient at each subsequent visit.  Any changes to analgesic use (new or stopped analgesics) will 
be recorded on the eCRF.  Pain medication will be classified into medication categories, using 
the World Health Organization analgesic ladder.  A medication category will be assigned based 
on the maximum analgesic therapy administered for that cycle on a routine basis.
BM frequency is a single item that asks about bowel movement frequency.
Bristol Stool Form Scale is a single item that asks about stool form (Lewis et al. 1997).
Loperamide doses is a single item that asks about number of loperamide doses.
The FACT GP5 is a single item from the FACT-G questionnaire that asks about how bothered 
the patient is about the side effects of treatment (Cella et al. 1993).
PRO-CTCAE is a patient-reported outcome measurement system developed by the National 
Cancer Institute to collect symptomatic AEs from cancer patients enrolled in clinical trials (Bash 
et al. 2014; Dueck et al. 2015).  The PRO CTCAE item library includes 78 symptomatic AE and 
a total of 124 total items-  some AEs include multiple items (e.g. frequency and/or severity 
and/or interference [NCI 2018]).  From this item library, 15 AEs (29 total items) were selected 
based on the most frequent patient-felt AEs reported in MONARCH 2 and the chemotherapy 
comparator FDA labels. 
The EORTC IL36 is an abridged 17-item version of the 30-item EORTC QLQ-C30 (Aaronson 
et al. 1993).  This version omits the 13 Symptom items and consists solely of the Global Health 
and Functional scales:
o
global health status/quality of life (2 items)
o
functional scales (15 total items addressing either physical, role, emotional, cognitive, or 
social functioning)


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The full EORTC QLQ-C30 is broadly used in cancer trials, validated, and available in over 80 
different languages. 
For each PRO, the population will include all patients who completed at least 1 baseline 
followed by at least 1 postbaseline assessment.
8.9.2.
Healthcare Resource Utilization
Data, associated with medical encounters, will be collected per SoA (Section 1.3) in the CRF by 
the investigator and study-site personnel for all patients.  
Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to describe utilization between arms and will include:

Hospitalizations (reason and duration)

Emergency room visits (reason)

Analgesic use (and other relevant concomitant medication as needed)

Growth factor use

Transfusions:  use and type


C O N FI D E N TI A L
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5 2
9.
St atistic al C o nsi der ati o ns
9. 1.
St atistic al H y p ot heses
T he pri mar y  o bject i ve of  t he st u d y is t o assess t he c o mpara bili t y of a be macicli b i n c om bi nat i on 
wi t h f ul vestra nt ( Ar m A) t o c he m ot hera p y ( Ar m B) wit h res pect t o O R R.  P r o gressi o n-free 
s ur vi val c o m para bilit y is a n i m p orta nt sec o n dar y e n d p oi nt for t he st u d y , a n d wi ll be assesse d
o nl y  if O R R c o m para bilit y is declare d, usi n g a gate kee pi n g testi n g strate g y.  T he c o m para bilit y 
will be de clare d if t here is hi g h c o nfi de nce (i.e., 8 0 % p osteri or pr o ba bilit y)  t hat t he tr ue effect of 
Ar m A is n ot w orse t ha n t hat of Ar m B b y m o re t ha n a s pecifie d mar gi n.  
T he h y p ot heses t o be teste d are: 

O R R c o m para bilit y :  T here is at least a n 8 0 % p oster i or pr o ba bility t hat tr ue O R R Ar m B –
tr ue O R R Ar m A < 1 0 %, w here 1 0 % is t he defi ne d mar gi n f or O R R c o m para bilit y

P F S c o m para bili t y ( gate d sec o n dar y e n d p oi nt):  T here is at least a n 8 0 % p osteri or 
pr o ba bilit y t hat tr ue P F S hazar d rati o Ar m A /Ar m B - 1 < 0. 2, w here 0. 2 is t he defi ne d ma r gi n 
f or P F S c o mpara bilit y . 
9. 2.
S a m ple Size Deter mi n ati o n
A p pr o xi matel y  3 0 0 pat ient s will be ra n d o mize d i n a 1: 1 rati o t o Ar m A a n d Ar m B f or a n 
esti mate d t otal of 1 5 0 pati e nt s per ar m.
T he pri mar y a nal ysis of O R R t o assess O R R c o mp ar a bilit y will  b e p erfor m e d a p pr o xi matel y 
6 m o nt hs after last patie nt e nteri n g treat me nt; t he fi nal a nal ysis o f P F S t o assess P F S 
c o mpara bili t y will  b e p erfor m e d, if O R R c o m para bilit y is declare d, w he n a p pr o xi matel y
1 8 0 P F S e ve nts i n t otal ha ve bee n o b ser ve d. 
O R R
C o m para bili t y of  O R R will be de clare d if t h e fol l owi n g Ba yesia n criteri o n is ac hie ve d i n t he 
pri mar y O R R a nal ysis : 
P os t erior P( tr ue O R R Ar m B – tr ue O R R Ar m A < 1 0 %) > 8 0 %
F ull detail re gar di n g t he Ba yesia n m o del f or O R R (i ncl u di n g pri or s pecificat i ons) will be 
pr o vi de d i n t he st atistical a nal ysis pla n ( S A P ). 
 
 
 
 
 
 
  
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
 
 
 
 
 
 
 
  
 
 
 
 
 
P F S
Pr o gressi o n -free s ur vi val c o m para bilit y will be decl are d if O R R c o m para bilit y is declare d A N D 
t he f o ll owi n g Ba yesia n crit erio n i s ac hie ve d i n t he fi nal P F S a nal ysis: 
P os t erior P ( H R – 1 < 0. 2) > 8 0 %, w here H R = tr ue hazar d Ar m A /tr ue hazar d Ar m B
F ull detail re gar di n g t he Ba yesia n m o del f or P F S (i ncl u di n g pri or s pecificati o ns) will be 
pr o vi de d i n t he S A P. 
C CI


C O N FI D E N TI A L
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5 4
Si m ulati o ns were c o n d ucte d t o e val uate n u m ber of P F S e ve nts a n d pr o ba bilit y of  declari n g 
 
 
 
 
 
 
 
 
 
 
 
  
C CI


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5 5
 
 
 
  
9. 3.
P o p ul ati o ns f or A n al yses
T he f o ll owi n g a nal ysis sets will be defi ne d f or t his st u d y :
I nte nti o n-t o-Tre at (I T T) p o p ul ati o n :  will i ncl u de all ra n d o mize d pat ient s.  T he I T T a nal ysis 
of  efficac y data will c o nsi der all ocat i on of pati e nt s t o treat me nt gr o u ps as ra n d o mize d a n d n ot b y 
act ual treat me nt recei ve d.  T his a nal ysis set will be use d f or all baseli ne a n d efficac y a nal yses. 
S afet y p o p ul ati o n :  will i ncl u de all ra n d o mize d pati e nt s w h o receive d a n y q ua nt ity of  st u d y 
treat me nt, re gar dless o f t heir eli gi bility f or t he st u d y.  T he safety e val uat i on will be perf or me d 
base d o n t he first d ose of st u d y treat me nt a pati e nt act uall y recei ve d, re gar dless of t he ar m t o 
w hic h he or s he was ra n d o mize d.  T he safet y a nal ysis set will be use d f or all d osi n g/e x p os ure, 
safety a nal yses, a n d health ec o n o mics a nal yses .
9. 4.
St atistic al A n al yses
9. 4. 1.  
Ge ner al St atistic al C o nsi der ati o ns
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  Lill y or its desig nee.
P os t erior m e dia ns a n d Ba yesia n cre di ble i nter vals will be re p orte d f or t he e n d p oi nts ( O R R a n d 
P F S) f or w hic h Ba yesia n a nal yses ha ve bee n s pecifie d.
All fre q ue ntist tests of treat me nt effects will be c o n d ucte d at a 2-si de d al p ha le vel of 0. 0 5, u nl ess 
ot her wi se state d, a n d all c o nfi de nce i nter vals ( CIs) will be gi ve n at a 2 si de d 9 5 % le vel.
A n y c ha n ge t o t he data a nal ysis met h o ds descri be d i n t he pr ot oc ol will re q uire a n a me n d me nt 
o nl y  if it c ha n ges a pri ncip al  feat ure of t he pr ot oc ol.  A n y ot her c ha n ge t o t he data a nal ysis 
met h o ds descri be d i n t he pr ot oc ol, a n d t he j ustificati o n f or ma ki n g t he c ha n ge, will be descri be d 
i n t he S A P a n d t he cli nical st u d y re p ort.  A d ditio n al  e x plor at or y  a nal yses of t he data will be 
c o n d ucte d as dee me d a p pr o priate.
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9.4.2.
Efficacy Analyses
Objective Response Rate is defined as the number of patients who achieve a best overall 
response of CR or partial response (PR) divided by the total number of patients randomized to 
the corresponding treatment arm (ITT population), based on investigator-assessed tumor 
responses.  Confirmations of CR and PR are not required.  Primary comparison between 
treatment arms will be based on the Bayesian decision rule as described in Section 9.2. The 80th
percentile of the posterior distribution for the difference in true ORR (true ORRArm B – true 
ORRArm A) will be calculated and compared to 10%. In addition, the median of the posterior 
distribution for ORR, with 95% equal-tailed credible interval, will be summarized for each 
treatment arm. 
Progression-free Survival is defined as the time from randomization until the first occurrence 
of documented disease progression per RECIST 1.1 criteria, or death from any cause in the 
absence of progressive disease.  Progression-free survival will be based on investigator-assessed
tumor responses; there will not be an independent central review of imaging data.  Patients 
known to be alive and without disease progression will be censored at the time of the last 
adequate tumor assessment (a detailed PFS event/censoring scheme is provided in the table 
below).  A (stratified) Bayesian Cox regression model will be used to estimate the PFS HR 
comparing Arm A and Arm B.  The 80th percentile of the posterior distribution of the HR 
comparing Arm A and Arm B will be calculated and compared to 1.2.  In addition, the posterior 
medians and associated 95% credible intervals for true median PFS by treatment arm will be 
provided. Sensitivity analyses for PFS will be described in the SAP.
Progression-free Survival 2:  Since exact progression date on post-therapies may not be 
available, in general, progression-free survival 2 (PFS2) is defined as the time from 
randomization to the discontinuation date of next-line (first line of post-discontinuation 
treatment), or starting date of the second line of post-discontinuation treatment or death from any 
cause, whichever is earlier.  If the patient is alive at the cutoff for analysis, and a PFS2 event has 
not been observed, PFS2 data will be censored on the last date the patient was known to be alive.  
A detailed definition of PFS2 will be described in the SAP. 


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PFS Event/Censoring Scheme
Situation
Date of Event or Censor
Event / Censor
Tumor progression or death
Earliest date of PD or death
Event
No tumor progression and no death
Date of last adequate radiological assessment or 
date of randomization (whichever is later)
Censored
Unless
No baseline radiological tumor assessment 
available
Date of randomization
Censored
No adequate post baseline radiological 
tumor assessment available 
and death reported after 2 scan intervals 
following randomization
Date of randomization
Censored
New anticancer treatment started 
(excluding maintenance endocrine therapy 
following chemotherapy) and no tumor 
progression or death within 14 days
Date of adequate radiological assessment prior 
to (start of new therapy +14 days) or date of 
randomization (whichever is later)
Censored
Tumor progression or death
documented immediately after 2 or more 
scan intervals following last adequate 
radiological tumor assessment or 
randomization (whichever is later)
Date of last adequate radiological assessment or 
date of randomization (whichever is later)
Censored
Abbreviations:  CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; SAP = statistical analysis plan; SD = stable disease. 
Notes: 
(1) Symptomatic deteriorations (i.e. symptomatic progressions, which are not radiologically confirmed) will not be 
considered as progression
(2) Adequate radiological tumor assessment refers to an assessment with one of the following responses:  CR, PR, 
SD or PD
(3) For definition of 2 scan intervals, including any adjustment for scan window, see SAP
Time to Response
Time to Response (TTR) is defined as the time from randomization until the date that 
measurement criteria for CR or PR (whichever is first recorded) are first met, per RECIST v1.1. 
Duration of Response
Duration of response is defined as the time from the date that measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date that disease is recurrent or 
documented disease progression is observed, per RECIST 1.1 criteria, or the date of death from 
any cause in the absence of documented disease progression or recurrence.
9.4.3.
Safety Analyses
All patients in the safety analysis set will be evaluated for safety and toxicity.
The MedDRA Version (25.0x [or higher]) will be used when reporting AEs by MedDRA terms.  
The MedDRA LLT will be used in the treatment-emergent computation.  Treatment-emergent 


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adverse events will be summarized by System Organ Class and by decreasing frequency of 
Preferred Term (PT) within the System Organ Class.
Safety analyses will include summaries of the following:

AEs, including severity in CTCAE grade 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 
9.4.4.
Other Analyses
9.4.4.1.
Patient-Reported Outcome (PRO)
The number of missing and incomplete questionnaires/assessments will be summarized for each 
instrument by visit and treatment arm, overall by treatment arm, and overall for the trial (all 
visits, all treatment arms).
Patient-reported outcomes are measured through electronic versions of the following:

Worst-pain NRS

BM Frequency

Bristol Stool Form Scale

Loperamide doses

FACT-GP5

PRO CTCAE

EORTC IL36
For each patient with data from baseline and at least 1 other visit, the maximum change from 
baseline score will be calculated and summarized for  PRO CTCAE, EORTC functional and
quality of life (QoL) scores.  
EORTC IL36 instrument data will be scored as described by Aaronson et al. 1993.  If not already 
addressed in the EORTC scoring manual (Fayers et al. 2001), descriptive statistics for each 
EORTC IL36 will be calculated and evaluated between arms.
Further patient-reported analysis details will be described in the SAP.
9.4.4.2.
Medical Resource Utilization
Utilization data will be summarized descriptively by healthcare resources used (HCRU) category
(hospitalization days and reasons, emergency room visit reasons, growth factor use, analgesic 
use and transfusions), including a frequency table with tabular statistics.  For categorical 
variables, frequency and the corresponding percentage will be derived and measures of central 
tendency and variability will be calculated for continuous variables by arm. Tests for differences 


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in proportion between treatment groups and between response groups may be performed as 
warranted (Chi-square for categorical variables, t-test for continuous variables and non-
parametric tests for non-normally distributed data). 
Further utilization analysis details will be described in the SAP.
9.4.4.3.
Subgroup Analyses 
A prespecified list of subgroups will be identified in the SAP.  The treatment effect within each 
subgroup will be summarized.  Subgroup analyses will include choice of chemotherapy prior to 
randomization.  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.
9.4.4.4.
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, randomized in the study, and treated, 
or discontinuing (overall and by reason for discontinuation).  A summary of all important 
protocol deviations will be provided.
9.4.4.5.
Patient Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population considered for regulatory approval.
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics. 
9.4.4.6.
Concomitant Therapy 
A summary of prior and concomitant medications by treatment arm will be reported.
9.4.4.7.
Treatment Compliance 
Study treatment that is administered intravenously will be administered at the investigator site; 
therefore, treatment compliance is assured.
Study treatment compliance for other study treatments will be assessed as the proportion of 
treatment that is actually taken, relative to what is expected, after accounting for protocol-
defined dose adjustments.  Study treatment taken will be derived from the difference between the 
total number of pills dispensed and returned over the course of the patient’s treatment.
9.4.4.8.
Biomarker Analyses
Biomarker analyses will be based on the subset of all enrolled patients from whom a valid assay 
result (according to laboratory guideline) has been obtained.  Correlative analyses will be 
performed to investigate associations between biomarkers and clinical endpoints as deemed 
appropriate.


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An exploratory objective of this study is to evaluate biomarkers relevant to abemaciclib, 
mechanism of action, the variable response to study drug(s), immune function, tumor 
microenvironment, and pathways associated with cancer.
9.5.
Interim Analyses 
One interim analysis of futility for ORR will be conducted approximately 6 months after the 
100th patient has been randomized.  The futility rule is described as follows: 
Posterior P(true ORRArm B – true ORRArm A < 10%) < 20%
An assessment committee (AC) will be established to conduct interim analysis.  The AC will 
include, at a minimum, Lilly Oncology Medical Director and statistician; Lilly study CRP/CRS 
will be excluded from the AC.  Details on AC membership will be described in the Lilly Interim 
Analysis Authorization Form.  Although the decision at the interim analysis will be made 
primarily based on the futility rule, AC members will also review and consider the totality of 
interim data to determine whether there are sufficient evidence to justify the termination of study 
treatment and/or enrollment due to futility.  


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10.
Supporting Documentation and Operational Considerations


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Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study patients.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
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.  
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
10.1.2.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the patient or his/her legally authorized representative and 
answer all questions regarding the study.

Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center.


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
The medical record must include a statement that written informed consent was 
obtained before the patient was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative and is kept on file.
Patients who are rescreened are required to sign a new ICF.
10.1.3.
Data Protection

Patients will be assigned a unique identifier by the investigator. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred.

The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the patient.

The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.4.
Dissemination of Clinical Study Data
Dissemination of study data will be performed according to all applicable Lilly and international 
policies.
10.1.5.
Data Quality Assurance
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training 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 verify data reported to detect potential errors 
In addition, the sponsor 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 the sponsor or 
its representatives and/or regulatory agencies at any time.  Investigators will be given notice 
before an audit occurs.


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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 the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, electronic Clinical Outcome Assessment (eCOA) data (questionnaires, scales, self-
reported diary data, rating scales etc.) will be directly recorded by the subject, into an instrument 
(for example, hand held smart phone or tablet, or by means of an interactive voice/web system).  
The eCOA data will serve as the source documentation and the investigator does not maintain a 
separate, written or electronic record of these data.  
Data collected via the sponsor-provided data capture system will be stored at third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and the results will be provided to the investigator for 
review and retention.  Data will subsequently be transferred from the central vendor to the Lilly 
data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
10.1.6.
Source Documents

Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.


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10.1.7.
Study and Site Closure
10.1.7.1.
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.
10.1.7.2.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.


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10.2.
Appendix 2:  Clinical Laboratory Tests

Local laboratory results are only required in the event that the central laboratory results 
are not available in time for inclusion/exclusion determination, study intervention 
administration, and/or response evaluation.  If a local sample is required, it is important 
that the sample for central analysis is obtained at the same time.  If there is an abnormal 
laboratory value or abnormal value for any other diagnostic or screening test (e.g., 
blood pressure increased, neutrophils decreased, etc.) and it is known to be related to a 
diagnosis (e.g., hypertension, neutropenia, etc.) this should be entered into the CRF.  Do 
not enter the test abnormality, enter the diagnosis or categorical term.

Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Investigators must document their review of each laboratory safety report.  Enrollment and 
treatment decisions may be based upon local laboratory results. Discrepancies between local and 
central laboratory results will not be considered a protocol deviation. 


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Clinical Laboratory Tests
Hematologya -Local laboratory
Leukocytes (WBC)
Basophils
Neutrophils
Erythrocytes (RBC)
Lymphocytes
Hemoglobin (HGB)
Monocytes
Hematocrit (HCT)
Eosinophils
Platelets (PLT)
Coagulation -Local laboratory
PT/INR
PTT
Urinalysis -Local laboratory
Blood
Protein
Glucose
Specific gravity
Ketones
Urine leukocyte esteraseb
pH
Clinical chemistrya - Central laboratory  
Serum concentrations of: 
ALT
Chloride
Albumin
Creatinine
Alkaline phosphatase
Glucose (random)
AST
Potassium
TBL
Protein
BUN or blood urea
Sodium
Calcium
Pregnancy Test (only for participants receiving ovarian suppression with a GnRH agonist) - Local laboratory  
Serum pregnancy test
Postmenopausal Confirmation Testing (only for participants <60 years, and amenorrheic for at least 12 months (in 
the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression))- Local laboratory  
FSH
Estradiol
Cystatin C- if clinically indicated
Cystatin C
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CRF = case report form; FSH = follicle stimulating hormone; GnRH = gonadotropin-releasing hormone; RBC= 
red blood cells; TBL = total bilirubin; WBC = white blood cells.
a
Treatment and enrollment decisions may be based on local laboratory results.
b Urine microscopy may be used in place of the urine leukocyte esterase assessment to test for the presence of 
WBCs.
Note:  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 be 
added together and reported on the CRF, unless the CRF specifically provides an entry field for bands.


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10.3.
Appendix 3:  Contraceptive Guidance and Collection of Pregnancy 
Information
No additional pregnancy information (other than that included in Section 1.3) will be collected in 
this study).
Please follow the contraceptive guidelines below. 
CONTRACEPTIVES
a ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods
b That Have Low User Dependency 

Intrauterine device (IUD)

Bilateral tubal occlusion

Vasectomized partner

(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  Spermatogenesis cycle is approximately 90 days.)
Highly Effective Methods
b That Are User Dependent 

Sexual abstinence
(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 intervention.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the patient.)
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and correctly.  Typical use failure rates differ from those when used 
consistently and correctly.
Note:  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this study.  Male condom 
and female condom should not be used together (due to risk of failure with friction).


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10.4.
Appendix 4:  Liver Safety:  Suggested Actions and Follow-up 
Assessments 
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, or its designee, CRP.
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 8.2.1.1 for guidance 
on appropriate test selection.

For testing selected, analysis is required to be completed by the Lilly designated central 
laboratory except for Microbiology.

Local testing may be performed in addition to central testing when required for 
immediate patient management.

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry  
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen Protein Adducts
Platelets
Alkaline Phosphatase Isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl Alcohol (EtOH)
Prothrombin Time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (Quantitative)
Hepatitis A Virus (HAV) Testing:
Immunoglobulin IgG (Quantitative)
    HAV Total Antibody
Immunoglobulin IgM (Quantitative)
    HAV IgM Antibody
Phosphatidylethanol (PEth)
Hepatis B Virus (HBV) Testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug Screen
    Hepatitis B surface antibody (Anti-HBs) 
Ethyl glucuronide (EtG)
    Hepatitis B core total antibody (Anti-HBc)
Other Serology


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    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA)
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a
    HBV DNA d
Anti-actin antibody b
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
    HCV antibody
    EBV antibody
    HCV RNA d
    EBV DNA d
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
    HDV antibody
    CMV antibody
Hepatitis E Virus (HEV) Testing:
    CMV DNA d
    HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA d
    HSV (Type 1 and 2) DNA d
Microbiology c
Liver Kidney Microsomal Type 1 (LKM-1) 
Antibod
Culture:
    Blood
    Urine
a This is not required if Anti-Actin Antibody is tested.
b This is not required if Anti-smooth muscle antibody (ASMA) is tested.
c  Assayed by Investigator-designated local laboratory ONLY; no Central Testing available.
d Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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10.5.
Appendix 5:  Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local
laboratory results only.
For serum creatinine concentration in mg/dL:
CrCl 
=
(140 – agea) × (wt) × 0.85 (if female), or × 1.0 (if male)
(mL/min)
72 × serum creatinine (mg/dL)
For serum creatinine concentration in µmol/L:
CrCl
=
(140 – agea) × (wt) × 0.85 (if female), or × 1.0 (if male)
(mL/min)
0.81 × serum creatinine (µmol/L)
a Age in years, weight (wt) in kilograms.
Source: Cockcroft and Gault 1976.


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10.6.
Appendix 6:  CTCAE 5.0 Diarrhea/Pneumonitis Definition
Diarrhea/Pneumonitis will be evaluated in this study using the criteria proposed by CTCAE v5.0:  
27 November, 2017:  Gastrointestinal Disorders; Respiratory, Thoracic and Mediastinal 
Disorders’.
Grade
Adverse Event
1
2
3
4
5
Gastrointestinal Disorders
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 limiting 
instrumental ADL
Increase ≥7 stools 
per day over 
baseline; 
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 an increase in frequency and/or loose or watery bowel movements
Respiratory, Thoracic, and Mediastinal Disorders
Pneumonitis
Asymptomatic; 
clinical or
diagnostic 
observations only;
intervention not 
indicated
Symptomatic; 
medical
intervention 
indicated;
limiting 
instrumental ADL
Severe symptoms;
limiting self care 
ADL; oxygen 
indicated
Life-threatening 
respiratory
compromise; 
urgent
intervention 
indicated (e.g.,
tracheotomy or 
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Abbreviation:  ADL = Activities of Daily Living.


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10.7.
Appendix 7:  Inducers and Strong Inhibitors of CYP3A 
The information in this appendix is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated.  
Strong Inducers of CYP3A
Carbamazepine
Rifapentine
Dexamethasone
Rifabutin
Phenobarbital/phenobarbitone
Rifampin
Phenytoin
St. John’s wort
Moderate Inducers of CYP3A
Bosentan
Primidone
Lenisurad
Telotristat ethyl
Modafinil
Strong Inhibitors of CYP3A
Aprepitant
Itraconazole
Ciprofloxacin
Ketoconazole
Clarithromycin
Nefazodone
Conivaptan
Posaconazole
Diltiazem
Troleandomycin
Erythromycin
Verapamil
Fluconazole


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10.8.
Appendix 8:  Abbreviations
Term
Definition
ABC
advanced breast cancer
AC
assessment committee
AE
adverse event:  Any untoward medical occurrence in a patients or clinical investigation 
subject administered a pharmaceutical product 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.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BID
twice a day, at least 6 hours apart
BM
bowel movement
BUN
blood urea nitrogen
CDK
cyclin-dependent kinase
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CMV
cytomegalovirus
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CR
complete response
CRF
case report form


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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.
CRS
clinical research scientist
CT
computer tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
D. Bil
Direct bilirubin
eCOA
electronic clinical outcome assessment
eCRF
DoR
electronic case report form
duration of response
EBV
Epstein-Barr virus
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EMA
European Medicine Agency
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EORTC IL36
European Organisation for Research and Treatment of Cancer quality of life 
questionnaire (abridged)
ERCP
endoscopic retrograde cholangiopancreatography
ET
endocrine therapy
FACT-GP5
Functional Assessment of Cancer Therapy- Side Effects
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GnRH
gonadotropin-releasing hormone
HCRU
healthcare resources used


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HDV
hepatitis D virus
HER2-
human epidermal growth factor receptor 2-negative
HR+
hormone receptor-positive
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IHC
ILD
Immunohistochemistry
Interstitial lung disease
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study 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 study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, 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.
IRB
Institutional Review Board
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 patient 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.
MATE
multidrug and toxin extrusion
MedDRA
Medical Dictionary for Regulatory Activities
MBC
metastatic breast cancer
MRCP
magnetic resonance cholangiopancreatography
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NRS
numeric pain rating scale


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ORR
objective response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PgR
progesterone receptor
PI
package insert
PO
by mouth
PR
partial response
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
PRO-CTCAE
patient reported outcome- Common Terminology Criteria in Adverse Events
PS
performance status
QoL
quality of life
RANK-L
receptor activator of nuclear factor kappa-Β ligand
RECIST
Response Evaluation Criteria in Solid Tumors
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. 
SoA
Schedule of Activities
SOC
standard of care
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.
TBL
TTR
total bilirubin
time to response 
ULN
upper limit of normal


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VTE
venous thromboembolic event


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10.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment a: (21-Jun-2019)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
Feedback from the FDA regarding inclusion and exlusion criteria, along with clarifications 
within the protocol, resulted in the need for an amendment. 
Section # and Name
Description of Change
Brief Rationale
Throughout protocol
Changed ABC (advanced breast 
cancer) to MBC (metastatic breast 
cancer); updated from “advanced” to 
“metastatic”
Clarification
1.3 Schedule of 
Activities, 4.3. 
Justification for 
Dose, 6.1. Study 
Intervention(s) 
Administered
Updated to align sections with 
inclusion of physician’s clinical 
practice in chemotherapy dose 
administration
Clarification
1.3 Schedule of 
Activities, 8.1. 
Efficacy 
Assessments
Addition of bodily areas to include 
in scans, change in frequency in 
bone scans, updated language 
regarding tumor assessment 
frequency to Q12W
Clarification
1.3 Schedule of 
Activities
Addition of “28 days” to Visit 
duration for Arm B, related to 
updates to Section 6.1
Clarification
1.3 Schedule of 
Activities
Updated language regarding 
RECIST criteria in the tumor 
assessments section
4.1. Overall Design
Clarification of text regarding 
standard chemotherapy
Clarification
4.2. Scientific 
Rationale for Study 
Design
Clarification of text regarding the 
number of prior ET
Clarification
5.1. Inclusion 
Criteria
Reduction of calculated creatinine 
clearance to ≥30mL/min 
Based on FDA feedback


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Section # and Name
Description of Change
Brief Rationale
5.2. Exclusion 
Criteria
Addition of language clarifying that 
systematic therapy does not include 
any ET for criteria 15
Clarification
5.2. Exclusion 
Criteria
Addition of safety language for 
exclusion criteria 22
Addition
5.4. Screen Failures
Addition of language clarifying 
rescreening and repeat laboratory 
testing is allowed once
Clarification 
6.1. Study 
Intervention(s) 
Administered
Addition of language to dose and 
schedule row for Arm B
Addition
6.6.3 Dose 
Suspension and 
Cycle Delay
Addition of new section discussing 
cycle delay and dose suspension
Addition
6.5. Concomitant 
Therapy
Addition of cautionary language to 
avoid CYP3A strong and moderate 
inducers 
Clarification
6.5. Concomitant 
Therapy
Deletion of examples of CYP3A 
inhibitors
Clarification 
6.6.1. Abemaciclib
Addition of row to Abemaciclib dose 
modification and management-
diarrhea table regarding Grade 2 
CTCAE language; Deletion of Grade 
4 row
Addition/Deletion
6.6.2. Fulvestrant 
and 
Chemotherapeutic 
Agents
Addition of language regarding 
participants being allowed to stay on 
abemaciclib if fulvestrant is 
discontinued
Clarification
8.2.1.1. Hepatic 
Safety Monitoring
Addition of language regarding 
additional diagnostic testing to rule 
out cause of increased liver enzymes 
Clarification
8.2.1.2. Venous 
Thromboembolic 
Events (VTEs)  
Addition of language regarding risk 
language of deep vein thrombosis 
and pulmonary embolism
Addition
8.2.1.3. Serum 
Creatinine Increased
Addition of language regarding dose 
adjustments
Addition


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Section # and Name
Description of Change
Brief Rationale
8.2.1.4. Interstitial 
Lung 
Disease/Pneumonitis
Addition of language regarding dose 
adjustments related to 
ILD/Pneumonitis
Addition
Throughout
Minor editorial and document 
formatting revisions
These are minor changes;
therefore, they have not been 
summarized.


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11.
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American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-
4013.


L e o  D o c u m e n t  I D  =  4 1 b 4 e 5 2 f - 3 1 3 f - 4 2 b 5 - b 5 d 6 - 1 0 0 9 7 2 3 2 c 7 d c
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 0 - F e b - 2 0 2 0  0 2 : 3 2 : 2 5  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 0 - F e b - 2 0 2 0  1 2 : 0 5 : 1 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
I3Y-MC-JPCU Statistical Analysis Plan Version 1 
 
A Multicenter, Open-Label, Randomized-Controlled Study of Abemaciclib, a CDK4 and 6 
Inhibitor, in Combination with Fulvestrant Compared to Chemotherapy in Women with HR 
Positive, HER2 Negative Metastatic Breast Cancer with Visceral Metastases 
 
NCT04031885 
 
Approval Date: 26-Jul-2019 
 


I 3 Y-M C -J P C U St ati sti c al A n al y si s Pl a n V er si o n 1
P a g e 1
L Y 2 8 3 5 2 1 9
1.
St ati sti c al A n al y si s Pl a n:  
I 3 Y-M C -J P C U : A M u lti c e nt er, O p e n-L a b el, R a n d o mi z e d, 
C o ntr oll e d P h a s e 4 St u d y  of A b e m a ci cli b, a C D K 4 a n d 6 
i n hi bit or, i n c o m bi n ati o n wit h F ul v e str a nt c o m p ar e d t o 
C h e m ot h er a p y  i n W o m e n wit h H R P o siti v e, H E R 2 
N e g ati v e A d v a n c e d Br e a st C a n c er wit h Vi s c er al 
M et a st a s e s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e a p pr o v al of Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s :  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
A b e m a ci cli b ( L Y2 8 3 5 2 1 9 )
T hi s i s a m ulti c e nt er, o p e n-l a b el, r a n d o mi z e d, c o ntr oll e d P h a s e 4 st u d y of a b e m a ci cli b i n 
c o m bi n ati o n wit h f ul v e str a nt c o m p ar e d t o p h y si ci a n c h oi c e of st a n d ar d c h e m ot h er a p y i n 
w o m e n wit h H R +, H E R 2 - l oc all y  a d v a n c e d or m et a st ati c bre a st c a n c er w h o h a v e p o or 
pr o g n o si s d u e t o vi s c er al m et a st a si s
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol I 3 Y-M C -J P C U
P h a s e 4
St ati sti c al A n al y si s Pl a n el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y o n d at e pr o vi d e d 
b el o w.
A p pr o v al D at e: 2 6- J ul- 2 0 1 9 G M T


I3Y-MC-JPCU Statistical Analysis Plan Version 1
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Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I3Y-MC-JPCU: A Multicenter, Open-
Label, Randomized, Controlled Phase 4 Study of Abemaciclib, a 
CDK4 and 6 inhibitor, in combination with Fulvestrant compared to 
Chemotherapy in Women with HR Positive, HER2 Negative 
Advanced Breast Cancer with Visceral Metastases..............................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................4
4.
Study Objectives.................................................................................................................5
4.1.
Primary Objective ..........................................................................................................5
4.2.
Secondary Objectives.....................................................................................................5
4.3.
Exploratory Objectives...................................................................................................5
5.
Study Design.......................................................................................................................6
5.1.
Summary of Study Design..............................................................................................6
5.2.
Determination of Sample Size ........................................................................................7
6.
A Priori Statistical Methods ..............................................................................................10
6.1.
General Considerations ................................................................................................10
6.1.1.
Populations ..........................................................................................................10
6.1.2.
Definitions and Conventions ................................................................................10
6.2.
Adjustments for Covariates ..........................................................................................11
6.3.
Handling of Dropouts or Missing Data.........................................................................11
6.4.
Multiple Comparisons/Multiplicity...............................................................................11
6.5.
Patient Disposition .......................................................................................................12
6.6.
Patient Characteristics ..................................................................................................12
6.6.1.
Demographics and Performance Status.................................................................12
6.6.2.
Baseline Disease Characteristics ..........................................................................12
6.6.3.
Historical Illnesses ...............................................................................................12
6.6.4.
Prior Therapies.....................................................................................................12
6.6.5.
Post-Study Treatment Discontinuation Therapies .................................................13
6.7.
Treatment Compliance .................................................................................................13
6.8.
Concomitant Therapy...................................................................................................13
6.9.
Efficacy Analyses ........................................................................................................13
6.9.1.
Primary Outcome and Methodology: Objective Response 
Rate .....................................................................................................................13
6.9.1.1.
Definition .......................................................................................................13
6.9.1.2.
Primary Analysis ............................................................................................14


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6.9.2.
Gated Secondary Efficacy Analyses: Progression-free 
Survival ...............................................................................................................14
6.9.3.
Other Secondary Efficacy Analyses .....................................................................16
6.9.3.1.
Progression-free Survival 2.............................................................................16
6.9.3.2.
Time to Response ...........................................................................................17
6.9.3.3.
Duration of Response .....................................................................................17
6.9.4.
Sensitivity Analyses.............................................................................................17
6.10. Health Outcomes/Quality-of-Life Analyses..................................................................17
6.10.1.
Patient-Reported Outcome (PRO) ........................................................................17
6.10.2.
Medical Resource Utilization ...............................................................................18
6.11. Safety Analyses............................................................................................................19
6.11.1.
Extent of Exposure...............................................................................................19
6.11.2.
Adverse Events ....................................................................................................19
6.11.3.
Deaths and Other Serious Adverse Events............................................................20
6.11.4.
Clinical Laboratory Evaluation.............................................................................20
6.11.5.
Vital Signs and Other Physical Findings...............................................................20
6.12. Subgroup Analyses.......................................................................................................21
6.13. Protocol Violations.......................................................................................................21
6.14. Interim Analyses and Data Monitoring.........................................................................22
6.15. Annual Report Analyses...............................................................................................22
6.16. Clinical Trial Registry Analyses...................................................................................22
7.
References ........................................................................................................................23


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Revision History
SAP Version 1 was approved prior to the first visit when a subject receives study drug or any 
other protocol intervention.


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4.
Study Objectives
4.1.
Primary Objective
To compare the efficacy (ORR) of abemaciclib in combination with fulvestrant to chemotherapy.
4.2.
Secondary Objectives

To further characterize the efficacy of abemaciclib in combination with fulvestrant 
compared to chemotherapy (PFS, time to response, DoR, PFS2)

To compare the safety and tolerability of abemaciclib in combination with fulvestrant to 
chemotherapy
4.3.
Exploratory Objectives

To evaluate PROs and HCRU for abemaciclib in combination with fulvestrant compared 
to chemotherapy

To assess the relationship between whole blood and clinical outcome

To assess the relationship between plasma biomarkers and clinical outcome


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5.
Study Design
5.1.
Summary of Study Design
Study JPCU is a multicenter, open-label, randomized, controlled Phase 4 study of abemaciclib, a 
CDK 4 and 6 inhibitor, in combination with fulvestrant compared to physician choice of standard 
chemotherapy in a patient population of post menopausal women with HR+, HER2- locally 
advanced or MBC who have poor prognosis due to visceral metastasis.
Patients will be randomized using the following stratification factors:  the presence of liver 
metastases (Yes/No), sensitivity to prior ET (sensitive versus primary resistance versus 
secondary resistance), and postmenopausal status (natural/surgical/therapeutic radiation versus 
gonadotropin-releasing hormone [GnRH] agonist use). 
Sensitivity to prior ET is defined as follows, and will be determined based on the patients’ most 
recent sensitivity status.  For example, if a patient met the definition of primary resistance on 
adjuvant ET and subsequently met the definition of secondary resistance on ET for MBC, the 
patient would be categorized as having secondary resistance.  
1. Primary resistance:  a relapse while on the first 2 years of adjuvant ET, or progressive 
disease (PD) within first 6 months of first-line ET for MBC, while on ET 
2. Secondary resistance:  a relapse while on adjuvant ET but after the first 2 years, or a 
relapse within 12 months of completing adjuvant ET, or PD ≥6 months after initiating ET 
for MBC, while on ET
3. Sensitive:  patients who do not meet the definition of primary resistance or secondary 
resistance will be considered to be sensitive
Patients who meet all criteria for enrollment will be randomly assigned 1:1 to: 
1. Arm A:  abemaciclib in combination with fulvestrant, or 
2. Arm B:  physician choice of standard chemotherapy (capecitabine, docetaxel, nab-
paclitaxel, or paclitaxel). 
Cross over between study treatments is not allowed in this study.  Additionally, post-
discontinuation therapy is neither specified nor restricted. 
Taken together, these data will be used to characterize the efficacy, safety and tolerability of 
abemaciclib in combination with fulvestrant compared to chemotherapy.  The study design is 
illustrated below.


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A b bre viati o ns:  A B C = a d va nce d breast ca ncer, E T = e n d ocri ne t hera p y; G n R H = g o na d otr o pi n -releasi n g h or m o ne;  
H E R 2 - = h u ma n e pi der mal gr o wt h fact or rece pt or 2-ne gati ve; H R + = h or m o ne rece pt or p ositi ve; N = n u m ber of 
e nr olle d patie nts; O R R = o bjecti ve res p o nse rate; R = ra n d o mizati o n; S O C = sta n dar d of care .
5. 2.
D et er mi n ati o n of S a m pl e Si z e
A p pr o xi matel y  3 0 0 p atie nts will be ra n d o mize d i n a 1: 1 rati o t o Ar m A a n d Ar m B f or a n 
esti mate d t otal of 1 5 0 patie nts per ar m. 
T he pri mar y  a nal ysis of O R R t o assess O R R c o m para bility will  b e p erfor m e d a p pr o xi matel y 
6 m o nt hs after l ast patie nt e nteri n g treat me nt; t he fi nal a nal ysis o f P F S t o assess P F S 
c o mpara bili t y will be perf or me d, if O R R c o m para bilit y is declare d, w he n a p pr o xi matel y 
1 8 0 P F S e ve nts i n t otal ha ve bee n o bser ve d. 
O R R
C o m para bili t y of O R R will be declare d if t he f oll owi n g Ba yesia n criteri o n is ac hie ve d i n t he 
pri mar y  O R R a nal ysis: 
P os t erior P(tr ue O R R Ar m B – tr ue O R RAr m A < 1 0 %) > 8 0 %
F ull  detail re gar di n g t he Ba yesia n m o del f or O R R (i ncl u di n g pri or s pecificati ons) is pr o vi de d i n 
Secti o n 6. 9. 1 . 
 
 
 
 
 
 
  
 
C CI


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P F S
Pr o gressi o n -free s ur vi val c o m para bilit y will be declare d if O R R c o m para bilit y is declare d A N D 
t he f o ll owi n g Ba yesia n cri t erio n i s ac hie ve d i n t he fi nal P F S a nal ysis: 
P os t erior P ( H R – 1 < 0. 2) > 8 0 %, w here H R = tr ue hazar d Ar m A /tr ue hazar dAr m B
 
 
 
 
C CI
C CI
C CI


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C
C
I


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6.
A Priori Statistical Methods
6.1.
General Considerations
6.1.1. Populations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Disposition summaries will be performed on the entered population, defined as all patients who 
sign the informed consent form.
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 analysis set will be used for all baseline and efficacy 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 he or she was randomized.  The safety analysis set will be used for all dosing/exposure, 
safety analyses, and health economics analyses.
6.1.2. Definitions and Conventions
Study drug refers to abemaciclib (LY2835219).
Study treatment refers to abemaciclib plus fulvestrant or single-agent chemotherapy of 
physician’s choice (capecitabine, docetaxel, nab-paclitaxel, or paclitaxel)
The date of randomization is the date the patient was randomly assigned to study treatment 
using the IWRS.
The date of first dose is the date of the first dose of study drug, fulvestrant, or single-agent 
chemotherapy.
The baseline value of a safety assessment is the last value observed prior to the first dose of 
study drug, fulvestrant, or single-agent chemotherapy.
The baseline value of an efficacy assessment is the last value observed prior to the date of 
randomization.  If a patient’s first assessment occurs after randomization but prior to the first 
dose, this assessment will be used as the baseline.
The study day of a safety event or assessment will be calculated as:

the difference between the date of the event or assessment and the date of first 
dose plus 1 for all events or assessments occurring on or after the day of first 
dose.  For example, if an event occurs on 08MAR2016 and the date of first 
dose was 06MAR2016, the study day of the event is 3.


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
the difference between the date of the event or assessment and the date of first 
dose for all events or assessments occurring before the day of first dose.  For 
example, if an event occurs on 05MAR2016 and the date of first dose was 
06MAR2016, the study day of the event is -1.
The study day of an efficacy event or assessment will be calculated as:

the difference between the date of the event or assessment and the date of 
randomization plus 1 for all events or assessments occurring on or after the 
date of randomization.

the difference between the date of the event or assessment and the date of 
randomization for all events or assessments occurring before the date of 
randomization.
One month is defined as 365/12 days.
Unless otherwise noted, summaries of continuous variables will include a mean, median, 
standard deviation, minimum, and maximum.
Unless otherwise noted, summaries of categorical variables will include the frequency and 
percentage (relative to the population being analyzed) of each category.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
6.2.
Adjustments for Covariates
The following baseline covariates will be the stratification factors for randomization: presence of 
liver metastases (Yes/No), sensitivity to prior ET (sensitive versus primary resistance versus 
secondary resistance), and postmenopausal status (natural/surgical/therapeutic radiation versus 
gonadotropin-releasing hormone [GnRH] agonist use).  These stratification factors are thought to 
be associated with clinical outcomes.  Balancing the 2 arms with respect to those factors will
further reduce the potential for bias and improve the power of the analyses. For example, our 
internal data indicate that postmenopausal status is an important prognostic factor: in Study I3Y-
MC-JPBL, the patients receiving GnRH agonist on abemaciclib arm (n=72) had a median PFS of 
28.6 months versus 15.5 months for those patients who were truly postmenopausal (n=371).
6.3.
Handling of Dropouts or Missing Data
With the exception of dates, missing data will not be imputed.  The method of imputation for any 
dates that are imputed is described in the relevant section.  Rules for determining date of 
progression or censor for PFS are defined in Table JPCU.6.1.
6.4.
Multiple Comparisons/Multiplicity
The primary endpoint is ORR comparability; PFS comparability is an important secondary 
endpoint, and will be statistically tested only if ORR comparability is declared, using a 
gatekeeping testing strategy.  The family-wise error rate, i.e. the probability of making one or 
more false positive claims due to multiple endpoint-related multiplicity, will be well controlled at 
no more than 20%, per simulations. 


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6.5.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, rescreened after screen failure, 
randomized in the study, and treated in the study, reasons for discontinuation from study 
treatment (safety population only), and reasons for discontinuation from study (ITT population 
only).  Reason for discontinuation from both study treatment and the study will be summarized 
by pre-determined categories.
6.6.
Patient Characteristics
6.6.1. Demographics and Performance Status
Patient demographics will be summarized.  Patient demographics will include age, race, 
ethnicity, height, weight, and body mass index.
6.6.2. Baseline Disease Characteristics
Disease characteristics will be summarized.  Disease characteristics will include the following:

Initial pathological diagnosis

Disease stage (Stage IIA, Stage IIB, etc.) at initial diagnosis and study entry

Histopathological diagnosis grade (G1, G2, etc.) at initial diagnosis and study entry

Baseline Eastern Cooperative Oncology Group (ECOG) performance status 
(PS)

HER2 status (negative/postive)

Progesterone receptor status (negative/postive) 

Estrogen receptor status (negative/postive)

Site of disease (liver, lung, etc.) 
6.6.3. Historical Illnesses
Historical illnesses are clinically relevant events in the past that ended before the screening visit.  
Historical illnesses (using Preferred Term(s) [PTs] from the most current version of the Medical 
Dictionary for Regulatory Activities [MedDRA®]) will be summarized.
6.6.4. Prior Therapies
Prior radiotherapy, surgery, and systemic therapy will be summarized.  Prior radiotherapy and 
surgery will be categorized by reason for regimen.  Prior systemic therapies will be categorized 
by type of regimen (endocrine therapy, chemotherapy, etc.) and reason for regimen (neoadjuvant, 
adjuvant, locally advanced, or metastatic).  Frequency of each specific therapy will be tabulated 
within each type of therapy and per reason for regimen.


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6.6.5. Post-Study Treatment Discontinuation Therapies
Therapies received following study treatment discontinuation will be summarized by arm.  
Therapies will be summarized overall and by category: endocrine therapy or 
targeted/chemotherapy.
6.7.
Treatment Compliance
Treatment compliance information for abemaciclib will be collected through pill counts at each 
cycle.  Compliance will be calculated as the ratio of total dose taken to the total assigned dose 
(minus any dose adjustments and doses omitted/withheld for medical or logistical reasons).  
Treatment compliance information for capecitabine will be collected through couting number of 
doses taken at each cycle.  Dosing information for fulvestrant, docetaxel, paclitaxel, and nab-
paclitaxel will be collected at each cycle/visit.
6.8.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization drug dictionary.  All concomitant medications will be summarized by 
number and percentage of patients for the safety population using the base name (without esters 
or salts).
6.9.
Efficacy Analyses
Unless otherwise noted, all efficacy analyses will be performed on the ITT population.
The stratification factors for the primary and secondary analyses are

Presence of liver metastases (Yes/No)

Sensitivity to prior ET (sensitive versus primary resistance versus secondary 
resistance)

Postmenopausal status (natural/surgical/therapeutic radiation versus GnRH agonist
use).
The stratification factors will be derived based on CRF data.  
Posterior medians and Bayesian credible intervals will be reported for ORR and PFS, for which 
Bayesian analyses have been specified.
All frequentist tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless 
otherwise stated; and all confidence intervals (CIs) will be given at a 2 sided 95% level.
6.9.1. Primary Outcome and Methodology: Objective Response Rate
6.9.1.1.
Definition
The primary endpoint of the study is objective response rate (ORR), which is defined as the 
number of patients who achieve a best overall response (BOR) of complete response (CR) or 


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parti al res p o nse ( P R) di vi de d b y t he t otal n u m ber of pati e nt s ra n d omize d t o t he c orres p o n di n g 
treat me nt ar m (I T T p o p ulat i on) , base d o n i n vesti gat or-assesse d t u m or res p o nses .
T he B O R c orres p o n ds t o t he best res p o nse rec or de d fr om t he start of t he st u d y tr e at me nt u ntil t he 
earliest of o bject i ve pr o gressi o n or start of  ne w a ntica ncer t hera p y (e xcl u di n g mai nte na nce 
e n d ocri ne t hera p y f oll owi n g st u d y  tr e at me nt ); co nfir mati o ns of C R a n d P R are n ot re q uire d.
6. 9. 1. 2.
Pri m ar y A n al y si s
Pri mar y c o m par is o n bet wee n treat me nt ar ms will be base d o n t he Ba yesia n decisi o n r ule as 
descri be d i n Secti o n 5. 2 . T he 8 0 t h perce ntile o f t he p osterior di stri b uti on f or t he differe nce i n 
tr ue O R R (tr ue O R R Ar m B – tr ue O R RAr m A ) will be calc ulate d a n d c o mpare d t o 1 0 % , t o deter mi ne 
if P ost eri or P(tr ue O R R Ar m B – tr ue O R RAr m A < 1 0 % ) > 8 0 %.  I n a d diti on, t he me dia n of t he 
p osteri or distri b ut i on f or O R R, wit h 9 5 % e q ual-taile d cre di ble i nter val, will be s u m marize d f or 
eac h treat me nt  ar m.
A n o bject i ve Ba yesia n a p pr oac h will be i m ple me nte d t o deri ve t he p osteri or distri b ut i on of t he 
tr ue ( u n k n o w n) q ua ntities of i nterest, O R R Ar m A a n d O R R Ar m B , c o n ditio nal o n t he o bser ve d da t a 
a n d pri or distri b ut i ons. F or Ar m A, t he j o i nt li keli h o o d f unct i on is bi n omial( ~ 1 5 0, O R R Ar m A )
a n d t he pri or distri b uti o n f or O R R Ar m A is t he ( wea kl y inf or mati ve) Jeffre ys pri or f or t he b i n omial 
class of li keli h o o d f u nct i ons, na mel y t he b et a distri b uti on wi t h bot h  s ha pe a n d scale para meters 
e q ual t o 1/ 2. Beca use t he beta pri ors are c o nj u gate f or t he bi n o mial li keli h o o ds, t he p osteri or 
di stri b uti on f or O R R Ar m A is a k n o w n beta distri b uti on. I n dee d, if  is t he n u m ber of o bser ve d 
res p o n ders i n   pati e nts ra n d o mize d t o Ar m A, t he p osteri or distri b ut i on is: 
[       |  ] ~    (  +. 5,   −  +. 5 ).
C orres p o n di n gl y f or Ar m B we ha ve: 
[       |  ] ~    (  +. 5,   −  +. 5 ).
N ote t hat beca use t he t w o j o i nt li keli h o o ds a n d pri or distri b uti ons f or O R R Ar m A a n d O R R Ar m B 
are i n de pe n de nt, t he t w o p osteri or distri b ut i ons are al s o i n de pe n de nt. T hat is: 
[       ,       |  ,  ] = [       |  ] ⋅[       |  ]
M o nte Carl o sa m pli n g (fr o m t he t w o i n de pe n de nt beta p osteri ors) will be use d t o a p pr o xi mate 
t he p osterior di stri b utio n of  t h e fu nct i onal O R R Ar m B – O R R Ar m A .  
T he pri mar y  a nal ysis of O R R t o assess O R R c o m para bility will  b e p erfor m e d a p pr o xi matel y 6 
m o nt hs after last pati e nt e nteri n g treat me nt. 
6. 9. 2.
G at e d S e c o n d ar y Effi c a c y A n al y s e s : Pr o gr e s si o n -fr e e S ur vi v al
Pr o gressi o n -free s ur vi val (P F S) i s a n i m p orta nt sec o n dar y e n d p oi nt of t he st u d y, a n d will be 
assesse d o nl y if O R R c o mpara bilit y is declare d, usi n g a gate kee pi n g testi n g strate g y.
P F S is defi ne d as t he ti me fr o m ra n d omizat i on u nt il t he first occ urre nce of d oc u me nte d disease 
pr o gressi o n per R E CI S T 1. 1 criteria, or deat h fr o m a n y ca use i n t he a bse nce of pr o gressi ve 
di sease.  P F S will be base d o n i n vesti gat or-assess e d t u mor res p o nses ; t here will n ot be a n 


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i n de pe n de nt ce ntral re vie w of i ma gi n g data.  Pa tie nt s k n o w n t o be ali ve a n d wit h o ut disease 
pr o gressi o n will be ce ns ore d at t he ti me of t he last a de q uate t u m or assess me nt (a detaile d P F S 
e ve nt/ce ns ori n g sc he me is pr o vi de d i n Ta ble J P C U. 6. 1 bel o w ).  A (stratifie d) Ba yesia n C o x 
re gressi o n m o del will be use d t o esti mate t he P F S H R c o m pari n g Ar m A a n d Ar m B.  T he 8 0t h
perce nt ile of t he p osteri or distri b uti on of t he H R c o m pari n g Ar m A a n d Ar m B will be calc u late d 
a n d c o m pare d t o 1. 2 , t o deter mi ne if P osteri or P ( H R – 1 < 0. 2) > 8 0 % . I n a d diti on, t he p osteri or 
me dia ns a n d ass ociate d 9 5 % cre di ble i nter vals f or tr ue me dia n P F S b y  tr e at me nt ar m will be 
pr o vi de d.
T he Ba yesia n m o del use d t o calc ulate t he P F S H R p osteri or will c o m bi ne t he Bresl o w partial 
li keli h o o d ( Bresl o w, 1 9 7 5) wit h a diff use, wea kl y-i nf or mat i ve pri or distri b uti on f or t he hazar d 
r atio. Let  = l o g  . A priori , we will ass u me  ~ ( 0, 1 0 0 ) w here t h e sec o n d ar g u me nt is t he 
varia nce. T he i n d uce d p osteri or distri b ut i on d oes n ot e xist i n cl ose d f or m, he nce Mar k o v C hai n 
M o nte Carl o ( M C M C) met h o ds will be use d t o ge nerate sa m ples fr o m t he a p pr o xi mate p osteri or 
di stri b uti on f or  (a n d t h us H R). N ote t hat si nce t he partial li keli h o o d is use d, t he Ba yesia n 
m o d el  is c om p lete wit ho ut s pecificat i on of a pri or m o del f or t he u n derl yi n g baseli ne hazar d 
f u ncti on.
Fi nal a nal ysis of P F S t o assess P F S c o m para bility will be perf or me d , if O R R c o mpara bilit y is 
decl are d, w he n a p pr o xi matel y  1 8 0 P F S e ve nts i n t otal ha ve bee n o bser ve d.


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Table JPCU.6.1.
PFS Event/Censoring Scheme
Situation
Date of Event or Censor
Event / Censor
Tumor progression or death
Earliest date of PD or death
Event
No tumor progression and no death
Date of last adequate radiological assessment or 
date of randomization (whichever is later)
Censored
Unless
No baseline radiological tumor assessment 
available
Date of randomization
Censored
No adequate post baseline radiological 
tumor assessment available 
and death reported after 2 scan intervals 
following randomization
Date of randomization
Censored
New anticancer treatment started 
(excluding maintenance endocrine therapy 
following chemotherapy) and no tumor 
progression or death within 14 days
Date of adequate radiological assessment prior to 
(start of new therapy +14 days) or date of 
randomization (whichever is later)
Censored
Tumor progression or death
documented immediately after 2 or more 
scan intervals following last adequate 
radiological tumor assessment or 
randomization (whichever is later)
Date of last adequate radiological assessment or 
date of randomization (whichever is later)
Censored
Notes: 
(1) Symptomatic deteriorations (i.e. symptomatic progressions, which are not radiologically confirmed) will not be 
considered as progression
(2) Adequate radiological tumor assessment refers to an assessment with one of the following responses: CR, PR, 
SD or PD
6.9.3. Other Secondary Efficacy Analyses
6.9.3.1.
Progression-free Survival 2
For patients who take maintenance endocrine therapy following study treatment, progression-
free survival 2 (PFS2) is defined as the time from randomization to the disease progression date 
on first-line treatment post discontinuation of maintenance endocrine therapy, discontinuation 
date of first-line treatment post discontinuation of maintenance endocrine therapy, or starting 
date of the second-line treaetment post discontinuation of maintenance endocrine therapy, or 
death from any cause, whichever is earlier.  For all other patients, PFS2 is defined as the time 
from randomization to the disease progression date on first-line treatment post discontinuation of 
study treatment, discontinuation date of first-line treatment post discontinuation of study 
treatment, or starting date of the second-line of post discontinuation of study treatment, or death 
from any cause, whichever is earlier.
If the patient is alive at the cutoff for analysis, and a PFS2 event has not been observed, PFS2 
data will be censored on the last date the patient was known to be alive.
A Kaplan-Meier (KM) analysis of PFS2 will be performed to estimate the PFS2 curve for each 
arm. Point estimates, CIs for PFS2 quartiles, and PFS2 rates will be calculated every 3 months 
for the first 12 months.


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6.9.3.2.
Time to Response
Time to Response (TTR) is defined as the time from randomization until the date that 
measurement criteria for CR or PR (whichever is first recorded) are first met, per RECIST v1.1, 
and will be calculated for patients with CR or PR only.
A KM analysis of TTR will be performed to estimate the TTR curve for each arm.  Point 
estimates and CIs for DoR quartiles will be calculated.
6.9.3.3.
Duration of Response
Duration of response is defined as the time from the date that measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date that disease is recurrent or 
documented disease progression is observed, per RECIST 1.1 criteria, or the date of death from 
any cause in the absence of documented disease progression or recurrence.  It will be calculated 
as date of progression or death – date of first response evaluation of CR or PR + 1 for patients 
with CR or PR only.  The DoR will be censored according to the same rules as PFS.
A KM analysis of DoR will be performed to estimate the DoR curve for each arm.  Point 
estimates, CIs for DoR quartiles, and DoR rates will be calculated every 3 months for the first 12 
months.
6.9.4. Sensitivity Analyses
Progression-Free Survival Sensitivity Analysis 1 (nonobjective progression as a PFS event): if 
a patient is discontinued from study treatment due to investigator-determined non-objective 
progression (for example, symptomatic deterioration), then the patient’s PFS time will be 
calculated using the date of non-objective progression as the progression date.
6.10. Health Outcomes/Quality-of-Life Analyses
The main analysis will be conducted in the safety population. 
For each instrument, the compliance rate by visit will be calculated as the number of patients 
with completed assessments at each visit divided by the number of patients in safety population 
at each visit.  Compliance rates and reasons for noncompliance for each instrument will be 
summarized by treatment arm.
6.10.1. Patient-Reported Outcome (PRO)
Patient-reported outcomes are measured through electronic versions of the following:

Worst-pain NRS

BM Frequency

Bristol Stool Form Scale

Loperamide doses

FACT-GP5

PRO CTCAE

EORTC IL36 


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Worst-pain NRS, BM Frequency, Bristol Stool Form Scale, and Loperamide doses are single-
item instruments and will be assessed daily.  For such instrument with daily data collection, 
weekly average will be calculated for each patient; all other instruments will be assessed weekly.  
For each instrument, weekly average or weekly data collection will be used as the data at each 
visit for data analyses.
For each patient with data from baseline and at least 1 other visit post-baseline, the change from 
baseline score by visit, by all post-baseline visits, and maximum change from baseline score will 
be calculated and summarized using descriptive statistics between arms for each instrument, 
except for PRO CTCAE.  Response to each item in PRO CTCAE will be treated as a categorical 
variable and will be summarized using descriptive statistics by visit between arms.
To describe and compare the Time to Deterioration (TTD) and also Time to Sustained 
Deterioration (TTSD) in the

“worst pain”  (2 point change)

FACT-GP5 (one category change)

PRO CTCAE (one category change)

EORTC IL36 (European Organisation for the Research and Treatment of Cancer Quality 
of Life Questionnaire-Core30 (EORTC QLQ-C30) functional scales, and Global 
Health/Quality of Life (GHS) scale (10 point change)). 
Pain Intensity:
Pain as assessed with the single “worst pain” NRS item, and will be characterized with 
descriptive non-inferential statistics based on a weekly average.  Treatment arm comparisons 
will be conducted through use of mixed model repeated measures (MMRM) specified with an 
unstructured covariance matrix and estimated with restricted maximum likelihood (REML) to 
address the small sample negative bias in the variance component when using the maximum 
likelihood (ML) estimator (that is, the ML estimator usually has lower mean-squared error 
[MSE] than the REML estimator).
EORTC IL36:
EORTC IL36 instrument data will be scored as described by Aaronson et al. 1993.  If not already 
addressed in the EORTC scoring manual (Fayers et al. 2001), descriptive statistics for each 
EORTC IL36 (functional scale and the Global Health Status/QOL scale) will be calculated and 
evaluated between arms.
6.10.2. Medical Resource Utilization
Utilization data will be summarized descriptively by healthcare resources used (HCRU) category 
(hospitalization days and reasons, emergency room visit reasons, growth factor use, analgesic 
use and transfusions), including a frequency table with tabular statistics.  For categorical 
variables, frequency and the corresponding percentage will be derived and measures of central 
tendency and variability will be calculated for continuous variables by arm. Tests for differences 
in proportion between treatment groups and between response groups may be performed as 


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warranted (Chi-square for categorical variables, t-test for continuous variables and non-
parametric tests for non-normally distributed data). 
Time to first opioid use by treatment arm, responder type, age, baseline PRO score may be 
explored.
6.11. Safety Analyses
6.11.1. Extent of Exposure
Drug exposure, dose intensity, and drug adjustment (dose omissions, increases, reductions, 
interruptions, and delays) for abemaciclib, fulvestrant, and single-agent chemotherapy of 
physician’s choice will be summarized for all treated patients per treatment arm.  Drug exposure 
will include summaries of cycles received per patient, duration on therapy, and cumulative dose.  
Dose intensity will be calculated as the actual cumulative amount of drug taken divided by the 
duration of treatment.  Relative dose intensity will be calculated as the actual amount of drug 
taken divided by the amount of drug prescribed times 100% (expressed as a percentage).  The 
summary of dose adjustments will include reasons for adjustments.
For abemaciclib, extent of exposure will be measured by pill counts.  Dose intensity will be 
expressed in mg/day.  The assigned cumulative dose while on study is 2 × 150 mg × number of 
days on treatment.
For fulvestrant, extent of exposure will be measured using the fulvestrant administration on the 
eCRF.  The assigned cumulative dose while on study is 500 mg × 2 + [500 mg × ceiling 
((number of days on treatment – 28)/28)].
For single-agent chemotherapy of physician’s choice, extent of exposure and assigned 
cumulative dose while on study will be measured based on data reported on the eCRF 
appropriate for the route of administration.
6.11.2. Adverse Events
Adverse event (AE) severity grades will be assigned by the investigator using Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  In addition, AE verbatim text 
will also be mapped by the sponsor or designee to corresponding terminology within MedDRA. 
Preexisting conditions are defined as AEs that either is ongoing at informed consent or end on or 
after informed consent.  
A treatment-emergent adverse event (TEAE) is defined as an AE that first occur or worsen in 
CTCAE grade after the first dose of study treatment. The MedDRA LLT will be used in the 
treatment-emergent computation.
A serious adverse event (SAE) is any AE during this study that results in one of the following 
outcomes:

death

initial or prolonged inpatient hospitalization 


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
a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
The following summaries and listings will be produced:

Overview of adverse events

Summary of TEAEs by preferred term (PT) (any grade and Grade ≥ 3)

Summary of TEAEs by system organ class (SOC) and PT (any grade and Grade ≥ 3)

Summary of TEAEs by SOC and PT and maximum grade (1-5)

Summary of SAEs by SOC and PT (any grade and Grade ≥ 3)

Summary of AEs as reason for study treatment discontinuation by SOC and PT

Listing of SAEs
The TEAE and SAE summaries will be produced for all TEAEs/SAEs and repeated for 
TEAEs/SAEs related to study treatment, where relationship of the AE to the study treatment will 
be assessed by the investigator (yes or no).
6.11.3. Deaths and Other Serious Adverse Events
A summary of all deaths, including reasons for deaths, will be provided.  All deaths, deaths on 
study treatment, deaths within 30 days of discontinuation of study treatment, deaths on study 
treatment or within 30 days of discontinuation of study treatment, and deaths after 30 days of 
discontinuation of study treatment will be summarized by reason for death.  For deaths due to 
AE, the preferred term will be provided.  In addition to the tabular summary, a by-patient listing 
of all deaths on study not attributed to study disease by the investigator will be provided.
6.11.4. Clinical Laboratory Evaluation
All relevant hematology and chemistry laboratory values will be graded according to CTCAE.  
These calculated grades will be summarized by cycle and maximum postbaseline grade over the 
entire study for each treatment arm.  Treatment-emergent changes will be summarized by the 
maximum postbaseline grade, and a shift table of baseline grade by maximum postbaseline grade 
will be produced.
6.11.5. Vital Signs and Other Physical Findings
Temperature, blood pressure, pulse rate, weight, and ECOG PS will be summarized by cycle.


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6.12. Subgroup Analyses
Subgroup analyses of ORR and PFS will be performed for each of following potential prognostic 
subgroup variables:

presence of liver metastases (Yes/No)

sensitivity to prior ET (sensitive versus primary resistance versus secondary 
resistance)

postmenopausal status (natural/surgical/therapeutic radiation versus GnRH 
agonist use)

number of organs involved (1 versus 2 versus 3+)

age (<65 years versus ≥65 years)

progesterone receptor status (positive versus negative)

baseline ECOG PS (0 versus 1)
Subgroup analyses of ORR and PFS will also be performed for each of the physician choice of 
standard chemotherapy that patient are randomized to or would receive (capecitabine and taxane 
[docetaxel, nab-paclitaxel, paclitaxel]).  Before a patient is randomized, the chemotherapy choice 
that the patient would receive if she was randomized to Arm B will be recorded in the Interactive 
Web Response System (IWRS).  A chemotherapy subgroup will consist of patients who are 
randomized to Arm B to receive the chemotherapy and those who are randomized to Arm A and 
would receive the chemotherapy per IWRS.  
If a level of a factor consists of fewer than 10% of randomized patients, analysis within that level 
will be omitted.
Analyses will be done within subgroup and, separately, across subgroups with a test of 
interactions of subgroups with treatment performed.  Estimated HRs and CIs for the 
within-subgroup analyses will be presented as a Forest plot along with p-values for tests of 
interactions between subgroup variables and treatment.
Other subgroup analyses may be performed as deemed appropriate.  If any safety analyses 
identify important imbalances between arms, subgroup analyses of these endpoints may be 
performed.
6.13. Protocol Violations
Important protocol violations that potentially compromise the data integrity and patients’ safety 
will be summarized by treatment group for all randomized patients.  These violations will 
include deviations that can be identified programmatically and those which can only be 
identified by the clinical research associate during monitoring.  Important protocol deviations are 
described in another document within the study Trial Master File.


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6.14. Interim Analyses and Data Monitoring
One interim analysis of futility for ORR will be conducted approximately 6 months after the 
100th patient has been randomized.  The futility rule is described as follows: 
Posterior P(true ORRArm B – true ORRArm A < 10%) < 20%
An assessment committee (AC) will be established to conduct interim analysis.  The AC will 
include, at a minimum, Lilly Oncology Medical Director and statistician; Lilly study CRP/CRS 
will be excluded from the AC.  Details on AC membership will be described in the Lilly Interim 
Analysis Authorization Form.  Although the decision at the interim analysis will be made 
primarily based on the futility rule, AC members will also review and consider the totality of 
interim data to determine whether there are sufficient evidence to justify the termination of study 
treatment and/or enrollment due to futility.
6.15. Annual Report Analyses
Annual report analyses, including Developmental Safety Update Report and Investigator’s 
Brochure analyses, are described in the LY2835219 Program SAP.
6.16. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.
Analyses provided for the CTR requirements include the following:

Summary of adverse events, provided as a dataset which will be converted to an XML 
file. Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by 
treatment group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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7.
References
Cox DR. Regression models and life-tables. Journal of Royal Statistical Society Ser B. 1972; 
74(2):187-220.


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