A Randomized, Open-Label, Phase 3 Study of Abemaciclib Combined With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone in Patients With High Risk, Node Positive, Early Stage, Hormone Receptor Positive, Human Epidermal Receptor 2 Negative, Breast Cancer
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Eli Lilly and Company

Protocol I3Y-MC-JPCF(e) 
 
 
A Randomized, Open-Label, Phase 3 Study of Abemaciclib Combined with Standard Adjuvant 
Endocrine Therapy versus Standard Adjuvant Endocrine Therapy Alone in Patients with High 
Risk, Node Positive, Early Stage, Hormone Receptor Positive, Human Epidermal Receptor 2 
Negative, Breast Cancer  
 
 
NCT03155997  
 
 
Approval Date: 18-Sep-2019 
 

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 1
L Y 2 8 3 5 2 1 9
m o n ar c h E: Pr ot o c ol I 3 Y -M C -J P C F ( e)
A R a n d o mi z e d, O p e n -L a b el, P h a s e 3 St u d y  of A b e m a ci cli b 
C o m bi n e d wit h St a n d ar d A dj u v a nt E n d o cri n e T h er a p y  v er s u s 
St a n d ar d A dj u v a nt E n d o cri n e T h er a p y  Al o n e i n P ati e nt s wit h 
Hi g h Ri s k, N o d e P o siti v e, E arl y  St a g e, H or m o n e R e c e pt or 
P o siti v e, H u m a n E pi d er m al R e c e pt or 2 N e g ati v e, Br e a st 
C a n c er
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 pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s.  It 
i s t h e pr o p ert y 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 n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o 
p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of a b e m a ci cli b ( L Y 2 8 3 5 2 1 9), u nl e s s s u c h p er s o n s ar e b o u n d 
b y  a c o nfi d e nti alit y a gr e e m e nt wit h 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 eg 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 Y 2 8 3 5 2 1 9)
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 A p pr o v e d b y Lill y : 1 0 M ar c h 2 0 1 7 .
A m e n d m e nt ( a) A p pr o v e d o n d at e:  1 1 O ct o b er 2 0 1 7
A m e n d m e nt ( b) A p pr o v e d o n d at e:  2 9 J u n e 2 0 1 8
A m e n d m e nt ( c) A p pr o v e d o n d at e:  1 9 D e c e m b er 2 0 1 8
A m e n d m e nt ( d) A p pr o v e d o n d at e:  2 5 J u n e 2 0 1 9
A p pr o v al D at e: 1 8- S e p- 2 0 1 9 G M T
A m e n d m e nt ( e) El e ctr o ni c all y Si g n e d a n d A p pr o v e d o n d at e pr o vi d e d b el o w.

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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................20
3.1.
Disease Background.....................................................................................................20
3.2.
Study Rationale............................................................................................................21
3.2.1.
Ki-67 Immunohistochemistry Assay ....................................................................23
3.3.
Benefit/Risk Assessment..............................................................................................23
4.
Objectives and Endpoints..................................................................................................24
5.
Study Design.....................................................................................................................26
5.1.
Overall Design .............................................................................................................26
5.2.
Number of Patients.......................................................................................................27
5.3.
End of Study Definition ...............................................................................................27
5.4.
Justification for Dose (Arm A) .....................................................................................28
6.
Study Population...............................................................................................................29
6.1.
Inclusion Criteria..........................................................................................................29
6.2.
Exclusion Criteria ........................................................................................................32
6.3.
Lifestyle Restrictions....................................................................................................34
6.4.
Screen Failures.............................................................................................................34
7.
Treatments........................................................................................................................35
7.1.
Treatments Administration...........................................................................................35
7.1.1.
Treatment Administration Guidance:....................................................................36
7.1.2.
Packaging and Labeling .......................................................................................36
7.2.
Method of Treatment Assignment ................................................................................36
7.2.1.
Selection and Timing of Doses.............................................................................37
7.3.
Blinding .......................................................................................................................37
7.4.
Abemaciclib Dosage Modification ...............................................................................38
7.4.1.
Abemaciclib Dose Adjustments............................................................................38
7.4.1.1.
Dose Adjustments...........................................................................................40
7.4.1.1.1.
Abemaciclib (Arm A) ...............................................................................40
7.4.1.1.2.
Standard of Care Endocrine Therapy of Physician’s 
Choice (Arms A and B) ............................................................................41
7.4.1.2.
Dose Delays and Omission .............................................................................41
7.4.1.2.1.
Study Treatment (Abemaciclib and/or Endocrine 
Therapy – Arms A and B).........................................................................41
7.5.
Preparation/Handling/Storage/Accountability...............................................................41

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 3
L Y 2 8 3 5 2 1 9
C CI
7. 6.
Treat me nt C o m plia nce ................................................................................................. 4 2
7. 7.
C o nc o mita nt T hera p y ...................................................................................................4 2
7. 7. 1.
S u p p orti ve Care ...................................................................................................4 3
7. 7. 1. 1.
S u p p orti ve Ma na ge me nt f or Diarr hea ( Ar m A) ...............................................4 3
7. 7. 1. 2.
T hera p y  for Fe brile Ne utr o pe ni a .....................................................................4 4
7. 7. 1. 3.
Gr o wt h Fact or T hera p y ...................................................................................4 4
7. 8.
Treat me nt after t he E n d of t he St u d y ............................................................................4 4
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................4 5
8. 1.
Di sc o nti n uatio n f r o m St u d y Treat me nt .........................................................................4 5
8. 1. 1.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d Patie nts ...............................................4 5
8. 2.
Di sc o nti n uatio n f r o m t he St u d y....................................................................................4 5
8. 3.
L ost t o F oll o w -U p ........................................................................................................4 6
9.
St u d y  Assess me nts a n d Pr oce d ures...................................................................................4 7
9. 1.
Efficac y Assess me nts ...................................................................................................4 7
9. 1. 1. 
R o uti ne S yste mic I ma gi n g ...................................................................................4 7
9. 1. 2.
A p pr o priate ness of Assess me nts ..........................................................................4 8
9. 2.
A d verse E ve nts ............................................................................................................4 8
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................4 9
9. 2. 2.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ...............................................5 0
9. 2. 3.
C o m plai nt Ha n dli n g .............................................................................................5 0
9. 3.
Treat me nt of O ver d ose ................................................................................................. 5 0
9. 4.
S afet y ...........................................................................................................................5 0
9. 4. 1.
Ot her Safet y Meas ures .........................................................................................5 1
9. 4. 2.
S af et y M o ni t ori n g:  He patic F u nct i on ( B ot h Ar ms) ..............................................5 1
9. 4. 2. 1.
S peci al He pat ic Safety Data C ollect i on ...........................................................5 1
9. 4. 3.
S af et y M o ni t ori n g:  Re nal Fu nct i on f or A be macicli b ...........................................5 2
9. 4. 4.
S af et y M o ni t ori n g:  Ve n o us T hr o m b oe m b olic E ve nts ( B ot h 
Ar ms) ...................................................................................................................5 2
9. 4. 5.
S af et y M o ni t ori n g: I L D/ P ne u m onit is ( B ot h Ar ms)..............................................5 3
9. 5.
P har mac o ki net ics .........................................................................................................5 3
9. 8.
Bi o m ar kers ...................................................................................................................5 4
9. 8. 1.
S a m ples f or Ki -6 7 I H C Testi n g ............................................................................5 4
9. 8. 1. 1.
Ki -6 7 A nal ysis f or Sec o n dar y  O bjecti ve.........................................................5 5
C CI
C CI

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 4
L Y 2 8 3 5 2 1 9
C CI
9. 9.
Heal t h Ec o n o mics........................................................................................................5 7
9. 9. 1.
Heal t h O ut c o mes ..................................................................................................5 7
9. 9. 1. 1.
Ge neral Well- bei n g a n d Breast Ca ncer Assess me nt 
( F A C T-B) .......................................................................................................5 8
9. 9. 1. 2.
E n d ocri ne T hera p y  a n d Fatig ue Assess me nt ( F A C T -E S, 
5 F A CI T Li brar y  Ite ms, F A CI T-F) ................................................................. 5 8
9. 9. 1. 3.
E Q - 5 D- 5 L ......................................................................................................5 8
9. 9. 2.
Res o urce Utilizati o n .............................................................................................5 9
1 0.
Stati stical C o nsi derati o ns ..................................................................................................6 0
1 0. 1.
S a m ple Si ze Deter mi nat i on ..........................................................................................6 0
1 0 . 2. P o p ul at i ons f or A nal yses..............................................................................................6 0
1 0. 3.
Stati stical A nal yses ......................................................................................................6 1
1 0. 3. 1.
Efficac y A nal yses ................................................................................................6 1
1 0. 3. 1. 1.
I n vasi ve Disease-Free S ur vi val .......................................................................6 1
1 0. 3. 1. 2.
O verall S ur vi val .............................................................................................6 3
1 0. 3. 1. 3.
Di sta nt Rela pse-Free S ur vi val .........................................................................6 3
1 0. 3. 1. 4.
A nal yses of Efficac y i n Ot her P o p ulat i ons ......................................................6 3
1 0. 3. 2.
S af et y A nal yses ....................................................................................................6 3
1 0. 3. 3.
Ot her A nal yses .....................................................................................................6 4
1 0. 3. 3. 1.
P ati e nt Dis p ositio n ..........................................................................................6 4
1 0. 3 . 3. 2.
P ati e nt C haracteristics ....................................................................................6 4
1 0. 3. 3. 3.
C o nc o mita nt T hera p y .....................................................................................6 4
1 0. 3. 3. 4.
P os t disc o nti n uatio n T hera p y ...........................................................................6 4
1 0. 3. 3. 5.
Treat me nt C o m plia nce ....................................................................................6 4
1 0. 3. 3. 6.
P har mac o ki net ic/ P har mac o d y na mic A nal yses ................................................6 5
1 0. 3. 3. 7.
Heal t h O ut c o me a n d Q ualit y of Life A nal yses ................................................6 5
1 0. 3. 4.
S u b gr o u p A nal yses ..............................................................................................6 5
1 0. 3. 5.
I nteri m A nal yses ..................................................................................................6 6
1 0. 3. 5. 1.
S af et y I nteri m A nal yses..................................................................................6 6
1 0. 3. 5. 2.
Efficac y/ F ut ility I nteri m A nal yses ..................................................................6 6
1 1.
Refere nces ........................................................................................................................6 7

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List of Tables
Table
Page
Table JPCF.2.1.
Schedule of Activities.............................................................................12
Table JPCF.4.1.
Objectives and Endpoints .......................................................................24
Table JPCF.7.1.
Treatment Regimens...............................................................................35
Table JPCF.7.2.
Abemaciclib Dose Adjustments for Treatment-Emergent, 
Related,* and Clinically Significant Adverse Events...............................39
Table JPCF.7.3.
Dose Adjustments of Abemaciclib..........................................................40
Table JPCF.10.1.
Rules for Determining Date of Event or Censor for Invasive 
Disease Free Survival.............................................................................62
Table JPCF.10.2.
Efficacy Information ..............................................................................63

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List of Figures
Figure
Page
Figure JPCF.5.1.
Illustration of study design......................................................................27

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 7
L Y 2 8 3 5 2 1 9
Li st of A p p e n di c e s
A p p e n di x
P a g e
C CI
A p pe n di x 1.
A b bre viat i ons a n d Defi nit i ons ................................................................7 1
A p pe n di x 2.
St u d y  G o ver na nce, Re g ulat or y, a n d Et hical C o nsi deratio ns ....................7 6
A p pe n di x 3.
Cli nical La b orat or y  Tests........................................................................7 9
A p pe n di x 4.
Hi g hl y  Effecti ve Met h o ds of C o ntrace pti o n f or Patie nts of 
Re pr o d ucti ve P ote ntial ...........................................................................8 0
A p pe n di x 5.
O mitte d ..................................................................................................8 1
A p pe n di x 6.
P har mac o ki net ics/ Ge netics/ Bi omar kers Sa m pli n g Sc he d ules ..................8 2
A p pe n di x 7.
He pati c M o nit orin g Tests f or Treat me nt -E m er ge nt A b n or malit y ............8 4
A p pe n di x 8.
Pr ot oc ol  J P CF I n d ucers a n d Str o n g I n hi bit ors of C Y P 3 A .......................8 5
A p pe n di x 9.
Pr ot oc ol  J P C F C T C A E 4. 0 3 Defi niti ons .................................................8 6
A p pe n di x 1 0.
Pr ot oc ol  J P C F Breast Ca ncer Rec urre nce a n d Ot her Ca ncer E ve nts........8 7
A p pe n di x 1 1.
Pr ot oc ol  J P C F:  E C O G Perf or ma nce Stat us............................................9 0
A p pe n di x 1 2.
Pr ot oc ol  J P C F:  G ui da nce f or Treat me nt of Ve n o us 
T hr o m b oe m b o lic E ve nt ..........................................................................9 1
 
 
 

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1. Synopsis
Protocol Title:  A Randomized, Open-Label, Phase 3 Study of Abemaciclib combined with 
Standard Adjuvant Endocrine Therapy versus Standard Adjuvant Endocrine Therapy Alone in 
Patients with High Risk, Node Positive, Early Stage, Hormone Receptor Positive, Human 
Epidermal Receptor 2 Negative, Breast Cancer
Rationale:  Study I3Y-MC-JPCF (JPCF; monarchE) is a Phase 3 study for patients with node-
positive, early stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 
2-negative (HER2-) breast cancer who completed definitive locoregional therapy (with or 
without neoadjuvant or adjuvant chemotherapy) and are at high risk for disease recurrence. The 
currently approved standards of care offered to this patient population are adjuvant cytotoxic 
chemotherapy and endocrine therapy.  Despite advances in therapeutic options for early stage 
breast cancer, a high-risk subpopulation receives suboptimum benefit and may demonstrate 
resistance to anti-estrogen therapy at the time of recurrence.  Therefore, improving the absolute 
benefit of adjuvant endocrine therapy is warranted in this high-risk subgroup given its 
cumulative rate of disease recurrence at 5 years is at least 15%.  This Phase 3 study will evaluate 
the potential for abemaciclib to enhance standard adjuvant endocrine therapy compared to 
standard adjuvant endocrine therapy alone in patients with node-positive, early stage, resected 
HR+, HER2- breast cancer at high risk of disease recurrence.  
Objectives and Endpoints:
Primary Objective: 

To evaluate the efficacy, in terms of invasive disease-free survival (IDFS), as defined by 
the STEEP System, for patients with HR+, HER2- early stage breast cancer for 
abemaciclib 150 mg twice daily plus adjuvant endocrine therapy versus adjuvant 
endocrine therapy alone
Secondary Objective:

To evaluate the efficacy, in terms of IDFS, for patients with HR+, HER2- early stage 
breast cancer with Ki-67 index ≥20% by central lab 

To evaluate the efficacy of abemaciclib plus adjuvant endocrine therapy versus adjuvant 
endocrine therapy alone in terms of distant relapse-free survival (DRFS) and overall 
survival (OS)

To assess the safety profile of abemaciclib plus adjuvant endocrine therapy compared to 
adjuvant endocrine therapy alone

To evaluate the relationship between abemaciclib exposure and clinical (efficacy and 
safety) outcomes

To evaluate abemaciclib plus adjuvant endocrine therapy, versus adjuvant endocrine 
therapy alone, in terms of general oncology and breast cancer self-reported health-related 
quality of life (Functional Assessment of Cancer Therapy [FACT]-Breast 37-item 
questionnaire), endocrine therapy-specific symptoms (Functional Assessment of Cancer 
Therapy - Endocrine Symptoms (Version 4) [FACT-ES] 19-item subscale and 2 

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Functional Assessment of Chronic Illness Therapy Item Library [FACIT] (Version 2) 
sourced items of cognitive symptoms and 3 FACIT-sourced items for bladder symptoms), 
and fatigue experienced during abemaciclib and/or endocrine therapy (FACIT-Fatigue 
13-item subscale)

To evaluate health status to inform decision modeling for health economic evaluation 
using the EuroQol five-dimension five-level questionnaire (EQ-5D-5L)
Overall Design: monarchE is a multicenter, randomized, open-label, Phase 3 study of standard 
adjuvant endocrine therapy of physician’s choice with or without abemaciclib in patients with 
high-risk, node-positive, early stage, HR+, HER2- breast cancer, who completed definitive 
locoregional therapy (with or without neoadjuvant or adjuvant chemotherapy).
Number of Patients:  The study will screen approximately 5200 patients, and approximately
4580 patients will be enrolled and subdivided into 2 cohorts:  those eligible based on nodal 
status, tumor size, or grade regardless of Ki-67 status (Cohort 1) and those with at least 1 
positive node and eligible exclusively based on a Ki-67 status (Cohort 2, patients not eligible 
based on degree of axillary lymph node involvement, tumor size or grade).    
Study Design:  Patients in both treatment arms will receive standard adjuvant endocrine therapy 
of physician’s choice (such as tamoxifen or an aromatase inhibitor, with or without ovarian 
function suppression per standard practice).  Patients in both arms may have up to 12 weeks of 
endocrine therapy following their last non-endocrine therapy (surgery, chemotherapy, or 
radiotherapy) prior to randomization, and the same or another endocrine therapy will be 
continued during the course of the study until meeting discontinuation criteria (Section 8).  
Adjuvant treatment with fulvestrant is not allowed at any time during the study.  Patients must be 
randomized within 16 months of definitive breast surgery for the current malignancy.  Patients 
randomized to the experimental arm will receive abemaciclib orally at 150 mg twice daily for up 
to 2 years or until discontinuation criteria are met, whichever occurs first.  Endocrine therapy 
will be taken as prescribed during the on-study treatment period (Years 1 and 2).  In Year 3 and 
beyond, standard adjuvant endocrine therapy will continue to complete at least 5 years per 
investigator’s discretion as part of standard of care.

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2. Schedule of Activities
The screening period for Cohort 1 is 3 months. The screening period for Cohort 2 is 6 months 
(tissue for Cohort 2 patients should be submitted within one month from the consent date).
In both Arms A and B, Day 1 is the first dose of treatment following randomization, that is,
abemaciclib and/or endocrine therapy (Arm A), or endocrine therapy (Arm B), regardless if the 
patient is receiving endocrine therapy immediately prior to randomization.  The first dose of 
abemaciclib and/or endocrine therapy should be initiated no later than 3 days following 
randomization. 
During Years 1 and 2 (the on-study treatment period), patients will return to clinic every 2 weeks 
(15 ± 3 days) for the first 2 months, monthly (30 ± 5 days) starting with Month 3 to Month 6, and 
every 3 months thereafter (every 90 ± 10 days until Visit 27).  Phone visits will happen monthly 
between the every 3 month visits.
All visits will be anchored to the previous clinic visit, with the exception of Visit 27.  Visit 27 
must be anchored to Visit 1 and must take place 24 months (±5 days) after Visit 1.  Unscheduled 
visits must be scheduled to complete the 2-year period between Visit 26 and Visit 27 if there are 
>40 days between Visit 26 and Visit 27.  These unscheduled visits should include assessments 
applicable for either a clinic visit (if the visit is happening in the clinic) or phone visit (if the visit 
is happening on the phone) using the schedule of assessments below as the guide.
For patients enrolled in Arm B who are unable to attend the required clinic visits, Visits 2, 4, 5, 
7, and 8 must take place as a phone visit if the clinic visit cannot be done.
Detection of symptoms suspicious of disease recurrence is highly important. The investigator or 
another medically qualified individual is expected to conduct a comprehensive and systematic 
assessment of these symptoms during clinic and phone visits. Of note, the protocol does not 
prohibit more frequent monitoring by imaging, if judged necessary by the investigator. 
The short-term follow-up visit takes place 30 days (±5 days) after 1 of the following time points, 
whichever occurs first:

after the completion of the 2-year on-study treatment period

after discontinuation criteria are met (Section 8.1) and decision is made for the patient to 
discontinue all study treatment (abemaciclib plus endocrine therapy in Arm A, endocrine 
therapy in Arm B) prior to the completion of the 2-year on-study treatment period
Note: For Arm A only, if a patient discontinues only one of the combination drugs (abemaciclib 
or endocrine therapy) prior to completion of the 2-year on-study treatment period for a reason 
other than an IDFS event per STEEP criteria (Appendix 10), she/he should continue the other 
drug until completion of the 2-year on-study treatment period or other discontinuation criteria are 
met (Section 8.1), whichever occurs first. 
After the short-term follow-up visit, ALL patients will enter the long-term follow-up period (see 
Table JPCF.2.1).  The long-term follow-up period begins the day after the short-term follow-up 

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visit and will continue up to Year 10 or study completion, whichever occurs first.  Long-term 
follow-up visits should occur approximately every 6 months (anchored to the previous visit) until 
the completion of Year 5, and then yearly starting in Year 6. For patients who are unable to 
attend the required clinic visits, long-term follow-up visits V803 and further must take place as a 
phone visit if the clinic visit cannot be done.
If a patient experiences an IDFS event other than distant recurrence or death, she/he will be 
followed for distant recurrence and survival, unless the patient is lost to follow-up, or withdraws
from the study.
Unscheduled visits (V997) and all procedures for the unscheduled visits are at the discretion of 
the investigator. Unscheduled visits may include physical examinations, vital signs, ECOG
performance status, concomitant medication, adverse event collection, disease symptoms 
assessment, central chemistry and hematology, return of study drug, or resumed dosing, if 
previously interrupted.
The windows for the schedule of assessments and administration of first dose are based on 
calendar days.

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Table JPCF.2.1.
Schedule of Activities
Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
Informed consent 
(Cohort 2 and/or 
main consent)
X
X
Main ICF may be signed up to 
3 months prior to randomization and 
must be signed prior to any study-
specific assessments are performed.  
Cohort 2 ICF may be signed up to 6 
months prior to randomization and 
must be signed prior to sending tissue 
to the central lab for Ki-67 testing.
Blood pregnancy 
test
X
See inclusion criteria [12],
Appendix 4.  Women of reproductive 
potential only.  Local regulations 
and/or institutional guidelines may 
require additional testing.

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Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
Physical exam 
(clinic visits only)
X
(X)
X
X
X
X
X
Height, weight, and appropriate body 
examination.  Height at baseline only 
and weight until STFU.  Does not 
need to be repeated on Day 1 if 
assessed 7 days prior to 
randomization.
Vital signs (clinic 
visits only)
X
(X)
X
X
X
X
Blood pressure, pulse, respiratory 
rate, temperature.  Do not need to be 
repeated on Day 1 if assessed 7 days 
prior to randomization.
ECOG PS (clinic 
visits only)
X
(X)
X
X
X
X
See Appendix 11.  Does not need to 
be repeated on Day 1 if assessed 7 
days prior to randomization.
Medical history
X
Includes alcohol and tobacco intake.
Concomitant 
medications
X
X
X
X
X
X
X
In LTFU, collection of regimen 
changes and associated start and stop 
dates for endocrine therapy, and post-
discontinuation therapy.
ECG (local)
X
As clinically indicated
Patient must be supine or near supine 
for approximately 5-10 minutes prior 
to collection and remain supine, but 
awake, during collection.

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Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
Adverse event 
assessment
X
X
X
X
X
X
X
See Section 9.2.  Assessments will be 
in clinic and over the phone between 
clinic visits.  In LTFU, all SAEs in 
both arms regardless of causality will 
be collected through Year 5.  For the 
entire duration of LTFU, only AEs 
related to study treatment and/or
study procedure will be collected.
Central 
hematology, 
chemistry, and 
cystatin C (clinic 
visits only)
X
(X)
X
X
X
X
See Appendix 3.  Do not need to be 
repeated on Day 1 if assessed 7 days 
prior to randomization (blood draw is 
required at Day 1 for 
pharmacogenetic and biomarker 
sample collection – see Appendix 6).  
Eligibility must be based on the last 
available screening laboratory results 
prior to randomization.  Enrollment 
and treatment decisions may be based 
on local laboratory results, but a 
specimen must also be sent to central 
laboratory.  Discrepancies between 
local and central laboratory results 
will not be considered protocol 
deviations.

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Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
PRO 
questionnaires
X
V6, V9
V15, 
V21, 
V27
X
V802, V803
See Section 9.9.
Bilateral breast 
imaging (such as 
mammogram or 
MRI)
Prior to randomization:  Patients must have bilateral breast imaging performed locally as part of routine standard of care prior to 
surgery or prior to randomization for the current breast cancer.  This is not required for patients who have had bilateral mastectomy.
Post randomization: Either at yearly intervals, as recommended per international standard guidelines, or according to local standards as 
part of routine medical care.  Patients who have had a mastectomy should be followed per local practice. 
See Appendix 10 for additional guidelines for the assessment of recurrence.
Abdominal ± 
pelvic imaging 
(such as CT, 
PET/CT, MRI, 
ultrasound)
Prior to randomization:  Abdominal ± pelvic imaging MUST be performed prior to randomization.  Abdominal ± pelvic imaging 
performed previously as part of routine care, any time in the process of or after diagnosing the patient with the current breast cancer 
diagnosis, may be used as the baseline assessment. 
Post randomization:  Performed locally ONLY if clinically indicated per investigator’s judgment (eg, if liver function tests deteriorate 
significantly). 
If PET/CT is performed, additional imaging modalities are not required.  See Appendix 10 for additional guidelines for the assessment 
of recurrence.
Chest imaging 
(such as PET/CT, 
CT, or x-ray 
[should include 
lateral and 
postero-anterior 
views])
Prior to randomization:  Chest imaging MUST be performed prior to randomization.  Chest imaging performed previously as part of 
routine care, any time in the process of or after diagnosing the patient with the current breast cancer diagnosis, may be used as the 
baseline assessment. 
Post randomization:  Performed locally ONLY if clinically indicated per the investigator’s judgment. 
If PET/CT is performed, additional imaging modalities are not required.  See Appendix 10 for additional guidelines for the assessment 
of recurrence.

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Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
Bone nuclear 
imaging (such as 
bone scan, PET 
scan or PET/CT)
Prior to randomization:  Full body bone imaging per standard clinical practice MUST be performed prior to randomization to discard or 
confirm potential distant disease.  Bone imaging performed previously as part of routine care, any time in the process of or after 
diagnosing the patient with the current breast cancer diagnosis, may be used as the baseline assessment.
Post randomization:  Performed locally and ONLY if clinically indicated per investigator’s judgment (for example, if patient is 
symptomatic for bone pain and/or if alkaline phosphatase is significantly elevated ≥3×ULN). 
If PET/CT is performed, additional imaging modalities are not required.  See Appendix 10 for additional guidelines for the assessment 
of recurrence.
Administer 
abemaciclib 
(Arm A)
At all clinic visits
See Sections 7.1 and 7.7.1.1.  Orally 
twice-daily (with minimum 6-hour 
separating doses) for up to 2 years or 
until discontinuation criteria met.
Administer 
endocrine therapy
As per standard of care
(X)
(X)
See inclusion criterion [7]
In STFU and LTFU, as applicable.
Administered as per physician’s 
choice.
Disease 
recurrence 
assessment
At every visit and as clinically indicated until distant disease 
recurrence or death
See Section 9.1 and Appendix 10.  
Disease recurrence information will 
be collected at any time point (clinic 
or phone visit).  Assessment for 
changes in symptoms and suggestive 
of disease recurrence.

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Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
Ki-67 tissue 
(untreated breast 
tissue)
X
See Section 9.8.1 and Appendix 6.  
As assessed by central laboratory 
when kit is available for both cohorts.  
Screening for potential Cohort 2 
patients is permitted after signing the 
Cohort 2 ICF ((tissue should be 
submitted within 1 month from 
consent date).
Ki-67 and 
exploratory 
biomarker tissue 
(post-neoadjuvant 
therapy)
X
See Section 9.8.1 and Appendix 6.  In 
addition to pretreatment sample, if 
available, send to central laboratory 
only for patients who received 
neoadjuvant therapy. Not applicable 
for patients who had a pCR following 
neoadjuvant therapy.

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Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
Tumor tissue for 
biomarkers
X
See Section 9.8 and Appendix 6.  
Confirm sample availability prior to 
randomization.  Breast tissue 
preferred; lymph node tissue is 
acceptable.
For patients who received 
neoadjuvant therapy, send both a pre-
and a post–neoadjuvant treatment 
tissue sample to the central laboratory
(unless the patient had a pCR).   
Plasma for 
biomarker
X
V6, V9
V27
V802, Y5
See Section 9.8 and Appendix 6.  At 
Day 1, must be taken before first 
dose.  V802 sample may be taken 
after V802 if missed at V802.
Y5 sample for patients on study 
without IDFS event
Pharmacokinetics
X
V3, V5
V6
Only for patients in Arm A assigned 
to PK in IWRS. See Section 9.5 and 
Appendix 6.  Ask the patient and 
record date and time of last 
abemaciclib dose prior to PK sample.  
V1 sample, 2 hours after abemaciclib 
dosing.  Other visits, any time after 
abemaciclib dosing.

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Study Period
Screening
On-Study Treatment Period (Y1-2)
Short-Term 
Follow-Up
Long-Term 
Follow-Up
Comments
Day
(relative to 
Visit 1)
−6 M
to R
−28
to R
−14
to R
Day 1 
(R+3D)
Q2W
(M1-2) 
(±3D)
Monthly
(M3-6) 
(±5D)
Monthly 
(M7-Y2) 
(±5D)*
30 Days
post DC 
(±5D)
Q6M
then Q12M 
(±28D)
Clinic visits: 1-9, 12, 15, 18, 21, 24, 
27
Phone visits:  10, 11, 13, 14, 16, 17, 
19, 20, 22, 23, 25, 26
LTFU:  Q6M through Y5; Q12M 
Y6-10.
*3 monthly clinic visits ± 10 days
Visit
601
Cohort 
2 only
0
1
2-5
6-9
10-27
801
≥802
Whole blood for 
pharmacogenetic 
analysis
X
See Appendix 6.  Whole blood 
sample required.
Recurrence tissue
and plasma
samples 
(biomarker)
Collect at time of local/regional and distant disease recurrence
See Section 9.8 and Appendix 6.
Tissue sample mandatory for patients 
who undergo biopsy to confirm 
recurrence.
Survival
X
Abbreviations: CRF = case report form; CT = computed tomography; D = day; DC = discontinuation; ECG = electrocardiogram; ECOG PS = Eastern 
Cooperative Oncology Group performance status; ICF = informed consent form; IWRS = interactive web-response system; LTFU = long-term follow-up; M 
= month(s); MRI = magnetic resonance imaging; pCR = pathological complete response; PET = positron emission tomography; PK = pharmacokinetics; PRO 
= patient-reported outcomes; Q2W = every 2 weeks; Q6M = every 6 months; Q12M = every 12 months; R = randomization; SAE = serious adverse event; 
STFU = short-term follow-up; V = visit; Y= year.

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3. Introduction
3.1.
Disease Background
Breast cancer is the most frequent cancer among women and is a major cause of cancer-related 
deaths worldwide.  It is estimated that more than 1.67 million new cases of breast cancer 
occurred worldwide in women in 2012 (Ferlay et al. 2015). In the United States, breast cancer is 
the most common malignancy diagnosed among women, and the second leading cause of cancer 
deaths in women, with 246,660 new cases of invasive breast cancer and 40,450 deaths estimated 
in 2016 (ACS 2016). About 1% of all breast cancers are diagnosed in men (Borgen et al. 1992;
Senkus et al. 2015). 
The hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative 
(HER2-) breast cancer subtype is the most prevalent of breast cancer subtypes and accounts for 
approximately 70% of all breast cancers (Howlader et al. 2014). 
Approximately 90% of patients with breast cancer are diagnosed at an early stage of their disease 
(Howlader et al. 2016). These patients are treated with curative intent and as such are candidates 
for local treatments including surgery followed very often by radiotherapy depending on the 
surgical approach and regional disease extension. After surgery, the indication of adjuvant 
systemic therapy is based on estimated individual risk of disease relapse and predicted sensitivity 
to available systemic therapies (that is, estrogen receptor [ER]/progesterone receptor and HER2 
status).  Most validated clinical and pathological features that may indicate a higher risk of 
distant disease relapse and therefore the need for adjuvant treatment include large primary tumor 
size, involvement and degree of involvement of axillary lymph nodes, and high histologic grade.
While gene expression profile of the primary tumor may be used to complement pathology 
assessment and gain additional prognostic and/or predictive information on the likelihood of 
disease relapse and chemosensitivity (Senkus et al. 2015), available deoxyribonucleic acid 
(DNA) microarray technologies are not yet part of routine practice in majority of countries and 
not globally accessible.  Ki-67 antigen (also known as antigen identified by monoclonal antibody 
Ki-67) is encoded by the MKI67 gene and is a nuclear protein expressed in all phases of the cell 
cycle other than the G0 phase and has been reported as an independent prognostic factor in early 
breast cancer (Dowsett et al. 2011). In HR+ breast cancer, patients with high levels of Ki-67 
have been shown to have higher disease recurrence rates while receiving adjuvant endocrine 
therapy following surgery. In the BIG 1-98 study (Viale et al. 2008), patients receiving letrozole 
with HR+ early breast cancer involving their axillary lymph nodes and low (≤11%) Ki-67 levels 
at baseline had a 4-year disease-free survival of 93% compared to 85% for patients with higher 
Ki-67 values (>11%). Currently, there is no consensus as to the precise baseline level of Ki-67 
that would differentiate a patient for being of higher or lower risk of disease recurrence whilst on 
adjuvant endocrine therapy. However, the majority of the panel of the St Gallen International 
Expert Consensus on the Primary Therapy of Early Breast Cancer 2015 was prepared to accept a 
threshold value of Ki-67 within the range of 20% to 29% (Vasconcelos et al. 2016) as indicative 
of high-risk group appropriate to receive adjuvant chemotherapy.  High-level Ki-67 expression 

I3Y-MC-JPCF(e) Clinical Protocol
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(that is, ≥20%) by immunohistochemistry (IHC) performed centrally is believed to be a valid 
factor for high-risk patient selection in Study I3Y-MC-JPCF (JPCF; monarchE).
Patients with lymph node-positive disease are most often candidates for chemotherapy. Standard 
adjuvant chemotherapy includes anthracycline and/or taxane-based regimen. Adjuvant 
endocrine therapy is indicated in all patients with detectable ER expression (defined as ≥1% of 
invasive cancer cells) irrespective of the use of chemotherapy (NCCN Version 2.2016).  The 
choice of endocrine agent (tamoxifen and/or one of the 3 selective aromatase inhibitors:  
anastrozole, letrozole, or exemestane) is primarily determined by the patient’s menopausal status.  
All aromatase inhibitors have shown similar antitumor efficacy and toxicity profiles in 
randomized studies in the adjuvant and pre-operative setting. Overall, international clinical 
guidelines (ESMO - Senkus et al. 2015, Saint Gallen International Expert Consensus - Coates et 
al. 2015) and NCCN guidelines (NCCN version 2.2016) align on recommendation of adjuvant 
endocrine therapy for at least 5 years, and for post-menopausal patients, aromatase inhibitors 
should be at least part of endocrine therapy. In pre-menopausal patients, standard endocrine 
therapy includes tamoxifen with or without ovarian suppression for 5 to 10 years, or an 
aromatase inhibitor for 5 years with ovarian suppression in selected patients at high risk of 
disease recurrence (that is, pretreated with chemotherapy) based on the TEXT and SOFT studies.
In postmenopausal patients, use of aromatase inhibitors (both non-steroidal and steroidal) and 
tamoxifen either sequentially, as monotherapy, or extended therapy for a total duration of 5 to 10 
years is a valid option. Men with breast cancer are treated similarly to postmenopausal women, 
considering testicular suppression with a GnRH analogue.
With current standard of care adjuvant therapy, approximately 30% of women with HR+ breast 
cancer initially diagnosed with early stage disease experience distant relapse with metastases 
(Reinert and Barrios 2015). Consequently, there is a critical need for more optimal adjuvant 
therapy in patients with early HR+ breast cancer who have a high likelihood of distant 
recurrence. 
3.2.
Study Rationale
Abemaciclib is an oral, selective, and potent ATP-competitive inhibitor of cyclin-dependent 
kinases 4 and 6 (CDK4 and CDK6, respectively).  CDK4 and CDK6 promote cell growth by 
facilitating the progression of cells from the G1 to the S-phase of the mammalian cell cycle.  
This promotion of cell growth occurs primarily by counteracting the effects of a growth 
suppressor protein known as the retinoblastoma (Rb) protein, whereby the reversal of Rb-
mediated suppression is achieved by the phosphorylation of this protein by CDK4 and/or CDK6.  
The CDK4/CDK6-Rb pathway is commonly altered in cancer cells, whereby the activation of 
this pathway contributes to enhanced growth.  Accordingly, in cancer cells, abemaciclib inhibits 
CDK4/CDK6-dependent phosphorylation of Rb, which subsequently blocks proliferation by 
inhibiting the progression of these cells from the G1 phase into the S and G2/M phases of the cell 
cycle.  
Continuously dosed abemaciclib has demonstrated robust single-agent clinical activity in both 
the JPBA Phase 1b study with a response rate of 33.3% across dose levels and the I3Y-MC-

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JPBN (JPBN; MONARCH 1) Phase 2 study with a response rate of 19.7% (at 200-mg dose 
twice daily), in patients with heavily pretreated HR+ metastatic breast cancer that is refractory to 
endocrine therapy (Patnaik et al. 2016; Dickler et al. 2016). 
Abemaciclib plus endocrine therapy resulted in statistically significant improvements in both 
progression-free survival (PFS) and response rate in HR+, HER2−advanced breast cancer in 
patients who progressed on or following endocrine therapy (I3Y-MC-JPBL [JPBL; MONARCH 
2]) and in patients receiving first-line treatment (I3Y-MC-JPBM [JPBM; MONARCH 3]). In 
MONARCH 2, the median PFS of abemaciclib plus fulvestrant was 16.4 months versus 9.3 
months in the control arm with HR=0.553 (95% CI:  0.449, 0.681), p<.0000001 (Sledge et al.
2017).  In MONARCH 3, median PFS was not reached in the abemaciclib plus aromatase 
inhibitor arm and was 14.7 months in the control arm, with an HR of 0.543 (95% CI 0.409 to 
0.723, p=.000021 [Di Leo et al. 2017]). Additionally, both studies had significant improvement 
in ORR.  In MONARCH 2 ORR in patients with measurable disease was 48.1% versus 21.3% in 
the control arm (95% CI:  42.6, 53.6), odds ratio = 3.42, p<.001.  In MONARCH 3, ORR in 
patients with measurable disease was 59.2% versus 43.8% in the control arm (95% CI:  53.3, 
65.1), odds ratio = 1.9, p=.004 (Di Leo et al. 2017; Sledge et al. 2017)
In the neoadjuvant breast cancer setting, Study I3Y-MC-JPBY (JPBY; neoMONARCH), a Phase 
2 open-label, randomized trial, showed an acceptable safety profile for abemaciclib (150 mg
twice daily) as monotherapy and in combination with anastrozole, with reduction of breast 
cancer tumor cell proliferation marker (Ki-67 index) to a significantly greater extent than 
anastrozole alone (Hurvitz et al. 2016).  
Abemaciclib has an acceptable safety profile in the respective patient populations studied in the 2 
Phase 3 trials (MONARCH 2 and MONARCH 3) in combination with endocrine therapy and the 
Phase 2 study (MONARCH 1), a monotherapy study.  The safety monitoring and corresponding 
dose adjustment guidelines used in these clinical studies effectively improved the tolerability 
profile of abemaciclib.  The most frequently reported adverse events ([AEs], >20%, consistently 
in these 3 studies) are: diarrhea, neutropenia, fatigue, nausea, vomiting, abdominal pain, 
decreased appetite, and anemia. Additionally, other clinically relevant AEs are venous 
thromboembolism (VTE, [including pulmonary embolism (PE) and deep vein thrombosis 
(DVT)]), ALT increased, AST increased, and interstitial lung disease (ILD)/pneumonitis.
The monarchE study aims to evaluate abemaciclib in combination with standard adjuvant 
endocrine therapy, in patients with node-positive, early stage, HR+, HER2-, invasive breast 
cancer at high risk of recurrence as determined by clinical and pathological features. Historical 
data estimate the 5-year disease-free survival rate for the monarchE-defined population between 
80% and 85%.  Therefore, at least 15% of the patient population intended to be enrolled into 
monarchE study fail to be cured by the current standard of care adjuvant therapy.  Optimizing 
standard adjuvant therapy by adding novel targeted therapies is warranted for patients with early 
breast cancer and at high risk of disease recurrence. 

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 2 3
L Y 2 8 3 5 2 1 9
3. 2. 1. Ki -6 7 I m m u n o hi st o c h e mi str y A s s a y
T he i n vest i gati o nal Ki-6 7 p har m D x Kit i s ma n ufact ure d b y Da k o N ort h A merica, I nc.  T his I H C 
assa y will be a G o o d Ma n ufact uri n g Practice ( G M P) verifie d assa y (t he kit pr ot o c o l a n d 
c o mp o ne nts are l o c k e d, m a n ufact ure d i n a G M P facilit y a n d a nal yticall y verifie d) a n d will 
c o mpl y  wit h r e gio n al re g ulat or y r e q uire me nts f or i n vesti gati o nal de vices. Da k o’s Ki-6 7 ki t is a 
sta n dar dize d I H C assa y t hat detects e x pressi o n of Ki -6 7 i n f or mali n-fi xe d paraffi n-e m be d de d 
(F F P E ) breast ca ncer tiss ue s peci me ns usi n g a Ki -6 7 A b t hat i s C E mar ke d.
 
 
 
 
 
 
 
 
 
  
A ke y  sec o n dar y e n d p oi nt is t o e val uate all pat ient s fr o m bot h  c o h orts w h o ha ve a Ki-6 7 i n de x 
≥2 0 %. 
 
3. 3.
B e n efit/ Ri s k A s s e s s m e nt
C CI
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, seri o us a d verse e ve nts ( S A Es) 
a n d reas o na bl y a nt ici pate d seri o us a d verse e ve nts of a be macicli b are t o be f o u n d i n t he 
I n vesti gat or’s Br oc h ure (I B).  
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks of sta n dar d of care 
e n d ocri ne t hera pies, s uc h as ta m o x ife n, a nastr oz ole, letr oz ole, e xe mesta ne, a n d G n R H a g o nist, 
ma y be f o u n d i n t he res pect i ve Patie nt I nf or mati on Leaflet, Pac ka ge I nsert, or S u m mar y  of 
Pr o d uct C haracteristics.  
C CI
C CI

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4. Objectives and Endpoints
Table JPCF.4.1 shows the objectives and endpoints of the study.
Table JPCF.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the efficacy, in terms of IDFS, for patients 
with HR+, HER2- early stage breast cancer for
abemaciclib plus adjuvant endocrine therapy versus 
adjuvant endocrine therapy alone.
IDFS, as defined by the STEEP System (Hudis et al. 
2007) (Section 10.3.1.1)
Secondary
To evaluate the efficacy, in terms of IDFS, for patients 
with HR+, HER2- early stage breast cancer with
pretreatment Ki-67 index ≥20% by central lab 
To evaluate the efficacy of abemaciclib plus adjuvant 
endocrine therapy versus adjuvant endocrine therapy 
alone in terms of DRFS and OS
IDFS, as defined by the STEEP System
Efficacy endpoints:

DRFS

OS
To assess the safety profile of abemaciclib plus adjuvant 
endocrine therapy compared to adjuvant endocrine 
therapy alone
Safety endpoints will include but are not limited to the 
following:

TEAEs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and physical 
examinations
To evaluate the relationship between abemaciclib, 
exposure and clinical (efficacy and safety) outcomes
Steady-state trough abemaciclib concentration (Cmin,ss), 
hazard ratio for IDFS, DRFS, OS, other efficacy and 
safety endpoints
To evaluate abemaciclib plus adjuvant endocrine 
therapy, versus adjuvant endocrine therapy alone, in 
terms of general oncology and breast cancer self-
reported health-related quality of life (FACT-B 37-item 
questionnaire), endocrine therapy-specific symptoms 
(the FACT-ES 19-item subscale and 2 FACIT-sourced 
items of cognitive symptoms and 3 FACIT-sourced 
items for bladder symptoms), and fatigue experienced 
during abemaciclib and/or endocrine therapy (the 
FACIT-F 13-item subscale).
To evaluate health status to inform decision modeling 
for health economic evaluation using the EQ-5D-5L.
Composite and single-item endpoints will be evaluated 
to examine differentiating effects of abemaciclib across 
study arms. Measurement will be undertaken using the 
FACT-B questionnaire for general oncology and breast 
cancer health-related quality of life; the FACT-ES 
subscale and additional FACIT-sourced items for 
cognitive and bladder endocrine therapy symptoms; and
the FACIT-F subscale to characterize this symptom 
know to be associated with oncology, endocrine therapy, 
and abemaciclib treatment. 
The EQ-5D-5L health state profile (the index score and 
the single-item health status measure) will be used to 
inform decision modeling for economic evaluations and 
this questionnaire will be coadministered with and after 
first completing the FACT/FACIT questionnaire, 
subscales, and additional items.

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 2 5
L Y 2 8 3 5 2 1 9
E x pl o rat or y
 
 
 
 
C CI
A b bre viati o ns:  D R F S = dista nt rela pse -free sur vi val; E Q - 5 D-5 L = E ur o Q ol fi ve -di me nsi o n fi ve -le vel q uesti o n naire; 
F A CI T -F = F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y - Fati g ue ( Versi o n 4); F A CI T -s o urce d 
ite ms = F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y Ite m Li brar y ( Versi o n 2) c o g niti ve s y m pt o ms ite ms 
( 2) a n d bla d der s y m pt o m ite ms ( 3); F A C T -B = F u ncti o nal Assess me nt of Ca ncer T hera p y - Br east ( Versi o n 4); 
F A C T -E S = F u ncti o nal Assess me nt of Ca ncer T hera p y - E n d ocri ne S y m pt o ms ( Versi o n 4); H R + = h or m o ne 
rece pt or p ositi ve; 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; I D F S = i n vasi ve disease -free 
s ur vi val; O S = o verall s ur vi val; S A E = seri o us a d verse e ve nt; T E A E = treat me nt-e mer ge nt a d verse e ve nt.

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5. Study Design
5.1.
Overall Design
The Phase 3 Study monarchE is a multicenter, randomized, open-label trial in patients with node-
positive, early-stage, resected HR+, HER2−breast cancer who completed definitive locoregional 
therapy (with or without neoadjuvant or adjuvant chemotherapy) and are at high risk of disease 
recurrence.  Figure JPCF.5.1 illustrates the study design.  Treatment with abemaciclib will be 
given for up to 2 years or until discontinuation criteria are met, whichever occurs first.  
Endocrine therapy will be taken as prescribed during the on-study treatment period (Years 1-2).  
In Year 3 and beyond, standard adjuvant endocrine therapy should continue for a duration of at 
least 5 years if deemed medically appropriate.  In a subset of patients, an investigational assay 
will be used to determine Ki-67 status. 
Standard adjuvant endocrine therapy is per physician’s choice (such as tamoxifen or an 
aromatase inhibitor, with or without ovarian function suppression per standard practice).  
Adjuvant treatment with fulvestrant is not allowed at any time during the study. Patients 
currently receiving standard adjuvant endocrine therapy at time of study entry may not have 
received more than 12 weeks of standard adjuvant endocrine therapy after completion of their 
last non-endocrine therapy (surgery, chemotherapy, or radiation) prior to randomization.  
Randomization must occur within a maximum of 16 months following the definitive breast 
cancer surgery.
In both treatment arms (Arm A: abemaciclib plus endocrine therapy; Arm B:  endocrine therapy 
alone), Day 1 is defined as the first dose of treatment following randomization, that is,
abemaciclib and/or endocrine therapy (for Arm A) or endocrine therapy alone (for Arm B), 
regardless if the patient is already receiving endocrine therapy at time of randomization. The 
first dose of study treatment (abemaciclib and/or endocrine therapy) should be taken no later than 
3 days of randomization.

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Abbreviations:  BID = twice daily; HER2 = human epidermal growth factor receptor 2 
negative; HR+ = hormone receptor-positive; ITT = intent to treat; Ki-67 = prognostic 
parameter; R = randomization.
Figure JPCF.5.1.
Illustration of study design.
5.2.
Number of Patients
Patients will be enrolled into 2 cohorts:  
1. Cohort 1: those with at least 1 positive node and eligible based on clinical pathological 
features (degree of axillary lymph node involvement, tumor size, and/or grade) regardless 
of Ki-67 status.  
2. Cohort 2: those with at least 1 positive node and eligible exclusively based on central Ki-67 
status. These patients would not be eligible based on degree of axillary lymph node 
involvement, tumor size, and/or histologic grade.
Approximately 4580 patients will be randomized within cohorts, in a 1:1 ratio to either up to 2 
years of abemaciclib plus standard adjuvant endocrine therapy or standard adjuvant endocrine 
therapy alone.  
Note that patients in Cohort 1 may also have high Ki-67, but Ki-67 testing prior to randomization 
is not required for this cohort.  
5.3.
End of Study Definition
The primary analysis of the primary endpoint, invasive disease-free survival (IDFS), will be 
performed after approximately 390 IDFS events have been observed in the Intent-to-Treat (ITT) 
population.  The study will be considered complete (that is, scientific evaluation will be complete 
[study completion]) following evaluation of overall survival (OS) as determined by Lilly.  
Investigators will continue to follow the study schedule for all patients until notified by Lilly that 

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study completion requirement has been met.  End of the study is the date of the last visit or last 
scheduled procedure for the last patient. 
5.4.
Justification for Dose (Arm A)
In monarchE, abemaciclib will be administered orally at 150 mg twice daily in Arm A, with at 
least 6-hours separating doses. The minimum separation of 6 hours was selected to approximate 
the tmax of abemaciclib and permit maximal absorption between doses. 
Collectively, results from the studies evaluating abemaciclib in the mBC setting (Studies JPBA, 
JPBH, MONARCH 1, MONARCH 2, and MONARCH 3), and in the early stage breast cancer 
setting (neoMONARCH), support the abemaciclib dose of 150 mg twice daily.  Study JPBA 
evaluated abemaciclib monotherapy at multiple dose levels in patients with advanced solid 
tumors.  The maximum tolerated dose of single-agent abemaciclib was defined as 200 mg twice 
daily, with the dose-limiting toxicity of Grade 3 fatigue (Patnaik et al. 2016).  The most common 
AEs experienced by patients receiving abemaciclib included diarrhea and neutropenia, 
predominantly of low-grade severity. 
Based on the safety, tolerability, and PK results from abemaciclib trials in breast cancer referenced 
above, the selected dose of abemaciclib in ongoing Phase 3 program (MONARCH 2 and 
MONARCH 3) and further clinical trials for patients with breast cancer is 150 mg twice daily 
when administered in combination with endocrine therapy.  Therefore, in monarchE Arm A, up to 
2 years of abemaciclib will be administered orally at 150 mg twice daily (with minimum of 6-
hour interval separating doses) in combination with standard adjuvant endocrine therapy of 
physician’s choice. 

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6. Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1.
Inclusion Criteria
A patient is eligible to be included in the study only if she/he meets all of the following criteria:
[1]
Female (regardless of menopausal status) or male ≥18 years of age (or of an 
acceptable age according to local regulations, whichever is older).
[2]
The patient has confirmed HR+, HER2-negative (HER2-), early stage resected
invasive breast cancer without evidence of distant metastases.

To fulfill the requirement for HR+ disease by local testing on primary 
disease specimen, tumor must be ER or PgR positive defined by 
immunohistochemistry (IHC) according to American Society of Clinical 
Oncology (ASCO)/College of American Pathologists (CAP) guidelines for 
hormone receptor testing (Hammond et al. 2010).

To fulfill the requirement of HER2- disease by local testing on primary 
disease specimen, tumor must be HER2- according to ASCO/CAP 
guidelines for HER2 testing (Wolff et al. 2018).
Patients with bilateral breast cancer (diagnosis of invasive tumors in both 
breasts simultaneously or within 6 months of each other) can be eligible if all 
lesions tested on both sides are HR+/HER2- and adequate surgery has been 
performed in both breasts (see inclusion criterion [3]).  The Lilly Clinical 
Research Physician and Clinical Research Scientist (CRP/CRS) must be 
consulted for all cases of bilateral breast cancer.
[3]
The patient must have undergone definitive surgery of the primary breast 
tumor(s).

With the exception of the situations described below, the margins of the 
resected specimen must be histologically free of invasive tumor and /or a 
component of ductal carcinoma in situ (DCIS) as determined by the local 
pathologist.  If pathologic examination demonstrates tumor at the line of 
resection, additional excisions may be performed to obtain clear margins.  
If tumor is still present at the resected margin after re-excision(s), the 
patient must undergo mastectomy to be eligible.  Of note, patients with 
margins positive for lobular carcinoma in situ (LCIS) are eligible without 
additional resection.

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
For patients who undergo mastectomy or wide local excision where deep 
margin abuts the pectoralis fascia, patients with microscopic positive 
margins are eligible as long as radiotherapy of the chest wall is 
administered prior to study entry. Patients with positive anterior margins 
may be eligible if there is no gross disease left behind (radiotherapy as per 
local guidelines).

Where surgical excision of supraclavicular or internal mammary nodes is 
not feasible, residual nodes should be irradiated in accordance with 
standard guidelines.

If given, radiation therapy (for example, post-mastectomy or post-
lumpectomy) should be administered according to standard guidelines. 
[4] The patient must have tumor tissue from breast (preferred) or lymph node for 
exploratory biomarker analysis available prior to randomization. 
Note:  Sites should confirm the availability of tumor tissue for exploratory 
analysis (Section 9.8.2.2) with the pathological laboratory prior to 
randomization  
[5]
Patients must be node positive (microscopic and macroscopic tumor 
involvement are allowed; ipsilateral internal mammary and supraclavicular 
lymph nodes are allowed, but will not count toward the number of positive 
lymph nodes) and fulfill one of the following criteria: 
A. Pathological tumor involvement in ≥4 ipsilateral axillary lymph nodes.
OR
B. Pathological tumor involvement in 1 to 3 ipsilateral axillary lymph node(s)
(for patients who received neoadjuvant therapy also cytological tumor 
involvement at time of initial diagnosis is allowed) and meet at least 1 of 
the following criteria:
1. Grade 3 as defined by a combined score of at least 8 points per the 
modified Bloom-Richardson grading system (Elston and Ellis 
1991), also known as the Nottingham scale, or equivalent following 
discussion with the Lilly CRP/CRS
–
pathological primary invasive tumor size ≥5 cm (for patients who 
received neoadjuvant therapy primary tumor size ≥5 cm on breast 
imaging is allowed).  Note: if tumor size is needed to meet 
eligibility criteria, patients with multifocal/multicentric tumors may 
be eligible based on the addition of diameters of the individual 
lesions following discussion with the Lilly CRP/CRS.
–
Ki-67 index of ≥20% (for Cohort 2) on untreated breast tissue as 
determined by the investigational assay (described in Section 3.2.1) 
at the Study JPCF central laboratory. See Section 9.8.1 for Ki-67 
sample requirements.

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[6]
The patient must be randomized within 16 months from the time of 
definitive breast cancer surgery.
[7]
If the patient is currently receiving or initiating standard adjuvant endocrine 
therapy at time of study entry, she/he may receive up to 12 weeks of 
endocrine therapy until randomization following the last non-endocrine 
therapy (surgery, chemotherapy, or radiation), whichever is last.
Use of GNRH analogues for ovarian suppression is not considered 
endocrine therapy for the purposes of this criterion.  Note: Adjuvant 
treatment with fulvestrant is not allowed.
[8]
Patients who received or will be receiving adjuvant chemotherapy must have 
completed adjuvant chemotherapy prior to randomization and patients must
have recovered (Common Terminology Criteria for Adverse Events
[CTCAE] Grade ≤1) from the acute effects of chemotherapy except for 
residual alopecia or Grade 2 peripheral neuropathy prior to randomization.  
Patients who are not candidates for adjuvant chemotherapy or decline 
chemotherapy are permitted. Patients may also have received neoadjuvant 
chemotherapy. A washout period of at least 21 days is required between last 
adjuvant chemotherapy dose and randomization (provided the patient did not 
receive radiotherapy).
[9]
Patients who received or will be receiving adjuvant radiotherapy must have 
completed radiotherapy prior to randomization, and patients must have 
recovered (Grade ≤1) from the acute effects of radiotherapy.  A washout 
period of at least 14 days is required between end of radiotherapy and 
randomization.
[10] The patient has recovered from surgical side effects following definitive 
breast surgery based on investigator discretion (for example, adequate 
wound healing complications or seroma complications). 
[11] Omit text; see Criterion [1]
[12] Women of reproductive potential must have a negative blood pregnancy test 
at baseline (within 14 days prior to randomization) and agree to use highly 
effective contraceptive methods to prevent pregnancy during the study and 
for 12 weeks following the last dose of study treatment. Males must agree to 
use an acceptable method of birth control and to not donate sperm during the 
study and for at least 12 weeks following the last dose of study treatment.  
Refer to Appendix 4 for definitions of highly effective methods of 
contraception. 
[13] The patient has a performance status ≤1 on the Eastern Cooperative 
Oncology Group (Appendix 11) scale (Oken et al. 1982).
[14] The patient has adequate organ function for all of the following criteria, as 
defined below.

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System
Laboratory Value
Hematologic
ANC
1.5 × 109/L
Note:  G-CSF cannot be administered to meet ANC 
eligibility criterion.
Platelets
100 × 109/L
Hemoglobin
8 g/dL
Note:  Patients may receive erythrocyte transfusions to 
achieve this hemoglobin level at the discretion of the 
investigator.  Initial treatment must not begin earlier than 
the day after the erythrocyte transfusion.
Hepatic
Total bilirubin
1.5 × ULN
Patients with Gilbert’s syndrome with a total bilirubin ≤2.0 
times ULN and direct bilirubin within normal limits are 
permitted.
ALT and AST
3 × ULN 
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; G-CSF = granulocyte colony-stimulating factor; ULN = upper limit of normal.
[15] The patient is able to swallow oral medications.
[16] The patient has given written informed consent prior to any study-specific 
procedures and is willing and able to make herself/himself available for the 
duration of the study and amenable and able to follow study schedule during 
treatment and follow-up.
6.2.
Exclusion Criteria
A patient will be excluded from the study if she/he meets any of the following criteria:
[17] The patient has metastatic disease (including contralateral axillary lymph 
nodes) or lymph node-negative breast cancer. Patients with inflammatory 
breast cancer are excluded.  Inflammatory carcinoma should not apply to a 
patient with neglected locally advanced breast cancer presenting late in the 
course of their disease (American Joint Committee on Cancer [AJCC] staging 
system for breast cancer 8th edition, Hortobagyi et al. 2017). The investigator 
should consult with the Lilly CRP/CRS regarding eligibility of patients with 
neglected inflammatoid disease.

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[18] Patients with a history of previous breast cancer are excluded, with the 
exception of ipsilateral DCIS treated by locoregional therapy alone ≥5 years 
ago.  Patients with a history of contralateral DCIS treated by local regional 
therapy at any time may be eligible.  Patients with a history of any other 
cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix), 
unless in complete remission with no therapy for a minimum of 5 years from 
the date of randomization are excluded.  For patients with a history of other 
non-breast cancers within 5 years from the date of randomization and 
considered of very low risk of recurrence per investigator’s judgment (for 
example, papillary thyroid cancer treated with surgery), eligibility is to be 
discussed with the Lilly CRP/CRS.
[19] Females who are pregnant or lactating.
[20] The patient has previously received treatment with any CDK4 and CDK6 
inhibitor.
[21] The patient is receiving concurrent exogenous reproductive hormone therapy 
(for example, birth control pills, hormone replacement therapy, or megestrol
acetate). Appropriate washout period between last dose of exogenous 
hormone therapy and randomization is up to the investigator’s medical 
judgment (for example, applying 5 times the half-life elimination rule). 
Note: topical vaginal estrogen therapy is permitted if all other non-hormonal 
options are exhausted.
[22] The patient has previously received endocrine therapy for breast cancer 
prevention (tamoxifen or aromatase inhibitors) or raloxifene.
[23] The patient has serious preexisting medical condition(s) that, in the judgment 
of the investigator, would preclude participation in this study (such as severe 
renal impairment, [for example, estimated creatinine clearance <30 mL/min],
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 clinically significant diarrhea).
[24] The patient has a personal history of any of the following conditions:  syncope 
of cardiovascular etiology, ventricular arrhythmia of pathological origin 
(including, but not limited to, ventricular tachycardia and ventricular 
fibrillation), or sudden cardiac arrest.  Exception:  patients with controlled 
atrial fibrillation for >30 days prior to randomization are eligible.  Any patient 
with a history of VTE (for example, DVT of the leg or arm and/or PE) will be 
excluded.  Patients with a history of venous catheter occlusion by thrombus 
that did NOT surround the catheter, and the lumen could be made patent by 
appropriate measures (for example, saline or thrombolytic agent), are not 
excluded.

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[25] The patient has active systemic infections (for example, bacterial infection 
requiring intravenous [IV] antibiotics at time of initiating study treatment, 
fungal infection, or detectable viral infection requiring systemic therapy) or 
viral load (such as known human immunodeficiency virus positivity or with 
known active hepatitis B or C [for example, hepatitis B surface antigen 
positive]). Screening is not required for enrollment.
[26] The patient has had major surgery within 14 days prior to randomization.
[27] The patient has received an experimental treatment in a clinical trial within the 
last 30 days or 5 half-lives, whichever is longer, prior to randomization, or is 
currently enrolled in any other type of medical research (for example: medical 
device) judged by the sponsor not to be scientifically or medically compatible 
with this study.  Co-enrollment to other studies may be allowed following 
consultation with the Lilly CRP/CRS.
6.3.
Lifestyle Restrictions
Patients should avoid consumption of grapefruit or grapefruit juice while receiving abemaciclib. 
Patients should not donate blood during the on-study treatment period and for 3 months after 
discontinuing study treatment. See Section 7.7 for additional guidance on concomitant therapy 
to avoid whenever possible. 
6.4.
Screen Failures
A patient who fails screening is allowed to screen again after signing a new informed consent 
form (ICF) and will be assigned a new patient number under the conditions specified in this 
section.
The Ki-67 expression result obtained under the first patient number can be moved to a new 
number in an effort to preserve patient tissue.  A patient may not be rescreened in an effort to 
obtain a different Ki-67 result.
Repeating of laboratory tests during the 3-month screening period does not constitute 
re-screening.  This includes one repeat for Ki-67 to determine Cohort 2 eligibility if Ki-67 
expression was not able to be determined by the patient’s initial sample.
The following patients may be eligible for rescreening in any of the following circumstances: 
-
A patient who has become eligible to enroll in the study as the result of a protocol 
amendment.
-
Patient status has changed such that the eligibility criterion that caused the patient to 
screen fail would no longer cause the patient to screen fail again.
-
A patient who completes screening and meets all inclusion and exclusion requirements 
but is unable to be enrolled due to extenuating circumstances (such as severe weather, 
death in family, child illness).
The investigator should contact the Lilly study team prior to rescreening a patient.

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7. Treatments
7.1.
Treatments Administration
Patients will be randomized to one of the following treatment arms: 

Arm A - Abemaciclib plus standard adjuvant endocrine therapy

Arm B - Standard adjuvant endocrine therapy alone
The monarchE protocol defines study treatment as abemaciclib and/or endocrine therapy during 
the first 2 years of the on-study treatment period. 
In both arms A and B, Day 1 of on-study treatment period is defined by the first dose of 
treatment following randomization, which means abemaciclib and/or endocrine therapy (in Arm 
A) or endocrine therapy (in Arm B), regardless if the patient is already receiving endocrine 
therapy prior to randomization. The first dose of abemaciclib and/or endocrine therapy should 
be taken no later than 3 days after randomization. 
The on-study treatment period ends after one of the following time points, whichever occurs
first:

after the completion of the 2-year on-study treatment period  

after discontinuation criteria are met (Section 8.1) and patient has discontinued all study 
treatment (abemaciclib plus endocrine therapy in arm A, endocrine therapy in Arm B) 
prior to the completion of the 2-year on-study treatment period  
Table JPCF.7.1 shows the treatment regimens.
Table JPCF.7.1.
Treatment Regimens
Dose and Schedule
Arm
Abemaciclib
Standard Adjuvant Endocrine Therapy
On Study Treatment Period (Years 1-2)
A
150 mg twice 
daily, with at 
least 6-hour 
separating doses
Standard adjuvant endocrine therapy of 
physician’s choice
Treatment with abemaciclib will be given 
for up to 2 years or until discontinuation 
criteria are met.  In both arms, treatment 
with endocrine therapy will be given until 
discontinuation criteria are meta
B
Not applicable
Standard adjuvant endocrine therapy of 
physician’s choice
a
Standard endocrine therapy will be taken as prescribed during the on-study treatment period (Years 1-2).  In 
Year 3 and beyond, continue standard adjuvant endocrine therapy to complete at least 5 years, if this is medically
appropriate.

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7.1.1. Treatment Administration Guidance:
Abemaciclib (Arm A):
Abemaciclib will be administered at a starting dose of 150 mg twice daily and it is provided as 
50-mg capsules or tablets.  Abemaciclib should be taken twice daily (with at least 6-hour 
separating doses) at the same time each day with a glass of water.  Patients should be instructed 
to swallow capsules or tablets whole and not open, chew, or crush.
Endocrine therapy (Arms A and B):
The investigator should refer to the product label for administration of standard-of-care 
endocrine therapy of choice. A switch to another standard endocrine therapy is allowed as per 
the investigator’s discretion only in the absence of an IDFS event (Appendix 10), during the on-
study treatment period.  Adjuvant treatment with fulvestrant is not allowed at any time during the 
study.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient/study site personnel,

verifying that instructions are followed properly by the patient,

maintaining accurate records of abemaciclib dispensing and collection as well as 
for other treatments provided locally by Lilly.  For all other treatments, follow 
local regulations,

at the end of the study returning all unused treatments provided by Lilly, 
including abemaciclib and locally provided other treatments, (not site sourced, see 
Section 7.1.2) to sites for destruction if the site has been approved for 
destruction. Sites not approved for destruction of treatments should return 
materials to Lilly, or its designee.
7.1.2. Packaging and Labeling
Abemaciclib will be provided by Lilly.  Clinical trial materials will be labeled according to the 
country’s regulatory requirements. All standard adjuvant endocrine therapy per physician’s 
choice (such as letrozole, anastrozole, exemestane, tamoxifen, or GnRH agonist) will be site 
sourced unless prohibited by local country regulation. 
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomly assigned to Arm A or Arm B.  
Approximately 4580 patients, will be enrolled and randomized 1:1 between the 2 arms.  
Randomization will occur within cohort and will be stratified by the factors outlined in 
Section 10.1.
The interactive web-response system (IWRS) will use randomization factors to assign treatment 
arm to each patient.

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The IWRS will be used to assign bottles containing open-label abemaciclib to each patient in 
Arm A.
7.2.1. Selection and Timing of Doses
During the on-study treatment period, a delay of study treatment due to holiday, weekend, 
inclement weather, or other unforeseen circumstances will be permitted for a maximum of 7 
consecutive days and not counted as a protocol deviation.  In exceptional cases, for planned 
delays (including but not limited to vacation or holidays), additional study treatment may be 
dispensed. In these cases, patients should return to the original visit schedule calculated from the 
last (clinic) visit within the visit window. 
In Arm A, abemaciclib will be administered orally at 150 mg twice daily, with at least 6-hour
separating doses on a continuous schedule.  Details on treatment administration are described in 
Section 7.1.  Treatment with abemaciclib will be given for up to 2 years or until discontinuation 
criteria are met (see Section 8).
Standard adjuvant endocrine therapy will be taken as prescribed during the on-study treatment 
period (Years 1-2). In Year 3 and beyond, standard endocrine therapy may be continued to 
complete at least 5 years according to standard of care and if deemed medically appropriate 
based on investigator discretion. A switch to another standard endocrine therapy is allowed as 
per the investigator’s discretion and in the absence of an IDFS event per STEEP criteria 
(Appendix 10), during the on-study treatment period.
In Arm A, timing of endocrine therapy administration relative to abemaciclib is up to the 
investigator.
7.3.
Blinding
This is a randomized, open-label study. Toxicities and laboratory abnormalities related to 
abemaciclib treatment (such as diarrhea, neutropenia, and creatinine increase) have the potential 
to unblind the study, justifying an open-label design. Randomization will occur using an IWRS.  
Assignment to treatment groups will be determined by a computer-generated random sequence.  
Each patient in this study will be aware of his or her own assigned treatment group.  At each 
investigative site, all staff involved in treating and caring for study patients will have full 
knowledge of treatment assignments for the patients under their care.
In order to maintain the scientific integrity of this trial, access to study data will be strictly 
controlled prior to the interim and final analyses. Access to the electronic data capture (eDC) 
system will be limited to those who require this information for their role and all access will be 
documented.
For the accumulated aggregate database, that is, the database to which Lilly statisticians (or those 
of its designee) have access, treatment assignment and other parameters that can disclose 
treatment assignment will be scrambled or masked.  Therefore, the sponsor and all investigative 
sites will remain blinded to treatment group assignments for the aggregate database until the 
database lock for the final analysis.  Scrambled treatment assignments will be used in the 

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reporting database until the study reaches its final analysis or the study is determined to be 
positive by the data monitoring committee (DMC).  During this time, analyses using unblinded 
treatment codes will be performed only at the interim analysis points specified in the 
protocol/statistical analysis plan (SAP).  
For those safety and efficacy analyses assigned to the DMC, only the designated Statistical 
Analysis Center (SAC), which is independent of the sponsor, will perform analyses on unblinded 
data, that is, an aggregate database with correct treatment assignments.  At the request of the 
sponsor, the SAC may provide pooled summary reports of the data to the sponsor (for example, a 
summary of AEs across the study). These reports will not include treatment arms. 
Further details are included in the study blinding plan.
7.4.
Abemaciclib Dosage Modification
7.4.1.Abemaciclib Dose Adjustments 
Table JPCF.7.2 is a guidance for management of treatment-emergent, related, and clinically 
significant AEs of abemaciclib. If an investigator would like to suspend or reduce doses without 
one of the criteria below being met, this is acceptable and would not be considered a protocol 
deviation.
Guidance on safety monitoring for hepatic function, renal function, and VTEs is outlined in 
Section 9.4.

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Table JPCF.7.2.
Abemaciclib Dose Adjustments for Treatment-Emergent, Related,* 
and Clinically Significant Adverse Events
Treatment-emergent laboratory abnormalities of neutrophil count decreased and/or ALT/AST 
increased, regardless of clinical significance, must follow the dose adjustment table below. For 
VTEs see monitoring and guidance in Section 9.4.4 and Appendix 12.
* Related means there is a reasonable causal relationship with abemaciclib.
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity 
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose reduction is 
NOT required.
Hematologic Toxicity 
Recurrenta Grade 3 or Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be 
reduced by 1 dose 
level. 
Hematologic Toxicity:  If 
patient requires 
administration of blood 
cell growth factors
Regardless of severity 
(Use of growth factors 
according to ASCO 
Guidelines)
Dose MUST be suspended 
for at least 48 hours after 
the last dose of blood cell 
growth factors was 
administered and until 
toxicity resolves to at least 
Grade 2.
Dose MUST be 
reduced by 1 dose 
level unless already 
performed for 
incidence of toxicity 
that led to the use of 
growth factor.
Non-hematologic Toxicityb
(except diarrhea, ALT/AST 
increased, ILD/pneumonitis 
and VTEd)
Persistent or recurrenta Grade 
2 that does not resolve with 
maximal supportive measures 
within 7 days to baseline or 
Grade 1, or Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
Diarrhea
  
Grade 2 that does not resolve 
within 24 hours to at least 
Grade 1
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose reduction is 
NOT required.
Diarrhea
Persistent or recurrenta Grade 
2 that does not resolve with 
maximal supportive measures, 
or requires hospitalization, or
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
ALT/AST Increased
Persistent or recurrenta Grade
2 (>3.0-5.0×ULN), or
Grade 3 (>5.0-20.0×ULN)c
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
ALT/AST Increased
Grade 4 (>20.0×ULN)
Abemaciclib therapy 
MUST be discontinued.
Abemaciclib 
therapy MUST be 
discontinued.
ALT/AST Increased
Elevation in AST and/or ALT 
>3 x ULN with total
bilirubin >2 x ULN, in the 
absence of cholestasis
Abemaciclib therapy 
MUST be discontinued
Abemaciclib 
therapy MUST be 
discontinued.
ILD/pneumonitis
Grade 2
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.

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ILD/pneumonitis
Grade 3 or Grade 4
Abemaciclib therapy 
MUST be discontinued
Abemaciclib 
therapy MUST be 
discontinued.
Abbreviations:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology; ILD = interstitial 
lung disease.
a
Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event). As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:
The patient showed stable hematological counts (Grade ≤2) during that timeframe
In the absence of any infectious sign or risk factor
The patient is benefiting from study treatment
b
Additional guidance for renal and hepatic monitoring is in Section 9.4.
c   Grade 3 ALT/AST increased is a trigger for additional assessments and possibly hepatic monitoring. See Section 
9.4 for additional guidance for hepatic monitoring.
d  For VTE, dose reduction of abemaciclib will be at the discretion of the investigator.
7.4.1.1.
Dose Adjustments
7.4.1.1.1. Abemaciclib (Arm A)
Dose adjustments as outlined in Table JPCF.7.3 are allowed. Abemaciclib should be reduced 
sequentially by 1 dose level.
For patients requiring dose reduction(s), any re-escalation to a prior dose level is permitted only 
after consultation with the Lilly CRP/CRS.  After re-escalation, subsequent dose adjustments 
should be based on the dose of abemaciclib that the patient is currently receiving.
Table JPCF.7.3.
Dose Adjustments of Abemaciclib
Dose Adjustment
Oral Dose
Frequency
0
150 mg
Twice daily with at least 6 hours between doses
1
100 mg
Twice daily with at least 6 hours between doses
2
50 mg
Twice daily with at least 6 hours between doses
If a patient receiving the 50-mg twice daily dose of abemaciclib requires further dose reduction, 
the patient must be discontinued from abemaciclib.
Patients undergoing surgery:

For minor surgeries and procedures (for example, ambulatory), investigators should treat 
as clinically indicated and closely monitor any signs of infection or healing 
complications.

For major surgeries, the recommendation is to suspend dosing of abemaciclib for at least 
7 days before and may be resumed as clinically indicated.

Consider monitoring neutrophils and platelets before surgery and before resuming 
abemaciclib. The scars should be aseptic and healing process be reasonable before 
resuming abemaciclib.

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
Dose suspensions ≥28 days must be discussed with Lilly CRP/CRS.  
7.4.1.1.2. Standard of Care Endocrine Therapy of Physician’s Choice (Arms A 
and B)
Dose adjustment for endocrine therapy (on-study treatment period and beyond) will be 
determined by the investigator and when applicable.  For Arm A, in the event that endocrine 
therapy is permanently discontinued for any reason other than an IDFS event per STEEP criteria 
(Appendix 10), a patient should continue to receive abemaciclib.  A switch to another endocrine 
therapy is permitted per physician’s choice as part of standard of care.  In the event that 
abemaciclib must be discontinued, a patient may continue to receive endocrine therapy per the 
investigator’s clinical judgment.
For patients in Arm B undergoing surgery, a determination regarding changes to endocrine 
therapy is as clinically indicated and determined by the investigator.
7.4.1.2.
Dose Delays and Omission
7.4.1.2.1. Study Treatment (Abemaciclib and/or Endocrine Therapy – Arms A and 
B)
Both dose suspension and delay of study treatment are permitted.  When a dose suspension or 
delay occurs related to toxicity (defined as an AE possibly related to study treatment per 
investigator judgment), the relevant drug (abemaciclib and/or endocrine therapy) may be 
suspended or delayed as determined by the investigator’s judgment and the other drug may be 
continued (see Table JPCF.7.2 for guidance on abemaciclib toxicity management).
Study treatment may be held up to 28 days to permit sufficient time for recovery from the 
toxicity. For patients not recovering from toxicity within 28 days, a delay >28 days is permitted 
upon agreement between the investigator and the Lilly CRP/CRS and abemaciclib dose 
adjustment is to be considered.
In the event of a study visit delay due to logistical reasons (for example, due to patient 
availability), the patient should continue on study treatment if the patient has adequate drug 
supply.  If a patient’s treatment is interrupted as a result of the patient not having sufficient drug 
supply, study treatment may be delayed up to 7 days (and not be considered a protocol violation).
In exceptional circumstances, a delay >7 days is permitted upon agreement between the 
investigator and the Lilly CRP/CRS.  Early distribution of study treatment is also permitted in 
certain circumstances (for example, planned vacation).
7.5.
Preparation/Handling/Storage/Accountability
For Arm A, abemaciclib will be supplied by Lilly as capsules or tablets for oral administration.  
Abemaciclib capsules or tablets should be stored according to the temperature range listed on the 
product label, and should not be opened, crushed, or chewed.  Patients should store the 
abemaciclib capsules or tablets in the original package provided and be instructed to keep all 
medication out of reach of children.

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7.6.
Treatment Compliance
Patient compliance with abemaciclib will be assessed by reconciliation at qualified visits. Study 
medication administration data will be recorded in the patient’s medical record and case report 
form (CRF).
Patients who are significantly noncompliant with abemaciclib may be discontinued from 
abemaciclib treatment.  A patient will be considered significantly noncompliant if she or he 
repeatedly misses more than 25% of abemaciclib doses between scheduled clinic visits.  
Similarly, a patient will be considered significantly noncompliant if she or he is judged by the 
investigator to have intentionally or repeatedly taken more than (≥125%) the prescribed amount 
of medication.  Abemaciclib dose suspensions or delays related to toxicity may occur and will 
not result in a patient being considered as noncompliant.
Patient compliance to standard endocrine therapy will be collected and recorded in the patient’s 
medical record and CRF. During the on-study treatment period (Y1-2), this comprises 
information on dosing, treatment omissions, changes in endocrine therapy, and treatment 
discontinuation.  During the long-term follow-up period, information on changes in endocrine 
therapy and treatment discontinuation will be recorded (refer to Section 2; Schedule of 
Activities).
7.7.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, concomitant 
medications, and supplements must be captured at each visit in the CRF.  Concomitant 
medications and supportive care therapies must also be documented at the time of 
discontinuation and at the short-term follow-up visit.
In general, the list of prohibited medications that affect patient eligibility or participation in the 
study are limited to endocrine therapy for breast cancer prevention, concurrent exogenous 
reproductive hormone therapy, and recent experimental treatment in a clinical trial.  Further 
details of these prohibited medications are provided in the exclusion criteria in Section 6.2.
There are a number of concomitant medications that should be substituted or avoided if possible, 
but do not affect patient eligibility or participation in the study.  It should be noted that for 
patients assigned to receive abemaciclib, investigators should consult with their local pharmacist 
to evaluate any potential concerns combining a concomitant medication with abemaciclib.  
Further details of the medications that should be substituted or avoided if possible are provided 
below and in Appendix 8.
Concurrent treatment with standard of care bone-modifying agents (such as bisphosphonates and 
denosumab) is permitted. With the exception of standard endocrine therapy for breast cancer, no 
other anticancer therapy will be permitted while patients are on study treatment unless previously 
discussed with the Lilly CRP/CRS. Of note, megestrol acetate and fulvestrant are not permitted.
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 

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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 8). 
Abemaciclib can be coadministered with drugs which are substrates of CYP enzymes.
Abemaciclib and/or its major metabolites inhibit the efflux transporters P-glycoprotein and 
breast cancer resistance protein and renal transporters organic cation transporter 2, multidrug and 
toxin extrusion protein 1 (MATE1) and MATE2-K at clinically relevant concentrations.  
Therefore, substrates of these transporters such as metformin and those with a narrow therapeutic 
index such as digoxin and dofetilide should be substituted or avoided if possible.
In the LTFU period, post-discontinuation therapies for the disease under study will be captured 
along with any regimen changes and start and stop dates for endocrine therapy.
7.7.1. Supportive Care
Patients should receive full supportive care to maximize quality of life (for example, antiemetics 
or standard of care bone-modifying agents) based on the judgment of the treating physician.  If it 
is unclear whether a therapy should be regarded as supportive care, the investigator should 
consult the Lilly CRP/CRS.  Use of any supportive care therapy should be reported on the CRF.
Guidelines regarding the use of other specific supportive care agents are presented below.
7.7.1.1.
Supportive Management for Diarrhea (Arm A)
At randomization, patients in Arm A should receive instructions on the management of diarrhea. 
Patients should be prescribed antidiarrheal therapy (for example, loperamide) on Visit 1. 
Sponsor will provide reimbursement for antidiarrheal therapy according to local laws.
In the event of diarrhea, provided antidiarrheal therapy should be initiated as early as possible
and site should follow the guidance below:

At the first sign of loose stools, the patient should initiate antidiarrheal therapy, if not 
already receiving such therapy (for example, loperamide), and notify the investigator/site 
for further instructions and appropriate follow-up.

Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess response within 24 hours. 

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to either baseline 
or Grade 1, study drug should be suspended until diarrhea is resolved to baseline or 
Grade 1.

When abemaciclib recommences, dosing should be adjusted as outlined in
Table JPCF.7.2 and Section 7.4.1.1.1.
In cases of significant diarrhea, Grade 2 through 4 (Appendix 9), which has not responded to 
interventions as outlined above, if the investigators are considering the addition of steroids to 
treat potential colitis, the sponsor strongly recommends an endoscopic procedure to document 
colitis prior to initiating steroids.

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In severe cases of diarrhea, the measuring of neutrophil counts and body temperature should be 
considered.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed.
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given IV fluid (IV hydration) and electrolyte replacement.
7.7.1.2.
Therapy for Febrile Neutropenia
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation of IV
antibiotic therapy.  Events that require a patient to be hospitalized are considered SAEs (see 
Section 9.2.1).
7.7.1.3.
Growth Factor Therapy
Growth factors cannot be administered to a patient to satisfy study inclusion criteria.
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2015).  
Dosing of abemaciclib must be suspended if the administration of growth factors is required and 
must not be recommenced within 48 hours of the last dose of growth factors having been 
administered.  Following the administration of growth factors, the dose of abemaciclib must be 
reduced by 1 dose level on recommencement, if a dose reduction for the specific event 
necessitating the use of the growth factors has not already occurred.
7.8.
Treatment after the End of the Study
Investigators will continue to follow Schedule of Activities (Section 2) for all patients until 
notified by Lilly that study completion has occurred. Study completion will occur following the 
final analysis of OS, as determined by Lilly.  

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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment (abemaciclib plus endocrine therapy 
combination in Arm A; endocrine therapy in Arm B) in the following circumstances:

the patient is enrolled in any other clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

investigator decision
o
the investigator decides that the patient should be discontinued from the study or 
study treatment
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug occurs prior to introduction of the new agent

patient decision
o
the patient requests to be withdrawn from the study or study treatment

sponsor decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP)

the patient becomes pregnant during the study; see Section 9.2 regarding regulatory 
reporting requirements on fetal outcome and breastfeeding

the patient is significantly noncompliant with study procedures and/or treatment

the patient experiences any of the IDFS events as per STEEP criteria (Appendix 10)

unacceptable toxicity
Patients who are discontinued from abemaciclib plus endocrine therapy combination in Arm A 
or endocrine therapy in Arm B will remain in the study and have short-term follow-up visit and 
long-term follow-up procedures performed as shown in the Schedule of Activities (Table 
JPCF.2.1).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a decision on whether or not the patient may remain on treatment will be 
made between the Lilly CRP/CRS and the investigator.  If both agree that it is medically 
appropriate to continue, the investigator must obtain documented approval from the Lilly 
CRP/CRS to allow the inadvertently enrolled patient to continue in the study with or without 
study treatment.
8.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

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
sponsor determines that participation in the study needs to be stopped for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP

the investigator decides that the patient should be discontinued from the study

the patient requests to be withdrawn from the study

the study has been completed as defined in Section 5.3.  
If a patient decides at any point during the trial that they do not wish to continue with the full 
study schedule of assessments but are still willing to provide important study information (for 
example, disease recurrence information and/or survival status information) then the patient 
should continue in the study and information should continue to be collected in the clinical 
database.  However, if a patient does not wish to have any further data collected, only then 
should they be considered as withdrawing consent from the study.  To minimize such cases of 
early withdrawal, the investigator should discuss the options with the patient.  If the patient is 
willing to provide information on the important study endpoints (disease recurrence and OS), 
she/he would remain in the study.
8.3.
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.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.
Study site personnel, or an independent third party, will attempt to collect the survival status for 
all randomized patients who are lost to follow-up, including randomized patients who do not 
receive study treatment, within legal and ethical boundaries.  Public sources may be searched for 
survival status information if allowed by local regulations.  If the patient’s survival status is 
determined, the survival status will be documented, and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect survival status information.

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9. Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study.
Appendix 3 provides a list of the laboratory tests that will be performed for this study.
Appendix 6 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Routine Systemic Imaging
For details, see Schedule of Activities (Section 2).
All applicable imaging will be done locally. No central imaging assessments will be performed 
during the study.  See the schedule of activities (Table JPCF.2.1) for detailed description of 
imaging and collection of disease recurrence information. 
During screening, at a minimum, an initial diagnostic/staging work-up since diagnosis is required 
prior to randomization. The appropriate imaging methods are per the investigator judgment. 
During treatment and follow-up, imaging is to be performed per the investigator’s judgment and 
according to routine standard practice. Importantly, for the purpose of disease recurrence 
documentation, Appendix 10 provides guidance for most appropriate methods, including where 
cytological and/or histopathological evidence of progression is required.
Detection of symptoms suspicious of disease recurrence is highly important. The investigator, or 
another medically qualified individual, is expected to conduct a comprehensive and systematic 
assessment of these symptoms during clinic and phone visits. Of note, the protocol does not 
prohibit more frequent monitoring by imaging, if judged necessary by the investigator. 
The primary endpoint of this study is IDFS as defined by the STEEP System (Hudis et al. 2007).  
Invasive disease-free survival time is measured from the date of randomization to the date of first 
occurrence of:

ipsilateral invasive breast tumor recurrence

regional invasive breast cancer recurrence

distant recurrence

death attributable to any cause

contralateral invasive breast cancer

second primary non-breast invasive cancer

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Patients for whom no event has been observed will be censored on the day of their last 
assessment for recurrence or date of randomization if no post-baseline clinic visit occurred.
Distant relapse-free survival (DRFS), a secondary endpoint, is defined as the time from 
randomization to distant recurrence or death from any cause, whichever occurs first.  For patients 
who experienced an IDFS event other than distant recurrence or death, assessments will continue 
to be performed until an event of distant recurrence, death, or study completion, whichever 
occurs first. 
Assessments will also be performed for patients who discontinue treatment without an IDFS 
event per STEEP criteria (Appendix 10) or who are randomized and never received study 
treatment.
See Section 10.3.1 for complete definitions of the efficacy endpoints. 
9.1.2. Appropriateness of Assessments
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology adjuvant trials. 
See Appendix 10 for details on breast cancer recurrence and other cancer events. Documentation 
of a breast cancer recurrence requires meeting at least one of the criteria defined in Appendix 10.  
Suspicious findings do not provide adequate documentation of a breast cancer recurrence and 
should not be an indication to alter study treatment. Tumor marker evaluations alone do not 
document breast cancer recurrence. 
9.2.
Adverse Events
The investigator will enter verbatim terms and assign toxicity grades according to CTCAE 
Version 4.0 (NCI 2009).
Investigators are responsible for:

monitoring the safety of patients in this study and for alerting Lilly or its designee to any 
AE that seems unusual, even if this AE may be considered an unanticipated benefit to 
the patient

the appropriate medical care of patients during the study,

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study treatment or the study, or that caused 
the patient to discontinue study treatment before completing the study.  The patient 
should be followed until the AE resolves, is no longer considered to be drug- or 
procedure-related, becomes stable or returns to baseline, the patient starts a new therapy, 
the patient dies or becomes lost to follow-up.  Frequency of follow-up evaluation is left 
to the discretion of the investigator.
Abnormal laboratory values should ONLY be reported as an AE if they are clinically relevant.

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Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
Adverse events will be collected after the main ICF is signed starting 28 days prior to 
randomization.  Adverse events for screen failures should only be collected if they are related to 
study procedures or are the reason for screen failure.  All events that occur between signing ICF 
and 28 days prior to randomization should be captured in the medical history form.  In addition, 
study site personnel will record via CRF any change in the preexisting conditions and any new 
conditions as AEs.  Investigators should record their assessment of the potential relatedness of 
each AE to study procedure or study treatment via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or other pathologies.  A “reasonable possibility” means that there is a 
cause and effect relationship between the study treatment and/or study procedure and the AE.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuations that result 
from AEs to Lilly or its designee via CRF, clarifying, if possible, the circumstances leading to 
the dose modification or discontinuation of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical events 
that may not result in death, be life-threatening, or require hospitalization may be 
considered serious, based upon appropriate medical judgment.
Although all AEs after signing the ICF and within 28 days of randomization are recorded in the 
CRF, SAE reporting begins after the patient has signed the ICF and has received study treatment.  
However, if an SAE occurs after signing the ICF, but prior to receiving study treatment, it needs 
to be reported ONLY if it is considered reasonably possibly related to study procedure.
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the SAE via a Lilly-approved method.  If alerts are issued via telephone, they are to 
be immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported.  However, to fulfill regulatory requirements, any pregnancy 

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should be reported following the SAE process to collect data on the outcome for both mother and 
fetus.
All SAEs must be collected for 5 years, regardless of causality, relatedness, or the arm to which 
the patient was initially randomized. Following the 5 years, if the investigator learns of any SAE, 
including death, at any time, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Investigators are not obligated to actively seek AEs in patients once they have discontinued 
and/or completed the study (the patient summary CRF has been completed).  
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events, including death, caused by disease recurrence should not be reported 
unless the investigator deems them to be possibly related to study treatment.
9.2.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the IB 
and that the investigator identifies as related to study treatment or study procedure.  United States 
21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated 
detailed guidance or national regulatory requirements in participating countries require the 
reporting of SUSARs.  Lilly has procedures that will be followed for the recording and expedited 
reporting of SUSARs that are consistent with global regulations and associated detailed 
guidance.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and 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.
9.3.
Treatment of Overdose
There is no known antidote to abemaciclib overdose.  In case of overdose, the patient should
receive supportive measures.  Refer to the Product Labels for each of the standard endocrine 
therapy of physician’s choice.
9.4.
Safety
Safety will be monitored by an independent DMC, as described in Section 7.3.  Lilly will 
periodically review evolving aggregate safety data within the study by appropriate methods.

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9.4.1. Other Safety Measures
For each patient, vital signs, laboratory tests, or other tests should be collected as shown in the 
Schedule of Activities (Section 2).  
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of study treatment should be reported to Lilly or its designee as an AE via 
CRF.
Additional information regarding guidance for monitoring hepatic function, renal function, VTE, 
and ILD/pneumonitis can be found in Sections 9.4.2, 9.4.3, 9.4.4, and 9.4.5. 
9.4.2. Safety Monitoring:  Hepatic Function (Both Arms)
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  If a study patient experiences elevated alanine aminotransferase/aspartate 
aminotransferase (ALT/AST) 5 × upper limit of normal (ULN), 
1. Abemaciclib should be held for patients in Arm A. Dose adjustments to the endocrine 
therapy and management of patients in Arm B will be at the discretion of the investigator, 
as clinically indicated.
2. For all patients, central hepatic chemistry (part of the hepatic kit) including ALT, AST, 
total bilirubin, direct bilirubin, gamma-glutamyl transferase (GGT), and creatine 
phosphokinase (CPK), should be tested within 3 to 5 days to confirm the abnormality and 
to determine if it is increasing or decreasing.
3. If the abnormality persists or worsens, hepatic monitoring tests in Appendix 7 should be 
performed using the central laboratory hepatic monitoring kit, clinical monitoring should 
be initiated in consultation with the Lilly CRP/CRS, and the hepatic monitoring CRFs 
should be completed (see Section 9.4.2.1).
4. Monitoring of ALT, AST, and total bilirubin should continue until levels normalize or 
return to approximate baseline levels.  Refer to Table JPCF.7.2 for guidance on dose 
adjustments of abemaciclib for patients with ALT/AST increased, or for other abnormal 
liver tests follow guidance for non-hematologic toxicities.
If clinically indicated, consider hepatobiliary ultrasound to assess for gallstones or gallbladder 
disease.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC (an advisory group for this study formed to protect 
the integrity of data; refer to Section 10.3.5) can conduct additional analyses of the safety data.
9.4.2.1.
Special Hepatic Safety Data Collection
If one or more of the following situations occur, there is a separate group of hepatic monitoring 
CRFs that must be completed related to hepatic function.

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
A repeat value 3 to 5 days after initial finding of elevation of serum ALT/AST≥5 
× ULN that persists or worsens

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests

occurrence of a hepatic event considered to be an SAE.
9.4.3.Safety Monitoring:  Renal Function for Abemaciclib
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function (Appendix 3).
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Table JPCF.7.2).
9.4.4.Safety Monitoring:  Venous Thromboembolic Events (Both 
Arms)
Venous thromboembolic events comprise PEs and DVTs; the latter occurs most often in the leg, 
but other veins, such as in the arm and cerebral veins, can be affected (Di Nisio et al. 2016). In
the metastatic breast cancer Phase 3 clinical trial programs (MONARCH 2 and MONARCH 3), 
VTEs were considered as AEs of special interest for abemaciclib.  Additional data on VTE is 
available in the IB.
If a patient experiences a VTE during treatment with abemaciclib, the patient should be treated 
as clinically indicated.  The patient should temporarily stop abemaciclib while anticoagulation is 
initiated.  After approximately 2 weeks of anticoagulation, the investigator may decide to restart 
abemaciclib based on his/her clinical judgment that it is appropriate for the patient to resume 
dosing.  For life-threatening (Grade 4) VTEs, abemaciclib should not be restarted until there is 
evidence of resolution of the VTE and a discussion with the Lilly CRP should occur prior to 
restarting abemaciclib. Refer to Appendix 12 for guidance on the management of patients on 
abemaciclib who experience a VTE while on study.
Data on all VTEs (DVT or PE) will be collected and some events may be adjudicated by an 
external Clinical Events Committee (CEC). The role of the CEC is to adjudicate defined clinical 
events, in a blinded, consistent, and unbiased manner throughout the course of a study. The 
importance of the CEC is to ensure that all events that have been reported to the CEC are judged 
uniformly by a single group, using the same definition adjudicated.

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9. 4. 5. S af et y M o nit ori n g: I L D/ P n e u m o niti s ( B ot h Ar m s)
I L D/ p ne u m onit is has bee n i de nt ifie d as a n a d verse dr u g reacti o n f or a be macicli b. A d dit i onal 
i nf or mat i on is a vaila ble i n t he I B.
As k y o ur pati e nts t o re p ort a n y ne w or w orse ni n g res p irat or y s y m pt o ms s uc h as c o u g h, d ys p nea, 
fe ver, a n d i n vesti gate a n d treat as per y o ur l ocal cli nical practice (incl u di n g c ortic oster oi ds as 
a p pr o priate). If I L D/ p ne u m onit is is s us pecte d, in vesti gat i ons m a y i ncl u de i ma gi n g s uc h as hi g h 
res olut i on c o m p ute d to m o gra p h y  ( H R C T), br o nc he oal ve o lar la va ge, a n d bi o ps y as cli nicall y 
i n dicate d.
Refer t o Ta ble J P C F. 7. 2 f or g uida nce o n d ose a dj ust m e nts of a be macicli b f or patie nts wit h
I L D/ p ne u m onit is (see A p pe n di x 9 f or C T C A E gra des). 
9. 5.
P h ar m a c o ki n eti c s
P har mac o ki net ic sa m ples will be c ollecte d i n a s u bset of a p pr o xi matel y 2 0 % of  pat ient s fr om 
Ar m A as s h o w n i n A p pe n di x 6 .  Bl o o d sa m ples will  be used t o deter mi ne t he c o nce ntrati o ns of 
a be macicli b a n d its meta b olites L S N 2 8 3 9 5 6 7 a n d L S N 3 1 0 6 7 2 6 .
A ma xi m u m of 3 sa m ples ma y be c ollecte d at a d diti o nal t i me p oi nts d uri n g t he st u d y if 
warra nte d a n d a gree d u p o n b y  t he i n vesti gat or a n d Lill y.
Bi oa nal y tic al sa m ples c ollecte d t o meas ure a be macicli b c o nce ntrati o ns will be retai ne d f or a 
ma xi m u m o f 1 y e ar fol l owi n g t he l ast patie nt visit for t he st u d y .
9. 6.
P h ar m a c o d y n a mi c s
See Secti o n 9. 8 .
9. 7.
P h ar m a c o g e n o mi c s or G e n eti c s
C CI
 
 
 
 
 
 
 
 

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9. 8.
Bi o m ar k er s
 
 
 
 
9. 8. 1.
S a m pl e s f or Ki -6 7 I H C T e sti n g
C CI
T he tiss ue sa m ple m ust be fr o m a F F P E
 bl oc k, ma y be 
eit her a tiss ue bl oc k ( pr eferre d) or fres h seriall y c ut u nstai ne d secti ons , c ut at 4-5 micr o n 
t hic k ness.  C y t olo gi cal sa m ples a n d fi ne-nee dle as pi rati on s peci me ns are n ot acce pta ble.  T u m or 
tiss ue s peci me ns m ust ha ve a de q uate e val ua ble t u m or cells f or a ce ntral la b orat or y t o perf or m 
assess me nt f or Ki-6 7 stat us.  D ue dili ge nce s h o ul d be use d t o e ns ure t hat t u m or s peci me ns ( n ot a 
n or m al a djace nt or a t u mor m ar gi n sa mple) are pr o vi de d.  A n ass ociate d pat h ol o g y  re p ort ma y 
als o be re q ueste d t o be se nt wi t h t he sa mples.  
T u m or s peci me ns s u b mitte d as a n F F P E tiss ue bl o c k will be ret ur ne d t o t he site, eit her at t he e n d 
of  st u d y or u p o n re q uest. F or C o h ort 2, F F P E bl oc ks ma y be ret ur ne d t o t he site i m me diatel y if 
t he pati e nt is dee me d n ot eli gi ble e xcl usi vel y base d o n Ki-6 7. 
Details f or t he ha n dli n g a n d s hi p pi n g of t u m or sa m ples will be pr o vi de d i n a se parate d oc u me nt 
pr o vi de d b y t he s p o ns or.
T he t u m or ti ss ue sa m ples f or ce ntral Ki-6 7 testi n g will be c o de d wit h t he patie nts’ n u m ber a n d 
st ore d f or u p t o a ma xi m u m o f 1 5 y ears after t he last patie nt visit f or t he st u d y, u nless lo c al  
re g ulat i ons a n d/ or E R Bs i m p ose s h ort ti me li mit s, at a facilit y selecte d b y t he s p o ns or.  T he 
sa m ples a n d a n y data ge nerate d fr o m t he m ca n o nl y be li n ke d bac k t o t he patie nt b y the 
i n vesti gati ve site pers o n nel.  T he d urati o n all o ws t he s p o ns or t o res p o n d t o re g ulat or y re q uests 
r elate d t o t he st u d y dr u g.  
 
 
 
 
C CI
C CI
C CI

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C o h ort 1
P atie nts i n C o h ort 1 are n ot re q uire d t o s u b mit a tiss ue sa m ple t o t he St u d y J P C F ce ntral
la b orat or y for Ki -6 7 testi n g pri or t o ra n d o mizati o n, b ut a sa m ple will be re q ueste d, w here 
a vaila ble, t o s u p p ort t he sec o n dar y a nal ysis relate d t o Ki- 6 7.
C o h ort 2
P ati e nts i n C o h ort 2 m ust s u b mit a n u ntreate d breast tiss ue sa m ple t o t he St u d y J P C F ce ntral
la b orat or y f or ce ntral deter mi nati on of Ki -6 7 stat us t o deter mi ne eli gi bility (ti ss ue s h o uld be 
s u b mitte d wit hi n o ne m ont h of si g ni n g t he c o nse nt) . T he sa m ple will be teste d usi n g t he 
i n vesti gati onal i n vitr o dia g n ostic me dical de vice, p har m D x Ki -6 7 Ki t, ma n ufact ure d b y  Da k o,
as descri be d i n Sect i on 3. 2. 1 .
9. 8. 1. 1.
Ki -6 7 A n al y si s f or S e c o n d ar y O bj e cti v e
Ce ntral  Ki-6 7 testi n g will use breast t u mor ti ss ue o btai ne d pri or t o a n y e x p os ure t o s yste mic 
t hera p y. F or patie nts w h o pre vi o usl y recei ve d ne oa dj u va nt s yste mic t hera p y, t u m or tiss ue is t o 
be o btai ne d fr o m i nit ial dia g n ostic bi o ps y. F or patie nts w h o ha d defi nit i ve breast s ur ger y as t heir 
i nitial tr e at me nt (t hat is, n o prior s yste mic t hera pies), t u m or tiss ue ca n be eit her fr o m defi nit i ve 
s ur ger y s peci me n or i nitial dia g n ostic bi o ps y.
 
 
 
 
 
 
C CI
 
 
 
 
  
 
 
 
 
 
C CI
C CI

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C CI
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
C CI

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9. 9.
H e alt h E c o n o mi c s
9. 9. 1.
H e alt h O ut c o m e s
T he self -re p orte d q uestio n nai res will be a d mi nistere d as s h o w n i n t he Sc he d ule of Act i vities
( Sectio n 2 ) i n c o u ntries w here t he q uesti o n naires ha ve bee n tra nslate d i nt o t he nati ve la n g ua ge of 
t he re gi o n a n d li n g uist icall y vali date d.
I ncl u de d i n t his st u d y are q uestio n naires t o e val uate t he pati e nt -re p orte d ge neral health -r elate d 
q ualit y of  life ( H R Q o L) effects of ca ncer a n d t he s pecific effects ass ociate d wit h e n d ocri ne 
t hera p y wit h or wit ho ut t he a d di tio n of  a be macicli b. Als o e v al uate d are self-re p orte d healt h 
di me nsi o ns a n d healt h stat us use d t o c o n d uct decisi o n m o deli n g f or healt h ec o n o mic e val uat i ons.
At  eac h ti me p oi nt ide nt ifie d i n t he Sc he d ule of Acti vit ies ( Secti o n 2 ), a pa per c o p y of eac h 
q uesti o n naire s h o ul d be a d mi nistere d t o t he patie nt pri or t o e xte nsi ve i nteract i on wi t h site staff, 
be gi n ni n g wit h t he m ost ge neral H R Q o L assess me nt (t he F u ncti o nal Assess me nt of C a ncer 
T hera p y  - Breast ( Versi o n 4) [ F A C T - B]) f oll owe d b y  t he F u ncti onal Assess me nt of Ca ncer 
T hera p y  - E n d ocri ne S y m pt o ms ( Versi o n 4) (F A C T -E S ) s u bscale. T hereafter, t he 
s y m pt o m-s pecific fati g ue s u bscale q uest i on naire s h o ul d be a d mi nistere d, a n d f oll o we d b y t he 2 
c o g nitive ite ms a n d 3 bla d der ite ms.  Last l y, t he E ur o Q ol  fi ve-di me nsi o n fi ve-le vel q uesti on naire 
(E Q - 5 D- 5 L) is a d mi nistere d. 
T he q uest i on naires s h o ul d al wa ys be c o m plet e d i n t he s pecifie d or der wit h t he F A C T/ F u nct i onal
Assess me nt of C hr o nic Ill ness T hera p y ( F A CI T ) c o nte nt a d mi nistere d first f o ll owe d b y 
a d mi nistrati o n of t he E Q - 5 D-5 L. F oll o wi n g t he or deri n g of ge neral c o nte nt t o t he s pecific 
c o nte nt, t he F A C T/ F A CI T b o o klet/ w or k b o o k will be se q ue nce d as f oll o ws:
1.
T he F A C T -B ( w hic h i ncl u des t he F A C T -G 2 7 well -bei n g meas ures — t he most ge neral  
ite ms/c o nstr ucts—
C CI
f oll owe d b y breast ca ncer -s pecific 1 0-ite m s u bscale)
2.
Starti n g o n a ne w s heet, F A C T -E S s u bscale

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3. Starting on a new sheet, Functional Assessment of Chronic Illness Therapy - Fatigue 
(Version 4) [FACIT-F] subscale
4. Starting on a new sheet, a single sheet of additional concerns
a) The 2 cognitive items, followed by 
b) The 3 bladder items
5. EQ-5D-5L
All the FACT/FACIT questionnaires, subscales, and items are scaled using a 5-point Likert 
rating ranging from 0 ‘not at all’ through 4 ‘very much’.  The recall period is the past 7 days. It 
usually takes 2 to 3 minutes to complete 10 questions.
9.9.1.1. General Well-being and Breast Cancer Assessment (FACT-B)
The 37-item FACT-B, which consists of the 27-item FACT-G and the 10-item breast cancer 
patient additional concerns subscale, was included to evaluate HRQoL in this adjuvant setting 
(Brady et al. 1997). 
9.9.1.2. Endocrine Therapy and Fatigue Assessment (FACT-ES, 5 FACIT Library 
Items, FACIT-F)
Comprising 19 items, the FACT-ES (for patients with Endocrine Symptoms Version 4) was 
designed to be coadministered with the FACT-B (Fallowfield et al. 1999). 
According to Fallowfield et al (1999), the 27-item FACT-G also includes 4 ET items (sleep, 
fatigue, nervousness, and nausea).  Given the potential of abemaciclib adjuvant treatment to 
cause fatigue, also included in this study is the 13-item FACIT-F subscale (Yellen et al. 1997). 
Bladder control and cognitive symptoms are often associated with ET, as was shown in the 
development of the Breast Cancer Prevention Trial (BCPT) Symptom Scales questionnaire 
(Stanton et al. 2005; Cella et al. 2008). Therefore, 3 items have been added for bladder control 
and 2 items have been added for cognitive symptoms, thereby updating the FACT-ES content 
coverage to match that reported in the BCPT research. These items were sourced from the 
FACIT item library (Functional Assessment of Chronic Illness Therapy Item Library Version 2). 
The 3 bladder items are: 

trouble controlling urine, 

more frequency than usual, and 

limiting activities.  
The cognitive items are listed in the FACIT system as memory items and include:

trouble remembering things and 

difficulty thinking clearly (remembering, concentrating).
9.9.1.3. EQ-5D-5L
EuroQol five-dimension five-level questionnaire is used to characterize overall health status by 
the evaluation of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) and a single visual analog scale (VAS) quantitative measure of health on a 
scale of 100 to 0 ranging respectively from “the best health you can imagine” and “the worst 
health you can imagine.” This single index score can be used as for quality of life adjustment in 

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the estimation of quality-adjusted life-years for use in cost-effectiveness analyses.  The VAS 
score, based on the patient’s self-rated health today, serves to compliment the EQ-5D-5L single 
index score. (EuroQol 2017). The EQ-5D-5L is assessed using a daily recall period (that is, the 
recall period is “today”) and completion time typically ranges from 2 to 3 minutes.
9.9.2. Resource Utilization
Utilization data overall and by arm will be summarized descriptively by category (for example, 
transfusions, antidiarrheal treatments, and hospitalization days) as appropriate.

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10.Statistical Considerations
10.1. Sample Size Determination
The study will be powered to approximately 85% assuming an IDFS hazard ratio of .73 at a 
cumulative 1-sided alpha of .025.  This requires approximately 390 events from across Cohort 1
and Cohort 2 by the time of the primary analysis after accounting for the interim efficacy and 
futility analyses described in Section 10.3.1.1.  The number of patients required to observe 
approximately 390 events was calculated using Cytel East 6 and the following additional 
assumptions about pooled population in the two cohorts:

Patients will enroll at a rate of 2, 8, 32, 60, 102, 140, 164, 188, 198, 206, 218, 238, 256, 
260/month for the first 14 months, respectively, and then kept at 276/month for the 
remainder of the enrollment period.

The time from first patient randomized to the observation of approximately 390 events 
will be approximately 4 years under the alternative hypothesis (hazard ratio of .73).

The probability of a patient dropping out over the first 5 years following randomization is 
10%.

The 5-year IDFS rate for the control arm is 82.5%. 
Under these assumptions, 4580 patients will be enrolled. 
Patients will be randomized 1:1, within each cohort, using the following stratification factors:

Prior treatment:  neoadjuvant chemotherapy vs adjuvant 
chemotherapy vs no chemotherapy 

Menopausal status: premenopausal vs postmenopausal (menopausal status to be 
determined by investigator and based upon the patient’s status at the time of 
diagnosis)

Region: North America/Europe vs Asia vs Other
If a patient received both neoadjuvant and adjuvant chemotherapy, the patient will be stratified 
as neoadjuvant chemotherapy.  Male patients will be stratified as postmenopausal at the time of 
randomization.
10.2. Populations for Analyses
The following populations will be defined for this study:
Intent-to-Treat (ITT) population: will include all randomized patients in Cohort 1 and Cohort 
2.  The ITT analysis of efficacy data will consider allocation of patients to treatment groups as 
randomized and not by actual treatment received.  This population will be used for baseline, 
efficacy, and health economics analyses. 
Safety or Randomized and Treated (RT) population:  will include all randomized patients in 
Cohort 1 and Cohort 2 who received any quantity of study treatment.  The safety evaluation will 
be performed based on the study regimen a patient actually received, regardless of the arm to 

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w hic h he or s he was ra n d o mize d.  T he safet y p o p ulat i on will be use d f or all d osi n g/e x p os ure, 
safety,  a n d res o urce utilizati on a nal yses.
Ki -6 7 Hi g h ( KI 6 7 H) p o p ul ati o n: will i ncl u de all ra n d o mize d pat ient s i n C o h ort 1 a n d C o h ort 2 
wi t h a ce ntrall y assesse d Ki-6 7 i n de x ≥2 0 %.  Sec o n dar y  efficac y a nal yses will be perf or me d o n 
t his p o p ulat i on.
 
 
 
 
 
P h ar m ac o ki netic p o p ul ati o n:   will i ncl u de a s u bset of a p pr o xi matel y 2 0 % of  pati e nts 
ra n d omize d t o Ar m A w h o recei ve d at least 1 d ose of a be macicli b a n d ha ve at least 1 p ost -
baseli ne e val ua ble P K sa m ple.
1 0. 3. St ati sti c al A n al y s e s
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 i ts desig nee.
All tests of treat me nt effects will be c o n d ucte d at a 1 -si de d alp ha le vel of . 0 2 5, u nless ot her wise 
state d.  U nless ot her wise state d, all c o nfi de nce i nter vals ( CIs) will be gi ve n at a 2- side d 
9 5 % level .
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 ust ificati 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.
1 0. 3. 1. Effi c a c y A n al y s e s
1 0. 3. 1. 1.
I n v a si v e Di s e a s e-Fr e e S ur vi v al
T he pri mar y  e n d p oi nt of t his st u d y is I D F S as defi ne d b y t he S T E E P S yste m ( H u dis et al. 2 0 0 7).  
I n vasi ve disease-free s ur vi val ti me is meas ure d fr o m t he date of ra n d omizat i on t o t he date of first 
occ urre nce of:
3.
i psilateral i n vasi ve breast t u m or rec urre nce
4.
r e gio nal i n vasi ve breast ca ncer rec urre nce
5.
di sta nt rec urre nce
6.
deat h attri b uta ble t o a n y ca use
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7. contralateral invasive breast cancer
8. second primary non-breast invasive cancer
Patients for whom no event has been observed will be censored on the day of their last
assessment for recurrence or date of randomization if no post-baseline assessment for recurrence
occurred.  The detailed censoring rules are described in Table JPCF.10.1.
Table JPCF.10.1.
Rules for Determining Date of Event or Censor for Invasive Disease 
Free Survival 
Situation
Date of Event or Censor
Event / Censor
IDFS event 
Date of earliest IDFS event
Event
No IDFS event
Date of last assessment for recurrence
Censored
Unless
No post-baseline disease recurrence 
assessment
Date of randomization
Censored
IDFS event documented after more than 12 
months (+ 28 days)* following the last 
disease recurrence assessment or 
randomization (whichever is later)
Date of last assessment for recurrence prior to the 
documented IDFS event, or date of 
randomization (whichever is later)
Censored
*12 months (+28 days) is the longest allowed interval between visits in long-term follow up period after Year 5 
defined by the schedule of activities 
Abbreviation:  IDFS = invasive disease-free survival.
The IDFS analysis to test the superiority of abemaciclib plus standard endocrine therapy to 
standard endocrine therapy will be performed on the ITT population and will use the log-rank 
test stratified by randomization factors.  The futility analysis for IDFS will be conducted when 
approximately 130 events have been observed in ITT population. Futility should be declared if 
the observed IDFS hazard ratio is greater than 1.05. There are 2 planned efficacy interim 
analyses and 1 planned final analysis for IDFS in this study, which will be performed after 
approximately 195, 293, and 390 events have been observed in the ITT population. The 
cumulative 1-sided alpha will be controlled at .025, with an alpha split of 0.00000001 for the 
futility analysis and 0.02499999 for the planned efficacy analyses. The cumulative 1-sided type I 
error rate of .02499999 for the 2 planned efficacy interim analyses and 1 planned final analysis
will be maintained using the Lan-Demets method (Demets and Lan, 1994). Specifically, the 
alpha spent at each efficacy interim analysis will be based on the exact number of IDFS events 
observed using the following O’Brien-Fleming type stopping boundary:





















k
k
t
t
2
/
1
1
2
1
*


.
Here, tk is the information fraction at time k, Φ is the standard normal cumulative distribution 
function, and Φ-1 is the standard normal quantile function. At the first efficacy interim analysis, 
the nominal 1-sided alpha level will be .0015 if exactly 195 IDFS events are observed. At the 
second efficacy interim analysis, the nominal 1-sided alpha level will be .0092 if exactly 293 

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 6 3
L Y 2 8 3 5 2 1 9
I D F S e ve nts are o bser ve d. If t he a nal yses are perf or me d at e xactl y 1 9 5 , 2 9 3 , a n d 3 9 0 e ve nts, 
t he n t he 1 -side d b o u n dar y  p-val ue at t he fi nal a nal ysis will be .0 2 2 0.
T he efficac y a n d f ut ility b o u n daries a n d pr o perties of t he desi g n are descri be d i n Ta ble 
J P C F.1 0. 2 .
T a bl e J P C F. 1 0 .2.
Effi c a c y I nf or m ati o n
A n al ysis P oi nt
A p pr o xi m ate 
N u m ber of I D F S 
E ve nts
H az ar d R ati o 
f or F utilit y
O ne -si de d 
B o u n d ar y 
p- v al ue f or 
Effic ac y
C u m ul ati ve 
P o wer 
U n der H 1
F utilit y
1 3 0
1. 0 5
N/ A a
N/ A
I nteri m 1
1 9 5
N/ A
. 0 0 1 5
. 2 2 2
I nteri m 2
2 9 3
N/ A
. 0 0 9 2
. 6 3 4
Fi nal 
3 9 0
N/ A
. 0 2 2 0b
. 8 6 1
A b bre viati o ns:  I D F S = i n vasi ve disease -free s ur vi val; N/ A = n ot a p plica ble.
a
A n ar bitrar y al p ha s plit of 0. 0 0 0 0 0 0 0 1 is a p plie d at t he f utilit y a nal ysis . 
b
De pe n de nt o n t he act ual n u m ber of e ve nts o bser ve d at eac h a nal ysis. 
I n a d diti on t o t he a nal ysis descri be d a b o ve, t he Ka pla n -Meier met h o d ( Ka pla n a n d Meier 1 9 5 8) 
will be use d t o esti mate t he I D F S c ur ves as well as I D F S rates at e ver y  1 2 mo nt hs f or eac h 
treat me nt gr o u p.  Als o, a stratifie d C o x pr o p orti o nal hazar d m o del ( C o x 1 9 7 2) wit h treat me nt as 
a fact or will be use d t o esti mate t he hazar d rati o a n d c orres p o n di n g 9 5 % CI wit h Wal d’s test 
p- val ue after a dj ust i n g f or t he sa me ra n d omizat i on varia ble s pecifie d f or t he pri mar y a nal ysis.  
A n a d dit i on al  u nstratifie d C o x re gressi o n m o del will be e m pl o ye d t o e x pl ore t he effects of 
pr o g n osti c varia bles, s uc h as t he stratificati o n varia bles a n d i ntri nsic/e xtri nsic fact ors.
1 0. 3. 1. 2.
O v er all S ur vi v al
O verall s ur vi val is defi ne d as t he ti me fr o m ra n d o mizat i on u nt il deat h fr om a n y ca use.  Details 
c o ncer ni n g O S a nal yses ca n be f o u n d i n t he S A P. 
1 0. 3. 1. 3.
Di st a nt R el a p s e -Fr e e S ur vi v al 
Di sta nt rela pse-free s ur vi val is defi ne d as t he ti me fr o m ra n d o mizati o n t o dista nt rec urre nce or 
deat h fr o m a n y ca use, w hic he ver occ urs first.  Details c o ncer ni n g D R F S a nal yses ca n be f o u n d 
i n t he S A P.
1 0. 3. 1. 4.
A n al y s e s of Effi c a c y i n Ot h er P o p ul ati o n s 
Details c o ncer ni n g a nal yses of efficac y  in KI 6 7 H ( Ki-6 7 hi g h), 
 
p o p ulat i ons ca n be f o u n d i n t he S A P.
1 0. 3. 2. S af et y A n al y s e s
C CI
All patie nts w h o recei ve at least 1 d ose of a n y st u d y t hera p y will be e val uate d f or safet y a n d 
t o xicit y.
T he Me dical Dicti o nar y  for R e g ul at or y Acti vities ( Me d D R A) Versi on 1 9. 0 ( or hi g her) will be 
use d w he n re p orti n g A Es b y Me d D R A ter ms.  T he Me d D R A L o wer Le vel Ter m will be use d i n 

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the treatment-emergent computation.  Treatment-emergent adverse events will be summarized by 
System Organ Class (SOC) and by decreasing frequency of Preferred Term within SOC.
Safety analyses will include summaries of the following:

adverse events, including severity and possible relationship to study treatment

serious adverse events, including possible relationship to study treatment

adverse events 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 
10.3.3. Other Analyses
10.3.3.1.
Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, as defined in the SAP, or 
discontinuing treatment or study (overall and by reason for discontinuation). 
A summary of all important protocol deviations will be provided.
10.3.3.2.
Patient Characteristics
Demographic data, disease characteristics, historical diagnoses, preexisting conditions, and prior 
therapies will be reported using descriptive statistics. 
10.3.3.3.
Concomitant Therapy
A summary of prior and concomitant medications by treatment arm will be reported.
10.3.3.4.
Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation anti-cancer therapies will 
be provided overall and by category and by drug name, where applicable.
10.3.3.5.
Treatment Compliance
Dose omissions, dose reductions, dose intensity, and patient compliance for abemaciclib will be 
summarized for all treated patients in Arm A.  
The actual cumulative dose of abemaciclib taken will be determined based on counting the 
number of capsules or tablets returned at each visit and subtracting that number from the number 
of capsules or tablets dispensed.  The expected cumulative dose to be taken will be determined 
based on the assigned dose and taking into account any dose reductions or omissions.  Treatment 
compliance to abemaciclib will be measured as a percentage of the actual cumulative dose 
divided by the expected cumulative dose. 
Dose intensity and treatment duration for standard endocrine therapy will be described for all 
treated patients in Arms A and B.  For the on-treatment period, dose omissions for standard 
endocrine therapy will be summarized. 

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 6 5
L Y 2 8 3 5 2 1 9
F or Ar m  A, reas o ns f or disc o nti n uati on of a be macicli b t hera p y  will be s u m marize d.  F or Ar ms A 
a n d B, reas o ns f or disc o nt i n uati o n of sta n dar d e n d ocri ne t hera p y will be s u m marize d.
1 0. 3. 3. 6.
P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s
P har mac o ki net ic a nal yses will be c o n d ucte d o n all patie nts w h o ha ve recei ve d at least 1 d ose of 
a be macicli b a n d ha ve e val ua ble P K sa m ples a n d s ufficie nt d osi n g i nf or mat i on. T he g oal is t o 
c o mplete P K a nal yses pri or t o i nteri ms, s o t hat e x p os ure -res p o nse a nal ysis ma y be c o n d ucte d as 
s o o n as t he efficac y a n d safety res p o nse data are a vaila ble. Meas ures will be ta ke n t o s u p p ort t he 
ti mel y a vaila bilit y of t he res ults of P K a nal yses. T hese meas ures will i ncl u de peri o dic tra nsfers 
f or r e vie w of d at a rele va nt t o P K a nal yses i ncl u di n g d osi n g a n d bi oa nal ytical r es ults. I n a d diti on,  
a n earl y s na ps h ot will occ ur w he n s ufficie nt P K sa m ples fr o m t he P K p o p ulati o n (a p pr o xi matel y 
2 0 % of  pati e nts fr o m Ar m A) ha ve bee n c ollecte d a n d a nal yze d. T hese s na ps h ots will use 
aliase d I Ds s o t hat t he a nal ysts will n ot k n o w t he act ual pat ient  I D.  N o safet y or efficac y d at a 
will be i ncl u de d i n t he earl y s na ps h ot P K datasets. Fi nall y, t his earl y P K a nal ysis will be 
c o n d ucte d b y a se parate tea m of P K a nal ysts, i n de pe n de nt of t he c ore st u d y t e a m. Res ults will 
n ot be s hare d o utsi de o f t he a nal ysis tea m u nt il t he st u d y tea m is u n bli n de d.
I n t he earl y P K s na ps h ot, mea n p o p ulati on P K para m eters for a be m acicli b (a n d meta b o lites, if 
warra nte d) i n plas ma (f or e xa m ple, cleara nce, e x p os ure, v ol u me of distri b uti o n) a n d 
i nter -i n di vi d ual P K varia bility will  be c o mp ute d usi n g n o nli near mi xe d effect m o deli n g 
( N O N M E M).
T he o bser ve d c o nce ntrati o ns of a be macicli b ma y be s u m marize d b y  time a n d d ose.
P har mac o d y na mic sa m ples will be c ollecte d as s pecifie d i n t he St u d y  Sc he d ule a n d P K a n d P D 
S a m pli n g Sc he d ule ( A p pe n di x 6 ).  R efer t o t hese attac h me nts (i ncl u di n g f o ot n otes) for i m p orta nt 
i nf or mat i on a b o ut t hese sa m ples a n d t heir c o llecti on.  
F urt her m ore, P D data (s uc h as ne utr o p hil c o u nts i n bl o o d) c ollecte d i n t his st u d y  ma y als o be 
a nal yze d b y mea ns of N O N M E M a n d c o n necte d t o t he p o p ulat i on P K m o del i n a P K/ P D m o del.
P har ma c o d y na mic data fr o m  all patie nts u n der g oi n g P D assess me nts will be a nal yze d.  
 
 
  
 
1 0. 3. 3. 7.
H e alt h O ut c o m e a n d Q u alit y of Lif e A n al y s e s
All heal t h o utc o me, q ualit y of life, a n d healt h utilizati o n a nal yses will be descri be d i n t he S A P. 
1 0. 3. 4. S u b gr o u p A n al y s e s
C CI
A pres pecifie d list of s u b gr o u ps, i ncl u di n g t h ose defi ne d b y t he stratificati on fact ors, will be 
i de ntifie d i n t he S A P.  T he treat me nt effect wit hi n eac h s u b gr o u p will be s u m marize d usi n g 
met h o ds s pecifie d i n t he S A P.  Ot her s u b gr o u p a nal yses n ot s pecifie d i n t he S A P ma y be 
perf or m e d as dee me d a p pr o priate.
C CI

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10.3.5. Interim Analyses
10.3.5.1.
Safety Interim Analyses
The DMC is responsible for providing external oversight of patient safety in Study JPCF 
independently of the Lilly study team and Lilly GPS. 
Safety interim analyses will be reviewed by the DMC at a frequency described in the DMC 
charter, but no less than approximately every 6 months while patients are still in the on-study 
treatment period. The safety interim analyses will be conducted to evaluate the overall safety 
profile of abemaciclib when given in combination with standard endocrine therapy.  
At each safety interim analysis, the DMC may recommend that the trial continue without 
modifications, continue with specific modifications, or be stopped for safety concerns.  There 
will be no prespecified rules for stopping the trial due to safety concerns.  The DMC members 
will review safety data at each safety interim analysis.  If a significant safety signal is identified, 
the DMC may recommend a protocol amendment, termination of enrollment, and/or termination 
of study treatment.  The recommendations of the DMC will be communicated to the Lilly Senior 
Management Designee (SMD) and, if necessary, an Internal Review Committee (IRC).
A limited number of Lilly representatives external to the study team may have access to 
treatment assignments as required for evaluation of selected SAEs for determination of 
regulatory reporting.
10.3.5.2.
Efficacy/Futility Interim Analyses
One futility analysis and two efficacy interim analyses are planned, as described in 
Section 10.3.1.1.
The efficacy interim analyses will be conducted to provide early efficacy information and could 
potentially result in early communication with regulatory agencies.  The DMC should 
recommend the sponsor be unblinded if the analysis of IDFS is significant as described in 
Section 10.3.1.1 and any additional criteria specified in the DMC charter are met. The SMD 
may convene an IRC to review the DMC’s recommendation prior to unblinding the study team.
The study will first be evaluated for futility. While the study may be stopped for futility at this 
analysis, the sponsor has no intent to stop the study at the two efficacy interim analyses, and all 
patients will continue follow-up for IDFS and OS until study completion.  Patients randomized 
to the control group will not be permitted to cross over to the experimental group in case early 
efficacy is observed during interim review, as this will confound the assessment of OS.  If the 
DMC makes a recommendation counter to this, for example, the DMC recommends crossing all 
patients over to the experimental treatment, Lilly will consult the FDA before any action is 
taken, as well as other regulatory agencies if deemed appropriate.
The unblinded analysis, including review of the efficacy along with the safety data, will be 
conducted by the DMC.  Study sites will receive information about interim results ONLY if they 
need to know about the safety of their patients.
Unblinding details are specified in the unblinding plan.

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Knox F, Thürlimann B, Price KN, Castiglione-Gertsch M, Gelber RD, Gusterson BA, 
Goldhirsch A. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in 
postmenopausal women with endocrine-responsive breast cancer:  results from Breast 
International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol.
2008;26(34):5569-5575.
Wolff AC, Hammond ME, Allison KH, Harvey BE, Mangu PB, Bartlett JM, Bilous M, Ellis IO, 
Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane 
LM, Dowsett M. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: 
American Society of Clinical Oncology/College of American Pathologists Clinical Practice 
Guideline Focused Update. J Clin Oncol. 2018:142(11):1364-1382.
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemia-
related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement 
system. J Pain Symptom Manage. 1997;13(2): 63-74. 

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 7 1
L Y 2 8 3 5 2 1 9
A p p e n di x 1.
A b br e vi ati o n s a n d D efi niti o n s
T er m
D efi niti o n
A E
a d verse e ve nt:  a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
patie nt a d mi nistere d a p har mace utical pr o d uct a n d t hat d oes n ot necessaril y ha ve a 
ca usal relati o ns hi p wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d 
u n i nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
as partate a mi n otra nsferase
B C P T
Br east Ca ncer Pre ve nti o n Trial
 
C A P
C olle ge of A merica n Pat h ol o gists
C D K 4
c ycli n -de pe n de nt ki nase 4
C D K 6
c ycli n -de pe n de nt ki nases 6
C E C
Cli nical E ve nts C o m mittee
CI
c o nfi de nce i nter val
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical
Scie nces
c oll e cti o n d at a b a s e
a c o m p uter data base w here cli nical trial data are e ntere d a n d vali date d
C R F
case re p ort f or m
C R P
Cli nical Researc h P h ysicia n:  a n i n di vi d ual res p o nsi ble f or t he me dical c o n d uct of t he 
st u d y.  Res p o nsi bilities of t he C R P m a y  be perf or me d b y a p h ysicia n, cli nical researc h 
scie ntist ( C R S), gl o bal safet y p h ysicia n, or ot her me dical officer.
C R S
Cli nical Researc h Scie ntist; als o see C R P defi niti o n
C T
c o m p ute d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
D CI S
C CI
d uctal carci n o ma i n sit u
C CI

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DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRFS
distant relapse-free survival
ECOG PS
Eastern Cooperative Oncology Group performance status
eDC
electronic data capture
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly.
EQ-5D-5L
EuroQol five-dimension five-level questionnaire
ERB
ethical review board
FACT-B
Functional Assessment of Cancer Therapy - Breast (Version 4)
FACT-ES
Functional Assessment of Cancer Therapy - Endocrine Symptoms (Version 4)
FACIT
Functional Assessment of Chronic Illness Therapy
FACIT-F
Functional Assessment of Chronic Illness Therapy - Fatigue (Version 4)
FFPE
formalin-fixed paraffin-embedded
FNA
fine-needle aspiration
G-CSF
granulocyte colony-stimulating factor
GCP
good clinical practice
GMP
Good Manufacturing Practice
GPS
Global Patient Safety
HER2-
human epidermal growth factor receptor 2 negative
HR+
hormone receptor positive
HRQoL
health-related quality of life
IB
Investigator’s Brochure
IBTR
ipsilateral breast tumor recurrence
ICF
informed consent form
ICH
International Conference on Harmonisation

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 7 3
L Y 2 8 3 5 2 1 9
I D F S
i n vasi ve disease-free s ur vi val
I H C
I m m u n ohis t oc he mistr y
I L D
i nterstitial l u n g disease
i nt eri m a n al y si s
A n i nteri m a nal ysis is a n a nal ysis of cli nical trial data c o n d ucte d bef ore t he fi nal 
re p orti n g data base is create d/l oc ke d.
i n v e sti g ati o n al 
pr o d u ct
A p har mace utical f or m of a n acti ve i n gre die nt or place b o bei n g teste d or use d as a 
refere nce i n a cli nical trial, i ncl u di n g pr o d ucts alrea d y i n t he mar ket w he n use d or 
asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a ut h orize d f or m, or 
mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d pr o d ucts use d t o 
gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
I R B
i nstit uti o nal re vie w b oar d
I R C
I nter nal Re vie w C o m mittee
I S H
in sit u h y bri dizati o n
I T T
i nte nt-t o-treat:  t he pri nci ple t hat asserts t hat t he effect of a treat me nt p olic y ca n be best 
assesse d b y e val uati n g o n t he basis of t he i nte nti o n t o treat a patie nt (t hat is, t he pla n ne d 
treat me nt re gi me n) rat her t ha n t he act ual treat me nt gi ve n.  It has t he c o nse q ue nce t hat 
patie nts all ocate d t o a treat me nt gr o u p s h o ul d be f oll o we d u p, assesse d, a n d a nal yze d as 
me m bers of t hat gr o u p irres pecti ve of t heir c o m plia nce t o t he pla n ne d c o urse of 
treat me nt.
I V
I ntra ve n o us
IW R S
i nteracti ve we b-res p o nse s yste m
KI 6 7 H p o p ul ati o n
Ki -6 7 Hi g h p o p ulati o n :  all ra n d o mize d patie nts i n C o h ort 1 a n d C o h ort 2 wit h ce ntrall y 
assesse d Ki -6 7 i n de x ≥2 0 %
L CI S
l o b ular carci n o ma i n sit u
Lill y
Eli Lill y a n d C o m pa n y
L T F U
l o n g-ter m f oll o w- u p
M A T E
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n
M e d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M RI
ma g netic res o na nce i ma gi n g
N O N M E M
n o nli n e ar mi xe d effect m o deli n g
O S
o verall s ur vi val
p C R
pat h ol o gical c o m plete res p o nse
C CI

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 7 4
L Y 2 8 3 5 2 1 9
P D
p har mac o d y na mic(s)
P E T
p ositr o n e missi o n t o m o gra p h y
P K
a s u bset of a p pr o xi matel y 2 0 % of ra n d o mize d patie nts fro m Ar m A w h o recei ve d at 
least 1 d ose of a be macicli b a n d ha ve at least 1 p ost baseli ne e val ua ble P K sa m ple
P K
P har mac o ki netic
p R b
p h os p h or ylate d reti n o blast o ma
P R O
patie nt -re p orte d o utc o me
r a n d o mi z e
t he pr ocess of assi g ni n g patie nts t o a n e x peri me ntal gr o u p o n a ra n d o m basis
R b
Reti n o blast o ma
r e p orti n g d at a b a s e
A p oi nt -i n-ti me c o p y of t he c ollecti o n data base.  T he fi nal re p orti n g data base is use d t o 
pr o d uce t he a nal yses a n d o ut p ut re p orts f or i nteri m or fi nal a nal yses of data.
r e-s cr e e n
t o scree n a patie nt w h o was pre vi o usl y declare d a scree n fail ure f or t he sa me st u d y
 
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
s cr e e n
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y.
s cr e e n f ail ur e
a patie nt w h o d oes n ot meet o ne or m ore criteria re q uire d f or partici pati o n i n a trial
S M D
Se ni or Ma na ge me nt Desi g nee
S O C
S y ste m Or ga n Class
st u d y dr u g
a be macicli b
st u d y tr e at m e nt
m o narc h E pr ot oc ol de fi nes st u d y treat me nt as a be macicli b a n d / or E T d uri n g t he first 
2 years of treat me nt. T he first d ose of st u d y treat me nt is t he first d ose of eit her 
a be macicli b or e n d ocri ne t hera p y f oll o wi n g ra n d o mizati o n.
S U S A R s
s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
T E A E
treat me nt-e mer ge nt a d verse e ve nt:   an u nt o war d me dical occ urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, or w orse ns relati ve 
t o t he pretreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt
t o p o
t o p ois o merase
U L N
u p per li mit of n or mal
C CI

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VAS
visual analog scale
VTE
venous thromboembolic event

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Appendix 2.
Study Governance, Regulatory, and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study,

ensuring that informed consent is given by each patient.  This includes obtaining the 
appropriate signatures and dates on the ICF prior to the performance of any study
procedures and prior to the administration of study treatment,

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial.
Ethical Review
Documentation of ERB/IRB approval of the protocol and the ICF must be provided to Lilly
before the study may begin at the investigative site(s).  Lilly or its representatives must approve 
the ICF, including any changes made by the ERBs/IRBs, before it is used at the investigative 
site(s).  All ICFs must be compliant with the International Conference on Harmonisation (ICH)
guideline on GCP.
The study site’s ERBs/IRBs should be provided with the following:

the current abemaciclib IB and updates during the course of the study

the ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 

applicable ICH GCP Guidelines

applicable laws and regulations
Some obligations of Lilly may be assigned to a third-party organization.
Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
Protocol Signatures
Lilly’s responsible medical officer will approve the protocol, confirming that to the best of his or
her knowledge, the protocol accurately describes the planned design and conduct of the study.

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After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
An investigator will be chosen by Lilly to serve as the clinical study report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the clinical study report coordinating investigator. 
The Lilly responsible medical officer and statistician will approve the final clinical study report 
for this study, confirming that to the best of his or her knowledge, the report accurately describes 
the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate,

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures,

make periodic visits to the study site,

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax,

review and evaluate CRF data and use standard computer edits to detect errors in data 
collection,

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide Lilly, 
applicable regulatory agencies, and applicable ERBs/IRBs with direct access to original source 
documents.
Data Capture System
An eDC system will be used in this study.  The site maintains a separate source for the data 
entered by the site into Lilly-provided eDC system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 

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documentation provided by the patient may include, for example, a paper questionnaire to collect 
patient-reported outcome measures (for example, a rating scale).
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB/IRB of the 
study site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 3.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology - central laboratorya
Leukocytes (WBC)
Erythrocytes (RBC)
Neutrophilsb
Hemoglobin
Lymphocytes
Hematocrit
Monocytes
Mean corpuscular volume
Eosinophils
Mean corpuscular hemoglobin concentration
Basophils
Platelets
Clinical Chemistry - central laboratorya
Serum Concentrations of:
Alanine aminotransferase
Calcium
Albumin
Chloride
Alkaline phosphatase
Creatinine
Aspartate aminotransferase
Potassium
Bilirubin, direct
Protein, total
Bilirubin, total
Sodium
Blood urea nitrogen or blood urea
Renal Panel - central laboratory (included in chemistry)
Cystatin-C - central laboratory (included in chemistry)
Pregnancy Test (for female patients of childbearing potential) - local laboratory
Serum  pregnancy test
Ki-67 - central laboratory
Abbreviations:  RBC = red blood cell; WBC = white blood cell.
a
Enrollment and treatment decisions may be based on local laboratory results. A duplicate sample must still be 
sent to the central laboratory.  Differences between these samples will not constitute a protocol deviation.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. When a manual differential is needed to report the neutrophils, the segmented and band forms should be 
reported together.

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Appendix 4.
Highly Effective Methods of Contraception for 
Patients of Reproductive Potential
Patients with reproductive potential (that is, non-postmenopausal patients) are instructed to use 
highly effective contraceptive methods.  The choice of the most effective and appropriate 
contraception method is up to the investigator’s judgment after discussion with the patient, 
taking into account age, pregnancy and other gyneco-obstetrical history, sexual activity, patients’ 
preference, acceptance of the contraception method, and potential adherence.
In patients with breast cancer, the use of estrogen-based hormonal contraception (includes the 
hormonal IUDs) is contraindicated, and the effect of progestin-based hormonal contraception 
remains unclear.
The Clinical Trial Facilitation Group has defined highly effective methods of contraception.1
Highly effective methods include the following:
•
intrauterine device
•
bilateral tubal occlusion
•
vasectomized partner2
•
sexual abstinence3
If the highly effective contraceptive methods are contraindicated or strictly declined by the 
patient, or in the event of sexual activity of low frequency, a combination of male condom with 
cap, diaphragm, or sponge with spermicide (double-barrier methods) is also considered an acceptable 
birth control method. 
Local regulation/guidelines are to be followed with regard to highly effective birth control 
method, if more restrictive.
1Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy testing in 
clinical trials. September 2014. Available at: http://www.hma.eu/fileadmin/dateien/ Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_ Contraception.pdf. Accessed May 02, 
2016.
2Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment 
of the surgical success.
3In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.

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Appendix 5.
Omitted

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Appendix 6.
Pharmacokinetics/Genetics/Biomarkers 
Sampling Schedules 
It is essential that the exact date and time of dose administration for the dose prior to PK 
sampling is recorded in the CRF based on patient interview.  The exact date and time of 
collection of each venous blood sample must also be recorded on the laboratory requisition.
Due to practical and logistical concerns, some deviation from the specified sampling is possible.  
Sites should keep in mind that drawing the sample and recording the actual time on the 
appropriate form are of principal importance. Differences from the time specified in the protocol 
are not considered protocol deviations as long as samples are collected and accurate dates and 
times are recorded in a timely manner on the appropriate forms.
Sampling Schedule for Pharmacokinetics—Arm A Cohorts 1 & 2
PK Sample 
Number
Visit (V) 
PK Sampling Timea
1
V01
2 h after abemaciclib dosed in clinic
2
V03
Any time after abemaciclib dosing
3
V05
Any time after abemaciclib dosing
4
V06
Any time after abemaciclib dosing
Abbreviation:  PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of concentrations of abemaciclib 
and its metabolites.

I 3 Y-M C -J P C F ( e) Cli ni c al Pr ot o c ol
P a g e 8 3
L Y 2 8 3 5 2 1 9
S a m pli n g S c h e d ul e f or G e n eti c s/ Bi o m ar k er s
S a m ple
C ollecti o n Ti me P oi nt
C o m me nt
T u m o r tiss ue f or ce ntral Ki-6 7 
eli gi bilit y c o nfir mati o n 
( C o h ort 2 o nl y)
Nee d u ntreate d b reast t u m or tiss ue 
s u b mitte d pri or t o ra n d o mizati o n
F or patie nts n ot eli gi ble base d o n 
n o dal stat us, t u m or size, or gra de 
T u m o r tiss ue f or ce ntral Ki-6 7 
( C o h ort 1)
Nee d u ntreate d breast t u m or tiss ue 
s u b mitte d as s o o n as p ossi ble 
f oll o wi n g ra n d o mizati o n
Sa m ple n ot ma n dat or y f or 
ra n d o mizati o n, b ut will be re q ueste d
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
 
 
C CI
C CI
C CI
C CI
C CI
C
C
I
C CI

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Appendix 7.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly CRP/CRS.d
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase
Recommended Autoimmune Serology
Aspartate aminotransferase
Anti-nuclear antibodya
Gamma-glutamyl transferase
Anti-smooth muscle antibodya
Creatine phosphokinase
Anti-actin antibodya
Abbreviations:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.
d
Consider hepatobiliary ultrasound to assess for gallstones or gallbladder disease.

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Appendix 8.
Protocol JPCF Inducers and Strong Inhibitors 
of CYP3A
The information in this table is provided for guidance to investigators and does not 
preclude the use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine
Dexamethasone
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lenisurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil

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Appendix 9.
Protocol JPCF CTCAE 4.03 Definitions
Diarrhea will be evaluated in this study using the criteria proposed by CTCAE v4.0 revised:  
CTCAE 4.03–June 14, 2010:  Gastrointestinal disorders.
Gastrointestinal Disorders
Grade
Adverse Event
1
2
3
4
5
Diarrhea
Increase of 
<4 stools per 
day over 
baseline; mild 
increase in 
ostomy output 
compared to 
baseline
Increase of 
4-6 stools per 
day over 
baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline
Increase of 
≥7 stools per 
day over 
baseline; 
incontinence; 
hospitalization 
indicated; 
severe increase 
in ostomy 
output 
compared to 
baseline; 
limiting 
self-care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition:  a disorder characterized by frequent and watery bowel movements
ILD/pneumonitis will be evaluated in this study using the criteria proposed by CTCAE v4.0 
revised:  CTCAE 4.03–June 14, 2010:  Respiratory, thoracic and mediastinal disorders.
Respiratory, Thoracic, and Mediastinal Disorders
Grade
Adverse Event
1
2
3
4
5
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

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Appendix 10. Protocol JPCF Breast Cancer Recurrence and 
Other Cancer Events
General instructions

Documentation of a breast cancer recurrence requires meeting at least one of the 
criteria defined below. If there is suspicion of recurrence, this must be confirmed by 
imaging or by cytological/histopathological assessment (biopsy/FNA), as described in 
Table APP.10.1.

Tumor marker evaluations alone do not document breast cancer recurrence.

Treatment of a breast cancer recurrence or second primary cancer will be at the 
discretion of the investigator.
Table APP.10.1.
Definitions for monarchE Endpoints
Endpoint
Invasive 
Ipsilateral 
Breast 
Tumor 
Recurrence
Local/Regional 
Invasive 
Recurrence
Distant 
Recurrence
Death 
from 
Any 
Cause
Invasive 
Contralateral 
Breast 
Cancera
Second 
Primary Non-
Breast 
Invasive 
Cancerb
Overall 
survivald
X
Invasive 
disease-free 
survivald
X
X
X
X
X
X
Distant 
relapse-free 
survivald
X
X
Confirmation 
requirementsc
Biopsy
Biopsy/FNA
Biopsy/FNA
or imaging
Biopsy
Biopsy/FNA 
or imaging
Abbreviations:  DCIS = ductal carcinoma in situ; FNA = fine needle aspiration; LCIS = lobular carcinoma in situ.
a
The term “contralateral invasive breast cancer” is preferred to “second primary breast cancer” as it is less 
ambiguous. Ipsilateral invasive breast cancers are presumed to be a recurrence.
b
This excludes squamous or basal cell skin cancers or new in situ carcinomas of any site like ipsilateral or 
contralateral DCIS/LCIS.
c
If bone is the only site of disease, imaging must be performed to confirm recurrence.
d
Hudis et al. 2007.
Local Recurrence:  Invasive Ipsilateral Breast Tumor Recurrence
An ipsilateral breast tumor recurrence (IBTR) event is defined as invasive breast cancer 
in the ipsilateral breast parenchyma or invasive breast cancer in the skin of the breast or 
the chest wall occurring after lumpectomy/mastectomy.
Acceptable methods for confirming local recurrence include core, incisional, or 
excisional biopsy.  Cytology alone will not be adequate to establish IBTR.

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Regional recurrence
Regional recurrence is defined as the development of tumor in the ipsilateral internal 
mammary, ipsilateral supraclavicular, ipsilateral infraclavicular, and/or ipsilateral axillary 
nodes, as well as the soft tissue of the ipsilateral axilla, following surgery.  Recurrence 
must be confirmed by biopsy or cytology.  However, if a patient meets criteria for distant 
metastatic disease, results of clinical exams alone will be sufficient to document regional 
recurrences.
Distant recurrence
Distant recurrence is defined as evidence of tumor in all areas other than the ones 
qualifying for local/regional recurrence as described above. The first distant 
recurrence after an event other than distant recurrence or death, must be reported.

Skin, Subcutaneous Tissue, and Lymph Nodes (Other Than Local or Regional)
Acceptable methods for confirming recurrence include positive cytology, aspirate 
or biopsy, or radiologic evidence of metastatic disease.

Bone Marrow
Acceptable methods for confirming recurrence include positive cytology, aspirate, 
biopsy, or MRI scan.

Lung
Acceptable methods for confirming recurrence include: (i) positive cytology, 
aspirate, or biopsy, or (ii) radiologic evidence of multiple pulmonary nodules that 
are judged to be consistent with pulmonary metastases.
Note: If a solitary lung lesion is found and no other lesions are present on lung 
tomograms, computed tomography (CT) scan, or MRI scan, further 
investigations, such as biopsy, needle aspiration, positron emission tomography 
(PET)-CT scan, or PET scan, should be performed.  Proof of neoplastic pleural 
effusion must be established by cytology or pleural biopsy.

Skeletal
Acceptable methods for confirming recurrence include: (i) x-ray, CT, or MRI 
evidence of lytic or blastic lesions consistent with bone metastasis, (ii) biopsy 
proof of bone metastases, or (iii) PET-CT scan, or PET scan clearly positive for 
bone metastases.  Where a positive bone scan finding is the only evidence of 
progression, the presence of bone scan lesions needs to be confirmed by CT, MRI,
or x-ray.
Note: If the diagnosis is equivocal by bone scan or radiologic evaluation, a 
biopsy is strongly recommended.  A bone scan with uptake limited to joints or in 

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a recent area of trauma (surgical or otherwise) cannot be used as a criterion for 
breast cancer recurrence. 

Liver
Acceptable methods for confirming recurrence include: (i) abdominal CT scan, 
liver scan, ultrasound, MRI, PET-CT scan, or PET scan consistent with liver 
metastases, or (ii) liver biopsy confirmation of the metastatic disease.
Note: If the radiologic findings are not definitive (especially with solitary liver 
nodules), a liver biopsy is recommended; however, if a biopsy is not performed, 
serial scans must be obtained to document stability or progression.

Central Nervous System
Acceptable methods for confirming recurrence include: (i) positive CT scan, 
PET-CT scan, PET scan, or MRI scan, usually in a patient with neurological 
symptoms, or (ii) biopsy or cytology (for a diagnosis of leptomeningeal 
involvement).
Invasive Contralateral breast cancer
Contralateral breast cancer is defined as evidence of invasive breast cancer in the 
contralateral breast or chest wall.  The diagnosis of a contralateral breast cancer must be 
confirmed by core, incisional, or excisional biopsy.  Cytology alone will not be adequate 
to document a contralateral breast cancer.
Second primary cancer
Second primary cancer is defined as any invasive non-breast cancer other than squamous 
or basal cell carcinoma of the skin.  The diagnosis of a second primary cancer must be 
confirmed histologically whenever possible.
Documentation requested following death

Autopsy reports should be secured whenever possible and should be retained in the 
patient’s medical records.

A copy of the death certificate should be retained in the patient’s medical records if it 
is readily available or if it contains important cause-of-death information that is not 
documented elsewhere.

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Appendix 11. Protocol JPCF: ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, for example, light 
house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair for more 
than 50% of waking hours
4
Completely disabled, cannot carry on any self-care, totally confined 
to bed or chair
5
Dead

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Appendix 12. Protocol JPCF: Guidance for Treatment of 
Venous Thromboembolic Event
Additional things to consider

A shorter duration of anticoagulation therapy may be considered in extenuating circumstances. 
Please contact the Lilly CRP/CRS to discuss. 

ESMO guidelines recommend changing endocrine therapy if a patient is on tamoxifen and 
develops a VTE

If patient continues on tamoxifen, consider keeping the patient on anticoagulation for the duration 
of treatment with tamoxifen.
Abbreviations:  CRP/CRS = clinical research physician/scientist; ET = endocrine therapy; PI = 
investigator; VTE = venous thromboembolic event.
* Patients with CTCAE grade 4 VTE should be stable, with clear clinical improvement and evidence of 
adequate anticoagulation before restarting abemaciclib.
^  Investigators should investigate exacerbation of existing (or development of new) VTE symptoms.
#  If the patient is not fully anticoagulated and experiences recurrence/progression of VTE, and the 
patient/investigator wishes to continue abemaciclib, please contact the Lilly CRP/CRS to discuss.
Figure App.12.1
Guidance for treatment of venous thromboembolic events for 
patients on abemaciclib

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A p p r o v a l  D a t e  &  T i m e :  1 8 - S e p - 2 0 1 9  0 7 : 2 5 : 1 0  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 :  
  
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P P D