Clinical trial NCT03703466
Conditions: Metastatic Breast Cancer
Sponsor: Eli Lilly and Company
Start date: 2018-11-28; Completion date: 2023-03-09
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to examine the side effects that participants with metastatic breast cancer experience when taking abemaciclib with or without food.

Detailed description:

Arms: arm 1: 200 mg abemaciclib given twice a day (BID) orally with a meal. arm 2: 200 mg abemaciclib given twice a day (BID) orally without a meal, taken in the modified fasted condition. arm 3: 200 mg abemaciclib given twice a day (BID) orally without regard for food.
Interventions: intervention 1: Abemaciclib
Intervention descriptions: intervention 1: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol I3Y-MC-JPCP(d) 
 
An Open-Label, Randomized Phase 2 Study of the Impact of Food on Tolerability when 
Receiving Abemaciclib for Patients with Previously Treated Hormone Receptor-Positive, 
HER2-Negative, Metastatic Breast Cancer 
 
NCT03703466 
 
Approval Date: 10-Feb-2020 


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Protocol I3Y-MC-JPCP(d)
An Open-Label, Randomized Phase 2 Study of the Impact of 
Food on Tolerability when Receiving Abemaciclib for 
Patients with Previously Treated Hormone Receptor-Positive, 
HER2-Negative, Metastatic Breast Cancer
Confidential Information
The information contained in this protocol is confidential and is intended for the use of clinical investigators.  It 
is the property of Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to 
persons not involved in the clinical investigation of abemaciclib (LY2835219), unless such persons are bound 
by a confidentiality agreement with Eli Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially 
confidential information exempt from public disclosure.  Eli Lilly and Company requests consultation 
regarding release/redaction prior to any public release.  In the United States, this document is subject to 
Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated 
without the written approval of Eli Lilly and Company or its subsidiaries.
Abemaciclib (LY2835219)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 05 June 2018
Amendment (a) Approved by Lilly:  08 August 2018
Amendment (b) Approved by Lilly:  18 January 2019
Amendment (c) Electronically Approved by Lilly:  14 July 2019
Amendment (d) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 10-Feb-2020 GMT


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Table of Contents
Section
Page
Protocol I3Y-MC-JPCP(d) An Open-Label, Randomized Phase 2 Study of 
the Impact of Food on Tolerability when Receiving Abemaciclib for 
Patients with Previously Treated Hormone Receptor-Positive, 
HER2-Negative, Metastatic Breast Cancer..........................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.1.1.
Background..........................................................................................................17
3.2.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Patients.......................................................................................................20
5.3.
End of Study Definition ...............................................................................................20
5.4.
Scientific Rationale for Study Design...........................................................................21
5.5.
Justification for Dose ...................................................................................................21
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle Restrictions....................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatments........................................................................................................................26
7.1.
Treatments Administered .............................................................................................26
7.1.1.
Packaging and Labelling ......................................................................................26
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27
7.3.
Blinding .......................................................................................................................27
7.4.
Dose Modification........................................................................................................27
7.4.1.
Special Treatment Considerations of Adverse Events of 
Special Interest.....................................................................................................27
7.4.1.1.
Dose Adjustments of Abemaciclib..................................................................29
7.4.1.2.
Dose Delays and Omission of Abemaciclib ....................................................30
7.5.
Preparation/Handling/Storage/Accountability...............................................................30


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7.6.
Treatment Compliance .................................................................................................30
7.7.
Concomitant Therapy...................................................................................................31
7.7.1.
Supportive Care ...................................................................................................32
7.7.1.1.
Supportive Management for Diarrhea .............................................................32
7.7.1.2.
Therapy for Febrile Neutropenia.....................................................................33
7.7.1.3.
Growth Factor Therapy...................................................................................33
7.8.
Treatment after the End of the Study............................................................................33
7.8.1.
Treatment after Study Completion........................................................................33
7.8.1.1.
Continued Access...........................................................................................33
8.
Discontinuation Criteria ....................................................................................................35
8.1.
Discontinuation from Study Treatment.........................................................................35
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................35
8.2.
Discontinuation from the Study....................................................................................35
8.3.
Lost to Follow-Up........................................................................................................36
9.
Study Assessments and Procedures ...................................................................................37
9.1.
Efficacy Assessments...................................................................................................37
9.1.1.
Electronic Patient Diary Assessment ....................................................................37
9.2.
Adverse Events ............................................................................................................37
9.2.1.
Serious Adverse Events........................................................................................38
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................39
9.2.3.
Complaint Handling.............................................................................................39
9.3.
Treatment of Overdose.................................................................................................40
9.4.
Safety...........................................................................................................................40
9.4.1.
Safety Measures...................................................................................................40
9.4.2.
Safety Monitoring ................................................................................................40
9.4.2.1.
Special Hepatic Safety Data Collection...........................................................40
9.4.2.2.
Safety Monitoring: Renal Function.................................................................40
9.4.2.3.
Safety Monitoring: Venous Thromboembolic Events......................................41
9.4.2.4.
Safety Monitoring: Interstitial Lung Disease/Pneumonitis ..............................41
9.4.2.5.
Diarrhea Safety Data Collection .....................................................................41
9.5.
Pharmacokinetics .........................................................................................................42
9.6.
Pharmacodynamics ......................................................................................................42
9.7.
Pharmacogenomics ......................................................................................................42
9.8.
Biomarkers...................................................................................................................42
9.9.
Health Economics ........................................................................................................42
10.
Statistical Considerations ..................................................................................................43
10.1. Sample Size Determination ..........................................................................................43
10.2. Populations for Analyses..............................................................................................43


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10.3. Statistical Analyses ......................................................................................................43
10.3.1.
Analyses Related to the Primary Objective...........................................................44
10.3.2.
Safety Analyses....................................................................................................44
10.3.3.
Other Analyses.....................................................................................................45
10.3.3.1.
Patient Disposition..........................................................................................45
10.3.3.2.
Patient Characteristics ....................................................................................45
10.3.3.3.
Treatment Compliance....................................................................................45
10.3.3.4.
Concomitant Therapy .....................................................................................45
10.3.3.5.
Pharmacokinetic/Pharmacodynamic Analyses ................................................45
11.
References ........................................................................................................................47
12.
Appendices .......................................................................................................................48


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List of Tables
Table
Page
Table JPCP.2.1.
Baseline Schedule of Activities ..............................................................12
Table JPCP.2.2.
On-Study-Treatment Schedule of Activities............................................13
Table JPCP.2.3.
Continued-Access Schedule of Activities................................................14
Table JPCP.3.1.
Incidence of Diarrhea .............................................................................16
Table JPCP.4.1.
Objectives and Endpoints .......................................................................19
Table JPCP.7.1.
Treatment Administration.......................................................................26
Table JPCP.7.2.
Dose Adjustments for Treatment-Emergent, Related*, and 
Clinically Significant Adverse Events of Abemaciclib............................28
Table JPCP.7.3.
Dose Adjustments of Abemaciclib..........................................................29


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List of Figures
Figure
Page
Figure JPCP.3.1.
Analysis of treatment-emergent adverse event of diarrhea in 
MONARCH 1. .......................................................................................17
Figure JPCP.5.1.
Illustration of study design......................................................................20
Figure JPCP.7.1.
Continued-access diagram. .....................................................................34


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................49
Appendix 2.
Clinical Laboratory Tests........................................................................53
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................54
Appendix 4.
Sampling Schedule .................................................................................57
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............58
Appendix 6.
Protocol JPCP Inducers and Inhibitors of CYP3A...................................59
Appendix 7.
Protocol JPCP CTCAE 4.03 Definitions.................................................60
Appendix 8.
Protocol JPCP:  ECOG Performance Status............................................61
Appendix 9.
Protocol I3Y-MC-JPCP Amendment (d) An Open-Label, 
Randomized, Phase 2 Study of the Impact of Food on Tolerability 
when Receiving Abemaciclib for Patients with Previously Treated 
Hormone Receptor-Positive, HER2-Negative, Metastatic Breast 
Cancer Summary....................................................................................62


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1.
Synopsis
Protocol Title:
An Open-Label, Randomized Phase 2 Study of the Impact of Food on Tolerability When 
Receiving Abemaciclib for Patients with Previously Treated Hormone Receptor-Positive, 
HER2-Negative Metastatic Breast Cancer
Rationale:
Abemaciclib is an oral, selective, and potent adenosine triphosphate (ATP)-competitive inhibitor 
of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6, respectively).  It is currently approved 
for use in certain geographies as a monotherapy or in combination with hormone therapy for the 
treatment of patients with advanced or metastatic hormone receptor-positive (HR+), human 
epidermal growth factor receptor 2-negative (HER2−) breast cancer.
MONARCH 1, a single-arm Phase 2 study of abemaciclib 200 mg twice daily (BID) as a single
agent in patients with refractory HR+, HER2−metastatic breast cancer (mBC), demonstrated 
that continuous dosing of single-agent abemaciclib was well tolerated and exhibited promising 
clinical activity (objective response rate [ORR] of 19.7% (95% confidence interval [CI]
13.3-27.5; 15% not excluded). The most common treatment-emergent adverse events (TEAEs) 
of any grade were diarrhea (90.2%), fatigue (65.2%), and nausea (64.4%).
MONARCH 2 was a randomized, double-blind Phase 3 study of abemaciclib in combination 
with fulvestrant in women with HR+, HER2−mBC who had progressed while receiving 
endocrine therapy. It demonstrated that abemaciclib 150 mg BID plus fulvestrant was effective,
with significantly improved progression-free survival (PFS; median 16.4 versus 9.3 months; 
hazard ratio [HR]=0.553; 95% CI 0.449, 0.681) and in patients with measurable disease an ORR 
of 48.1% (95% CI 42.6,53.6) compared with 21.3% (95% CI 15.1, 27.6) in the control arm. The 
most common TEAEs in the abemaciclib versus placebo arms were diarrhea (86.4% versus 
24.7%), neutropenia (46.0% versus 4.0%), nausea (45.1% versus 22.9%), and fatigue (39.9% 
versus 26.9%).
MONARCH 3 was a randomized, double-blind Phase 3 study of abemaciclib in combination 
with an aromatase inhibitor as initial therapy in women with HR+, HER2−mBC. It 
demonstrated that abemaciclib 150 mg BID plus a nonsteroidal aromatase inhibitor (NSAI) was 
effective as initial therapy, significantly improving PFS (median 28.18 versus 14.76 months; 
HR=0.540; 95% CI 0.418, 0.698); p=.000002).  In patients with measurable disease, the ORR 
was 61% in the abemaciclib arm compared to 45.5% in the placebo arm (p=.003). The most 
common TEAEs in the abemaciclib versus placebo arms were diarrhea (82.3% versus 32.2%), 
neutropenia (43.7% versus 32.3%), fatigue (41.3% versus 33.5%), and nausea (41.3% versus 
20.5%).
Diarrhea is a frequently associated adverse event (AE) with abemaciclib and has been reported in 
MONARCH 1, MONARCH 2, and MONARCH 3 studies (Verzenio® United States Package 


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Insert [USPI]).  Diarrhea typically occurs within the first month of treatment and the incidence 
decreases over the duration of treatment.
Although food can change the bioavailability (BA) of a drug and may have clinically significant 
consequences, this has not been shown to be the case with abemaciclib. A food effect study has 
been conducted that evaluated the impact feeding status had on the exposure of abemaciclib. It 
was demonstrated that a high-fat, high-calorie meal (approximately 800 to 1000 calories with 
150 calories from protein, 250 calories from carbohydrate and 500 to 600 calories from fat) 
administered to healthy subjects increased the area under the concentration versus time curve 
(AUC) of abemaciclib and its active metabolites by 9% and increased maximum concentration 
(Cmax) by 26% (Verzenio® USPI). These changes in exposure were not clinically significant. 
Currently, abemaciclib is recommended to be taken with or without food (Verzenio® USPI).
In certain circumstances food may mitigate the local gastrointestinal (GI) toxicity of some drugs 
and this effect may be independent to any relationship between the feeding state and systemic 
absorption of the drug. To assess if the incidence and severity of the diarrhea associated with 
abemaciclib may be altered, this study in patients with previously treated HR+, HER2−mBC
will evaluate the incidence of dose reductions, dose interruptions, and/or treatment 
discontinuations due to severe diarrhea (≥Grade 3) or prolonged Grade 2 diarrhea (>7 days 
duration) when abemaciclib monotherapy is administered (200 mg orally [PO] BID) in the 
following feeding states; when abemaciclib is taken with a meal, when abemaciclib is taken in 
the modified fasted condition (defined as at least 1 hour before or 2 hours after a meal), or when 
abemaciclib is administered without regard to food in patients.


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Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate and summarize incidence of severe diarrhea 
(≥Grade 3) or prolonged Grade 2 diarrhea (defined as >7 
days duration), including the incidence of dose 
reductions, dose interruptions, and/or treatment 
discontinuations due to severe diarrhea or prolonged 
Grade 2 diarrhea over the first 3 cycles when 
abemaciclib is administered:

with a meal

without a meal, taken in the modified fasted 
condition

without regard to food

Incidence of severe diarrhea (≥Grade 3)

Incidence of prolonged Grade 2 diarrhea (defined 
as >7 days duration)

Dose reductions due to diarrhea

Dose interruptions due to diarrhea

Treatment discontinuations due to diarrhea

Utilization of antidiarrheals 
Secondary
To assess safety and toxicity profile of abemaciclib
To evaluate PK parameters of abemaciclib and its 
metabolites
The safety endpoints evaluated will include, but are not 
limited to, the following:

Overall safety

incidence and severity of TEAEs, SAEs, deaths, 
and clinical laboratory abnormalities
Steady-state concentrations of abemaciclib and its 
metabolites LSN2839567 and LSN3106726
Abbreviations:  PK = pharmacokinetic; SAE = serious adverse event; TEAE = treatment-emergent adverse event.


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Overall Design:
Study I3Y-MC-JPCP (JPCP) is a multicenter, randomized, open-label Phase 2 study evaluating 
the impact of food on the incidence of severe diarrhea (≥Grade 3) or prolonged Grade 2 diarrhea
(>7 days duration) when receiving abemaciclib monotherapy 200 mg PO BID during the first 3 
cycles of study treatment for patients with previously treated HR+, HER2−mBC.
Number of Patients:
The study will screen approximately 100 patients, of whom approximately 60 evaluable patients 
with HR+, HER2−mBC will be enrolled and randomized 1:1:1 to 1 of the 3 treatment arms as 
defined by different administration conditions.  Randomization will be stratified by region.
Treatment Arms and Duration:
Treatment will be given in an outpatient setting and will continue until the patient is no longer 
receiving clinical benefit or other discontinuation criteria have been fulfilled.  Abemaciclib will 
be taken on Days 1 to 28 of a 28-day cycle for each treatment arm.  The primary outcome phase 
will consist of the first 3 cycles of treatment.  Patients will continue to receive abemaciclib in the 
extension phase starting with Cycle 4, Day 1.  Abemaciclib may be taken without regard to food 
in the extension phase.
Study 
Arm
Drug
Dose, 
mg
Route of 
Administration
Dose 
Frequency
Administration Conditions
1
Abemaciclib
200
Oral
BID
Take with a meal
2
Abemaciclib
200
Oral
BID
Take without a meal; at least 1 hour before 
or 2 hours after a meal (modified fasted 
condition)
3
Abemaciclib
200
Oral
BID
Take without regard to food
Abbreviation:  BID = twice a day.


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2. Schedule of Activities
Table JPCP.2.1.
Baseline Schedule of Activities
Relative Day Prior to C1D1
28
14
7
Instructions
Procedure
Informed consent
X
ICF must be signed before any protocol-specific
procedures are performed.
Physical exam
X
Include height, weight, and vital signs (temperature, 
blood pressure, pulse rate, and respiration rate).
ECOG performance status
X
Medical history
X
Including assessment of preexisting conditions, 
historical illnesses, substance usage (such as alcohol
and tobacco), and other relevant habit assessments.
Current medication
X
Includes 14 days prior to initiation of abemaciclib 
treatment.
AE collection
CTCAE Version 4.0
X
To be reported only after study eligibility is confirmed. 
See Section 9.2 for reporting expectations.
Radiologic imaging and 
measurement of palpable or 
visible lesions
X
Baseline assessments will be done at the investigator’s 
discretion based on the standard of care.
ECG
X
Local ECG.
Hematology
X
Central lab sample collected.  Although local sample 
results can be used for clinical management, a central 
sample must still be submitted.
Clinical chemistry
X
Pregnancy test
X
Females of child bearing potential must have a negative 
serum pregnancy test within 7 days of the first dose of 
abemaciclib.
Patient diary (e-diary)
X
Dispense e-diary 1 week prior to C1D1 in order to 
obtain approximately 7 full days of information on 
number of stools and use of antidiarrheal medication, in 
order to have a baseline for the patient.
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CTCAE = Common Terminology Criteria for Adverse 
Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; e-diary = electronic patient 
diary; ICF = informed consent form.


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Table JPCP.2.2.
On-Study-Treatment Schedule of Activities
Primary Outcome Phase
Extension 
Phase
30 Day 
Follow-
Upa
Cycle 1
Cycle 2
Cycle 3
Cycle 4-N
Visit 801
Day within a Cycle
1
15±1
1
15±1
1
1
Procedure
Instructions
Abemaciclib
X
X
X
X
Take BID on Days 1 through 28 of each cycle.
Physical exam
X
X
X
X
X
Perform prior to dispensing of abemaciclib. Include 
weight, temperature, blood pressure, pulse rate, 
respiration rate.
Concomitant medication
X
X
X
X
X
X
X
Throughout study as needed.
AE collection
X
X
X
X
X
X
X
Grading using CTCAE Version 4.0.
ECOG performance 
status
X
X
X
Radiologic imaging and 
measurement of 
palpable or visible
lesions
Efficacy assessments will be done at the investigator’s 
discretion based on the standard of care to confirm 
eligibility to receive abemaciclib.
ECG
Only perform local additional evaluations in the setting of 
cardiac symptoms and/or at the discretion of the 
investigator.
Hematology
X
X
X
X
X
X
X
3 days prior to scheduled visit, unless more frequent 
assessment is clinically indicated; see Appendix 2.
Clinical chemistry
X
X
X
X
X
X
X
Pharmacokinetics
X
X
X
X
X
For all sample collection details, see Appendix 4.
Patient Diary (e-diary)
X
X
X
X
X
Patients will record daily information on the number of 
stools, diarrhea, use of loperamide and the timing of the 
abemaciclib intake relative to their meals  
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; e-diary = electronic patient diary; ICF = informed consent form.
a
Follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the primary outcome or extension
phase of the study and lasts approximately 30 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or 
she has explicitly provided permission and consent. 


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Table JPCP.2.3.
Continued-Access Schedule of Activities
Study Treatment
Follow-Upa
Instructions
Cycle
30-Day Follow-Up
Visit
501
502-5XX
901
Procedure
Abemaciclib
X
X
Take BID on Days 1 through 28 of each cycle.
AE collection
X
X
X
Grading using CTCAE Version 4.0.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009).
a
Continued-access follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the continued-access 
period and lasts approximately 30 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.


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3. Introduction
3.1.
Study Rationale
Abemaciclib is an oral, selective, and potent adenosine triphosphate (ATP)-competitive inhibitor 
of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6, respectively).  It is currently approved 
for use in certain geographies as a monotherapy or in combination with hormone therapy for the 
treatment of patients with advanced or metastatic hormone receptor-positive (HR+), human 
epidermal growth factor receptor 2-negative (HER2−) breast cancer.
MONARCH 1, a single-arm Phase 2 study of abemaciclib 200 mg twice daily (BID) as a single
agent in patients with refractory HR+, HER2−metastatic breast cancer (mBC), demonstrated 
that continuous dosing of single-agent abemaciclib was well tolerated and exhibited promising 
clinical activity (objective response rate [ORR] of 19.7% (95% confidence interval [CI]
13.3-27.5; 15% not excluded). The most common treatment-emergent adverse events (TEAEs) 
of any grade were diarrhea (90.2%), fatigue (65.2%), and nausea (64.4%).
MONARCH 2 was a randomized, double-blind Phase 3 study of abemaciclib in combination 
with fulvestrant in women with HR+, HER2−mBC who had progressed while receiving 
endocrine therapy. It demonstrated that abemaciclib 150 mg BID plus fulvestrant was effective,
with significantly improved progression-free survival (PFS; median 16.4 versus 9.3 months; 
HR=0.553; 95% CI 0.449, 0.681) and in patients with measurable disease an ORR of 48.1% 
(95% CI 42.6,53.6) compared with 21.3% (95% CI 15.1, 27.6) in the control arm. The most 
common TEAEs in the abemaciclib versus placebo arms were diarrhea (86.4% versus 24.7%), 
neutropenia (46.0% versus 4.0%), nausea (45.1% versus 22.9%), and fatigue (39.9% versus 
26.9%).
MONARCH 3 was a randomized, double-blind Phase 3 study of abemaciclib in combination 
with an aromatase inhibitor as initial therapy in women with HR+, HER2−mBC. It 
demonstrated that abemaciclib 150 mg BID plus a nonsteroidal aromatase inhibitor (NSAI) was 
effective as initial therapy, significantly improving PFS (median 28.18 versus 14.76 months; 
HR=0.540; 95% CI 0.418, 0.698); p=.000002).  In patients with measurable disease, the ORR 
was 61% in the abemaciclib arm compared to 45.5% in the placebo arm (p=.003). The most 
common TEAEs in the abemaciclib versus placebo arms were diarrhea (82.3% versus 32.2%), 
neutropenia (43.7% versus 32.3%), fatigue (41.3% versus 33.5%), and nausea (41.3% versus 
20.5%).
Diarrhea is a frequently associated adverse event (AE) with abemaciclib and has been reported in 
MONARCH 1, MONARCH 2, and MONARCH 3 studies (Verzenio® United States Package 
Insert [USPI]; Table JPCP.3.1).


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Table JPCP.3.1.
Incidence of Diarrhea
Study
Patients
N
All Grades
(%)
Grade 3
(%)
Grade 4
(%)
MONARCH 1
200 mg PO BID monotherapy
132
90
20
0
MONARCH 2
150 mg PO BID with fulvestrant
441
86
13
0
MONARCH 3
150 mg PO BID with aromatase inhibitor
327
81
9
0
Abbreviations:  BID = twice daily; PO = orally.
Diarrhea incidence was greatest during the first month of abemaciclib dosing. In MONARCH 3, 
the median time to onset of the first diarrhea event was 8 days and the median duration of 
diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time 
to onset of the first diarrhea event was 6 days and the median duration of diarrhea for Grades 2 
and 3 were 9 days and 6 days, respectively.  In MONARCH 1, the median time to onset of the 
first diarrhea event was 7 days and the median duration of diarrhea for Grades 2 and 3 were 
7.5 and 4.5 days, respectively.
In MONARCH 3, 19% of patients with diarrhea required a dose omission and 17% required a 
dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 
22% required a dose reduction. In MONARCH 1, 26% of patients with diarrhea required a dose 
omission and 23% required a dose reduction. The time to onset and resolution for diarrhea were 
similar across MONARCH 1, MONARCH 2, and MONARCH 3 studies.
Diarrhea typically occurs within the first month of treatment and the incidence decreases over the 
duration of treatment. It is predictable and manageable with over-the-counter medications. The 
supportive diarrhea management guidelines (Sections 7.2.1 and 7.7.1) incorporated in the 
MONARCH study protocols, including early use of antidiarrheal agents and dose adjustments, 
appeared to have been effective in limiting the recurrence, duration, and severity of diarrhea. 
The majority of diarrhea events recovered or resolved and the rate of discontinuation due to 
diarrhea was low. In MONARCH 1 (Figure JPCP.3.1), the incidence of diarrhea reduced by end 
of Cycle 3, with no Grade 3 and 10.6% Grade 2 events.


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Source:  fgdiav11_90day.pdf.
Figure JPCP.3.1.
Analysis of treatment-emergent adverse event of diarrhea in 
MONARCH 1.
Although food can change the bioavailability (BA) of a drug and may have clinically significant 
consequences, this has not been shown to be the case with abemaciclib. A food effect study has 
been conducted that evaluated the impact feeding status had on the exposure of abemaciclib. It 
was demonstrated that a high-fat, high-calorie meal (approximately 800 to 1000 calories, with 
150 calories from protein, 250 calories from carbohydrate and 500 to 600 calories from fat) 
administered to healthy subjects increased the area under the concentration versus time curve 
(AUC) of abemaciclib and its active metabolites by 9% and increased maximum concentration 
(Cmax) by 26%. (Verzenio® USPI). These changes in exposure were not clinically significant.
Currently, abemaciclib is recommended to be taken with or without food (Verzenio® USPI).
In certain circumstances food may mitigate the local gastrointestinal (GI) toxicity of some drugs 
and this effect may be independent to any relationship between the feeding state and systemic 
absorption of the drug. To assess if the incidence and severity of the diarrhea associated with 
abemaciclib may be altered, this study in patients with previously treated HR+, HER2−mBC
will evaluate the incidence of dose reductions, dose interruptions, and/or treatment 
discontinuations due to severe diarrhea (≥Grade 3) or prolonged Grade 2 diarrhea (>7 days 
duration) when abemaciclib monotherapy is administered (200 mg orally [PO] BID) in the 
following feeding states; when abemaciclib is taken with a meal, when abemaciclib is taken in 
the modified fasted condition (defined as at least 1 hour before or 2 hours after a meal), or when 
abemaciclib is administered without regard to food in patients.
3.1.1. Background
Abemaciclib is an oral, selective, and potent ATP-competitive inhibitor of CDK4 and CDK6.  
CDK4 and CDK6 promote cell growth by facilitating the progression of cells from the G1 to the 


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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 single-agent clinical activity in both the 
I3Y-MC-JPBA (JPBA) Phase 1b study, with a response rate of 33.3% across dose levels, and the 
I3Y-MC-JPBN (JPBN; MONARCH 1) Phase 2 study, with a response rate of 19.7% (at 200-mg 
dose BID), in patients with heavily pretreated HR+ mBC that is refractory to endocrine therapy 
(Patnaik et al. 2016; Dickler et al. 2017).  Additionally, abemaciclib plus endocrine therapy 
resulted in statistically significant improvements in both 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]).
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. Abemaciclib was approved in the United States for use in the treatment 
of HR+, HER2−mBC based on the above referenced clinical studies.
3.2.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated AEs of abemaciclib are to be found in the Investigator’s Brochure 
(IB).


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4. Objectives and Endpoints
Table JPCP.4.1 shows the objectives and endpoints of the study.
Table JPCP.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate and summarize incidence of severe diarrhea 
(≥Grade 3) or prolonged Grade 2 diarrhea (defined as >7 
days duration), including the incidence of dose 
reductions, dose interruptions, and/or treatment 
discontinuations due to severe diarrhea or prolonged 
Grade 2 diarrhea over the first 3 cycles when 
abemaciclib is administered:

with a meal

without a meal, taken in the modified fasted 
condition

without regard to food

Incidence of severe diarrhea (≥Grade 3)

Incidence of prolonged Grade 2 diarrhea 
(defined as >7 days duration)

Dose reductions due to diarrhea

Dose interruptions due to diarrhea

Treatment discontinuations due to diarrhea

Utilization of antidiarrheals
Secondary
To assess safety and toxicity profile of abemaciclib
To evaluate the PK parameters of abemaciclib and its 
metabolites
The safety endpoints evaluated will include, but are not 
limited to, the following:

Overall safety

incidence and severity of TEAEs, SAEs, 
deaths, and clinical laboratory abnormalities
Steady-state concentrations of abemaciclib and its 
metabolites LSN2839567 and LSN3106726
Abbreviations:  PK = pharmacokinetic; SAE = serious adverse event; TEAE = treatment-emergent adverse event.


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5. Study Design
5.1.
Overall Design
Study I3Y-MC-JPCP (JPCP) is a multicenter, randomized, open-label Phase 2 study evaluating 
the impact of food on the incidence of severe diarrhea (≥Grade 3) or prolonged Grade 2 diarrhea
(>7 days duration) when receiving abemaciclib monotherapy 200 mg PO BID during the first 3 
cycles of study treatment for patients with previously treated HR+, HER2−mBC.  
Randomization will be 1:1:1 to the 3 food administration conditions, and randomization will be 
stratified by region.
Figure JPCP.5.1 illustrates the study design.
Abbreviations:  HER2−= human epidermal growth factor receptor 2-negative; HR+ =
hormone receptor-positive; mBC = metastatic breast cancer; N = number of patients.
Figure JPCP.5.1.
Illustration of study design.
5.2.
Number of Patients
The study will screen approximately 100 patients, of whom approximately 60 evaluable patients 
with HR+, HER2−mBC will be enrolled and randomized 1:1:1 to 1 of the 3 treatment arms as 
defined by different administration conditions. Randomization will be stratified by region.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
Refer to Figure JPCP.7.1 for a depiction of study completion, the continued-access period, and 
end of study.


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5.4.
Scientific Rationale for Study Design
Refer to Section 3.1.
5.5.
Justification for Dose
As the incidence of reported diarrhea was greatest in MONARCH 1 for both overall grades and 
Grade 3, this study will enroll patients who are deemed suitable by their physician for treatment 
with abemaciclib monotherapy at the recommended dose of 200 mg orally BID.


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6. Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
have a diagnosis of HR+, HER2−mBC

To fulfill the requirement of HR+ disease, a breast cancer must 
express, by immunohistochemistry (IHC), at least 1 of the hormone 
receptors (estrogen receptor [ER] or progesterone receptor [PgR])
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, a breast cancer must not 
demonstrate, at initial diagnosis or upon subsequent biopsy, 
overexpression of HER2 by either IHC or in-situ hybridization
according to ASCO/CAP guidelines for HER2 testing (Wolff et al. 
2013). Although not required as a protocol procedure, a patient with a 
new metastatic lesion should be considered for biopsy (whenever 
possible) to reassess HER2 status prior to study entry if clinically 
indicated.
[2]
have all of the following:

Recurrent, locally advanced, unresectable or mBC

Prior treatment with disease progression following anti-estrogen 
therapy for locally advanced or metastatic disease

Prior treatment with at least one chemotherapy regimen for locally 
advanced or metastatic disease. Patients are eligible if they 
discontinue chemotherapy prior to demonstrating disease progression

No prior treatment with CDK4 and CDK6 inhibitor
[3]
have the presence of measurable or nonmeasurable disease as determined by 
investigator.
[4]
are of an acceptable age to provide informed consent according to the local 
regulations and are at least 18 years of age, male or female (regardless of 
menopausal status).
[5]
have a performance status (PS) of ≤1 on the Eastern Cooperative Oncology 
Group (ECOG) scale (Oken et al. 1982)


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[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures, including keeping records in 
the electronic patient diary (e-diary) as required by study protocol.
[7]
have discontinued all previous treatments for cancer and recovered from the 
acute effects of therapy.  All patients who experienced diarrhea as a side effect 
of previous therapy must have recovered to ≤Grade 1 prior to enrollment. 
Patients must have discontinued from previous treatments, as shown below:
Previous Treatment
Length of Time Prior to First Dose of 
Study Treatment
Cytotoxic therapies
21 days
Targeted agents (small-molecule inhibitors)
5 half-lives or 28 days, whichever is 
shorter
Hormonal therapy
≥21 days
Biologic agents (other than immunotherapy)
21 days
Limited field radiotherapy for palliative intent
14 days 
Other radiotherapy
28 days
Major surgery
14 days
Immunotherapy
21 days
[8]
have adequate organ function, as defined below:
System
Laboratory Value
Hematologic
ANC
1.5×109 cells/L. Note: G-CSF should not be 
administered to meet ANC eligibility criterion.
Platelets
100×109/L
Hemoglobin
Transfusions to increase the patient’s
hemoglobin level to 8 g/dL are permitted; 
however, study treatment must not begin 
until at least 1 day after the transfusion.
8 g/dL
Hepatic
Total bilirubina
1.5×ULN
ALT and AST
3×ULN 
Renal
Serum creatinine
1.5×ULN
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; ANC = absolute 
neutrophil count; G-CSF = granulocyte–colony-stimulating factor; ULN = upper limit of normal.
a
Gilberts syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are 
eligible.


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[9]
men with partners of child-bearing potential or women of child-bearing 
potential must agree to use a medically approved contraceptive method during 
and for at least 3 weeks following the last dose of abemaciclib (eg, 
intrauterine device [IUD], nonhormonal birth control pills, or barrier method).  
If condoms are used as a barrier contraceptive, a spermicidal agent should be 
added as double barrier protection.
[10] women of child-bearing potential must have a negative pregnancy test 
documented within 7 days prior to treatment.
[11] have an estimated life expectancy that will permit the patient to complete 3 
cycles of treatment.
[12] are able to swallow tablets/capsules.
[13] have given written informed consent prior to any study-specific procedures
(refer to Appendix 3, Study Governance, Regulatory, and Ethical 
Considerations).
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] are currently receiving treatment in a clinical study involving an 
investigational product or are enrolled into any other type of medical research 
judged not to be scientifically or medically compatible with this study.
[15] have a serious concomitant systemic disorder (for example, active infection or 
a GI disorder causing clinically significant symptoms such as nausea, 
vomiting or diarrhea [such as Crohn’s disease, ulcerative colitis], or profound 
immune suppression) or a serious preexisting medical condition (for example, 
history of major surgical resection involving the stomach or small bowel) that, 
in the opinion of the investigator, would compromise/preclude the patient’s 
ability to adhere to the protocol.
[16] have symptomatic central nervous system (CNS) malignancy or metastasis 
(screening not required).
Patients with treated CNS metastases are eligible for this study if they are not 
currently receiving corticosteroids (discontinued steroids at least 7 days prior 
to study treatment initiation) and/or anticonvulsants and their disease is 
asymptomatic and radiologically stable for at least 30 days.
[17] have a symptomatic human immunodeficiency virus (HIV) infection or 
symptomatic activated/reactivated hepatitis A, B, or C (screening is not 
required).
[18] have a personal history of any of the following conditions:  syncope of
cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or 
sudden cardiac arrest. Exceptions are:

patients with ablated Wolfe Parkinson White are eligible


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
patients with controlled atrial fibrillation for >30 days prior to 
randomization are eligible.
[19] have a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy 
for a minimum of 3 years.
[20] had major surgery within 14 days prior to randomization to allow for 
post-operative healing of the surgical wound. Note: a surgery qualifies as 
major per investigators/surgeon judgement based on the required recovery 
period, both from general patient status and post-operative healing 
perspective.
[21] are breastfeeding.
[22] have received treatment with a drug that has not received regulatory approval 
for any indication within 14 or 21 days of the initial dose of study drug for a 
nonmyelosuppressive or myelosuppressive agent, respectively.
6.3.
Lifestyle Restrictions
This is a lifestyle restriction study examining the relationship between timing of food and 
administration of abemaciclib, evaluating its impact on severe diarrhea (≥Grade 3) or prolonged 
Grade 2 diarrhea (>7 days duration); see Sections 7.1 and 7.6, administration conditions and 
defined adherence.
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
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened up to 1 time.  The interval between re-screenings 
should be at least 2 weeks.  When re-screening is performed, the individual must sign a new 
informed consent form (ICF) and will be assigned a new identification number.
Repeating of laboratory tests during the screening period does not constitute re-screening.


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7. Treatments
7.1.
Treatments Administered
Abemaciclib monotherapy will be administered 200 mg PO BID with specific administration 
conditions.  Patients will be instructed to take their daily doses of abemaciclib either with a meal, 
without a meal in a modified fasting state (defined as at least 1 hour prior to or 2 hours after a 
meal), or without regard to food for the first 3 cycles.  Patients will be requested to record the 
abemaciclib dosing and administration conditions followed in a diary. Abemaciclib will be taken 
on Days 1 to 28 of a 28-day cycle for each treatment arm.  Table JPCP.7.1 shows the treatment 
regimens.
Patients will be instructed to commence loperamide at the first sign of loose stools and thereafter 
as per local label. See Section 7.7.1.1 for supportive management guidance. Patients will be 
required to record loperamide dose and frequency in a diary. Loperamide will be supplied or 
reimbursed by the sponsor according to local laws. If additional antidiarrheals are prescribed by 
the physician, they should be entered on the concomitant medication CRF.
Table JPCP.7.1.
Treatment Administration
Study 
Arm
Drug
Dose, mg
Route of 
Administration
Dose 
Frequency
Administration Conditions
1
Abemaciclib
200
Oral
BID
Take with a meal
2
Abemaciclib
200
Oral
BID
Take without a meal; at least 1 hour 
before or 2 hours after a meal (modified 
fasted condition)
3
Abemaciclib
200
Oral
BID
Take without regard to food
Abbreviation:  BID = twice a day.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drug and planned duration of each individual’s 
treatment to the patient/study-site personnel/legal representative.

verifying that instructions are followed properly the first 3 cycles.  Abemaciclib is 
taken as per the assigned study arm outlined in Table JPCP.7.1.

maintaining accurate records of abemaciclib dispensing and collection.

returning all unused medication to Lilly, or its designee at the end of the study, 
unless the site is authorized by Lilly or its designee to destroy unused medication, 
as allowed by local law.

educating the patient on the management of diarrhea as per Section 7.7.1.1.
7.1.1. Packaging and Labelling
Abemaciclib will be provided by Lilly and will be labeled according to the country’s regulatory 
requirements.


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7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomly assigned to 1 of the 3 treatment 
arms.  Assignment to treatment arms will be determined by a computer-generated random 
sequence using an interactive Web-response system (IWRS).  Randomization will be stratified 
by region.
7.2.1. Selection and Timing of Doses
During the on-study treatment period (primary outcome phase and extension phase), 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 Day 1.
For each study arm, abemaciclib will be administered orally at 200 mg BID, with at least 6 hours
separating doses on a continuous schedule and as assigned by administration conditions for each 
study arm.  Details on treatment administration are described in Section 7.1.  Treatment with 
abemaciclib will be given until evidence of disease recurrence or other discontinuation criteria 
are met (see Section 8).
7.3.
Blinding
This is an open-label study.
7.4.
Dose Modification
7.4.1. Special Treatment Considerations of Adverse Events of Special 
Interest
Table JPCP.7.2 presents dose adjustments to occur IF the event was related to abemaciclib. Any 
questions related to dose adjustments may be discussed with Lilly CRP.


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Table JPCP.7.2.
Dose Adjustments for Treatment-Emergent, Related*, and Clinically 
Significant Adverse Events of Abemaciclib
Toxicity Type
Toxicity Profile and 
Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose reduction is NOT 
required.
Hematologic Toxicity
Recurrenta Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic Toxicity
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic Toxicity:  If 
patient requires 
administration of blood 
cell growth factors
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 increased, and 
ILD/pneumonitis)
Persistent or recurrent 
Grade 2 that does not 
resolve with maximal 
supportive measures 
within 7 days to baseline 
or Grade 1.
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Non-Hematologic 
Toxicityb (except diarrhea, 
ALT increased, and 
ILD/pneumonitis)
Grade 3 and 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 recurrent 
Grade 2 that does not 
resolve with maximal 
supportive measures, or 
any Grade of diarrhea that 
requires hospitalization
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
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 Increasedc
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.


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ALT Increasedc
Grade 4 (>20.0×ULN)
Abemaciclib therapy 
MUST be discontinued.
Abemaciclib therapy 
MUST be discontinued.
ALT Increasedc with 
increased total bilirubin, in 
the absence of cholestasis
Grade 3 increased ALT 
(˃5.0 x ULN) with total 
bilirubin >2 x ULN
Abemaciclib therapy 
MUST be discontinued
Abemaciclib therapy 
MUST be discontinued
ILD/Pneumonitisb
Grade 2 that persists or 
recurs despite maximal 
supportive measures and 
does not return to baseline 
or Grade 1 within 7 days
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade ≤1
Dose MUST be reduced 
by 1 dose level.
ILD/Pneumonitisb
Grade 3 or 4
Abemaciclib therapy 
MUST be discontinued
Abemaciclib therapy 
MUST be discontinued
Abbreviation:  ALT = alanine aminotransferase; ASCO = American Society of Clinical Oncology; ILD = interstitial 
lung disease.
Note:  MUST = mandatory.
* Related means there is a reasonable causal relationship with abemaciclib.
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 first 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 hepatic monitoring, renal, and ILD/pneumonitis is provided in Sections 9.4.2.1, 9.4.2.2, 
and 9.4.2.4.
c
Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See 
Section 9.4.2.1 for additional guidance for hepatic monitoring.
7.4.1.1.
Dose Adjustments of Abemaciclib
Dose adjustments as outlined in Table JPCP.7.3 are allowed.  Abemaciclib must 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.  After re-escalation, subsequent dose adjustments should 
be based on the dose of abemaciclib that the patient is currently receiving.
Table JPCP.7.3.
Dose Adjustments of Abemaciclib
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Twice daily with at least 6 hours between doses
1
150 mg
Twice daily with at least 6 hours between doses
2
100 mg
Twice daily with at least 6 hours between doses
3
50 mg
Twice daily with at least 6 hours between doses
If a patient receiving the 50-mg BID dose of abemaciclib requires further dose reduction, the 
patient must be discontinued from study treatment.


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7.4.1.2.
Dose Delays and Omission of Abemaciclib
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), abemaciclib may be suspended or delayed as determined by the investigator’s 
judgment (see Table JPCP.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.
Patients not recovering from toxicity within 28 days should be considered for discontinuation of 
study treatment.  In exceptional circumstances, a delay >28 days is permitted upon agreement 
between the investigator and the Lilly CRP and abemaciclib dose adjustment is to be considered.
Patients undergoing surgery should have abemaciclib suspended. For minor surgeries and
procedures (eg, ambulatory), consultation with the Lilly CRP is not required.  For major 
surgeries, the recommendation is to suspend dosing of abemaciclib for at least 7 days before, and 
for up to 14 days after, the procedure.  Consider monitoring neutrophils and platelets before 
surgery and before resuming abemaciclib. The scars should be aseptic and healing process 
reasonable before resuming abemaciclib. This is all monitored to prevent infection and 
hemorrhagic and/or healing complications.  For minor surgeries, investigators should treat as 
clinically indicated and closely monitor any signs of infection or healing complications.
All patients who require palliative radiation should have their treatment held. This must be 
discussed and agreed with Lilly CRP; see Section 7.7.
In the event of study treatment delay due to logistical reasons (for example, due to holiday, 
weekend, inclement weather, or other unforeseen circumstances), the patient should continue on 
study treatment if the patient has adequate drug supply.  If a patient’s treatment is interrupted as 
a result of not having sufficient drug supply, study treatment may be delayed up to a maximum 
of 7 consecutive days (and not be considered a protocol violation).  In exceptional circumstances, 
an additional delay up to 7 days is permitted upon agreement between the investigator and the 
Lilly CRP.
7.5.
Preparation/Handling/Storage/Accountability
Abemaciclib will be supplied by Lilly as tablets/capsules for oral administration.  Abemaciclib 
tablets/capsules 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 
tablets/capsules in the original package provided and be instructed to keep all medication out of 
reach of children.
7.6.
Treatment Compliance
Patient compliance with study medication and completion of patient e- diary will be assessed at 
each visit.  Compliance will be assessed by counting returned tablets/capsules and e-diary 
review. The e-diary will be supplied by Lilly.  Deviations from the prescribed dosage regimen 
should be recorded on the case report form (CRF). Patients who are deemed noncompliant will 


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receive additional training, as required, and the importance of compliance with the protocol will 
be reinforced. 
Patients who are significantly noncompliant with abemaciclib and administration conditions may 
be discontinued from abemaciclib treatment after discussion/consultation with the Lilly CRP.  A 
patient will be considered noncompliant or if she/he misses more than 25% of abemaciclib doses 
during the first 3 cycles of treatment.  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.
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.
No other anticancer therapy will be permitted while patients are on study treatment.  Of note, 
megestrol acetate as an appetite stimulant is permitted.
Concurrent treatment with standard-of-care bone-modifying agents (such as bisphosphonates or 
receptor activator of nuclear factor kappa B ligand [RANKL]-targeting agents) is permitted.
Abemaciclib is extensively metabolized through oxidation by cytochrome P450 (CYP)3A.  In 
clinical drug interaction studies, coadministration of clarithromycin, a strong CYP3A inhibitor, 
increased exposure (AUC) to abemaciclib by 3.4-fold (Study I3Y-MC-JPBE) and 
coadministration of rifampin, a strong CYP3A inducer, decreased exposure to abemaciclib by 
95% (Study I3Y-MC-JPBF).  Therefore, grapefruit or grapefruit juice as well as inducers and 
inhibitors of CYP3A should be substituted or avoided if possible (Appendix 6).
All patients may receive supportive therapy with dexamethasone, preferably ≤7 days, if clinically 
indicated.  Patients requiring more than 7 days of dexamethasone therapy will not incur a 
protocol deviation.
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.
No other chemotherapy, immunotherapy, cancer-related hormone therapy, experimental drugs, 
or herbal supplements intended to treat cancer will be permitted while the patients are on this 
study.


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Palliative radiation therapy is permitted after discussion with and agreement of the Lilly CRP or 
designee for irradiating small areas of painful metastases that cannot be managed adequately 
using systemic or local analgesics. Such areas must not be an identified target lesion if Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 is used to measure disease and must not 
constitute progressive disease or meet RECIST criteria for progressive disease. Any 
symptomatic deterioration or clinical disease progression requiring, in the opinion of the 
investigator, other forms of specific antitumor systemic therapy, will be cause for discontinuation 
of study therapy.
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study.  Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the case 
report form.
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).  Patients will receive supportive care based on the 
judgment of the treating physician.  If it is unclear whether a therapy should be regarded as 
supportive care, the investigator should consult the Lilly CRP.  Use of any supportive care 
therapy should be reported in the CRF.
Guidelines regarding the use of other specific supportive care agents are presented below.
7.7.1.1.
Supportive Management for Diarrhea
Patients should receive instructions on the management of diarrhea and prescribed antidiarrheal 
therapy (protocol recommended loperamide) on Day 1.  The antidiarrheal agent, loperamide is 
not for prophylactic use, and should only be used in the event of diarrhea.  Loperamide will be 
supplied or reimbursed by the sponsor according to local laws.  In the event of diarrhea, provided 
loperamide antidiarrheal therapy should be initiated as early as possible and the site should 
follow the guidance below:

At the first sign of loose stools, the patient should initiate loperamide antidiarrheal 
therapy, if not already receiving such therapy, 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 loperamide therapy within 24 hours to either baseline or 
Grade 1, abemaciclib should be suspended until diarrhea is resolved to baseline or 
Grade 1.

When abemaciclib recommences, dosing should be adjusted as outlined in
Table JPCP.7.2 and Section 7.4.1.1.


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In cases of significant diarrhea, Grades 2 through 4 (Appendix 7), that have not responded to 
interventions as outlined above, if the investigators are considering the addition of steroids to 
treat potential colitis, the sponsor strongly recommends an endoscopic procedure to document 
colitis prior to initiating steroids.
In cases of severe diarrhea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered.
If diarrhea is severe (requiring intravenous [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 should not be administered to a patient to satisfy study inclusion criteria.
Growth factors may be administered in accordance with ASCO guidelines (Smith et al. 2015).  
Dosing of abemaciclib must be suspended if the administration of growth factors is required and 
must not be recommenced within 48 hours of the last dose of growth factors having been 
administered.  Following the administration of growth factors, the dose of abemaciclib must be 
reduced by 1 dose level on recommencement, if a dose reduction for the specific event 
necessitating the use of the growth factors has not already occurred.
7.8.
Treatment after the End of the Study
Not applicable.
7.8.1. Treatment after Study Completion
Study completion will occur when the last enrolled patient completes up to Cycle 4 Day 1.  
Investigators will continue to follow the Schedule of Activities (Section 2) for all patients until 
notified by Lilly that study completion has occurred.
7.8.1.1.
Continued Access
The continued-access period will apply to this study only if at least 1 patient is still on 
abemaciclib when study completion occurs.
Patients who are still on abemaciclib at the time of study completion may continue to receive 
abemaciclib in the continued-access period if they are experiencing clinical benefit and no undue 
risks.


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Figure JPCP.7.1.
Continued-access diagram.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment in the following circumstances:

the patient is treated in any other clinical study involving an investigational 
product or enrolled into any other type of medical research judged not to be 
scientifically or medically compatible with this study

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or treatment
as described in Section 7.6

the patient has evidence of disease progression

the patient experiences unacceptable toxicity

the patient has had 3 dose reductions and experiences an AE that would cause a 
fourth dose reduction

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 abemaciclib will occur prior to introduction of the new 
agent

the investigator decides that the patient should be discontinued from abemaciclib

the patient requests to be discontinued from abemaciclib.
Patients who are discontinued from abemaciclib will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CRP to allow the 
inadvertently enrolled patient to continue in the study with or without abemaciclib.  Patients who 
are discontinued from abemaciclib will have safety follow-up procedures performed as shown in 
the Schedule of Activities (Section 2).
8.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

the investigator decides that the patient should be discontinued from the study


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
the patient requests to be withdrawn from the study

the patient’s legal representative requests that the patient be discontinued from the 
study

the study has been completed as defined in Section 5.3.
Patients who are discontinued from the study will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2).
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.


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9. Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study.
Appendix 2 provides a list of the laboratory tests that will be performed for this study.
Appendix 4 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
Efficacy assessments are not applicable in this study. However, the investigator is required to 
confirm that the patient is still deriving benefit from study treatment and has no evidence of 
disease progression.
9.1.1. Electronic Patient Diary Assessment
Electronic patient diary (e-diary) assessment will collect number of bowel movements and 
diarrhea, thereby increasing the validity of measures reported by the patient and minimizing 
transcription errors in recording the measures. The use of e-diaries should also allow more 
frequent and timely interactions between investigator and patients. The system will be used to 
collect timing of abemaciclib doses taken relative to the time of their closest meal. Additionally, 
the e-diary system will incorporate reminders for patients to complete their diary.
Physicians and designated clinical staff will have access to the e-diary portal (secure web-based 
site) with the ongoing near real-time updating of patient reported diarrhea. Manual inspection of 
data will support patient safety monitoring, as well as the potential for reaching an optimum 
diarrhea management. Investigative staff can assess clinical data via the e-diary portal and 
recommend on dosing adjustments. 
An instruction manual will be provided to patients and investigative sites. Additional instruction 
and training will be provided to the investigative sites regarding data collection, review, retention 
and archival processes. In the event of e-diary malfunction or loss, the patient will be instructed 
to immediately contact the investigative site for instructions regarding replacement of the 
equipment.
9.2.
Adverse Events
The investigator will use Common Terminology Criteria for Adverse Events (CTCAE),
Version 4.0 (NCI 2009) to assign severity grades.


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Investigators are responsible for:

monitoring the safety of patients who have entered into this study and for alerting 
Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient

the appropriate medical care of patients during the study

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or 
otherwise medically important, considered related to study treatment or the study, 
or that caused the patient to discontinue abemaciclib before completing the study.  
The patient should be followed until the event resolves, stabilizes with appropriate 
diagnostic evaluation, or is reasonably explained.  Frequency of follow-up 
evaluation is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via electronic data entry the occurrence 
and nature of each patient’s preexisting conditions, including clinically significant signs and 
symptoms of the disease under treatment in the study.  In addition, study site personnel will 
record via electronic data entry 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 
abemaciclib and/or study procedure via electronic data entry.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies. A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications and/or treatment discontinuations that 
result from AEs to Lilly or its designee via electronic data entry, clarifying, if possible, the 
circumstances leading to the dose modification, delay and/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


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
important medical events that may not be immediately life-threatening or result in 
death or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above.
Although all AEs after signing the ICF are recorded by the site in the electronic data entry, SAE 
reporting to Lilly begins after the patient has signed the ICF and has received abemaciclib.  
However, if an SAE occurs after signing the ICF, but prior to receiving abemaciclib, it needs to 
be reported ONLY if it is considered reasonably possibly related to study procedure.
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly approved method.  If alerts are issued via telephone, they are 
to be immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
Pregnancy (during maternal or paternal exposure to abemaciclib) does not meet the definition of 
an AE, but should be reported.  However, to fulfill regulatory requirements any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to abemaciclib.
9.2.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  
United States 21 CFR 312.32 and Regulation (EU) No. 536/2014 and the associated detailed 
guidances or national regulatory requirements in participating countries require the reporting of 
SUSARs.  Lilly has procedures that will be followed for the recording and expedited reporting of 
SUSARs that are consistent with global regulations and associated detailed guidances.
9.2.3. Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, to monitor quality, and to facilitate 
process and product improvements.


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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
Refer to the IB, Section 7.3.9.
9.4.
Safety
9.4.1. Safety Measures
For each patient, electrocardiograms (ECGs), vital signs, laboratory tests, or other tests should be 
collected as shown in the Schedule of Activities (Section 2).
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of abemaciclib should be reported to Lilly or its designee as an AE via 
electronic data entry.  Refer to Section 9.2 for details on the recording of AEs.
9.4.2. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
Refer to Section 9.4.2.1 for details regarding hepatic safety data collection in the event of 
particular circumstances.
9.4.2.1.
Special Hepatic Safety Data Collection
If a study patient experiences elevated ALT5×ULN and elevated TBL2×ULN, or 
ALT8×ULN, liver tests (Appendix 5), including ALT, AST, TBL, direct bilirubin, 
gamma-glutamyl transferase (GGT), and creatine phosphokinase (CPK), should be repeated 
within 3 to 5 days to confirm the abnormality and to determine if it is increasing or decreasing.  
If the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by 
the investigator, based on the hepatic monitoring tests (Appendix 5) and in consultation with the 
Lilly CRP.  Monitoring of ALT, AST, and TBL should continue until levels normalize or return 
to approximate baseline levels.  Additional diagnostic testing should be considered to rule out 
cause of increased liver enzymes per the investigator’s discretion
Hepatic data (Appendix 5) should be collected in the event that 1 or more of the following 
conditions is met for the patient during the course of the study:

ALT≥5×ULN and TBL≥2×ULN

ALT≥8×ULN 

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
9.4.2.2.
Safety Monitoring: Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  


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Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Table JPCP.7.2).
A serum cystatin C will be collected with the central chemistry laboratory sample.
9.4.2.3.
Safety Monitoring: Venous Thromboembolic Events
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. In 
studies with single-agent abemaciclib use in the mBC population or other tumor types, no 
increased rates of VTEs were observed as compared to the incidence of VTEs for these particular 
patient populations who were treated with other anticancer agents. 
At this time, the mechanism underlying the association between abemaciclib and the occurrence 
of VTEs is not known.  Monitor patients for signs and symptoms of deep vein thrombosis and 
pulmonary embolism and treat as medically appropriate.
9.4.2.4.
Safety Monitoring: Interstitial Lung Disease/Pneumonitis
Interstitial lung disease (ILD)/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. The majority of events observed in clinical trials were Grade 1 or Grade 2 with 
serious cases and fatal events reported. Additional information is available in the IB.
Ask your patients to report any new or worsening pulmonary symptoms such as dyspnea, cough, 
and fever, and investigate and treat as per your local clinical practice (including corticosteroids
as appropriate). If ILD/pneumonitis is suspected, investigations may include imaging, such as 
high resolution computed tomography, broncheoalveolar lavage, and biopsy as clinically 
indicated.
Refer to Table JPCP.7.2 for guidance on dose adjustments of abemaciclib for patients with
ILD/pneumonitis (see Appendix 7 for CTCAE grades). Discontinue abemaciclib in cases of 
severe ILD/pneumonitis.
9.4.2.5.
Diarrhea Safety Data Collection
Diarrhea events will be collected in an e-diary. If the patient experiences diarrhea, the patient 
should record this in the e-diary, including the potential use of loperamide. The patient should 
contact the site as necessary. Reports of diarrhea will be graded according to CTCAE


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version 4.0 by the investigator based upon data collected in e-diary and in consultation with the 
patient. All episodes of diarrhea must be reported as (S)AEs via electronic data entry.
9.5.
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected as shown in Section 2 and Appendix 4.  Blood 
samples will be used to determine the concentrations of abemaciclib and metabolites 
LSN2839567 and LSN3106726.
A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon by the investigator and Lilly.
Bioanalytical samples collected to measure abemaciclib concentration and metabolism and/or 
protein binding will be retained for a maximum of 2 years following the last patient visit for the 
study.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
Not applicable.
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
Health economics and medical resource utilization parameters will not be evaluated in this study.


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10.
Statistical Considerations
10.1. Sample Size Determination
The primary objective of this study is to evaluate the impact of 3 different meal settings on the 
incidence of severe diarrhea (≥Grade 3) or prolonged Grade 2 diarrhea (>7 days duration) as well 
as dose reductions, dose interruptions, and treatment discontinuations due to diarrhea, and 
utilization of antidiarrheals for patients receiving abemaciclib monotherapy.  This study will 
enroll up to approximately 100 patients to obtain approximately 20 patients who complete the 
primary outcome phase per meal administration condition.  Randomization will be 1:1:1 to the 3 
administration conditions and randomization will be stratified by region.  The sample size is 
based on regulatory guidance, not statistical powering.
10.2. Populations for Analyses
The following analysis sets will be defined for this study:
Intention-to-treat (ITT) analysis set: will include all randomized patients.  The ITT analysis 
of efficacy data will consider allocation of patients to treatment groups as randomized and not by 
actual treatment received.  This analysis set will be used for all baseline analyses and patient 
dispositions.
Per-protocol analysis set: will include all randomized patients who receive at least 1 dose of 
abemaciclib and do not have any major protocol violations that could potentially affect the 
conclusions of the study, such as significant noncompliance with meal administration conditions 
or abemaciclib administration.  This analysis set will be used for sensitivity analyses related to 
the primary objective.
Safety analysis set:  will include all randomized patients who received any quantity of study 
treatment, regardless of their eligibility for the study. The safety evaluation will be performed 
based on the cohort assignment. The safety analysis set will be used for analyses related to the 
primary objective and for all dosing/exposure and safety analyses.
Pharmacokinetic analysis set:  will include all enrolled patients who received at least 1 dose of 
abemaciclib and have at least 1 postbaseline evaluable PK sample and evaluable dosing 
information.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
No hypothesis tests are planned for this study.  The analysis of this study will be descriptive 
only, except for possible exploratory analyses as deemed appropriate.  Parameter estimates, 
including CIs, if relevant, and summary statistics will be reported.  Unless otherwise stated, all 
CIs will be given at a 2-sided 95% level.  For continuous variables, summary statistics will 
include number of patients, mean, median, standard deviation, minimum, and maximum.  
Categorical endpoints will be summarized using number of patients, frequency, and percentages.  
Missing data will not be imputed.


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Analyses related to the primary objective, safety analyses, and other analyses will be 
summarized by treatment arm for the primary outcome phase (first 3 cycles).  In addition, 
analyses may be repeated by combining all patients in the safety population and summarizing 
data for the primary outcome phase and extension phase combined.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report (CSR).  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
10.3.1. Analyses Related to the Primary Objective
The primary analysis will evaluate each meal administration condition group for measures 
related to diarrhea in the first 3 cycles using the safety analysis set.  Secondary analyses will be 
repeated using the per-protocol population.

Incidence of severe diarrhea (≥Grade 3)

Incidence of prolonged Grade 2 diarrhea (defined as >7 days duration)

Dose reductions due to diarrhea

Dose interruptions due to diarrhea

Treatment discontinuations due to diarrhea

Utilization of antidiarrheals.
10.3.2. Safety Analyses
All patients who receive at least 1 dose of abemaciclib will be evaluated for safety and toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA®) Version 21.0 (or higher) will be 
used when reporting AEs by MedDRA terms.  The MedDRA Lower Level Term (LLT) will be 
used in the treatment-emergent computation.  Treatment-emergent AEs will be summarized by 
System Organ Class (SOC) and by decreasing frequency of Preferred Term (PT) within SOC.
Safety analyses will include summaries of the following:

adverse events, including severity and possible relationship to abemaciclib

serious adverse events, including possible relationship to abemaciclib

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.


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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 (overall and by reason for discontinuation).  A summary of all important protocol 
deviations will be provided.
10.3.3.2. Patient Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population considered for regulatory approval.
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics.
10.3.3.3. Treatment Compliance
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
for the first 3 cycles will be summarized for all treated patients by treatment arm.
Study treatment compliance will be assessed as the proportion of treatment that is actually taken, 
relative to what is expected, after accounting for protocol-defined dose adjustments.  Study 
treatment taken will be derived from the difference between the total number of tablets/capsules 
dispensed and returned over the course of the first 3 cycles.
Compliance to the administration condition will be assessed as the proportion of doses during the 
first 3 cycles of treatment that are taken during the meal window allowed by the assigned 
administration condition.  For each dose of abemaciclib taken during the first 3 cycles, the 
patient will record the administration condition in a diary.
10.3.3.4. Concomitant Therapy
A summary of prior and concomitant medications will be reported.
10.3.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic analyses will be conducted on all patients who have received at least 1 dose of 
abemaciclib and have evaluable PK samples and sufficient dosing information.
Mean population PK parameters for abemaciclib (and metabolites, if warranted) in plasma (for 
example, clearance, exposure, volume of distribution) and inter-individual PK variability will be 
computed using nonlinear mixed-effect modeling (NONMEM).  Steady-state exposures for each 
individual will be calculated based on the available dosing and concentration information using 
the previously developed population PK model.
The observed concentrations of abemaciclib may be summarized by time and dose.


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Furthermore, pharmacodynamic data (such as, time to first diarrhea event or severity of first 
diarrhea event) collected in this study may also be analyzed by means of NONMEM and 
connected to the population PK model in a pharmacokinetic/pharmacodynamics (PK/PD) model.


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11.
References
Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers H, Hudis CA, 
O’Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, 
a Phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients 
with HR+/HER2−breast cancer, after chemotherapy for metastatic disease. Clin Cancer Res. 
2017;23:5218-5224.
Di Nisio Marcello, van Es Nick, Büller HR. Deep vein thrombosis and pulmonary embolism. 
Lancet. 2016;388(10063):3060-3073.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, 
Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, 
Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, 
Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, 
Wittliff JL, Wolff AC. American Society of Clinical Oncology/College of American 
Pathologists guideline recommendations for immunohistochemical testing of estrogen and 
progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784-2795.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. 2009.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655.
Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, 
Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, 
Nguyen TS, Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, 
Flaherty KT, Wen PY, Shapiro GI. Efficacy and safety of abemaciclib, an inhibitor of CDK4 
and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. 
Cancer Discov. 2016;6(7):740-753.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Carwford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. 
Recommendations for the use of WBC growth factors: American Society of Clinical Oncology
clinical practice guideline update. J Clin Oncol. 2015;33(28):3199-3122.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, 
Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, 
Press MF, Spears PA, Vance GH, Viale G, Hayes DF. Recommendations for human epidermal 
growth factor receptor 2 testing in breast cancer: American Society of Clinical 
Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 
2013;31(31):3997-4013.


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12.
Appendices


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Appendix 1. Abbreviations and Definitions
Term
Definition
AE
Adverse event:  any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-versus-time curve
CAP
College of American Pathologists
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum concentration
CNS
central nervous system
CPK
creatine phosphokinase
CR
complete response
CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer.
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DVT
deep venous thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group


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end of study
Date of the last visit or last scheduled procedure shown in the Schedule of Activities 
(Section 2) for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ER
estrogen receptor
ERB
ethical review board
EU
European Union
GCP
good clinical practice
G-CSF
granulocyte-colony-stimulating factor
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation (formerly the International Conference on 
Harmonisation)
IHC
immunohistochemistry
ILD
interstitial lung disease
interim analysis
An analysis of clinical study data conducted before the final reporting database is 
created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
institutional review board


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ITT
intention-to-treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IUD
intrauterine device
IV
intravenous
IWRS
interactive Web-response system
LLT
MedDRA Lower-Level Term
Lilly
Eli Lilly and Company
MATE
multidrug and toxin extrusion protein
MedDRA
Medical Dictionary for Regulatory Activities
NONMEM
nonlinear mixed-effect modeling
PE
pulmonary embolism
PFS
progression-free survival
PK
pharmacokinetic(s)
PK/PD
Pharmacokinetic/
PS
performance status
PT
MedDRA Preferred Term
randomize
The process of assigning patients to an experimental group on a random basis.
Rb
retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study.
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
screen failure
A patient who does not meet 1 or more criteria required for participation in a study.


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SOC
MedDRA System Organ Class
study completion
Occurs when the last enrolled patient completes up to Cycle 4 Day 1, as determined by 
Lilly.
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent at baseline, or worsens relative to 
the baseline state, and does not necessarily have to have a causal relationship with this 
treatment.
ULN
upper limit of normal
VTE
venous thromboembolic event


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Appendix 2. Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology – laboratorya
Local
Central
Leukocytes (WBC)
X
Neutrophilsb
X
Lymphocytes
X
Monocytes
X
Eosinophils
X
Basophils
X
Erythrocytes (RBC)
X
Hemoglobin (HGB)
X
Hematocrit (HCT)
X
Mean corpuscular volume (MCV)
X
Mean corpuscular hemoglobin concentration (MCHC)
X
Platelets (PLT)
X
Clinical Chemistry – laboratory
Local
Central
Serum Concentrations of:
Alanine aminotransferase (ALT)
X
Albumin
X
Alkaline phosphatase
X
Aspartate aminotransferase (AST)
X
Bilirubin, direct
X
Bilirubin, total
X
Blood urea nitrogen (BUN) or blood urea
X
Calcium
X
Cholesterol
X
Creatinine
X
Cystatin C
X
Glucose, nonfasting
X
Magnesium
X
Potassium
X
Sodium
X
Pregnancy Test (for female patients of child-bearing potential) -
laboratory
Local
Central
Serum pregnancy test
X
Abbreviations:  CRF = case report form; RBC = red blood cells; WBC = white blood cells.
a
Treatment decisions can be based on local laboratory results.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. When a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.


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Appendix 3. Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient/patient’s legal representative understands the nature of 
the study, the potential risks and benefits of participating in the study, and that the 
patient’s participation is voluntary

ensuring that informed consent is given by each patient/patient’s legal 
representative.  This includes obtaining the appropriate signatures and dates on 
the ICF prior to the performance of any study procedures and prior to the 
administration of abemaciclib.

providing a copy of the signed ICF(s) to the patient/patient’s legal representative
and retaining a copy of the signed ICF in the site file

answering any questions the patient/patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that 
may be relevant to the patient’s/patient’s legal representative’s willingness to 
continue the patient’s participation in the study.
Ethical Review
Documentation of ethical review boards (ERBs)/institutional review boards (IRBs) 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 Council for Harmonisation (ICH) guideline on GCP.
Regulatory Considerations
This study will be conducted in accordance with the protocol and 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 study.


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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.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
Lilly’s responsible medical officer and statistician will approve the final CSR 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 verify data reported to detect potential errors.
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
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system will be used in this study for the collection of CRF data.  The 
investigator maintains a separate source for the data entered by the investigator or designee into 


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sponsor-provided electronic data capture system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the sponsor-provided data capture system(s) will be stored at  a third party. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the 
ERB/IRB of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4. Sampling Schedule
Pharmacokinetic samples should be taken at the same time as the hematology and clinical 
chemistry samples.  In the appropriate forms, record date and time of the sample, and the date 
and time of the dose that was taken prior to the PK sample.
Sampling Schedule for Pharmacokinetics
Cycle 1
Cycle 2
Cycle 3
Procedure
Day 1
Day 15
Day 1
Day 15
Day 1
Pharmacokinetics
Prior to the first 
dose
In conjunction with 
other laboratory 
samples
In conjunction with 
other laboratory 
samples
In conjunction with 
other laboratory 
samples
Note: PK Sampling may be done at same time as hematology and clinical chemistry labs (+/- 1 day on Cycle 1
Day 15 and Cycle 2 Day 15 per Section 2 Schedule of Activities)


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


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Appendix 6. Protocol JPCP Inducers and Inhibitors of 
CYP3A 
The information in this table is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lenisurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
a    Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if clinically 
indicated


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Appendix 7. Protocol JPCP 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
1
2
3
4
5
Adverse Event
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 activities of 
daily living (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 8. Protocol JPCP: 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 9. Protocol I3Y-MC-JPCP Amendment (d) 
An Open-Label, Randomized Phase 2 Study of the 
Impact of Food on Tolerability when Receiving 
Abemaciclib for Patients with Previously Treated 
Hormone Receptor-Positive, HER2-Negative, 
Metastatic Breast Cancer Summary
Overview
Study I3Y-MC-JPCP(d), an open-label, randomized Phase 2 study of the impact of food on 
tolerability when receiving abemaciclib for patients with previously treated hormone 
receptor-positive, HER2-negative, metastatic breast cancer, has been amended.  The new 
protocol is indicated by amendment (d) and will be used to conduct the study in place of any 
preceding version.

Table JPCP.7.2 was updated to include dose modification and delay guidance for 
interstitial lung disease (ILD)/pneumonitis events that aligns with the updated 
Investigator’s Brochure.

Section 7.7. was updated to align with the updated Investigator’s Brochure

To cluster all special safety monitoring guidance under Section 9.4.2. Safety Monitoring:
o
Section 9.4.3. was changed to Section 9.4.2.2.
o
Section 9.4.4. was changed to Section 9.4.2.3.
o
Section 9.4.5. was changed to Section 9.4.2.4.
o
Section 9.4.6. was changed to Section 9.4.2.5.

Section 9.4.2.4 was updated to align with the updated Investigator’s Brochure.

Appendix 1 was updated to include interstitial lung disease (ILD).

Appendix 6was updated to align with changes made in Section 7.7 and to include 
moderate inducers and additional stronginhibitors of CYP3A.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Table JPCP.7.2. Dose Adjustments for Treatment-Emergent, Related*, and 
Clinically Significant Adverse Events of Abemaciclib 
Non-Hematologic 
Toxicityb (except diarrhea,
and ALT increased, and 
ILD/pneumonitis)
Persistent or recurrent 
Grade 2 that does not 
resolve with maximal 
supportive measures 
within 7 days to baseline 
or Grade 1.
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Non-Hematologic 
Toxicityb (except diarrhea,
and ALT increased, and 
ILD/pneumonitis)
Grade 3 and 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
ILD/Pneumonitisb
Grade 2 that persists or 
recurs despite maximal 
supportive measures and 
does not return to baseline 
or Grade 1 within 7 days
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade ≤1
Dose MUST be reduced 
by 1 dose level.
ILD/Pneumonitisb
Grade 3 or 4
Abemaciclib therapy 
MUST be discontinued
Abemaciclib therapy 
MUST be discontinued
Abbreviation:  ALT = alanine aminotransferase; ASCO = American Society of Clinical Oncology; ILD = interstitial 
lung disease.
b
Additional guidance for renal hepatic monitoring, renal hepatic monitoring, and ILD/pneumonitis is provided in 
Sections 9.4.2.1, 9.4.2.2, and 9.4.2.4.
Section 7.7. Concomitant Therapy
All patients may receive supportive therapy with dexamethasone, preferably ≤7 days, if clinically 
indicated.  Patients requiring more than 7 days of dexamethasone therapy will not incur a 
protocol deviation
Abemaciclib can be coadministered with drugs which are substrates of CYP enzymes.
The results from in vitro studies in cultured human hepatocytes indicate that abemaciclib and its
major metabolites, LSN2839567 and LSN3106726, downregulate mRNA of CYPs, including
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A, at clinically relevant
concentrations. The mechanism of mRNA downregulation and its clinical relevance are not yet
understood. Therefore, care should be taken when coadministering substrate drugs of the above


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CYPs with narrow therapeutic margin (Appendix 6). The information in Appendix 6 is provided
for guidance to investigators and does not preclude the use of these medications if clinically
indicated.
9.4.3 9.4.2.2 Safety Monitoring: Renal Function
9.4.4 9.4.2.3 Safety Monitoring: Venous Thromboembolic Events
9.4.5 9.4.2.4 Safety Monitoring: Interstitial Lung Disease/Pneumonitis
Interstitial lung disease (ILD)/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib.  The majority of events observed in clinical trials were Grade 1 or Grade 2 with 
serious cases and fatal events reported. Additional information is available in the IB.
Ask your patients to report any new or worsening pulmonary symptoms such as dyspnea, cough, 
and fever, and investigate and treat as per your local clinical practice (including corticosteroids
as appropriate). If ILD/pneumonitis is suspected, investigations may include imaging, such as 
high resolution computed tomography, broncheoalveolar lavage, and biopsy as clinically 
indicated.
Interstitial lung disease (ILD)/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. The majority of events observed in the abemaciclib clinical trial program were 
Grade 1 or Grade 2 with serious cases and fatal events reported. Additional information is 
available in the IB.
Ask your patients to report any new or worsening respiratory symptoms such as cough, dyspnea, 
fever, and investigate and treat as per your local clinical practice (including corticosteroids as 
appropriate). If ILD/pneumonitis is suspected, investigations may include imaging such as high 
resolution computed tomography (HRCT), broncheoalveolar lavage, and biopsy as clinically 
indicated.
For patients who develop radiological changes suggestive of ILD/pneumonitis and have few or 
no symptoms (Grade 1), no dose modifications are required.  For ≥Grade 3 or persistent or 
recurrent Grade 2 ILD/pneumonitis events, abemaciclib should be suspended until toxicity 
resolves to baseline or Grade 1, and resumed at the next lower dose.
Refer to Table JPCP.7.2 for guidance on dose adjustments of abemaciclib for patients with 
ILD/pneumonitis (see Appendix 7 for CTCAE grades). Discontinue abemaciclib in cases of 
severe ILD/pneumonitis.
9.4.6 9.4.2.5 Diarrhea Safety Data Collection


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Appendix 1. Abbreviations and Definitions:
ILD
interstitial lung disease
Appendix 6. Protocol JPCP Inducers and Inhibitors of CYP3A or Substrates of CYPs with 
Narrow Therapeutic Range
The information in this table is provided for guidance to investigators and does not preclude the use 
of these medications if clinically indicated.
Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 
≤7 days, if clinically indicated.
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine


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


Leo Document ID = 14aeb397-eefd-42aa-a681-bdfa09095501
Approver: 
Approval Date & Time: 07-Feb-2020 18:09:12 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 10-Feb-2020 19:37:59 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan for I3Y-MC-JPCP 
 
An Open-Label, Randomized Phase 2 Study of the Impact of Food on Tolerability when 
Receiving Abemaciclib for Patients with Previously Treated Hormone Receptor-Positive, 
HER2-Negative, Metastatic Breast Cancer 
 
NCT03703466 
 
Approval Date: 08-Nov-2018 


I3Y-MC-JPCP Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan for I3Y-MC-JPCP:  An 
Open-Label, Randomized Phase 2 Study of the Impact of 
Food on Tolerability when Receiving Abemaciclib for 
Patients with Previously Treated Hormone 
Receptor-Positive, HER2-Negative, Metastatic Breast 
Cancer
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries..
Abemaciclib (LY2835219)
Open-Label, Randomized Phase 2 Study of the Impact of Food on Tolerability when 
Receiving Abemaciclib for Patients with Previously Treated Hormone Receptor-Positive, 
HER2-Negative, Metastatic Breast Cancer
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I3Y-MC-JPCP
[Phase 2]
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 08-Nov-2018 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for I3Y-MC-JPCP:  An Open-Label, 
Randomized Phase 2 Study of the Impact of Food on Tolerability 
when Receiving Abemaciclib for Patients with Previously Treated 
Hormone Receptor-Positive, HER2-Negative, Metastatic Breast 
Cancer ................................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................4
4.
Study Objectives.................................................................................................................5
4.1.
Primary Objective ..........................................................................................................5
4.2.
Secondary Objectives.....................................................................................................5
5.
A Priori Statistical Methods ................................................................................................6
5.1.
Sample Size Determination ............................................................................................6
5.2.
General Considerations ..................................................................................................6
5.2.1.
Populations ............................................................................................................6
5.2.2.
Definitions and Conventions ..................................................................................7
5.2.3.
Handling of Dropouts and Missing Data.................................................................7
5.3.
Patient Disposition .........................................................................................................8
5.4.
Demographics and Baseline Characteristics....................................................................8
5.4.1.
Demographics........................................................................................................8
5.4.2.
Disease Characteristics...........................................................................................9
5.4.3.
Historical Illnesses and Prior Therapies..................................................................9
5.4.4.
Concomitant Therapy.............................................................................................9
5.5.
Treatment Compliance ...................................................................................................9
5.6.
Post-discontinuation Therapy .......................................................................................10
5.7.
Efficacy Analysis .........................................................................................................10
5.8.
Analysis Related to Primary Objective .........................................................................10
5.9.
Safety Analysis ............................................................................................................11
5.9.1.
Extent of Exposure...............................................................................................11
5.9.2.
Adverse Events ....................................................................................................11
5.9.3.
Deaths..................................................................................................................12
5.9.4.
Clinical Laboratory Evaluation.............................................................................12
5.9.5.
Vital Signs, Physical Examinations, and other Observations 
Related to the Study.............................................................................................13
5.10. Other Analyses.............................................................................................................13
5.10.1.
Pharmacokinetic/Pharmacodynamic Analyses......................................................13


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5.10.2.
Additional Reports to Support Clinical Trial Registry (CTR) 
Reporting Results.................................................................................................13
6.
References ........................................................................................................................14


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3.
Revision History
SAP Version 1 was approved prior to the first visit when a subject receives study drug or any 
other protocol intervention.


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of the study is evaluate and summarize incidence of severe diarrhea 
(≥Grade 3) or prolonged Grade 2 diarrhea (defined as >7 days duration), including the incidence 
of dose reductions, dose interruptions, and/or treatment discontinuations due to severe diarrhea 
or prolonged Grade 2 diarrhea over the first 3 cycles when abemaciclib is administered:

with a meal

without a meal, taken in the modified fasted condition

without regard to food
The endpoints for the primary objective include:

Incidence of severe diarrhea (≥Grade 3)

Incidence of prolonged Grade 2 diarrhea (defined as >7 days duration)

Dose reductions due to diarrhea

Dose interruptions due to diarrhea

Treatment discontinuations due to diarrhea

Utilization of antidiarrheals
4.2.
Secondary Objectives
The secondary objectives of the study are:

To assess safety and toxicity profile of abemaciclib (i.e. to evaluate overall safety
incidence and severity of TEAEs, SAEs, deaths, and clinical laboratory 
abnormalities)

To evaluate the PK parameters of abemaciclib and its metabolites (i.e. to evaluate 
Steady-state concentrations of abemaciclib and its metabolites LSN2839567 and 
LSN3106726)


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5.
A Priori Statistical Methods
5.1.
Sample Size Determination
The primary objective of this study is to evaluate the impact of 3 different meal settings on the 
incidence of severe diarrhea (≥Grade 3) or prolonged Grade 2 diarrhea (>7 days duration) as well 
as dose reductions, dose interruptions, and treatment discontinuations due to diarrhea, and 
utilization of antidiarrheals for patients receiving abemaciclib monotherapy.  This study will 
enroll up to approximately 100 patients to obtain approximately 20 patients who complete the 
primary outcome phase per meal administration condition.  Randomization will be 1:1:1 to the 3 
administration conditions and randomization will be stratified by region.  The region is defined 
as: AMERIT (Russia, Ukraine, Turkey) vs Non-AMERIT (Belgium, Spain, Australia). The 
sample size is based on regulatory guidance, not statistical powering.
5.2.
General Considerations
5.2.1.
Populations
The following analysis sets will be defined for this study:
Intention-to-treat (ITT) analysis set: will include all randomized patients.  The ITT analysis 
of efficacy data will consider allocation of patients to treatment groups as randomized and not by 
actual treatment received.  This analysis set will be used for all baseline analyses and patient 
dispositions.
Per-protocol (PP) analysis set: will include all randomized patients who receive at least 1 dose
of abemaciclib and do not have any major protocol violations that could potentially affect the 
conclusions of the study, such as significant noncompliance with meal administration conditions 
or abemaciclib treatment administration. This analysis set will be used for sensitivity analyses 
related to the primary objective.
For study Arm 1 (take abemaciclib with meal) and Arm 2 (take abemaciclib without meal), the 
PP analysis set will include all randomized patients who receive at least 1 dose of abemaciclib 
and who are at least 75% compliant with meal administration conditions and abemaciclib 
treatment administration.
For study Arm 3 (take abemaciclib without regard to food), the PP analysis set will include all 
randomized patients who receive at least 1 dose of abemaciclib and who are at least 75% 
compliant with abemaciclib administration.
Safety analysis set:  will include all randomized patients who received any quantity of study 
treatment, regardless of their eligibility for the study. The safety evaluation will be performed 
based on the cohort assignment. The safety analysis set will be used for analyses related to the 
primary objective and for all dosing/exposure and safety analyses.
Pharmacokinetic analysis set:  will include all enrolled patients who received at least 1 dose of 
abemaciclib and have at least 1 postbaseline evaluable PK sample and evaluable dosing 
information.


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5.2.2. Definitions and Conventions
Study drug or study treatment refers to abemaciclib.
The date of first dose is the date of the first dose of study drug.
The baseline value of a safety/efficacy assessment is the last value observed prior to the first 
dose of study drug.
The study day of a safety/efficacy event or assessment will be calculated as:

The difference between the date of the event or assessment and the date of first dose 
plus 1 for all events or assessments occurring on or after the day of first dose. For 
example, if an event occurs on 08JUN2014 and the date of first dose was 
06JUN2014, the study day of the event is 3.

The difference between the date of the event or assessment and the date of first dose 
for all events or assessments occurring before the day of first dose. For example, if 
an event occurs on 05JUN2014 and the date of first dose was 06JUN2014, the study 
day of the event is -1.
One month is defined as 365/12 days.
Unless otherwise noted, summaries of continuous variables will include a mean, median, 
standard deviation, minimum, and maximum.
Unless otherwise noted, summaries of categorical variables will include the frequency and 
percentage (relative to the population being analyzed) of each category.
5.2.3. Handling of Dropouts and Missing Data
General rules for imputing dates related to AE or concomitant therapy:

Onset date of an AE or start date of a concomitant therapy:
o
If only the day is missing, the date will be set to:

First day of the month that the event occurred, if the onset yyyy-mm is after 
the yyyy-mm of first study treatment.

The day of the first study treatment, if the onset yyyy-mm is the same as
yyyy-mm of the first study treatment.
o
If both the day and month are missing, the complete date will be set to:

January 1 of the year of onset, if the onset year is after the year of the first
study treatment.

The date of the first dose, if the onset year is the same as the year of the first 
study treatment.

Resolution date of an AE or end date of a concomitant therapy:


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o
If only the day is missing, the date will be set to the last day of the month of the
occurrence, or to the date of death if the patient died in the same month.
o
If both the day and month are missing, the date will be set to 31 December of the
year of occurrence.
If a date is completely missing, then the AE will be considered treatment-emergent. In case of
additional therapies, the therapy will be considered concomitant.
General rule for imputing other dates: If a date variable is needed for an analysis, use the
following general rule to impute incomplete date:

If the date has no missing year and month but the day is missing, then assign 
Day 1 to the day

If the date has no missing year, but has missing month, then assign January to 
the month.
However, after imputation, check if the imputed date is logically consistent with other relevant
date variable(s) and make appropriate correction if necessary. For example, if a visit start date
was 10 May 2015 and a tumor assessment date was xx May 2015 (missing day) but it was known 
that it occurred after that visit, then after imputation, the tumor assessment date became 01 May 
2015. In this case, the imputed tumor assessment date should be compared to the visit start date 
and then corrected to be the visit start date, 10 May 2015.
Safety analysis: The following rule for missing data processing will apply for safety analysis:

Missing classifications concerning study medication relationship will be 
considered as related to study medication (both components).

If the AE onset date is missing or partial, the date will be compared as far as 
possible with the date of first dose of study medication when determining 
whether or not the AE is present at baseline. In this case, the AE will be 
assumed to be treatment emergent, unless there is clear evidence (through 
comparison of partial dates) to suggest that the AE started prior to the first
dose of study medication.
5.3.
Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients randomized, treated, as well as number and percentage of 
patients completing the study or discontinuing the study (by study arms/overall and by reason for 
discontinuation).  A summary of all important protocol deviations will be provided.
5.4.
Demographics and Baseline Characteristics
5.4.1. Demographics
Demographic characteristics will be summarized by study arms using descriptive statistics for 
randomized as well as for treated patients by race, ethnicity, age, age groups (<65 years, ≥65 


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years), height, weight, body mass index (BMI), country and region (AMERIT vs Non-
AMERIT). 
5.4.2. Disease Characteristics 
Disease characteristics will be summarized by study arms using descriptive statistics for 
randomized as well as for treated patients. Disease characteristics will include the following: 
disease diagnosis, basis for diagnosis, and disease stage. In addition, the disease charateristics 
will include duration of disease (initial diagnosis to date of first dose), baseline Eastern 
Cooperative Oncology Group Performance Status (ECOG PS), HER2 status, Progesterone 
Receptor (PR) status and Estrogen Receptor (ER) status. 
5.4.3.  Historical Illnesses and Prior Therapies 
Historical illnesses are events in the past that ended before the date informed consent is signed.  
Historical illnesses (coded according to the Medical Dictionary for Regulatory Activities 
[MedDRA]) will be listed for all treated patients. 
Prior therapies, including systemic therapy, radiotherapy and surgeries will be listed for all 
randomized patients.  Prior radiotherapy and systemic therapy will be summarized by the number 
of patients with at least one of each type of treatment, as well as by reason for regimen (e.g., 
palliative, curative, etc.).  Additionally, the number of regimens of prior systemic therapy and 
(where available) the reason for prior regimens will be summarized. 
5.4.4. Concomitant Therapy 
Concomitant medications will be summarized by study arms and listed for the safety population. 
5.5. Treatment Compliance 
Treatment compliance information for study drug will be collected through capsule counts at 
each visit.  The estimate of percent abemaciclib treatment compliance will be given by: 
Percent Treatment Compliance = 
ୟୡ୲୳ୟ୪ ୡ୳୫୳୪ୟ୲୧୴ୣ ୢ୭ୱୣ ୲ୟ୩ୣ୬
ୣ୶୮ୣୡ୲ୣୢ ୡ୳୫୳୪ୟ୲୧୴ୣ ୢ୭ୱୣ ୲୭ ୠୣ ୲ୟ୩ୣ୬ x 100 
 
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed over 
the course of the first 3 cycles.  The expected cumulative dose to be taken will be determined 
based on the assigned dose and taking into account any dose reductions or omissions. 
Compliance to the administration condition for Arm 1 and Arm 2 will be assessed as the 
proportion of doses during the first 3 cycles of treatment that are taken during the meal window 
allowed by the assigned administration condition. 
The allowed meal window for Arm 1 (taken with a meal) would be taking abemaciclib during a 
meal or within 30 minutes of end of meal. 


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The allowed meal window for Arm 2 (taken without a meal) would be taking abemaciclib greater 
than 60 minutes before start of meal or taking abemaciclib greater than 120 minutes after end of 
meal.
There is no window for Arm 3 as the abemaciclib is taken without regard to food.
For each dose of abemaciclib taken during the first 3 cycles, the patient will record the 
administration condition in a diary. The compliance to the administration condition will be based 
on the available data obtained from diary.
Compliance with Morning Dose Diary, Evening Dose Diary and Bowel Movements Diary will 
be calculated as the proportion of the actual number of diaries and expected number of diaries.
In addition, timing of dose administration condition with respect to food intake timing may be 
summarized by study arms for morning and evening dose separately based on ediary. 
5.6.
Post-discontinuation Therapy
The numbers and percentages of patients reporting post-discontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.
5.7.
Efficacy Analysis
Efficacy assessments are not applicable in this study.  However, the investigator is required to 
confirm that the patient is still deriving benefit from study treatment and has no evidence of 
disease progression.
5.8.
Analysis Related to Primary Objective
The primary objective of the study includes the evaluation of the following endpoints over the 
first 3 cycles (primary outcome phase):

Incidence of severe diarrhea (≥Grade 3)

Incidence of prolonged Grade 2 diarrhea (defined as >7 days duration)

Dose reductions due to diarrhea

Dose interruptions due to diarrhea

Treatment discontinuations due to diarrhea

Utilization of antidiarrheals
Analyses for each of these endpoints related to the primary objective will be summarized by 
treatment arm using safety analysis set population.  For descriptive purpose, the odds ratios with 
95% confidence intervals along with exact p-value using Fisher’s Exact test will be produced for 
comparing arms with each other. In addition, incidence of severe diarrhea (≥Grade 3) and 
incidence of prolonged Grade 2 diarrhea (defined as >7 days duration) will be combined into one 
endpoint.  Dose reductions due to diarrhea, Dose interruptions due to diarrhea and Treatment 
discontinuations due to diarrhea will be combined into another combined endpoint. These two 


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combined endpoints will be summarized and analyzed using the same approach mentioned 
above.
The analysess for each of the endpoints related to the primary objective will be repeated using 
per-protocol analysis set population as a sensitivity analysis.
5.9.
Safety Analysis
5.9.1. Extent of Exposure
All patients who receive at least 1 dose of abemaciclib (i.e. the safety analysis set population) 
will be evaluated for safety and toxicity and exposure.
For abemaciclib, extent of exposure will be measured by pill counts and summarized by 
cumulatively.  The summary will include the total dosages taken and dose intensities.  Dose 
intensity will be calculated as the ratio of total dose taken to the assigned cumulative dose.  The 
assigned cumulative dose for each patient during each cycle is 150 mg per dose × 2 doses per 
day × 21 days = 6300 mg.  The assigned cumulative dose while in this study is 150 mg per dose 
× 2 doses per day × number of days on treatment.
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated patients by treatment arm based on data from the first 3 cycles 
as well as based on data from entire treatment period (i.e. first 3 cycles plus extension phase)
separately.
5.9.2. Adverse Events
All patients who receive at least 1 dose of abemaciclib (i.e. the safety analysis set population) 
will be evaluated for safety and toxicity.
Primary analysis of adverse events will be performed based on data from the first 3 cycles.  The 
secondary analyses of the adverse events will be done based on data from entire study period.
The Medical Dictionary for Regulatory Activities (MedDRA) Version 21.0 (or higher) will be 
used to map reported AEs to MedDRA terms. The MedDRA Lower Level Term (LLT) will be 
used in the treatment emergent computation. Treatment-emergent adverse events (TEAEs) will 
be summarized by System Organ Class (SOC) and by decreasing frequency of Preferred Term 
(PT) within the SOC. Preferred terms identified by Medical as clinically identical or 
synonymous will be grouped together under a single consolidated PT.  For example, 
‘Neutropenia’ and ‘Neutrophil count decreased’ will be reported as ‘Neutropenia’. All listings 
and summaries will use the PT resulting from this process. The National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 will serve as the reference 
document for grading the severity of all AEs and other symptoms.  Preexisting conditions are 
defined as AEs that begin prior to the first dose of study drug.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline. 


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A serious adverse event (SAE) is any AE during this study that results in one of the following 
outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition above.
Safety analyses will include summaries of the following by treatment arm:

treatment-emergent adverse events, including severity and possible relationship to 
abemaciclib

serious adverse events, including possible relationship to abemaciclib

treatment-emergent adverse events leading to dose adjustments

discontinuations from study treatment due to AEs or death

Maximum Post Baseline Treatment Emergent CTCAE Lab Toxicities

treatment-emergent abnormal changes in vital signs.
5.9.3. Deaths
All deaths in this study that are not attributed to study disease by the investigator will be listed 
along with the reason for death, if known.  For those deaths attributed to an AE, the listing will 
include the PT of the AE. A summary of deaths including reasons for death will be produced.
In addition, a listing of all deaths including those due to study disease along with reason for 
death (if known) will be produced. 
5.9.4. Clinical Laboratory Evaluation
A patient listing of all abnormal laboratory data will be provided with a flag for values outside of 
the laboratory normal range as well as investigator site, patient identifier, age, gender, race, 
weight, and visit.  Abnormal results will be listed separately for the safety population. In 
addition, the treatment emergent laboratory events will be summarized in table. 
In addition to the investigator-reported AEs, all relevant hematology and chemistry laboratory 
values will be graded according to CTCAE version 4.0. These derived values will be included 
on the listings of laboratory data.


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5.9.5. Vital Signs, Physical Examinations, and other Observations 
Related to the Study
All vital signs including blood pressure and heart rate will be listed for all enrolled patients.
5.10. Other Analyses
5.10.1. Pharmacokinetic/Pharmacodynamic Analyses
Abemaciclib PK analyses will be conducted on all patients who have received at least 1 dose of
study treatment and have had samples collected (see PK sampling schedule in Appendix 4 of the 
protocol). Pharmacokinetic (PK) analyses will be performed according to a separate PK/PD
analysis plan.
5.10.2. Additional Reports to Support Clinical Trial Registry (CTR) 
Reporting Results
Analyses provided for the Clinical Trial Registry (CTR) requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML 
file. Both SAEs and ‘Other’ AEs will be summarized by treatment group and 
by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.

For each SAE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event (if certain subjects cannot be at risk 
for some reason, for example, gender-specific AEs, then the study team must 
adjust the number to only include the patients at risk)
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, a threshold for 
frequency of ‘Other’ AEs can be implemented rather than presenting all 
‘Other’ AEs.  For example, ‘Other’ AEs that occur in fewer than 5% of 
patients in any treatment group may not be included if a 5% threshold is 
chosen.  The frequency threshold must be less than or equal to the allowed 
maximum of 5%.

The completers in the study is defined as the subjects who have completed three 
cycles of the study treatment.


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6.
References
National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology Criteria 
for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. 2009.


Leo Document ID = 0021d666-32e5-4c11-bf34-d7a654e83fc4
Approver: 
Approval Date & Time: 08-Nov-2018 19:49:49 GMT
Signature meaning: Approved
PPD