Clinical trial NCT02688088
Conditions: Neoplasm Metastasis
Sponsor: Eli Lilly and Company
Start date: 2016-03-08; Completion date: 2021-01-06
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is known as a "drug interaction study" and is being done to see how abemaciclib may affect the blood levels of a drug mixture of commonly used drugs (caffeine, warfarin, dextromethorphan, and midazolam) when taken in combination with abemaciclib. Each participant will complete screening and four study periods in a fixed sequence, with the option to continue to receive abemaciclib in a safety extension phase. All participants will complete a safety follow-up.

Detailed description:

Arms: arm 1: Single dose of drug cocktail: 100 milligram (mg) caffeine,10 mg warfarin, 30 mg dextromethorphan, and 0.2 mg midazolam administered orally on Day 1 in Period 1. arm 2: 200 mg Abemaciclib administered orally every 12 hours (Q12H) on Days 1 - 12 in Period 2 with a single dose of drug cocktail: 100 mgcaffeine,10 mg warfarin, 30 mg dextromethorphan, and 0.2 mg midazolam administered orally on Day 8 in Period 2. arm 3: 200 mg Abemaciclib administered orally Q12H on Days 13 to 28 in Period 3. Participants may continue to receive abemaciclib until discontinuation criteria are met. arm 4: 200 mg Abemaciclib administered orally Q12H on Days 1 to 28 in Period 4. Participants may continue to receive abemaciclib until discontinuation criteria are met. arm 5: 200 mg Abemaciclib administered orally Q12H on Days 1 to 28 onwards in extension period. Participants may continue to receive abemaciclib until discontinuation criteria are met.
Interventions: intervention 1: Drug Cocktail intervention 2: Abemaciclib
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally

Protocol documents:
Prot_000.pdf: 
I3Y-MC-JPCB Protocol (d) 
 
Effects of Multiple Doses of Abemaciclib on the Pharmacokinetics of Cytochrome P450    
(CYP) 1A2, CYP2C9, CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients 
 
NCT02688088 
 
Approval Date: 22-Sep-2016 


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
Page 1
Abemaciclib (LY2835219)
1. Protocol I3Y-MC-JPCB(d)
Effects of Multiple Doses of Abemaciclib on the 
Pharmacokinetics of Cytochrome P450 (CYP) 1A2, CYP2C9, 
CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
abemaciclib (LY2835219), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Abemaciclib (LY2835219)
This Phase 1 study is an open-label, 4-period, fixed-sequence study to investigate the 
effect of abemaciclib on pharmacokinetics of caffeine (CYP1A2 substrate), warfarin 
(CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), and midazolam (CYP3A 
substrate) in patients with advanced and/or metastatic cancer, followed by a safety 
extension phase.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  06 October 2015.
Amendment (a) Electronically Signed and Approved by Lilly:  21 December 2015
Amendment (b) Electronically Signed and Approved by Lilly:  25 January 2016
Amendment (c) Electronically Signed and Approved by Lilly:  24 March 2016
Amendment (d) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 22-Sep-2016 GMT


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
2. Synopsis
Oncology Protocol Synopsis:  Study I3Y-MC-JPCB
Name of Investigational Product:
Abemaciclib (LY2835219)
Title of Study:  Effects of Multiple Doses of Abemaciclib on the Pharmacokinetics of Cytochrome P450 (CYP) 
1A2, CYP2C9, CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, Dextromethorphan, and Midazolam) in 
Cancer Patients
Number of Planned Patients:  Up to 48 patients may be 
enrolled in order that 22 patients complete Periods 1 and 2.
Phase of Development: 1
Length of Study:  
Screening:  Up to 30 days
Period 1:  7 days 
Period 2:  12 days
Periods 3 & 4:  16 & 28 days, respectively
Safety extension:  Patients are allowed to continue receiving abemaciclib in 28-day cycles until disease progression 
or other reason for discontinuation per investigator’s assessment.
Objectives:  
The primary objective of this study is to assess the effect of abemaciclib on the pharmacokinetics (PK) of caffeine 
(CYP1A2 substrate), warfarin (CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), and midazolam 
(CYP3A substrate) in cancer patients after multiple oral doses of abemaciclib.
The secondary objectives of this study are:

to characterize the tolerability of coadministration of abemaciclib with caffeine, warfarin, 
dextromethorphan, and midazolam following multiple doses of abemaciclib in cancer patients.

to assess the effect of abemaciclib on blood pressure and pulse rate following multiple doses of 
abemaciclib in cancer patients.
The exploratory objectives of this study are:

to determine the effect of abemaciclib on the pharmacodynamics (PD) of a single dose of warfarin as 
measured by international normalized ratio (INR).

to assess the effect of abemaciclib on markers of renal function, including creatinine, cystatin-C, kidney 
injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL).

to characterize bowel habits via a patient diary and a stool assessment tool (Bristol Stool Chart). 

to characterize diarrhea experienced via patient reported outcome data based on selected individual items 
from existing patient reported outcomes (PRO) scales (FACIT-D) as well as custom-generated PRO 
items.
Study Design:  
This will be an open-label, four-period, fixed-sequence study, followed by a safety extension phase, in patients 
with advanced and/or metastatic cancer.  
The drug cocktail of 100 mg caffeine, 10 mg warfarin, 30 mg dextromethorphan, and 0.2 mg midazolam will be 
administered orally as a single dose on 2 occasions: Day 1 in Period 1, and in combination with abemaciclib on 
Day 8 of Period 2, after 7 days of 200 mg abemaciclib every 12 hours (Q12H) dosing.  After completing Period 2, 
patients will continue to receive abemaciclib at a dose of 200 mg Q12H (or a modified dose) through the end of 
Periods 3 and 4, in 28-day cycles, and then may continue in a safety extension phase until discontinuation criteria 
are met.  


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Abemaciclib (LY2835219)
Diagnosis and Main Criteria for Inclusion and Exclusion:  
Patients may be included in the study if they meet the following criteria: have histological or cytological evidence 
of a diagnosis of cancer that is advanced and/or metastatic; are ≥18 years of age; have adequate organ function; 
have a performance status of ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale; and have discontinued 
all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, cancer-related hormone 
therapy, and investigational therapy) for at least 21 days for myelosuppressive agents or 14 days for 
nonmyelosuppressive agents prior to receiving study drug and have recovered from the acute effects of therapy 
(treatment related toxicity resolved to baseline), except for residual alopecia.
Investigational Product, Dosage, and Mode of Administration:  
Abemaciclib
Abemaciclib will be supplied as 50-mg capsules as the 25% w/w formulation (C3) for oral administration.
Drug Cocktail
This will include: commercially available caffeine citrate solution (20 mg/mL) for oral administration; 
commercially available warfarin (brand name Coumadin) as 5-mg tablets for oral administration; commercially 
available dextromethorphan as 15-mg liquid gel capsules for oral administration; and commercially available 
midazolam syrup (2 mg/mL) for oral administration. 
Planned Duration of Treatment:  
Period 1
On Day 1, 10 mL of 20-mg/mL caffeine citrate solution, 2 × 5-mg tablets of warfarin, 2 × 15-mg liquid gel 
capsules of dextromethorphan, and 0.1 mL of 2-mg/mL midazolam syrup will be coadministered
Period 2
On Days 1 to 12, 4 × 50-mg capsule of abemaciclib will be administered orally in the morning and evening.  On 
Day 8, abemaciclib will be coadministered with 10 mL of 20 mg/mL caffeine citrate solution, 2 × 5-mg tablets of 
warfarin, 2 × 15-mg liquid gel capsules of dextromethorphan, and 0.1 mL of 2-mg/mL midazolam syrup.
Periods 3, 4, and Safety Extension Phase
Patients receive an abemaciclib dose of 200 mg Q12H (or modified dose as applicable) on a 28-day cycle until 
discontinuation criteria are met.
Criteria for Evaluation:  
Safety:  Adverse events (AEs), clinical laboratory evaluations, vital signs, ambulatory blood pressure monitoring 
(ABPM), electrocardiograms (ECGs), bowel habits, renal function markers, and CYP genotyping.
Bioanalytical:  Plasma concentrations of caffeine, S-warfarin, dextromethorphan, midazolam, and abemaciclib.  
Pharmacokinetic:  The primary parameters for analysis will be maximum observed drug concentration (Cmax), 
area under the concentration versus time curve from zero to infinity (AUC[0-∞]), and time of maximum observed 
drug concentration (tmax).
Efficacy:  Tumor assessments.
Evaluation Methods:  
Safety:  Safety data will be listed and summarized as appropriate.
Pharmacokinetic:  Pharmacokinetic parameter estimates will be evaluated to delineate effects of drug interaction. 
Caffeine, warfarin, dextromethorphan, and midazolam administered in the absence of abemaciclib will represent 
the reference treatments and be analyzed separately.  Each drug administered with abemaciclib will represent the 
test treatments.  Log-transformed Cmax and AUC(0-∞) estimates will be evaluated in a linear mixed-effects analysis 
of variance model with a fixed effect for treatment and a random effect for subject.  The treatment differences will 
be back-transformed to present the ratios of geometric means and the corresponding confidence intervals (90% 
CIs).
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference based on the 
observed medians, 90% CIs, and p-values from the Wilcoxon test will be calculated.
Trough plasma concentrations of abemaciclib will be listed.


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Abemaciclib (LY2835219)
3. Table of Contents
Effects of Multiple Doses of Abemaciclib on the 
Pharmacokinetics of Cytochrome P450 (CYP) 1A2, CYP2C9, 
CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients
Section
Page
1.
Protocol I3Y-MC-JPCB(d)  Effects of Multiple Doses of Abemaciclib on the 
Pharmacokinetics of Cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6, and 
CYP3A Substrates (Caffeine, Warfarin, Dextromethorphan, and Midazolam) in 
Cancer Patients ...................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................4
4.
Abbreviations and Definitions...........................................................................................10
5.
Introduction ......................................................................................................................14
5.1.
Rationale and Justification for the Study ......................................................................14
5.2.
Objectives ....................................................................................................................15
5.2.1.
Primary Objective ................................................................................................15
5.2.2.
Secondary Objectives...........................................................................................15
5.2.3.
Exploratory Objectives.........................................................................................15
5.3.
General Introduction to Abemaciclib............................................................................16
5.3.1.
Clinical Experience with Abemaciclib..................................................................16
5.3.2.
Nonclinical Toxicology........................................................................................18
5.4.
Rationale for Selection of Dose....................................................................................18
6.
Investigational Plan...........................................................................................................20
6.1.
Study Population..........................................................................................................20
6.1.1.
Inclusion Criteria .................................................................................................20
6.1.2.
Exclusion Criteria ................................................................................................21
6.2.
Summary of Study Design............................................................................................23
6.2.1.
Safety Extension Phase ........................................................................................26
6.2.2.
Study Completion and End of Trial......................................................................26
6.2.3.
Determination of Sample Size..............................................................................26
6.3.
Discontinuations ..........................................................................................................27
6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................27
6.3.2.
Discontinuation of Patients from Study or Study Drug .........................................28
6.3.3.
Patients Lost to Follow-Up...................................................................................28
6.3.4.
Discontinuation of Study Sites .............................................................................29


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Abemaciclib (LY2835219)
6.3.5.
Discontinuation of the Study................................................................................29
7.
Treatment..........................................................................................................................30
7.1.
Materials and Supplies .................................................................................................30
7.2.
Study Drug Administration ..........................................................................................30
7.2.1.
Dosing Schedule ..................................................................................................31
7.2.2.
Dose Adjustments ................................................................................................32
7.3.
Method of Assignment to Treatment ............................................................................35
7.4.
Blinding .......................................................................................................................35
7.5.
Concomitant Therapy...................................................................................................35
7.5.1.
Interactions of Concomitant Medications with Abemaciclib.................................35
7.5.2.
Interactions of Concomitant Medications with Drug Cocktail...............................36
7.6.
Treatment Compliance .................................................................................................37
7.6.1.
Evaluable Patients................................................................................................38
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data Collection.......................39
8.1.
Safety Evaluations........................................................................................................39
8.1.1.
Safety Data Collection and Review ......................................................................39
8.1.2.
Adverse Events ....................................................................................................39
8.1.3.
Other Safety Measures .........................................................................................43
8.1.4.
Safety Monitoring ................................................................................................45
8.1.5.
Complaint Handling.............................................................................................46
8.2.
Sample Collection and Testing.....................................................................................46
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................46
8.2.2.
Samples for Drug Concentration and Pharmacodynamic Measurements...............47
8.2.3.
Samples for Evaluation of Renal Function............................................................48
8.2.4.
Samples for Tailoring Biomarkers........................................................................48
8.2.5.
CYP Genotype Evaluation ...................................................................................49
8.3.
Efficacy Evaluations ....................................................................................................49
8.3.1.
Prestudy...............................................................................................................49
8.3.2.
During the Study..................................................................................................49
8.3.3.
Poststudy Follow-Up............................................................................................50
8.4.
Procedure/Sampling Compliance..................................................................................50
9.
Data Management Methods...............................................................................................51
9.1.
Data Quality Assurance................................................................................................51
9.2.
Data Capture Systems ..................................................................................................51
9.2.1.
Case Report Form ................................................................................................51
9.2.2.
Ancillary Data......................................................................................................52
10.
Data Analyses ...................................................................................................................53
10.1. General Considerations ................................................................................................53


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Abemaciclib (LY2835219)
10.2. Patient Disposition .......................................................................................................53
10.3. Patient Characteristics ..................................................................................................53
10.4. Safety Analyses............................................................................................................53
10.5. Pharmacokinetic Analyses............................................................................................54
10.6. Pharmacodynamic Analyses.........................................................................................54
10.7. Efficacy........................................................................................................................55
10.8. Interim Analyses ..........................................................................................................55
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................56
11.1. Informed Consent.........................................................................................................56
11.2. Ethical Review.............................................................................................................56
11.3. Regulatory Considerations ...........................................................................................56
11.3.1.
Investigator Information.......................................................................................57
11.3.2.
Protocol Signatures ..............................................................................................57
11.3.3.
Final Report Signature .........................................................................................57
12.
References ........................................................................................................................58


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Abemaciclib (LY2835219)
List of Tables
Table
Page
Table JPCB.7.1. Toxicity Dose Adjustments and Delays of Abemaciclib for Study JPCB........33
Table JPCB.7.2. Dose Adjustments for Abemaciclib during Period 3, Period 4, and 
Safety Extension............................................................................................34
Table JPCB.8.1. Adverse Event and Serious Adverse Reporting Guidelines for Study 
JPCB .............................................................................................................43


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List of Figures
Figure
Page
Figure JPCB.6.1. Study design..................................................................................................25


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Abemaciclib (LY2835219)
List of Attachments
Attachment
Page
Attachment 1.
Protocol JPCB Study Schedule ......................................................................60
Attachment 2.
Protocol JPCB Clinical Laboratory Tests.......................................................66
Attachment 3.
Protocol JPCB Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................68
Attachment 4.
Protocol JPCB Recommendations for Reporting 
Serious Adverse Events .................................................................................69
Attachment 5.
Protocol JPCB Eastern Cooperative Oncology Group (ECOG) 
Performance Status........................................................................................70
Attachment 6.
Protocol JPCB Sampling Summary................................................................71
Attachment 7.
Protocol Amendment I3Y-MC-JPCB(d) Summary Effects of Multiple 
Doses of Abemaciclib on the Pharmacokinetics of Cytochrome P450 
(CYP) 1A2, CYP2C9, CYP2D6, and CYP3A Substrates (Caffeine, 
Warfarin, Dextromethorphan, and Midazolam) in Cancer Patients.................72


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4. Abbreviations and Definitions
Term
Definition
ABPM
ambulatory blood pressure monitoring
AE
adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology 
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from zero to infinity
AUC(0-tlast)
area under the concentration versus time curve from time zero to time t, where t 
is the last time point with a measurable concentration 
AUCINR
area under the INR curve
audit
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s).
CDK
cyclin-dependent kinase
CI
confidence interval
Cmax
maximum observed drug concentration
CNS
central nervous system
complaint
Any written, electronic, or oral communication that alleges deficiencies related
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.


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Abemaciclib (LY2835219)
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
CRF/eCRF
case report form/electronic case report form:  Sometimes referred to as clinical 
report form, a printed or electronic form for recording study participants’ data 
during a clinical study, as required by the protocol.
CP
clinical pharmacologist
CRP
clinical research physician
CRS
clinical research scientist
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last 
patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least one dose of study treatment. 
enter
Patients who are entered in the trial are those who have signed the informed 
consent form directly or through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board:  A board or committee 
(institutional, regional, or national) composed of medical and nonmedical 
members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical study are protected.
ESA
erythroid-stimulating agents 
GCP
good clinical practice
IB
Investigator’s Brochure
IC50
50% inhibition concentration 
ICF
informed consent form
ICH
International Conference on Harmonization
informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the 
trial that are relevant to the patient’s decision to participate.  Informed consent 
is documented by means of a written, signed and dated informed consent form.


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Abemaciclib (LY2835219)
INR
international normalized ratio
INRmax
maximum observed INR response
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for datalock.
investigational 
product (IP)
A pharmaceutical form of an active substance or placebo being tested or used as 
a reference in a clinical trial.  Investigational product includes a product with a 
marketing authorization when used or assembled (formulated or packaged) in a 
way different from the authorized form, used for an unauthorized indication or 
used to gain further information about the authorized form
investigator
A person responsible for the conduct of the clinical study at a study site.  If a 
study is conducted by a team of individuals at a study site, the investigator is the 
responsible leader of the team and may be called the principal investigator.
KIM-1
kidney injury molecule-1 
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NGAL
neutrophil gelatinase-associated lipocalin 
NSCLC
non-small-cell lung cancer 
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
patient
A subject with a defined disease.
PD
pharmacodynamic(s) 
PK
pharmacokinetic(s)
PRO
patient reported outcomes 
Q12H
every 12 hours 
RECIST
Response Evaluation Criteria in Solid Tumors
re-screen
to screen a patient who was previously declared a screen failure for the same 
study
SAE
serious adverse event
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 trial.  In this 
study, screening involves invasive or diagnostic procedures and/or tests (for 
example, blood draws).  For this type of screening, informed consent for these 
screening procedures and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study.


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Abemaciclib (LY2835219)
screen failure
A patient who does not meet one or more criteria required for participation in a 
trial
sponsor
The party who takes responsibility for the initiation, management and/or 
financing of a clinical study.
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life associated with the terminal rate constant
TEAE
treatment-emergent adverse event
tmax
time of maximal plasma concentration
TPO
third-party organization
ULN
upper limit of normal


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Abemaciclib (LY2835219)
Effects of Multiple Doses of Abemaciclib on the 
Pharmacokinetics of Cytochrome P450 (CYP) 1A2, CYP2C9, 
CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients
5. Introduction
5.1.
Rationale and Justification for the Study
Study JPCB is a Phase 1 study designed to investigate the effect of multiple doses of abemaciclib 
on the pharmacokinetics (PK) of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6, and CYP3A 
substrates in patients with advanced and/or metastatic cancer.
Abemaciclib is an orally administered small molecule that is a potent and selective dual inhibitor 
of the cyclin-dependent kinases (CDKs) 4 and 6.  The goal of inhibiting CDK4 and CDK6 is to 
prevent cell cycle progression through the G1 restriction point, thus arresting tumor growth.
Abemaciclib at doses of 200 mg every 12 hours (Q12H) is being developed for the treatment of 
advanced cancer, including metastatic breast cancer and Stage IV non-small-cell lung cancer.
Abemaciclib has been administered orally on Days 1 through 28 of a 28-day cycle.  In Study 
JPBA, the maximum tolerated dose for humans when administered as a single agent was 200 mg 
Q12H.  Based upon a higher incidence of Grade 3 diarrhea when abemaciclib 200 mg Q12H was 
administered in combination with nonsteroidal aromatase inhibitors, the dose being explored in 
combination with nonsteroidal aromatase inhibitors in Study JPBM is 150 mg Q12H.
In vitro in human liver microsomes, abemaciclib and its major circulating metabolites 
LSN2839567 (M2) and LSN3106726 (M20) did not inhibit directly or in a time-dependent 
manner the catalytic activities of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, 
and CYP3A at clinically relevant concentrations.  Furthermore, abemaciclib and its metabolites 
did not induce the catalytic activities of CYP1A2, CYP2B6, and CYP3A.  Thus, collectively, 
these in vitro data suggest that abemaciclib and its metabolites do not interact directly with the 
above CYPs, and that drug interactions are unlikely due to CYP inhibition or induction when 
abemaciclib is coadministered with substrate drugs of the above CYPs.
Although abemaciclib and its major metabolites did not inhibit any of the CYPs directly in 
human liver microsomes, down regulation of mRNA of CYPs, including CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6, and CYP3A by abemaciclib and/or its major circulating 
metabolites LSN2839567 (M2) and LSN3106726 (M20), was observed at clinically relevant 
concentrations in cultured human hepatocytes.  The observed mRNA down regulation was 
>50%, concentration dependent and not due to toxicity to cells.  The mechanism of this down 
regulation and its clinical relevance (in vitro to in vivo correlation) are presently not understood.  
Thus, in the absence of additional in vitro data there is a potential for abemaciclib and its major 
metabolites to interact with substrate drugs of the above CYPs when coadministered (EMA 
Guidance 2012; PMDA Draft Guidance 2013).


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Abemaciclib (LY2835219)
Under this circumstance, regulatory agencies recommend conducting a clinical drug interaction 
study using a cocktail approach (EMA Guideline 2012; PMDA Draft Guideline 2013).  Drugs 
used in such a cocktail should be selective for the specific CYP enzymes, should not interact 
with each other, and ultimately should be safe when administered.  One such cocktail is a 
modified Coopertown 5 + 1 cocktail which includes caffeine (CYP1A2), warfarin (CYP2C9), 
omeprazole (CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A), and has been 
administered to patients with advanced cancers (excluding primary liver tumors) (Goh et al. 
2010; Ma et al. 2006).  In this study, based on the in vitro data, only caffeine, warfarin, 
dextromethorphan, and midazolam will be included in the cocktail.  
Secondary and exploratory objectives of this study are to collect closely-monitored data on blood 
pressure, diarrhea, and renal function that will further characterize the safety and tolerability of 
abemaciclib in patients.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonization (ICH) guidelines, 
and applicable regulatory requirements.
5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to assess the effect of abemaciclib on the PK of caffeine 
(CYP1A2 substrate), warfarin (CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), and 
midazolam (CYP3A substrate) in cancer patients after multiple oral doses of abemaciclib.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the tolerability of coadministration of abemaciclib with caffeine, warfarin, 
dextromethorphan, and midazolam following multiple doses of abemaciclib in cancer 
patients.

to assess the effect of abemaciclib on blood pressure and pulse rate following multiple 
doses of abemaciclib in cancer patients.
5.2.3. Exploratory Objectives
The exploratory objectives of this study are:

to determine the effect of abemaciclib on the pharmacodynamics (PD) of a single dose of 
warfarin as measured by international normalized ratio (INR).

to assess the effect of abemaciclib on markers of renal function, including 
creatinine, cystatin-C, kidney injury molecule-1 (KIM-1), and neutrophil 
gelatinase-associated lipocalin (NGAL).

to characterize bowel habits via a patient diary and a stool assessment tool (Bristol Stool 
Chart). 


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Abemaciclib (LY2835219)

to characterize diarrhea experienced via patient reported outcome data based on selected 
individual items from existing patient reported outcomes (PRO) scales (FACIT-D) as 
well as custom-generated PRO items.
5.3.
General Introduction to Abemaciclib
Abemaciclib is a selective and potent small molecule CDK4 and CDK6 dual inhibitor with broad 
antitumor activity in preclinical pharmacology models, acceptable physical and PK properties, 
and an acceptable toxicity profile in nonclinical species.  This compound demonstrates 
significant inhibition of tumor growth as monotherapy in multiple human xenograft models 
including models for: colorectal cancer, glioblastoma multiforme, acute myeloid leukemia, 
melanoma, mantle cell lymphoma, and non-small-cell lung cancer (NSCLC).  
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) may be found in the Investigator’s Brochure (IB).  Information on AEs 
expected to be related to the investigational product may be found in Section 7 (Development 
Core Safety Information) of the IB.  Information on serious adverse events (SAEs) expected in 
the study population independent of drug exposure and that will be assessed by the sponsor in 
aggregate, periodically during the course of the study, may be found in Section 6 (Effects in 
Humans) of the IB.
5.3.1. Clinical Experience with Abemaciclib
Abemaciclib has been evaluated in multiple Phase 1 clinical pharmacology studies, including 
4 studies completed in healthy subjects and 2 studies completed in cancer patients.  Three 
Phase 1 studies are ongoing in healthy subjects and several Phase 1 studies are underway in 
cancer patients.
Phase 2 studies are ongoing in metastatic breast cancer and mantle cell lymphoma patients and 
Phase 3 studies are ongoing in patients with metastatic breast cancer and in patients with 
Stage IV NSCLC.
5.3.1.1.
Pharmacokinetics of Abemaciclib and Its Major Metabolites
The time course of abemaciclib concentration in plasma shows a median time of maximum 
observed drug concentration (tmax) ranging from 4 to 6 hours postdose.  Abemaciclib has a 
half-life associated with the terminal rate constant (t1/2) ranging from 17 to 38 hours and showed 
no dose dependent change in clearance.  The time to steady state following multiple Q12H doses 
of abemaciclib is approximately 5 days.
Based on in vitro data, the major human circulating metabolites LSN3106726 (M20) and 
LSN2839567 (M2) are active with potency similar to abemaciclib.  The t1/2 was longer for 
metabolites than that of abemaciclib, with mean values of 36 and 32 hours for M2 and M20, 
respectively.  
Additional information on the PK properties of abemaciclib, including the PK at steady state 
after repeated abemaciclib administration, is available in the IB.  The majority of abemaciclib is 


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Abemaciclib (LY2835219)
eliminated in feces (81%) with approximately 3% of the dose eliminated in urine.  Abemaciclib 
is extensively metabolized primarily via CYP3A.
5.3.1.2.
Clinical Activity Data
Abemaciclib has demonstrated evidence of clinical activity in several tumor types.  In Study 
JPBA, radiographic responses were achieved in previously treated patients with breast cancer, 
NSCLC, and melanoma.  For hormone receptor-positive breast cancer, overall response rate was 
31% (11/36 patients) and disease control rate was 81% (29/36 patients).
5.3.1.3.
Clinical Safety Data
Safety data for 352 patients treated with abemaciclib in 6 studies show that the most common 
treatment-emergent AEs (TEAEs; ≥10%) possibly related to study drug for patients receiving 
abemaciclib either as a single agent, with endocrine therapy, or with chemotherapy, are diarrhea 
(64.2%), nausea (44.3%), fatigue (39.8%), neutropenia (27.0%), vomiting (24.1%), 
thrombocytopenia (21.3%), leukopenia (21.0%), anemia (17.6%), decreased appetite (17.6%), 
and increased blood creatinine (14.5%).  The majority of deaths reported for patients in the 
studies with available safety data were due to study disease.
Preliminary safety data from Study JPBH, a Phase 1b study evaluating the safety and tolerability 
of abemaciclib in combination with endocrine therapies (including anastrozole) in patients with 
HR+, HER2- mBC, have shown an AE profile for abemaciclib administered at 200 mg every 
12 hours in combination with endocrine therapies that is consistent with the profile observed in 
the Study JPBA mBC single agent cohort.  However, at the 200-mg dose, the incidence of 
treatment-emergent Grade 3 diarrhea was greater in combination with endocrine therapies than 
when abemaciclib was administered alone (25.7% and 13.6%, respectively).  Although diarrhea 
occurred in 62.5% of patients in the dose-confirmation phase of Study JPBA (57.1% of patients 
at the 150-mg dose and 68.0% of patients at the 200-mg dose), this diarrhea was mostly Grade 1 
or Grade 2 and was manageable with standard anti-diarrheal agents.  There have been no patient 
discontinuations due to diarrhea.
In one study, a total of 16 patients were taking warfarin while also taking abemaciclib: one 
patient each at abemaciclib doses of 100 mg Q12H and 225 mg daily, 6 patients at 200 mg 
Q12H, and 8 patients at 150 mg Q12H.  Two patients in this group of 16 patients had an AE
potentially related to increased warfarin exposure that could potentially occur if CYP2C9 activity 
was decreased.  One patient had Grade 1 epistaxis and an increased INR on Day 28 of the study 
while taking a dose of 200 mg abemaciclib Q12H.  One patient had a Grade 3 upper 
gastrointestinal hemorrhage on Day 179 of the study while taking a dose of 150 mg abemaciclib 
Q12H.Increases in serum creatinine of approximately 20% to 40% above baseline have been 
observed across healthy subject and cancer patient studies.  In vitro preliminary data from 
transporter inhibition studies have shown that abemaciclib and its major metabolites inhibit 
multiple drug and toxin extrusion transporter 1.  Thus, the observed transient increases in serum 
creatinine are likely to be due to inhibition of tubular secretion of creatinine by this transporter 
without clinically meaningful alterations in renal function (Schützer et al. 2010; Imamura et al. 
2011; Lepist et al. 2014).


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Abemaciclib (LY2835219)
Changes in blood pressure and pulse rates have been seen in studies with abemaciclib.  In 
healthy subjects enrolled in Study JPBG, small decreases in mean blood pressure and increases 
in mean pulse rates were observed up to 24 hours following dosing with abemaciclib in each 
study period.  Maximal mean changes were up to -5.0 mmHg for systolic blood pressure 
and -4.3 mmHg for diastolic blood pressure, and up to 4.3 bpm increases in pulse rate.  In cancer 
patients enrolled in Study JPBA, decreases in blood pressure were observed following dosing 
with abemaciclib on Days 8, 15, 22, and 28 of Cycle 1 and Day 28 of Cycles 2 through 6.  
Maximal median changes were up to -6 mmHg for diastolic blood pressure (Cycle 1 Day 28) and 
-5 mmHg for systolic blood pressure (Cycle 1 Day 22).  Decreases from baseline in pulse rate 
were observed on Days 15 and 22 of Cycle 1, as well as on Day 28 of Cycles 3 through 6, with 
maximal median change in pulse rate being -6.0 bpm (Cycle 6 Day 28).  To date there is no 
evidence of an effect of abemaciclib on QT interval.
5.3.2. Nonclinical Toxicology
To support human clinical studies, the toxicity profile of abemaciclib has been effectively 
characterized in rat and dog through a package of repeat-dose toxicology, safety pharmacology, 
and genetic toxicology studies.  These studies demonstrate an acceptable safety profile with 
toxicities that are generally considered to be monitorable and reversible.  
The nonclinical toxicology studies consisted of 28-day repeat-dose studies in rats at doses of 10, 
30, and 50 mg/kg/day (60, 180, and 300 mg/m2, respectively) and in dogs at doses of 1, 3, and 
10 mg/kg/day (20, 60, and 200 mg/m2, respectively).  Dose-responsive hematotoxicity, indicated 
by cytopenias and bone marrow hypocellularity, and gastrointestinal injury were the most 
prominent adverse effects observed in both rats and dogs.  In addition, effects on male 
reproductive tract were also observed.  These changes were generally consistent with 
antiproliferative effects and demonstrated partial or complete reversibility within the 28-day 
recovery period in both species.  Importantly, the toxicities associated with abemaciclib in 
preclinical studies have generally been observed with multiple or repeated dosing, consistent 
with its cell cycle-related mechanism of action.  
No important compound-related findings were observed in safety pharmacology studies of the 
cardiovascular system, respiratory system, or central nervous system (CNS) in preclinical studies.  
Although the 50% inhibition concentration (IC50) was not precisely determined in an in vitro 
model (IC50 >1.65 M), no QTc prolongation was observed in dogs at doses up to 10 mg/kg; 
therefore, the risk for QTc prolongation to occur in humans is considered low.  
For more details about the results of the nonclinical toxicology studies, please refer to 
Section 5.2.1 of the IB.
5.4.
Rationale for Selection of Dose
A drug cocktail containing oral doses of 2 mg/kg caffeine, 10 mg warfarin, 40 mg omeprazole, 
30 mg dextromethorphan, and 0.075 mg/kg midazolam has been studied previously (Ma et al. 
2006), with no safety concerns raised.  Another study evaluating this cocktail of drugs in patients 
with advanced cancer also had no safety concerns raised (Goh et al. 2010).  Therefore, the drug 


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Abemaciclib (LY2835219)
cocktail proposed in the current study, which contains 100 mg caffeine, 10 mg warfarin, 30 mg 
dextromethorphan, and 0.2 mg midazolam, is expected to be safe and well tolerated. 
Abemaciclib 
A dose of 200 mg Q12H was selected for this study and is supported by the safety data from a 
cancer patient study in which the highest dose explored was 275 mg Q12H, and the maximum 
tolerated dose was identified as 200 mg Q12H based on dose-limiting toxicity of Grade 3 fatigue 
observed in 2 of 3 patients at 275 mg Q12H.  Likewise, the 200-mg dose is supported by safety 
data from healthy subject studies.  The available nonclinical toxicology data also supports the 
dose selected for this study.  The 200-mg dose is also being investigated in the Phase 2 and 
Phase 3 single agent studies of abemaciclib in cancer patients.
At the conclusion of the drug interaction portion of the study, patients may continue to receive 
abemaciclib through Cycle 2 at the investigator’s discretion.  In the safety extension phase, 
patients will receive abemaciclib at a dose of 200 mg Q12H (or modified as applicable) on a 
28-day cycle until discontinuation criteria are met.


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Abemaciclib (LY2835219)
6. Investigational Plan
6.1.
Study Population
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.  Prospective approval of protocol 
deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, 
are not permitted.
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to enrollment.
[1]
Have histological or cytological evidence of a diagnosis of cancer that is 
advanced and/or metastatic.  The patient must be, in the judgment of the 
investigator, an appropriate candidate for experimental therapy after available 
standard therapies have failed to provide clinical benefit for their disease.
[2]
Are 18 years of age.
[3]
Have given written informed consent prior to any study-specific procedures.
[4]
Have adequate organ function, including:

Hematologic:  Absolute neutrophil count 1.5 x 109/L, platelets 100 x 
109/L, and hemoglobin 8 g/dL.  Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator.  Initial treatment must not begin until 1 day after the 
erythrocyte transfusion.  

Hepatic:  Direct bilirubin 1.5 times upper limits of normal (ULN), 
alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 
2.5 times ULN.  PT or INR 1.2 times ULN and PTT1.2 times ULN.

Renal:  Serum creatinine no greater than ULN.
[5]
Have other clinical laboratory test results within normal reference range or 
results with acceptable deviations that are judged to be not clinically 
significant by the investigator.
[6]
Have a performance status of 2 on the Eastern Cooperative Oncology Group 
(ECOG) scale (refer to Attachment 5).
[7]
Have discontinued all previous therapies for cancer (including chemotherapy, 
radiotherapy, immunotherapy, cancer-related hormone therapy, and 
investigational therapy) for at least 21 days for myelosuppressive agents or 
14 days for nonmyelosuppressive agents prior to receiving study drug and 
have recovered from the acute effects of therapy (treatment related toxicity 
resolved to baseline), except for residual alopecia.


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Abemaciclib (LY2835219)
At the discretion of the investigator, hormone refractory prostate cancer 
patients who are stable on gonadotropin-releasing hormone agonist therapy 
may have that treatment continued while they are enrolled in Study JPCB.  
Other hormonal treatments used for non-cancer indications (or cancer-induced 
indications, for example megestrol acetate to treat anorexia) may also be 
allowed at the discretion of the investigator.
Exemptions will be permitted on a case-by-case basis after prior approval by 
the Lilly clinical research physician (CRP)/clinical pharmacologist (CP) or 
designee if the investigator believes the patient’s risk of recurrence and death 
is very low. Curatively treated nonmelanoma skin cancer or in situ carcinoma 
of any origin is allowed.
[8]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[9]
If male or female with reproductive potential, agree to use medically approved 
contraceptive precautions during the trial and for 3 months following the last 
dose of study drug.  In addition, male patients must not donate sperm during 
the trial and for 3 months following the last dose of study drug.
[10] If female with child bearing potential, must have a negative serum pregnancy 
test within 3 days of the first dose of study drug.
[11] Have an estimated life expectancy, in the judgment of the investigator, that 
will permit the patient to complete the drug interaction phase and at least 
1 cycle of abemaciclib (if the patient were to participate in the safety 
extension).
[12] Are able to swallow capsules or tablets.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[13] Have received treatment within 28 days of the initial dose of study drug with 
an investigational product (non-cancer-related therapies) or non-approved use 
of a drug or device (other than the study drug used in this study) or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
[14] Have a personal history of any of the following conditions:  presyncope or 
syncope of either unexplained or cardiovascular etiology, ventricular 
arrhythmia (including but not limited to ventricular tachycardia and 
ventricular fibrillation), or sudden cardiac arrest.


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Abemaciclib (LY2835219)
[15] Have known active uncontrolled or symptomatic CNS metastases,
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical 
symptoms, cerebral edema, and/or progressive growth. Patients with a history 
of CNS metastases or cord compression are eligible if they have been 
definitively treated (eg, radiotherapy, stereotactic surgery) and are clinically 
stable off anticonvulsants and steroids for at least 4 weeks before 
randomization.
[16] Have a primary liver tumor.
[17] Have a clinically significant abnormal electrocardiogram (ECG) with any (but 
not limited to) the following findings:  persistent and significant ventricular 
arrhythmia, evidence of acute myocardial ischemia, or QTc prolongation 
(defined as QT interval corrected for heart rate using Bazett’s formula 
>470 msec).
[18] Have preexisting medical conditions that, in the judgment of the investigator, 
would preclude participation in this study (for example, history of major 
surgical resection involving the stomach or small bowel, nausea, vomiting, 
diarrhea, or malabsorption syndromes).
[19] Have lymphoma or leukemia.
[20] Have any history of receiving an autologous or allogeneic stem-cell or bone 
marrow transplant
[21] For Periods 1 and 2:

Require treatment with inducers or inhibitors of CYP1A2, CYP2C9, 
CYP2D6, and CYP3A within 14 days before the first dose of study 
drug through the end of Period 2

Require treatment with substrate drugs of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6, and CYP3A with narrow therapeutic 
indices, at the discretion of the investigator following discussion and 
agreement with the Lilly CRP/CP or designee.
Note: Following Period 2 and during the remainder of the study:
Inducers and inhibitors of CYP3A, as well substrate drugs of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6, and CYP3A with narrow therapeutic indices should be 
avoided (see Section 7.5 Concomitant Therapy).
[22] Require continued treatment with other drugs that are contraindicated with 
caffeine, warfarin, dextromethorphan, or midazolam.
[23] Have a known hypersensitivity to caffeine, warfarin, dextromethorphan, or 
midazolam.
[24] Are pregnant or lactating females.


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Abemaciclib (LY2835219)
[25] Have active bacterial, fungal, and/or known significant viral infection (for 
example, human immunodeficiency virus antibodies, hepatitis B surface 
antigen, or hepatitis C antibodies).  Screening of these infections are not 
required for enrollment.
[26] History or presence of significant bleeding disorders that is, hematemesis, 
melanena, other known gastrointestinal bleeding (within the last 3-6 months) 
with significant risk of recurrence, severe or recurrent epistaxis, hemoptysis, 
clinically overt hematuria, or intracranial hemorrhage.
[27] Have a history of major head trauma (with loss of consciousness) within the 
past year or minor head trauma (without loss of consciousness) within the last 
3 months prior to screening.
6.2.
Summary of Study Design
This will be an open-label, 4-period, fixed-sequence study, followed by a safety extension phase, 
in patients with advanced and/or metastatic cancer.
The drug cocktail of 100 mg caffeine, 10 mg warfarin, 30 mg dextromethorphan, and 0.2 mg 
midazolam will be administered orally as a single dose on 2 occasions: Day 1 in Period 1, and in 
combination with abemaciclib on Day 8 of Period 2, after 7 days of 200 mg abemaciclib Q12H 
dosing.  After completing Period 2, patients will continue to receive abemaciclib at a dose of 
200 mg Q12H (or a modified dose) through the end of Periods 3 and 4, in 28-day cycles, and 
then may continue in a safety extension phase until discontinuation criteria are met.  Patients 
who do not complete dosing and PK sampling through Period 2 may be replaced.
Patients will be provided with an electronic diary from the baseline visit through the end of 
Cycle 2 to record the time and date of abemaciclib administration, anti-diarrhea medications 
taken, and bowel habits and any changes.
The study design is illustrated in Figure JPCB.6.1.


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Abemaciclib (LY2835219)
Period 1
Patients will report to the study site within 7 days prior to the first dose of drug cocktail dosing 
for baseline safety assessments, initial diary training, and bowel habit assessment, and PRO scale 
completion.  Patients will also be fitted with an ambulatory blood pressure monitor (ABPM) 
device for a 12-hour acclimation period between Days -7 to -2.  Patients will begin collecting 
daily baseline diary assessments for bowel habits following the baseline visit.  Patients will 
report to the study site on Day -2 or Day -1 prior to procedures and dosing on Day 1 for 24-hour 
ABPM measurements, which will serve as the baseline.  Patients will then report to the study site 
prior to dosing on Day 1.  On Day 1, patients will receive the drug cocktail, with single oral 
doses of 100 mg caffeine, 10 mg warfarin, 30 mg dextromethorphan, and 0.2 mg midazolam 
coadministered at the same time.  Serial blood samples will be collected to determine the 
concentrations of caffeine, S-warfarin, dextromethorphan, and midazolam.  Patients will be 
present at the study site for at least 12 hours after dosing, and then return to the study site on an 
outpatient basis for the collection of PK and/or PD samples.
Period 2
Period 2 will begin no earlier than 7 days after the cocktail dose in Period 1.  Prior to 
abemaciclib dosing, safety assessments will be collected.  Patients will receive the first dose of 
200 mg abemaciclib at the study site and then will be released with a sufficient supply of 
abemaciclib for 8 days taken Q12H.  Patients will report to the study site between Days 5 to 7 
and will be fitted with an ABPM device for a 24-hour measurement after multiple doses of 
abemaciclib.  Patients will report to the study site on Day 8 and will be coadministered 
abemaciclib and the drug cocktail in the morning.  Serial blood samples will be collected after 
dosing on Day 8 to determine the concentrations of caffeine, S-warfarin, dextromethorphan, and 
midazolam.  Blood samples will also be collected for the measurement of trough concentrations 
of abemaciclib.  Patients will be present at the study site for at least 12 hours after dosing with 
the drug cocktail, and then released with a sufficient supply of abemaciclib.  Patients will return 
to the study site on an outpatient basis for the collection of PK and/or PD samples.
Period 3 and 4
After completing Period 2, it is anticipated that patients will continue 200 mg abemaciclib Q12H 
during Periods 3 and 4 for assessment of bowel changes. This will complete Cycles 1 and 2 of 
abemaciclib treatment, as depicted in Figure JPCB.6.1.
Safety monitoring will be conducted throughout the entire study duration.
Refer to Attachment 1 for the Study Schedule.


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Abemaciclib (LY2835219)
Abbreviations:  ABPM = ambulatory blood pressure monitoring; PK = pharmacokinetics; PRO = patient reported outcomes; Q12H = every 12 hours.
ABPM will be performed at following times: 12-hour acclimation period between Days -7 to -2 in Period 1, 24-hour period between Day -2 and dosing on Day 1 
in Period 1, and 24-hour period between Days 5 to 8 in Period 2.
Figure JPCB.6.1.
Study design.


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Abemaciclib (LY2835219)
6.2.1. Safety Extension Phase
Patients who participate in the safety extension phase of the study will receive an abemaciclib 
dose of 200 mg Q12H (or modified dose as applicable) on a 28-day cycle until discontinuation 
criteria are met (eg, disease progression, death, or unacceptable toxicity (Section 6.3). If 
interruptions in dosing are required for significant periods of time (> 14 days) continuation of 
treatment with abemaciclib may be considered if felt to be in the best interest of the patient’s 
care and upon discussion with the medical monitor. Tumor re-staging may be allowed and will 
be documented when necessary.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.  Any AEs 
discovered during the safety extension phase will be collected.
The patient’s participation in the safety extension period will be completed after therapy is 
discontinued.  A follow-up assessment should occur approximately 10 days after the last 
abemaciclib dose is given.  If a patient is required to begin a new treatment or investigational 
product, the follow-up assessment may take place sooner following discontinuation of study 
treatment.
While efficacy is not a primary objective of Study JPCB, responses will be followed and 
recorded by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria for solid 
tumors.  Response data will be collected and tabulated.
6.2.2. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) after all patients have completed treatment and their safety summary visit.  “End of 
trial” refers to the date of the last visit or last scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up.
6.2.3. Determination of Sample Size
Up to 48 patients may be enrolled in order that 22 patients complete Periods 1 and 2.
Caffeine
For caffeine area under the concentration time curve (AUC), the intra-subject variability 
(coefficient of variation) was estimated to be 21.0% (Blanchard and Sawers 1983); 22 patients 
will provide a precision of 0.13 on the log scale with 90% power. 
Warfarin
For warfarin AUC, the intra-subject variability (coefficient of variation) was estimated to be 7% 
(Steinijans et al. 1995); 22 patients will provide a precision of 0.04, with 90% power, which 
corresponds to 4.4% on the log scale. For warfarin Cmax, the intra-subject variability was 


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Abemaciclib (LY2835219)
estimated to be 8% (Steinijans et al. 1995); 22 patients will provide a precision of 5.0% on the 
log scale with 90% power.
Dextromethorphan 
For dextromethorphan AUC, the intra-subject variability (coefficient of variation) was estimated 
to be 33.7% (derived from a previous study); 22 patients will provide a precision of 0.20, with 
90% power, which corresponds to 22.4% on the log scale. For dextromethorphan Cmax, the 
intra-subject variability was estimated to be 32.1% (derived from a previous study); 22 patients 
will provide a precision of 21.3% on the log scale with 90% power.
Midazolam
For midazolam AUC, the intra-subject variability (coefficient of variation) was estimated to be 
16.1% (derived from a previous study); 22 patients will provide a precision of 0.10, with 90% 
power, which corresponds to 10.4% on the log scale. For midazolam Cmax, the intra-subject 
variability was estimated to be 26.4% (derived from a previous study); 22 patients will provide a 
precision of 17.3% on the log scale with 90% power.
ABPM
Using an intra-subject standard error of 9.48 mmHg in systolic blood pressure from Study JPBA, 
a sample size of 22 completed patients will provide more than 90% coverage probability that the 
half-width of the 90% confidence interval (CI) for the difference in means will be approximately 
6 mmHg. The intra-subject standard error of diastolic blood pressure was estimated to be 
6.78 mmHg and will provide more than 90% coverage probability that the half-width of the 90% 
CI is in difference of means to be 4.3 mmHg.
6.3.
Discontinuations
The reason for and date of discontinuation will be collected for all patients.  The date of 
discontinuation (for any of the above reasons) from study treatment is to be reported on the 
electronic case report form (eCRF).  Patients who discontinue will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
6.3.1. Discontinuation of Patients Inadvertently Enrolled
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified. A discussion must occur between 
the sponsor CRP and the investigator to determine whether the patient may continue in the study, 
with or without investigational product.  Inadvertently enrolled patients may be maintained in the 
study and on investigational product when the Lilly CRP agrees with the investigator that it is 


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Abemaciclib (LY2835219)
medically appropriate for that patient. The patient may not continue in the study with or without 
investigational product if the Lilly CRP does not agree with the investigator’s determination that 
it is medically appropriate for the patient to continue. The investigator must obtain documented 
approval from the Lilly CRP to allow the inadvertently enrolled patient to continue in the study 
with or without investigational product.
6.3.2. Discontinuation of Patients from Study or Study Drug 
Patients who are discontinued from the study drug early will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
In addition, patients will be discontinued from the study drug and/or from the study in the 
following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
the investigator/physician decides that the patient should be discontinued from the 
study or study drug(s).
o
the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug(s) occurs prior to introduction of the other 
agent.

Patient Decision
o
the patient requests to be discontinued from the study or study drug.

Sponsor Decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP.

The patient has evidence of progressive disease.

The patient experiences unacceptable toxicity.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).
6.3.3. Patients Lost to Follow-Up
A patient would 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.


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Abemaciclib (LY2835219)
6.3.4. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for any 
scientific, medical, safety, regulatory, ethical, or other reasons consistent with applicable laws, 
regulations, and GCP.
6.3.5. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges discontinuation of the study necessary for any scientific, medical, safety, 
regulatory, ethical, or other reasons consistent with applicable laws, regulations, and GCP.


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Abemaciclib (LY2835219)
7. Treatment
7.1.
Materials and Supplies
Abemaciclib
Abemaciclib will be supplied as 50-mg capsules as the 25% w/w formulation (C3) for oral 
administration.  The capsules should be stored at room temperature according to the range 
provided on the product label and not opened, crushed, or dissolved.
Drug Cocktail
The drug cocktail containing caffeine, warfarin, dextromethorphan, and midazolam will be 
sourced by the study sites.
Caffeine
Commercially available caffeine citrate solution (20 mg/mL) for oral administration.
Warfarin
Commercially available warfarin (brand name Coumadin) as 5-mg tablets for oral 
administration.
Dextromethorphan 
Commercially available dextromethorphan as 15-mg liquid gel capsules for oral administration.
Midazolam
Commercially available midazolam syrup (2 mg/mL) for oral administration. 
All clinical study materials will be labeled according to the country’s regulatory requirements 
and stored according to the manufacturer’s instructions.
7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agent(s) to the site personnel or patient,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensation, and collection, and returning or 
destroying all unused medication to Lilly or its designee at the end of the study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
The first dose of abemaciclib will be given to the patient at the site.  The date and time of the 
dose should be documented in the research records.  While patients are outside the study site, 
they will be asked to self-administer doses of abemaciclib. The actual time of all abemaciclib 


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Abemaciclib (LY2835219)
dose administrations will be recorded in the patients’ diary during Period 1, Period 2, Period 3,
and Period 4.
7.2.1. Dosing Schedule
Period 1
On Day 1, 10 mL of 20-mg/mL caffeine citrate solution (100 mg caffeine), 2 × 5-mg tablets of 
warfarin, 2 × 15-mg liquid gel capsules of dextromethorphan, and 0.1 mL of 2-mg/mL 
midazolam syrup will be coadministered orally with approximately 240 mL of room temperature 
water, in a sitting position.
Patients should not consume food beginning 1 hour before and ending 1 hour after taking study 
drugs.
Period 2
On Days 1 to 12, 4 × 50-mg capsules of abemaciclib will be administered orally in the morning 
and evening with approximately 240 mL of room temperature water, in a sitting position.  
Abemaciclib should be taken at approximately the same time each day.  On Day 8, abemaciclib 
will be coadministered with 10 mL of 20-mg/mL caffeine citrate solution (100 mg caffeine), 
2 × 5-mg tablets of warfarin, 2 × 15-mg liquid gel capsules of dextromethorphan, and 0.1 mL of 
2-mg/mL midazolam syrup with approximately 240 mL of room temperature water, in a sitting 
position.  On Day 8 (coadministration with the drug cocktail), patients should not consume food 
beginning 1 hour before and ending 1 hour after taking study drugs.  
If a patient has an INR >2 after the first dose of warfarin, the patient may receive the drug 
cocktail without warfarin in Period 2 and receive abemaciclib once their INR has stabilized or 
returned to baseline.  
If a patient misses or vomits a dose of abemaciclib, that dose should be omitted (see Section 7.6
for compliance).  Patients will be asked to take each dose of study drug within +/- 2 hours of the 
planned dose time or consider the dose a missed dose. 
Periods 3, 4 and Safety Extension Phase  
From Cycle 1, Period 3 and on Days 1 to 28 in each cycle (Cycle 2 onwards), 4 × 50-mg capsule 
of abemaciclib will be taken orally in the morning and evening.  Abemaciclib should be taken at 
approximately the same time each day.  
A delay of 7 days in the start of a cycle (Day 1) for justifiable reasons (for example, inclement 
weather, holidays, or weekends) other than toxicity will be permitted and does not constitute a 
protocol violation.  A delay of 14 days in the start of a cycle (Day 1) to allow for recovery from 
toxicity will be permitted and does not constitute a protocol violation.  A longer delay may be 
allowed for the start of Cycle 1 (or Period 2), if necessary.  In cases where Cycle 1 (abemaciclib 
dosing) is significantly delayed from tumor staging during screening, baseline staging may be 
repeated. If there is any question, this may be discussed with the study medical monitor.


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If a patient requires omission of >25% of doses for tolerability at the reduced dose level, then 
treatment may continue if the investigator determines that the patient is receiving clinical benefit.
For patients requiring dose reduction(s) due to toxicity, reescalation to a prior dose level is not 
permitted without prior discussion and agreement with the Lilly CRP/CP or designee.
7.2.2. Dose Adjustments
Period 2
Dose interruptions or adjustments should be avoided in Period 2 but are allowed if necessary due 
to toxicity.
Upon the first sign of diarrhea, patients should be treated with loperamide and supportive care 
before the abemaciclib dose is omitted or adjusted (see Section 8.1.3.4.1).  If diarrhea is Grade 2 
or worse and does not resolve within 1 day with loperamide and supportive care treatment, then 
the dose should be suspended (until the toxicity resolves to at least Grade 1) and the dose of 
study drug may be reduced to 150 mg Q12H.  Further dose modification due to diarrhea should 
be discussed with the Lilly CRP/CP or designee, and continuation in study determined jointly as 
described in Section 7.6.
If it is deemed the patient must be replaced due to dosing omissions or dose reductions, the 
patient may continue on study to receive abemaciclib and complete all other study procedures for 
secondary and exploratory study objectives.
Periods 3, 4, and Safety Extension
Dose adjustments are allowed during Period 3, Period 4, and the safety extension phase, both 
within a cycle and between cycles following Table JPCB.7.1.  Study drug dose reductions are 
outlined in Table JPCB.7.2.
Before the start of each cycle, drug-related toxicities (except alopecia and fatigue) must resolve 
to either baseline or at least Grade 2.  The start of a cycle may be delayed up to 14 days to allow 
sufficient time for recovery.  Patients not recovering from toxicity within 14 days should be 
discontinued from the study.


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Abemaciclib (LY2835219)
Table JPCB.7.1.
Toxicity Dose Adjustments and Delays of Abemaciclib for 
Study JPCB
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Neutropenia/thrombocytopenia
Section 7.2.2.1
Grade 3 which lasts 7 days
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion.
Neutropenia/thrombocytopenia 
Section 7.2.2.1
Recurrent Grade 3 (on later cycle)
which lasts 7 days
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion.
Neutropenia/thrombocytopenia  
Section 7.2.2.1
Grade 4 which lasts 3 days
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic toxicity:  Patient 
requires administration of 
white blood cell growth 
factors
Section 7.2.2.1
Regardless of severity
(Growth factors use according to 
ASCO Guidelines)
Dose MUST be suspended 
for at least 48 hours after 
the last dose of white blood 
cell growth factors was 
administered and until 
toxicity resolves to at least 
Grade 2.
Dose MUST be reduced 
by 1 dose level unless 
already performed for 
incidence of toxicity that 
lead to the use of white 
blood cell growth factor.
Nonhematologic Toxicity 
(except diarrhea)
Section 7.2.2.2.1
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 7 days 
to baseline or Grade 1
Dose MAY be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Nonhematologic Toxicity 
Section 7.2.2.2.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Section 7.2.2.2.2
Requires hospitalization or Grade 3 
or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Section 7.2.2.2.2
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 
24 hours to at least Grade 1
Dose SHOULD be 
suspended until toxicity 
resolves to at least Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Diarrhea
Section 7.2.2.2.2
Diarrhea recurs despite maximal 
supportive measures after resuming 
same dose level after initial 
Grade 2 diarrhea
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Abbreviation:  ASCO = American Society of Clinical Oncology.
Note:  MAY = per the investigator’s clinical judgment; SHOULD = not mandatory but highly recommended; 
MUST = mandatory.


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Table JPCB.7.2.
Dose Adjustments for Abemaciclib during Period 3, Period 4, and 
Safety Extension
Dose adjustment
Oral dose
Frequency
0
200 mg
Q12H
1
150 mg
Q12H
2
100 mg
Q12H
3
50 mg
Q 12H
7.2.2.1.
Hematologic Toxicity
If a patient experiences Grade 4 neutropenia/thrombocytopenia, which lasts 3 days, then dosing 
must be suspended (until the toxicity resolves to at least Grade 2) and the dose of abemaciclib 
must be reduced as outlined in Table JPCB.7.2.
If a patient experiences Grade 3 neutropenia/thrombocytopenia, which lasts 7 days, then dosing 
must be suspended (until the toxicity resolves to at least Grade 2) and the dose of abemaciclib 
may be reduced by 1 dose level.  If the patient experiences a recurrent episode of Grade 3 
neutropenia/thrombocytopenia in a later cycle, which lasts 7 days, then dosing must be 
suspended (until the toxicity resolves to at least Grade 2) and the dose of abemaciclib may be 
reduced by 1 dose level.
If a patient requires administration of white blood cell growth factors, the dose of study drug 
must be suspended for at least 48 hours after the last dose of white blood cell growth factors was 
administered and until toxicity resolves to at least Grade 2, then reduced by 1 dose level, if a 
dose reduction for the specific event necessitating the use of the white blood cell growth factors 
has not already occurred.
Before the start of each cycle, hematologic toxicity possibly related to abemaciclib must resolve 
to at least Grade 2.
7.2.2.2.
Nonhematologic Toxicity
7.2.2.2.1. Dose Adjustments for Other Nonhematologic Toxicity
If a patient experiences ≥ Grade 3 nonhematologic toxicity possibly related to abemaciclib, then 
dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 1) and 
the dose of abemaciclib must be reduced as outlined in Table JPCB.7.2.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 7.2.2.2.2) possibly related to abemaciclib that does not resolve with maximal 
supportive measures within 7 days to either baseline or Grade 1, then dosing may be suspended 
(until the toxicity resolves to either baseline or at least Grade 1) and the dose of abemaciclib may 
be reduced as outlined in Table JPCB.7.2.
Before the start of each cycle, nonhematologic toxicity (except alopecia and fatigue) possibly 
related to abemaciclib must resolve to either baseline or at least Grade 1.


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Abemaciclib (LY2835219)
7.2.2.2.2. Diarrhea
A patient experiencing diarrhea requiring hospitalization (irrespective of grade, that is, requiring 
intravenous [IV] rehydration) or severe diarrhea (Grade 3 or 4) must have study treatment 
suspended (until the toxicity resolves to at least Grade 1) and should have the study drug dose 
reduced by 1 dose level as outlined in Table JPCB.7.2.
If a patient experiences persistent or recurrent diarrhea that does not resolve with maximal 
supportive measures (refer to Section 8.1.3.4.1) within 24 hours to at least Grade 1, then study 
treatment should be suspended (until the toxicity resolves to at least Grade 1) and the dose of 
study drug may be reduced by 1 dose level as outlined in Table JPCB.7.2 at the discretion of the 
investigator.  If the same dose level was resumed and diarrhea recurs despite maximal supportive 
measures, the dose of study drug must be reduced by 1 dose level as outlined in Table JPCB.7.2.
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive the fixed-sequence of 
treatments in this study.
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study, except for those 
described in Inclusion Criterion [7] in Section 6.1.1.
The need for radiotherapy will be cause for early discontinuation from the study, with the 
exception of palliative radiotherapy, which is permitted if not being utilized for disease 
progression.  In addition, any disease progression requiring other forms of specific antitumor 
therapy will also necessitate early discontinuation from the study.
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications must be captured on the case report form (CRF).  Patients will be provided with a 
paper diary in which to record the start and stop times of new concomitant medications and
medications taken as needed from the baseline visit until the end of Period 2.
7.5.1. Interactions of Concomitant Medications with Abemaciclib
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.5.1.1.
CYP Interactions
Agents considered to be CYP3A inhibitors and CYP3A inducers are excluded from use 14 days 
before the first dose of study drug and through the end of Period 2.  It is recommended that 
CYP3A inducers and CYP3A inhibitors, as well substrate drugs of CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6, and CYP3A with narrow therapeutic indices be avoided.


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Abemaciclib (LY2835219)
7.5.1.2.
Endocrine Therapy
Since functional loss of Rb activity is associated with resistance to hormonal therapy in breast 
and prostate cancers (reviewed in Knudsen and Knudsen 2008), patients with prostate cancer 
progressing on endocrine therapies may in certain cases have that treatment continued while 
receiving study drug.  Patients with breast cancer who are receiving aromatase inhibitors 
(letrozole, anastrozole, or exemestane) or antiestrogens (fulvestrant or tamoxifen) may not 
participate, as the abemaciclib starting dose for this subset of patients is 150mg Q12H. Patients 
with prostate cancer may continue to receive luteinizing-hormone-releasing hormone analogue 
therapy (leuprolide, goserelin, or triptorelin) during the study.  In addition, hormone replacement 
therapy initiated before study entry may be continued.
7.5.1.3.
Growth Factors
Patients should receive full supportive care during the trial. Growth factors should not be 
administered to enable a patient to satisfy study inclusion criteria. Growth factors may be used 
in accordance with American Society of Clinical Oncology (ASCO) guidelines (Smith et al. 
2015) if clinically indicated.  Dosing of study drug must be suspended if the administration of 
white blood cell 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 white 
blood cell growth factors, the dose of study drug must be reduced by one dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.  Before the start of each cycle, hematologic toxicity must resolve to either baseline or 
at least Grade 2.
Erythroid-stimulating agents (ESAs, including erythropoietin and darbepoetin) or transfusions 
should not be administered to enable a patient to satisfy study inclusion criteria.  Both ESAs and 
transfusion therapy may be used in accordance with American Society of Hematology and 
ASCO guidelines (Rizzo et al. 2010), if clinically indicated.
7.5.2. Interactions of Concomitant Medications with Drug Cocktail
Caffeine, warfarin, dextromethorphan, and midazolam are substrates of CYP1A2, CYP2C9, 
CYP2D6, and CYP3A, respectively.  Thus, drugs that are known inducers and/or inhibitors of 
CYP1A2, CYP2C9, CYP2D6, and CYP3A are specifically excluded prior to 14 days of drug 
cocktail administration and throughout Periods 1 and 2.  Since caffeine is one of the substrate 
drugs being evaluated in this study, consumption of caffeine-containing beverages and foods 
must be avoided at least 5 days prior to drug cocktail administration and throughout Periods 1 
and 2. Subjects must also refrain from consuming grape fruit juice, Seville oranges, and St. 
John’s wort 14 days prior to the cocktail administration and throughout Periods 1 and 2.
The investigator should refer to the prescribing label for each drug within the cocktail for 
additional information about the potential for drug interactions.  
For information about contraindications of other drugs indicated in combination with the drug 
cocktail, investigators should refer to the contraindications section of the package inserts.


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Abemaciclib (LY2835219)
7.6.
Treatment Compliance
The drug cocktail will be administered orally twice at the study site, under the direction of the 
investigator in Periods 1 and 2.  As a result, a patient’s compliance with drug cocktail 
administration is ensured for these periods.  
Patients are expected to be compliant with all doses of study medication.  Patients should attend 
scheduled clinic visits and must comply with study criteria under their control.  Deviation(s) 
from the prescribed dosage regimen should be recorded on the CRF.  
Patient compliance with abemaciclib will be assessed when patients return to the clinic during 
Periods 2, 3, and 4.  Compliance will be assessed through review of patient diary, direct 
questioning, and counting of returned tablets.  Deviation(s) from the prescribed dosage regimen 
should be recorded on the CRF.
If a patient misses 2 or more of the planned doses of abemaciclib within 3 consecutive days prior 
to the drug cocktail dose in Period 2, the patient will need to be replaced, or dosing with the drug 
cocktail may be delayed to allow for adequate exposure. Delay should only occur on a 
case-by-case basis following discussion and agreement with the Lilly CRP/CP or designee. 
Likewise, if dose reduction is required to less than 150mg Q12H or if dose interruptions or 
omissions are deemed necessary during Period 2 for greater than 4 consecutive doses at any time, 
the patient may recommence dosing of abemaciclib with delay of Period 2 drug cocktail dosing 
so that abemaciclib steady state is achieved (5-7 days). 
During the safety extension phase, patient compliance with abemaciclib will be assessed and 
recorded at each visit by counting returned capsules. 
Similarly, a patient may be considered noncompliant if he or she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication.  Any 
missed doses will be omitted and not replaced.  In the event of a missed dose, a patient should 
resume and continue dosing beginning with the next scheduled dose.  Potential discontinuation 
of a patient due to study drug noncompliance will be discussed between the investigator and the 
Lilly CRP/CP or designee before making the final determination for discontinuation. If a patient 
is discontinued because of study drug noncompliance, the patient may be replaced.
The following procedures will be employed to ensure appropriate drug accountability:
•
Drug accountability will be emphasized at the study initiation.
•
Drug accountability will be monitored throughout the study.
•
Each patient should be instructed to return all study drug packaging and unused material 
to the study site at each visit.  The study site will keep a record of all study drug dispensed to and 
returned by the patients throughout the study.  Study site personnel will return or destroy (as 
requested) all unused study drug for all patients.


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Abemaciclib (LY2835219)
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug.
Any patient who does not complete the drug interaction portion of the study (Periods 1 and 2, 
including all of the PK sampling) at a dose of either 200 mg Q12H or 150 mg Q12H will be 
deemed nonevaluable for the drug interaction analyses and should be replaced after consultation 
with the investigator(s) and the Lilly CRP/CP or designee to ensure adequate PK data to evaluate 
the drug interaction. Patients who are deemed nonevaluable for drug interaction analyses may 
continue on study, receive abemaciclib, and complete all other study procedures for secondary 
and exploratory study objectives. 


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8. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
The safety and tolerability of abemaciclib have been assessed in nonclinical toxicology studies 
and the results from these studies are detailed in the IB.  This Phase 1 study contains detailed 
safety monitoring that will permit initial characterization of the safety profile of abemaciclib in 
patients.  Study procedures and their timing, including collection of blood and urine samples, are 
described in the Study Schedule (Attachment 1).
Standard laboratory tests, including chemistry, hematology, and urinalysis panels, will be 
performed.  A pregnancy test will be administered if applicable.  Other clinical laboratory tests 
will also be collected.  Attachment 2 lists the specific tests that will be performed for this study. 
Vital signs, ABPM, and ECGs will also be performed.  
8.1.1. Safety Data Collection and Review
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 investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JPCB.8.1 presents a summary of AE and SAE reporting guidelines.  
8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
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 medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
vital sign measurements, and so on that occur should also be reported to Lilly or its designee as 
an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect.


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Abemaciclib (LY2835219)
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the Study Schedule.  Patients 
will be provided with a paper diary in which to record the start and stop times of all AEs 
experienced from the baseline visit until the end of Period 2.
The Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will serve as the 
reference document for choosing appropriate terminology for, and grading the severity of, all 
AEs and other symptoms.  All AEs observed will be graded using CTCAE v 4.0.  Any minor 
version of CTCAE v 4.0 (for example, Version 4.03) may be used for this study.  Minor CTCAE 
v 4.0 updates from the NCI will not necessitate a protocol amendment.  For AEs without 
matching terminology within the CTCAE v 4.0 criteria, the investigator will be responsible for 
selecting the appropriate system organ class and assessing severity grade based on the intensity 
of the event.  Note that both CTCAE term (actual or coded) and severity grade must be selected 
by study site personnel and collected on the CRF.  This collection is in addition to verbatim text 
used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities dictionary.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breastfeeding should be collected, if feasible, for regulatory 
reporting and drug safety evaluation.
Upon documentation of pregnancy, the patient must be removed from the study and treatment 
with study drug(s) must be stopped immediately.
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition 
all AEs related to protocol procedures are reported to Lilly or designee.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via the eCRF the circumstances and data
leading to any such dosage reduction or discontinuation of treatment. 
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure or study drug via the eCRF.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.


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
Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1.
Serious Adverse Events
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for underlying preexisting conditions that are already 
recorded in the patient’s medical history at the time of study enrollment should not be considered 
SAEs.  Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

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. 
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor and the SAEs will be entered in the 
Lilly Safety System.


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Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the informed consent form (ICF).  For patients who do not 
enroll in the trial (that is, have not received at least 1 dose of abemaciclib), only AEs and SAEs 
related to protocol procedures are required to be collected.
8.1.2.2.2. On Study Treatment
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study drug 
to when he/she receives the last dose of study drug.
8.1.2.2.3. Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
during the follow-up visit must be reported to Lilly or its designee.  For patients not continuing 
in the safety extension phase, the follow-up visit should occur after a washout period of at least 
10 days from the last abemaciclib dose in Period 2.  For patients participating in the safety 
extension phase, a follow-up visit should occur approximately 10 days after the last abemaciclib 
dose.  At this follow-up visit, the patient will be required to have specific safety assessments 
(Attachment 1).  The timing of these safety assessments are outlined in Attachment 1.
Following the safety assessments, which mark the end of the follow-up visit, the patient will be 
discontinued from the study, unless there is an ongoing AE or SAE that is possibly related to 
study drug.  In this instance, the patient should be followed in subsequent follow-up visits until 
the event is resolved, the event is no longer considered to be drug-related, the event becomes 
stable or returns to baseline, a new treatment is initiated for the patient, or the patient dies or is 
lost to follow-up.
If it is deemed to be in the best interest of the patient to start a new anticancer treatment prior to 
the scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this 
case, the follow-up assessments should be completed prior to the initiation of the new therapy.
After the follow-up visit, AEs are not required to be reported unless the investigator feels the 
AEs were related to either study drug or a protocol procedure. If an investigator becomes aware 
of SAEs believed to be related to protocol procedures or study drug, the investigator should 
report the SAE to the sponsor, and the SAE will be entered in the Lilly Safety System.


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8.1.2.3.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the 
Development Core Safety Information or in the IB and that the investigator identifies as related 
to study drug or procedure.  The United States 21 CFR 312.32, the European Union Clinical 
Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulatory regulations and the associated detailed guidances.
8.1.2.4.
Summary of Adverse Event/Serious Adverse Event Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JPCB.8.1.
Table JPCB.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study JPCB
Timing
Types of AEs/SAEs Reported 
Prestudy (baseline assessments)
(Starts at the signing of informed consent and ends 
just before the first dose of study drug)
Preexisting conditions
All AEs/SAEs possibly related to protocol 
procedures
On therapy
(Starts at first dose of study drug(s) and ends at last 
dose of study drug[s])
All AEs/SAEs regardless of relatedness
Follow-up visit
End of Period 2:  starts after the last PK sample and 
ends when end of study safety assessments are 
completed
Safety extension:  starts just after the last dose of 
study drugs and ends when end of study safety 
assessments are completed
All AEs/SAEs regardless of relatedness
Subsequent follow-up visits, if necessary 
Ongoing or new AEs/SAEs possibly related to 
study drug or protocol procedures
Abbreviations:  AE = adverse event; PK = pharmacokinetic; SAE = serious adverse event.
8.1.3. Other Safety Measures
8.1.3.1.
Vital Signs
Blood pressure, pulse rate, and body temperature will be measured as specified in the Study 
Schedule and as clinically indicated (Attachment 1).
Blood pressure and pulse rate should be measured after at least 5 minutes supine,
semi-recumbent, or sitting; the position should be recorded.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between the sponsor and investigator.


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8.1.3.2.
Ambulatory Blood Pressure Monitoring
Blood pressure and pulse rate will be measured using an ABPM device over a 12-hour period for 
acclimation and over 24-hour periods for study assessments as specified in the Study Schedule 
(Attachment 1).
The ABPM device will be fitted to the patient’s nondominant arm and will record ambulatory 
blood pressure and pulse rate every 30 minutes during the day (for example, 0700 hours to 
2200 hours) and every 2 hours at night (for example, 2200 hours to 0700 hours). For each 
24-hour ABPM collection period, patients will be encouraged to maintain light activity (that is, 
walking) and keep their same routine during the ABPM collection period.  ABPM data will not 
be used for patient management.
8.1.3.3.
Electrocardiograms
For each patient, a 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Patients must be supine or semi-recumbent for approximately 5 to 10 minutes 
before ECG collection and remain supine or semi-recumbent but awake during ECG collection.  
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs (more replicates) than expected at a particular time point is allowed to 
ensure high quality records. 
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation.
8.1.3.4.
Bowel Habits
8.1.3.4.1. Diarrhea Management
In the event of diarrhea, supportive measures should be initiated as early as possible.  These 
include the following: 

Upon enrollment, patients should receive instructions in the event that a patient would 
experience diarrhea 

At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (e.g. 
loperamide) and notify the investigator/site for further instructions and appropriate 
follow-up. 

Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear liquids 
per day). 

Site personnel should assess response within 1 day. 


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
If diarrhea does not resolve with anti-diarrheal therapy within 1 day to either baseline or 
Grade 1, abemaciclib should be suspended or the dose may be reduced until diarrhea is 
resolved to baseline or Grade 1 (see Section 7.2.2). 

When abemaciclib recommences, dosing should be adjusted as outlined in 
Table JPCB.7.1. 
In severe cases of diarrhea, measuring neutrophil counts and body temperature and proactively 
managing diarrhea with anti-diarrheal agents should be considered.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed.
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given IV fluid (IV hydration) and electrolyte replacement.
Osmolality will be measured to assist with evaluation of any change in volume.  In severe cases 
of diarrhea, the measuring of neutrophil counts and body temperature and proactive management 
of diarrhea with anti-diarrheal agents should be considered.
8.1.3.4.2. Patient Diary
An electronic patient diary to collect date and time of bowel movements, a Bristol Stool Chart,
and drug administration will be completed daily by the patient, starting at baseline and required 
through end of Period 2.  Patients participating in Period 3 and 4 should continue completing 
diary entries through end of Period 4.  Patients will also receive a paper diary in which to record 
the start and stop times of all AEs, new concomitant medications and medications taken as 
needed from the baseline visit until the end of Period 2.
8.1.3.4.3. Patient Reported Outcomes
Collection of PRO data will help characterize diarrhea as an exploratory analysis based on:

Single daily items generated by the team

Weekly items based on the FACIT-D
Patient reported questionnaires should be completed by patients when a language translation is 
available in which the patient is fluent or literate.
At each time point identified in the Study Schedule (Attachment 1), a copy of the PRO items 
should be completed by the patient prior to extensive interaction with site staff and study drug 
administration.
8.1.4. Safety Monitoring
The Lilly CRP/Clinical Research Scientist (CRS) will monitor safety data throughout the course 
of the study.
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical research scientist, and periodically review:


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
trends in safety data,

laboratory analytes,

AEs,

if a study patient experiences elevated ALT >5X ULN and elevated total bilirubin >2X 
ULN, clinical and laboratory monitoring should be initiated by the investigator. 
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CP or designee regarding collection of specific 
recommended clinical information and follow-up laboratory tests (see Attachment 3).
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to comparator drugs or concomitant drugs are reported directly to the 
manufacturers of those drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.  
Attachment 6 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 


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are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Samples for Drug Concentration and Pharmacodynamic 
Measurements 
8.2.2.1.
Pharmacokinetic Samples
At the visits and times specified in the Study Schedule (Attachment 1), venous blood samples 
will be collected to determine the plasma concentrations of abemaciclib, caffeine, S-warfarin, 
dextromethorphan, and midazolam.  A maximum of 3 samples may be collected at additional 
time points during the study if warranted and agreed upon between both the investigator and 
Lilly.  Instructions for the collection and handling of blood samples will be provided by the 
sponsor.  The actual date and time (24-hour clock time) of each sampling will be recorded.
These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of each analyte will be assayed using a validated method.
The PK samples will be stored at a facility designated by the sponsor.
The remaining plasma from the samples collected for PK may be pooled and used for 
exploratory metabolism work as deemed appropriate.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.  
8.2.2.2.
Pharmacodynamic Samples
At the visits and times specified in the Study Schedule (Attachment 1), venous blood samples 
will be collected to determine INR (see Attachment for the blood sampling summary).  Analysis 
of PT or INR will be performed by local labs. Local labs for PT or INR will be collected for 
patient management and PD analyses. 
Guidance Regarding Elevation of the INR
Patients will receive a single dose of warfarin (10 mg) as part of the drug cocktail in Period 1 and 
Period 2:
Period 1: If a patient has an INR >2 after the first dose of warfarin, the patient should not 
receive warfarin again in the drug cocktail in Period 2, but may be allowed to enter 
Period 2 and receive abemaciclib once their INR has stabilized or returned to baseline.  
The patient may be replaced.
Period 2: For any patient found to have an INR 4 after the administration of warfarin in 
Period 2, further abemaciclib dosing should be held until the INR stabilizes or returns to 
baseline (refer to Section 7.2.2).
Additionally the following guidance is provided (Cushman et al. 2014):


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
If the INR is >4 but <9, and there is no significant bleeding, oral vitamin K (1 to 2.5 mg) 
is recommended.

If the INR is 9, and there is no significant bleeding, oral vitamin K (2.5 to 5 mg) is 
recommended.

In the case of significant bleeding, additional supportive care is recommended (for 
example, prothrombin complex concentrates and vitamin K 10 mg, by oral or slow 
intravenous infusion).
The INR should be repeated according to the Study Schedule (Attachment 1); additional INR 
samples may be collected daily, if needed, until the INR has returned to baseline. The final 
decision as to whether to administer vitamin K or other therapy should take into account the 
investigator’s assessment of the patient.
Lilly should be notified in the case of the INR elevations as described above. 
The samples will be identified by the patient number (coded) and stored for up a maximum of 
1 year after the last patient visit for the study at a facility selected by the sponsor.  
8.2.3. Samples for Evaluation of Renal Function
At the visits and times specified in the Study Schedule (Attachment 1), venous blood samples 
(approximately 5 mL each) will be collected to determine serum concentrations of renal markers, 
including creatinine, cystatin-C, and NGAL, and urine samples (at least 5 mL and up to 120 mL) 
will be collected to determine urinary concentrations of renal markers, including creatinine, 
KIM-1, and NGAL.  These laboratory tests will be performed by a central laboratory selected by 
Lilly.  Other markers of renal function may be evaluated if deemed appropriate.
The samples will be identified by patient number and will be stored for up to a maximum of 
15 years after the last patient visit for the study.
8.2.4. Samples for Tailoring Biomarkers 
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.  
Samples will be stored and analysis may be performed on biomarker variants thought to play a 
role in cancer, including, but not limited to, genes involved in regulation of the cell cycle to 
evaluate their association with observed clinical outcomes to abemaciclib. 
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to study drug.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 


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drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
8.2.5. CYP Genotype Evaluation
A single blood sample will be collected from patients to determine the CYP2C9, CYP2D6, 
CYP3A4, and CYP3A5 genotype status during screening.
8.3.
Efficacy Evaluations
Refer to Attachment 1 for details regarding the timing of specific efficacy measures.  
Tumor assessments will be conducted per standard of care.  Response and progression for tumors 
will be evaluated using RECIST version 1.1 (Eisenhauer et al. 2009).
8.3.1. Prestudy
No more than 4 weeks before enrolling in the study, each patient’s full extent of disease will be 
assessed by 1 or more of the following relevant radiological tests for tumor measurement:

computed tomography (CT) scan

magnetic resonance imaging (MRI)

chest x-ray

bone scan
No more than 2 weeks (14 days) prior to enrolling in the study, each patient’s full extent of 
disease will also be assessed with:  

tumor measurement of palpable or visible lesions (refer to RECIST 1.1)

evaluation of tumor markers, if indicated
8.3.2. During the Study
At the intervals stated in the Study Schedule (Attachment 1), efficacy will be examined in each 
patient by the following evaluations:  

ECOG performance status (Attachment 5) 

tumor measurement of palpable or visible lesions  

imaging studies of involved disease sites should be repeated in appropriate patients per 
standard of care, approximately every 2 cycles (approximately 4 to 8 weeks).  This 
should include the same methods and techniques used at baseline to ensure that any 
response may be validated.  


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All lesion assessments, whether by physical examination or radiological methods, must be 
repeated by the same method at least 4 weeks following the initial observation of an objective 
response for response confirmation.
8.3.3. Poststudy Follow-Up
The poststudy evaluation period will begin when the patient discontinues treatment from the 
safety extension period for any reason and will end approximately 10 days following the last 
abemaciclib dose, when another therapy is initiated, or when the patient dies.  Reasonable efforts 
will be made to follow any patient with an ongoing complete response or partial response at the 
time of study discontinuation.  In appropriate patients, tumor measurements and imaging studies 
will be performed at 4- to 8-week intervals up until 30 days after final abemaciclib dose, when 
another therapy is initiated, when there is disease progression, or when the patient dies.  All 
patients will be evaluated for ECOG performance status (Attachment 5) at the poststudy
follow-up visit.
8.4.
Procedure/Sampling Compliance
Every attempt will be made to enroll patients who have the ability to understand and comply 
with instructions.  Noncompliant patients may be discontinued from the study.
The collection times of safety assessments, PK samples, and efficacy measurements are given as 
targets, to be achieved within reasonable limits.  The scheduled time points may be subject to 
minor alterations; however, the actual collection time must be correctly recorded on the eCRF.
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.


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9. Data Management Methods
9.1.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection

conduct a quality review of the database. 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable IRB/ERBs 
with direct access to the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome measures (for example, a rating scale), a daily dosing schedule or an
event diary. 
If information reported during an office visit differs from that recorded in the paper diaries, the 
source data (collected during patient interview) will supersede for purposes of collection in the 
CRF.
For data handled by a data management third-party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to the Lilly data 
warehouse, using standard Lilly file transfer processes.


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For data handled by the sponsor internally, CRF data and some or all data that are related will be 
managed by the sponsor and stored electronically in the sponsor’s system.
9.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central vendor’s database 
system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.  
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly data warehouse. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Data from ePRO forms (if used) will be transferred from the ePRO vendor to the Lilly data 
warehouse.


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10.
Data Analyses
10.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
CRP/CP or designee, pharmacokineticist, and statistician.  The CRP/CP and statistician will also 
be responsible for the appropriate conduct of an internal review for both the final study report 
and any study-related material to be authorized by Lilly for publication.
Pharmacokinetic analyses will be conducted on data from patients who have received at least 
1 dose of the study drug and have had samples collected.  
10.2. Patient Disposition
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
10.3. Patient Characteristics
Patient characteristics will include a summary of the following:

patient demographics including age, sex, screening height and weight, and screening 
body mass index will be reported

baseline disease characteristics

prior disease-related therapies 

concomitant medications.
Other patient characteristics will be summarized as deemed appropriate.
10.4. Safety Analyses
All patients who receive at least 1 dose of study drug will be evaluated for safety and toxicity.  
Adverse event terms and severity grades will be assigned by the investigator using CTCAE, 
Version 4.0).
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

dose adjustments 

clinical laboratory values including markers of renal function

vital signs 

ABPM data

ECGs

bowel habit data
-
diarrhea diary and stool assessment
-
diarrhea-related ePRO items


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An exploratory safety analysis will assess the impact of abemaciclib on markers of renal 
function, levels of creatinine, cystatin-C, KIM-1, and NGAL at predose (baseline) will be 
compared to postdose levels and results will be summarized using standard descriptive statistics.
Further analysis details will be described in the statistical analysis plan. 
10.5. Pharmacokinetic Analyses
Pharmacokinetic parameter estimates for caffeine, S-warfarin, dextromethorphan, and 
midazolam will be calculated by standard noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax, AUC from zero to infinity (AUC[0-∞]), and 
tmax.  Other noncompartmental parameters, such as AUC from time zero to time t, where t is the 
last time point with a measurable concentration (AUC[0-tlast]), time of t1/2, apparent clearance, 
and apparent volume of distribution may be reported.  Additional exploratory analyses on the 
components of the drug cocktail or abemaciclib will be performed if warranted by data.
Pharmacokinetic parameter estimates will be evaluated to delineate effects of drug interaction. 
Caffeine, warfarin, dextromethorphan, and midazolam administered in the absence of 
abemaciclib will represent the reference treatments and be analyzed separately.  Each drug 
administered with abemaciclib will represent the test treatments.  Log-transformed Cmax and 
AUC(0-∞) estimates will be evaluated in a linear mixed-effects analysis of variance model with 
a fixed effect for treatment and a random effect for subject.  The treatment differences will be 
back-transformed to present the ratios of geometric means and the corresponding 90% CIs.
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs, and p-values from the Wilcoxon test will be 
calculated.
The inter- and intra-subject variability will be reported for each probe drug.
Trough plasma concentrations of abemaciclib will be listed.
10.6. Pharmacodynamic Analyses
Area under the INR curve (AUCINR) and maximum observed INR response (INRmax) will be 
calculated to quantify the action of warfarin.
The PD parameters AUCINR and INRmax will be evaluated statistically to delineate the effect of 
abemaciclib on INR.  A linear mixed-effects model with log-transformed PD parameter as a 
response variable, predose INR as a covariate, treatment as a fixed effect, and subject as a 
random effect.  For each of these PD parameters, the statistical inference will be made using the 
test treatment of warfarin + abemaciclib and the reference treatment of warfarin in the absence of 
abemaciclib.  The geometric means for the treatments and the ratios of geometric means for 
AUCINR and INRmax, between the test and reference treatments with 90% CIs will be established.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
Page 55
Abemaciclib (LY2835219)
10.7. Efficacy
The study was not designed to make an efficacy assessment.  However, any tumor response data 
will be tabulated.
10.8. Interim Analyses
An interim analysis, which will serve as the final analysis for the primary objective, is planned 
for this study.  This interim analysis will be completed after the last patient has completed 
Period 2.
Patients will be allowed to continue receiving abemaciclib during Period 3, 4, and the safety 
extension phase until discontinuation criteria are met (such as progressive disease or 
unacceptable toxicity).  A final analysis and final study report will be completed after the last 
patient visit has occurred for this extension phase.
Two additional interim analyses may be conducted:  one analysis will be conducted after 
approximately half of the patients have completed Periods 1 and 2, as a preliminary assessment 
of the magnitude of any observed effect on blood pressure.  No changes to the study design are 
planned.  Another analysis will be conducted after the last patient has completed Period 4 and a 
preliminary study report will be written.  
Unplanned interims may be conducted if deemed necessary by Lilly study team.
This is an open-label study.  Data may be analyzed while the trial is ongoing.  An Assessment 
Committee will not be formed.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
11.
Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient or legal representative before the study is started.  This includes obtaining the appropriate 
signatures, time of consent, and dates on the ICF prior to the performance of any protocol 
procedures and prior to the administration of study drug. 
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the ICH guideline on GCP.  
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
11.3. Regulatory Considerations
This study will be conducted in accordance with:
1) 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 
2) the ICH GCP Guideline [E6]
3) applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the sponsor will be assigned to a TPO.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data.
11.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
11.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
11.3.3. Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
12.
References
Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin 
Pharmacol. 1983;24(1):93-98.
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, 
Version 5, DCTD, NCI, NIH, DHHS. 2009. Draft 2015.
Cushman M, Lim W, Zakai, NA.  Clinical Practice Guide on Antithrombotic Drug Dosing and 
Management of Antithrombotic Drug-Associated Bleeding Complications in Adults 
http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/2869.aspx. February 
2014.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
EMA CPMP/EWP/560/95/Rev. 1 Corr. 2.  Guideline on the investigation of drug interactions. 
2012.
Goh BC, Reddy NJ, Dandamudi UB, Laubscher KH, Peckham T, Hodge JP, Suttle AB, 
Arumugham T, Xu Y, Xu CF, Lager J, Dar MM, Lewis LD. An evaluation of the drug 
interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine 
kinase inhibitor, using a modified Cooperstown 5 + 1 cocktail in patients with advanced solid 
tumors. Clin Pharmacol Ther. 2010;88(5):652-659.
Imamura Y, Murayama N, Okudaira N, Kurihara A, Okazaki O, Izumi T, Inoue K, Yuasa H, 
Kusuhara H, Sugiyama Y. Prediction of fluoroquinolone-induced elevation in serum creatinine 
levels: a case of drug-endogenous substance interaction involving the inhibition of renal 
secretion. Clin Pharmacol Ther. 2011;89(1):81-88.
Knudsen ES, Knudsen KE. Tailoring to RB: tumour suppressor status and therapeutic response. 
Nat Rev Cancer. 2008;8(9):714-724.
Lepist E-I, Zhang X, Hao J, Huang J, Kosaka A, Birkus G, Murray BP, Bannister R, Cihlar T, 
Huang Y, Ray AS. Contribution of the organic anion transporter OAT2 to the renal active 
tubular secretion of creatinine and mechanism for serum creatinine elevations caused by 
cobicistat. Kidney Int. 2014;86:350-357.
Ma JD, Nafziger AN, Villano SA, Gaedigk A, Bertino JS Jr. Maribavir pharmacokinetics and the 
effects of multiple –dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, 
CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase in healthy adults. Antimicrob 
Agents Chemother. 2006;50(4):1130-1135.
Midazolam 1 mg/mL Solution for Injection or Infusion. Summary of Product Characteristics. 
https://www.medicines.org.uk/emc/medicine/25804. Accessed on December 12, 2014.
Midazolam Hydrochloride Syrup [Prescribing Information]. Columbus, OH: Roxane 
Laboratories, Inc.; 2002. Revised September 2012.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
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(6):649-655.
Pharmaceuticals Medical Devices Agency (PMDA) Draft Guideline on Drug Interactions. 2013. 
Guideline on Drug Interactions.
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, 
Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR. American Society of 
Hematology/American Society of Clinical Oncology clinical practice guideline update on the 
use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 
2010;28(33):4996-5010.
Schutzer KM, Svensson MK, Zetterstrand S, Eriksson UG, Wahlander K. Reversible elevations 
of serum creatinine levels but no effect on glomerulus filtration during treatment with the 
direct thrombin inhibitor AZD0837. Eur J Clin Pharmacol. 2010; 66(9):903-910.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. 
Recommendations for the Use of White Blood Cell Growth Factors: American Society of 
Clinical Oncology Clinical Practice Guideline Update. J Clin Onc 2015, 
http://jco.ascopubs.org/content/early/2015/07/08/JCO.2015.62.3488.full. Accessed 
October 01, 2015.
Steinijans VW, Sauter R, Hauschke D, Diletti E, Schall R, Luus HG, Elze M, Blume H, 
Hoffman C, Franke G et al. Reference tables for the intrasubject coefficient of variation in 
bioequivalence studies. Int J Clin Pharmacol Ther. 1995;33(8):427-430.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Attachment 1.Protocol JPCB Study Schedule


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
Page 61
Abemaciclib (LY2835219)
Study I3Y-MC-JPCB Study Schedule for Screening, and Periods 1 and 2
Screen
Period 1:  
Drug cocktail
Period 2 (Cycle 1, Days 1-12):  
Abemaciclib + drug cocktail  
Early
discharge/
follow upa
Study Day
≤ -30 
Baseline 
≤ -7
-1
1
2-7
1
2-7
8
9-12
Informed consent
Xq
Medical historym
X
Pregnancy test (if 
applicable)
X
Xb
Urinalysis
X
Xb
X 
(Day 7)
X
(Day 9)
X
Renal markers
Predosel
Predose
8 hr
24, 72 h
(Days 9, 
11)
Hematology and 
serum chemistry
X
Xb
X 
(Day 7)
Predose, 
8hj,r
24, 72 h
(Days 9, 
11)
X
Physical exam & 
ECOG status
X
Xb,c
Predosec
24 h
(Day 9)c
Xc
Weight
X
X
X
X
Vital signsd
X
Xb
Predose, 2, 
8 h
24 h
(Day 2)
Predose, 
2, 8 h
24 h
(Day 2)
Predose, 
2, 8 h
24 h
(Day 9)
X
ABPMe
0-12 h
0-24 h
(Day 5-8)e
0-24 h
ECGf
X
X
Predose, 2, 
8 h
24 h
(Day 2)
Predose
Predose, 
2, 8 h
24 h
(Day 9)
X
INR (PD and 
safety)n
Predose, 
8 hr
24, 48, 
72, 96 h
Predose, 
8 hr
24, 48, 
72, 96 h
AEs & con medso
Throughout study
Bowel habit/dosing 
Patient diary
Daily from Baseline through the end of Cycle 2 (Period 4)
Bowel habit 
Patient outcomes
X
Predose
Predose
Day7
Abemaciclib Q12H
Day 1k
Day 2-7
Day 8k
Day 9-12
Drug cocktail 
administration
X
Xs
PK sampling 
abemaciclibg
Predose
(Day 7)
Predose
Predose 
(Day 9)
PK sampling 
caffeineg 
Predose, 
0.5, 1, 2, 3, 
4, 6, 8, 
12 h
24, 48 h
Predose, 
0.5, 1, 2, 
3, 4, 6, 8, 
12 h 
24, 48 h
PK sampling 
warfaring,p
Predose, 1, 
2, 4, 6, 8, 
10 h
24, 48, 
72, 96 h
Predose, 
1, 2, 4, 6, 
8, 10 h
24, 48, 
72, 96 h


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Screen
Period 1:  
Drug cocktail
Period 2 (Cycle 1, Days 1-12):  
Abemaciclib + drug cocktail  
Early
discharge/
follow upa
Study Day
≤ -30 
Baseline 
≤ -7
-1
1
2-7
1
2-7
8
9-12
PK sampling 
dextromethorphang
Predose, 
1, 2, 4, 6, 
8, 10 h
24, 48, 
72 h
Predose, 
1, 2, 4, 6, 
8, 10 h
24, 48, 
72 h
PK sampling 
midazolamg
Predose,
0.5, 1, 2, 3, 
4, 6, 8,12 h
24 h
Predose, 
0.5, 1, 2, 
3, 4, 6, 8, 
12 h 
24 h
Pharmacogenetic
sample
Xh
CYP genotyping 
sample
Xh
Tumor assessment 
Xi
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; con meds = concomitant 
medications; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; exam = examination; 
INR = international normalized ratio; h = hour(s); PD = pharmacodynamic; PK = pharmacokinetic; 
Q12H = every 12 hours.
a
Patients who discontinue early from the study should return for a discharge visit after a washout period of at least 
10 days from the last abemaciclib dose to perform the same assessments as required at the follow-up visit.  If a 
patient completes Periods 1 and 2, it is expected that the patient will enter Period 3.  If patients do not enter 
Period 3 after completing required serial blood sampling in Period 2, patients will have a discharge visit after a 
washout period of at least 10 days from the last abemaciclib dose.
b
Serum pregnancy test should be repeated if >3 days from Day 1.
c
Directed physical examination. Directed examination on Day 9 to include assessment for evidence of bleeding.
d
Vital signs will be collected before any blood samples at the specified time.  Supine, semi-recumbent, or sitting
blood pressure, heart rate, and body temperature will be obtained.  Vital signs can be omitted, if already taken as 
part of routine standard of care on the day informed consent is taken.
e
An ABPM device will be fitted for a 12-hour acclimation period between Days -7 to -2 in Period 1.  Following 
the acclimation period, baseline ABPM assessments will be performed over a 24-hour period between Day -2 
and dosing on Day 1 in Period 1.  In Period 2, ABPM assessments will be performed over a 24-hour period once 
between Days 5 to 8; no other procedures should be performed during this ABPM assessment.
f
Patients must be supine or semi-recumbent for approximately 5 to 10 minutes before ECG collection and remain 
supine or semi-recumbent but awake during ECG collection.  ECGs should be collected prior to any blood draws 
scheduled at the same time point, and ECGs should preferably be collected before (rather than just after) meals.  
ECGs may be obtained at additional times, when deemed clinically necessary.
g
All sample times are relative to the administration of the drug cocktail, except for the trough abemaciclib 
samples.  PK sample collection times are nominal; actual times should be recorded.  Separate blood samples, 
2 mL each, will be collected for the drug concentration measurements of abemaciclib, caffeine, 
dextromethorphan, midazolam, and warfarin.  
h
Obtain only once after enrollment and eligibility is confirmed. This sample can be taken during the baseline visit 
or at Predose Period 1, Day 1 once eligibility is confirmed.  
i
Radiological tumor assessment can be omitted if prior scan is within approximately 4 weeks.  See Section 8.3 for 
additional information.
j
Serum creatinine only.
k
The first dose of abemaciclib on Day 1 should take place at the study site.  Patients will report to the study site on 
Day 8 and will be coadministered abemaciclib and the drug cocktail in the morning.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
l
Includes 2 blood samples collected for central laboratory assessment of renal markers in serum.
m To include the recording of the use of alcohol, tobacco, nicotine replacement therapy, and caffeine.
n
If warfarin is not dosed in Period 2 cocktail, the INR sampling throughout Period 2 is not required; however, the 
INR may be assessed at the investigator’s discretion for safety purposes.
o
Patients will be provided with a paper diary in which to record the start and stop times of all AEs, new 
concomitant medications and medications taken as needed from the baseline visit until the end of Period 2.
p
If warfarin is not dosed in Period 2 cocktail, the warfarin PK sampling throughout Period 2 is not required.
q
Date and time of informed consent will be recorded.
r
The 8-hour postdose sample may be drawn within ±2 hours (thus, at the 6 hour postdose or 10 hour postdose 
time point at the discretion of the site).  The actual time of collection must be recorded. 
s
Cocktail may be administered without warfarin in Period 2 if patient has an INR >2 after receiving warfarin in 
Period 1 (Section7.2.1).


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Abemaciclib (LY2835219)
Study I3Y-MC-JPCB Study Schedule for Periods 3 and 4
Study Day
Period 3
Cycle 1, Days 13-28
Period 4 a
Cycle 2
Follow-upb
Directed physical exam & 
ECOG status
X
X
Vital signsc & weight
Xc
X
Renal biomarkers
Days 1, 14f, 28
Bowel habit/dosing 
Patient diary
X
(Daily)
Daily
(Days 1 through 28)g
Bowel habit 
Patient outcomes
Days 14, 21
Days 1, 7, 14, 21, 28d
Hematology & serum 
chemistry
Days 1, 14f, 28
X
AEs & con meds
X
X
X
Abemaciclib Q12H
X
Daily
Tumor assessment 
Xe
X
Abbreviations:  AE = adverse event; con meds = concomitant medications; ECOG = Eastern Cooperative Oncology 
Group; exam = examination; Q12H = every 12 hours.
a
Patients will be required to return to the site on Day 1 of each 28-day cycle (±4 days).
b
For patients who will not participate in the safety extension, the follow-up assessment will occur approximately 
10 days after the end of the second cycle.
c
Vital signs will be collected before any blood samples at the specified time. Supine, semi-recumbent, or sitting
blood pressure, heart rate, and temperature will be obtained.
d
Cycle 2, Day 28 patient outcomes may be completed before any procedures on Day 1 of Cycle 3.
e
Radiological tumor assessment should be performed on Day 28 (±14 days).
f
Cycle 2, Day 14 labs (+/- 2 days).
g
Patient diary will extend through the end of Period 4 if longer than 28 days.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Study I3Y-MC-JPCB Study Schedule for Safety Extension Phase
Study Day
Safety extension: 
abemacicliba
Follow-upb
Directed physical exam & 
ECOG status
X
X
Vital signsc & weight
X
X
ECGe
X
Hematology, serum 
chemistry, & urinalysis
X
X
AEs & con meds
X
X
Abemaciclib 
administration 
X
Tumor assessment 
Xd
X
Abbreviations:  AE = adverse event; con meds = concomitant medications; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; exam = examination.
a
Patients will be required to return to the site on Day 1 of each 28-day cycle (±4 days).
b
For patients participating in the safety extension, the follow-up assessment will occur approximately 10 days 
after the planned end of the last cycle.
c
Vital signs will be collected before any blood samples at the specified time.  Supine, semi-recumbent, or sitting
blood pressure, heart rate, and temperature will be obtained.
d
Radiological tumor assessment should be performed on Day 28 (±14 days).  Imaging studies should be 
performed at the end of every 2 cycles (approximately every 4 to 8 weeks) up until 30 days after final 
abemaciclib dose, when another therapy is initiated, when there is disease progression, or when the patient dies
per standard of care until objective progression is observed based on the efficacy measurement criteria described 
in Section 8.3.  If a patient is discontinued from the study, repeat radiology may be omitted if progressive disease 
can be documented quantitatively with clinical measurements.
e
Patients must be supine or semi-recumbent for approximately 5 to 10 minutes before ECG collection and remain 
supine or semi-recumbent but awake during ECG collection.  ECGs should be collected prior to any blood draws 
scheduled at the same time point, and ECGs should preferably be collected before (rather than just after) meals.  
ECGs may be obtained at additional times, when deemed clinically necessary.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Attachment 2.Protocol JPCB Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total and direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils
Alanine aminotransferase 
Lymphocytes
Aspartate aminotransferase 
Monocytes
Gamma-glutamyl transpeptidase
Eosinophils
Blood urea nitrogen 
Basophils
Creatinine
Platelets
Uric acid
Calcium
Coagulation parametersa, f
Glucose, random
aPTT
Albumin
PT
Total protein
INR
Magnesium
Phosphorus
Chloride
Urinalysisa
Lactate dehydrogenase
Specific gravity
Osmolality
pH
Protein
Renal Biomarkersb
Glucose
Cystatin-C c
Ketones
NGAL c, d
Blood
KIM-1 d
Urine leukocyte esterase
Creatinine c, d
Serum Urine Pregnancy Test
(females of child bearing potential only)
CYP2C9, CYP2D6, CYP3A4, and CYP3A5
genotypinge


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Abbreviations:  RBC = red blood cells; WBC = white blood cells; aPTT = activated partial thromboplastin time, 
CYP = cytochrome P450; INR = international normalized ratio; KIM-1 = kidney injury molecule-1; 
NGAL = neutrophil gelatinase-associated lipocalin; PT = prothrombin time.
a
Performed by local laboratory for safety management and the central laboratory for reporting purposes at all 
timepoint, except screening when only a local laboratory will be used.
b
Performed by a central laboratory (not performed at screening).
c
Venous blood samples will be collected for serum tests.
d
Urine samples (at least 5 mL and up to 120 mL) will be collected and tested.
e
Performed at baseline only
f
Coagulation parameters need not be measured in Period 2 if warfarin is not included in the Period 2 drug 
cocktail.


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Abemaciclib (LY2835219)
Attachment 3.Protocol JPCB 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/CP or designee.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Anti-smooth muscle antibodya
CPK 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Attachment 4.Protocol JPCB Recommendations for 
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report a SAE, please have the following information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, and weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalization), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug & Protocol Procedures
Concomitant Drug Therapy

indication, total daily dose, duration of treatment, start date, action taken
In Case of Death

cause, autopsy finding (if available), date, relationship to study drug and protocol 
procedures.


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Abemaciclib (LY2835219)
Attachment 5.Protocol JPCB Eastern Cooperative Oncology 
Group (ECOG) Performance Status
Eastern Cooperative Oncology Group (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 performance of a light or sedentary nature, for example, 
light housework, 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 more than 
50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair
5
Dead
Source:  Oken et al. 1982.


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Abemaciclib (LY2835219)
Attachment 6.Protocol JPCB Sampling Summary
This table summarizes the maximum number of samples, volumes for all sampling, and tests 
during the study.  The summary below provides estimates. More samples could be required in 
the case of retests, additional health monitoring (if needed), or for patients continuing treatment 
beyond the protocol-specified number of cycles in the study.  Fewer samples may actually be 
taken (for example, patients who discontinue from the study).
Protocol I3Y-MC-JPCB Sampling Summary (Periods 1 to 4)
Purpose
Maximum Amount 
per Sample (mL)
Maximum 
Number 
Samples
Maximum 
Total Amount
(mL)
Screening tests (local lab)a
7.5
1
7.5
Serum pregnancy test, if 
applicableb
5
2
10
Clinical laboratory tests (local 
lab)a
7.5
10
75
Clinical laboratory tests 
(central lab)a
15
10
150
Renal markers
5
8
40
Safety and PD INR
2
12
24
Drug concentrations:
Caffeine 
Warfarin
Dextromethorphan
Midazolam
Abemaciclib
2
2
2
2
2
22
22
20
20
3
44
44
40
40
6
Pharmacogenetic sample 
10
1
10
CYP genotyping sample
10
1
10
Catheter flush
1
18
18
Additional PK sampling, if 
applicable 
3
5
15
Provision for unscheduled 
labs
-
-
30
Total
563.5
Total rounded for clinical 
purposes
570
Abbreviation:  INR = international normalized ratio; PD = pharmacodynamic; PK = pharmacokinetic.
a
Additional samples may be drawn if needed for safety purposes.
b
Blood volume may vary.


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Abemaciclib (LY2835219)
Attachment 7.Protocol Amendment I3Y-MC-JPCB(d) 
Summary Effects of Multiple Doses of Abemaciclib on the 
Pharmacokinetics of Cytochrome P450 (CYP) 1A2, CYP2C9, 
CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients
Overview
Protocol I3Y-MC-JPCB [Effects of Multiple Doses of Abemaciclib on the Pharmacokinetics of 
Cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients] 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 of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

In order to explain how AEs and concomitant medications are to be recorded 
during the study, information regarding a paper diary to be issued to patients
has been added.  

As INR is measured in order to monitor any adverse anticoagulant effects of 
warfarin, the protocol has been revised to allow any subject with INR >2 after 
the first dose of warfarin to receive abemaciclib once their INR has stabilized 
or returned to baseline, and for the patient to receive drug cocktail without 
warfarin in Period 2.  Flexibility has been added regarding replacement of 
such patients to allow assessment of the impact of the missing warfarin PK 
data on the overall analysis, prior to the decision being made to replace the 
subject.  

The abemaciclib dose adjustment criteria have been amended and clarification 
given to the requirement for dose reduction following administration of white 
blood cell growth factors only.

A ±2 hour window of flexibility has been allowed, if necessary, around the 
8 hour postdose renal marker, hematology and serum chemistry, and INR 
sampling time point, in order to ensure samples can be analyzed on the day 
they are drawn.  

Minor clarifications have been added and minor typographical and formatting edits 
were made throughout the document for clarity and consistency.  


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
6.1.1.Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drugenrollment.
6.1.2.Exclusion Criteria
[13] Have received treatment within 28 days of the initial dose of study drug with 
an investigational product (non-cancer-related therapies) or non-approved use 
of a drug or device (other than the study drug used in this study) or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
6.2.
Summary of Study Design
This will be an open-label, 4-period, fixed-sequence study, followed by a safety extension phase, 
in patients with advanced and/or metastatic cancer.
The drug cocktail of 100 mg caffeine, 10 mg warfarin, 30 mg dextromethorphan, and 0.2 mg 
midazolam will be administered orally as a single dose on 2 occasions:  Day 1 in Period 1, and in 
combination with abemaciclib on Day 8 of Period 2, after 7 days of 200 mg abemaciclib Q12H 
dosing.  After completing Period 2, patients will continue to receive abemaciclib at a dose of 
200 mg Q12H (or a modified dose) through the end of Periods 3 and 4, in 28-day cycles, and 
then may continue in a safety extension phase until discontinuation criteria are met.  Patients 
who do not complete dosing and PK sampling through Period 2 may be replaced.
Patients will be provided with an electronic diary from the baseline visit through the end of 
Cycle 2 to record the time and date of abemaciclib administration, any constipation or
anti-diarrhea medications taken, and bowel habits and any changes.
6.2.1.Safety Extension Phase
Patients who participate in the safety extension phase of the study will receive an abemaciclib 
dose of 200 mg Q12H (or modified dose as applicable) on a 28-day cycle until discontinuation 
criteria are met (eg, disease progression, death, or unacceptable toxicity (Section 6.3).  If 
interruptions in dosing are required for significant periods of time (> 14 days) continuation of 
treatment with abemaciclib may be considered if felt to be in the best interest of the patient’s 
care and upon discussion with the medical monitor.  Tumor re-staging may be allowed and will 
be documented when necessary.


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Abemaciclib (LY2835219)
7.2.1.Dosing Schedule
Period 2
On Days 1 to 12, 4 × 50-mg capsules of abemaciclib will be administered orally in the morning 
and evening with approximately 240 mL of room temperature water, in a sitting position.  
Abemaciclib should be taken at approximately the same time each day.  On Day 8, abemaciclib 
will be coadministered with 10 mL of 20-mg/mL caffeine citrate solution (100 mg caffeine), 
2 × 5-mg tablets of warfarin, 2 × 15-mg liquid gel capsules of dextromethorphan, and 0.1 mL of 
2-mg/mL midazolam syrup with approximately 240 mL of room temperature water, in a sitting 
position.  On Day 8 (coadministration with the drug cocktail), patients should not consume food 
beginning 1 hour before and ending 1 hour after taking study drugs.  
If a patient has an INR >2 after the first dose of warfarin, the patient may receive the drug 
cocktail without warfarin in Period 2 and receive abemaciclib once their INR has stabilized or 
returned to baseline.  
If a patient misses or vomits a dose of abemaciclib, that dose should be omitted (see Section 7.6
for compliance).  Patients will be asked to take each dose of study drug within +/- 2 hours of the 
planned dose time or consider the dose a missed dose. 
Periods 3, 4 and Safety Extension Phase  
From Cycle 1, Period 3 and on Days 1 to 28 in each cycle (Cycle 2 onwards), 4 × 50-mg capsule 
of abemaciclib will be taken orally in the morning and evening.  Abemaciclib should be taken at 
approximately the same time each day.  
A delay of 7 days in the start of a cycle (Day 1) for justifiable reasons (for example, inclement 
weather, holidays, or weekends) other than toxicity will be permitted and does not constitute a 
protocol violation.  A delay of 14 days in the start of a cycle (Day 1) to allow for recovery from 
toxicity will be permitted and does not constitute a protocol violation.  A longer delay may be 
allowed for the start of Cycle 1 (or Period 2), if necessary.  In cases where Cycle 1 (abemaciclib 
dosing) is significantly delayed from tumor staging during screening, baseline staging may be 
repeated.  If there is any question, this may be discussed with the study medical monitor.


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Abemaciclib (LY2835219)
Table JPCB.7.1.
Toxicity Dose Adjustments and Delays of Abemaciclib for 
Study JPCB
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Neutropenia/thrombocytopenia
Section 7.2.2.1
Grade 3 which lasts 7 days
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion.
Hematologic Toxicity
Neutropenia/thrombocytopenia
Section 7.2.12.1
Recurrent Grade 3 (on later cycle) 
which lasts 7 days
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUSTMAY be 
reduced by 1 dose level –
investigator’s discretion.
Hematologic Toxicity 
Neutropenia/thrombocytopenia
Section 7.2. 12.1
Grade 4 which lasts 3 days
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic toxicity:  Patient 
requires administration of 
white blood cell growth 
factors
Section 7.2. 12.1
Regardless of severity
(Growth factors use according to 
ASCO Guidelines)
Dose MUST be suspended 
for at least 48 hours after 
the last dose of white blood 
cell growth factors was 
administered and until 
toxicity resolves to at least 
Grade 2.
Dose MUST be reduced 
by 1 dose level unless 
already performed for 
incidence of toxicity that 
lead to the use of white 
blood cell growth factor.
Nonhematologic Toxicity 
(except diarrhea)
Section 7.2.2.2.1
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 7 days 
to baseline or Grade 1
Dose MAY be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Nonhematologic Toxicity 
Section 7.2.2.2.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Section 7.2.2.2.2
Requires hospitalization or Grade 3 
or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Section 7.2.2.2.2
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 
24 hours to at least Grade 1
Dose SHOULD be 
suspended until toxicity 
resolves to at least Grade 1.
Dose MAY be reduced 
by 1 dose level -
investigator's discretion.
Diarrhea
Section 7.2.2.2.2
Diarrhea recurs despite maximal 
supportive measures after resuming 
same dose level after initial 
Grade 2 diarrhea
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
Abbreviation:  ASCO = American Society of Clinical Oncology.
Note:  MAY = per the investigator’s clinical judgment; SHOULD = not mandatory but highly recommended; 
MUST = mandatory.


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Abemaciclib (LY2835219)
7.2.2.1.
Hematologic Toxicity
If a patient experiences Grade 4 hematologic toxicityneutropenia/thrombocytopenia, which lasts 
3 days, then dosing must be suspended (until the toxicity resolves to at least Grade 2) and the 
dose of abemaciclib must be reduced as outlined in Table JPCB.7.2.
If a patient experiences Grade 3 hematologic toxicityneutropenia/thrombocytopenia, which lasts 
7 days, then dosing must be suspended (until the toxicity resolves to at least Grade 2) and the 
dose of abemaciclib may be reduced by 1 dose level.  If the patient experiences a recurrent 
episode of Grade 3 hematologic toxicityneutropenia/thrombocytopenia in a later cycle, which 
lasts 7 days, then dosing must be suspended (until the toxicity resolves to at least Grade 2 and the 
dose of abemaciclib mustmay be reduced by 1 dose level.
If a patient requires administration of white blood cell growth factors, the dose of study drug 
must be suspended for at least 48 hours after the last dose of white blood cell growth factors was 
administered and until toxicity resolves to at least Grade 2, then reduced by 1 dose level, if a 
dose reduction for the specific event necessitating the use of the white blood cell growth factors 
has not already occurred.
Before the start of each cycle, hematologic toxicity possibly related to abemaciclib must resolve 
to at least Grade 2.
7.5.
Concomitant Therapy
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study, except for those 
described in Inclusion Criterion [7] in Section 6.1.1.
The need for radiotherapy will be cause for early discontinuation from the study, with the 
exception of palliative radiotherapy, which is permitted if not being utilized for disease 
progression.  In addition, any disease progression requiring other forms of specific antitumor 
therapy will also necessitate early discontinuation from the study.
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications must be captured on the case report form (CRF).  Patients will be provided with a 
paper diary in which to record the start and stop times of new concomitant medications and 
medications taken as needed from the baseline visit until the end of Period 2.
7.5.1.3.
Growth Factors
Patients should receive full supportive care during the trial.  Growth factors should not be 
administered to enable a patient to satisfy study inclusion criteria.  Growth factors may be used 
in accordance with American Society of Clinical Oncology (ASCO) guidelines (Smith et al. 
2015) if clinically indicated.  Dosing of study drug must be suspended if the administration of 
white blood cell 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 white 
blood cell growth factors, the dose of study drug must be reduced by one dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
Page 77
Abemaciclib (LY2835219)
occurred.  Before the start of each cycle, hematologic toxicity must resolve to either baseline or 
at least Grade 2.
Erythroid-stimulating agents (ESAs, including erythropoietin and darbepoetin) or transfusions 
should not be administered to enable a patient to satisfy study inclusion criteria.  Both ESAs and 
transfusion therapy may be used in accordance with American Society of Hematology and 
ASCO guidelines (Rizzo et al. 2010), if clinically indicated. If a patient requires administration 
of blood cell growth factors, the dose of study drug must be reduced by one dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.  Before the start of each cycle, hematologic toxicity must resolve to either baseline or 
at least Grade 2.
7.6
Treatment Compliance
If a patient misses 2 or more of the planned doses of abemaciclib within 3 consecutive days prior 
to the drug cocktail dose in Period 2, the patient will need to be replaced, or dosing with the drug 
cocktail may be delayed to allow for adequate exposure.  Delay should only occur on a 
case-by-case basis following discussion and agreement with the Lilly CRP/CP or designee.  
Likewise, if dose reduction is required to less than 150mg Q12H or if dose interruptions or 
omissions are deemed necessary during Period 2 for greater than 43 consecutive doses at any 
time, the patient may recommence dosing of abemaciclib with delay of Period 2 drug cocktail 
dosing so that abemaciclib steady state is achieved (minimum 5-7 days)will need to be replaced.  
8.1.2.Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
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 medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
vital sign measurements, and so on that occur should also be reported to Lilly or its designee as 
an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect.
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the Study Schedule.  Patients 
will be provided with a paper diary in which to record the start and stop times of all AEs 
experienced from the baseline visit until the end of Period 2.
8.1.3.1. Vital Signs
Blood pressure, pulse rate, and body temperature will be measured as specified in the Study 
Schedule and as clinically indicated (Attachment 1).


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Abemaciclib (LY2835219)
Blood pressure and pulse rate should be measured after at least 5 minutes supine or,
semi-recumbent, or sitting; the position should be recorded.
8.1.3.3. Electrocardiograms
For each patient, a 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Patients must be supine or semi-recumbent for approximately 5 to 10 minutes 
before ECG collection and remain supine or semi-recumbent but awake during ECG collection.  
8.1.3.4.2.
Patient Diary
An electronic patient diary to collect date and time of bowel movements, a Bristol Stool Chart, 
and drug administration will be completed daily by the patient, starting at baseline and required 
through end of Period 2.  Patients participating in Period 3 and 4 should continue completing 
diary entries through end of Period 4.  Patients will also receive a paper diary in which to record 
the start and stop times of all AEs, new concomitant medications and medications taken as 
needed from the baseline visit until the end of Period 2.
8.2.2.2. Pharmacodynamic Samples
At the visits and times specified in the Study Schedule (Attachment 1), venous blood samples 
will be collected to determine INR (see Attachment for the blood sampling summary).  Analysis 
of PT or INR will be performed by local labs.  Local labs for PT or INR will be collected for 
patient management and PD analyses. 
Guidance Regarding Elevation of the INR
Patients will receive a single dose of warfarin (10 mg) as part of the drug cocktail in Period 1 and 
Period 2:
Period 1:  If a patient has an INR >2 after the first dose of warfarin, the patient should not 
receive warfarin again in the drug cocktail in Period 2, but may be allowed to enter the 
studyPeriod 2 and receive abemaciclib once their INR has stabilized or returned to 
baseline.  The patient should may be replaced.
Period 2:  For any patient found to have an INR 4 after the administration of warfarin in 
Period 2, further abemaciclib dosing should be held until the INR stabilizes or returns to 
baseline (refer to Section7.2.2).
9.2.1 Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome measures (for example, a rating scale), a daily dosing schedule or an 
event diary. 


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
If information reported during an office visit differs from that recorded in the paper diaries, the 
source data (collected during patient interview) will supersede for purposes of collection in the 
CRF.
For data handled by a data management third-party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to the Lilly data 
warehouse, using standard Lilly file transfer processes.
11.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient or legal representative before the study is started.  This includes obtaining the appropriate 
signatures, time of consent, and dates on the ICF prior to the performance of any protocol 
procedures and prior to the administration of study drug. 


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Abemaciclib (LY2835219)
Study I3Y-MC-JPCB Study Schedule for Screening, and Periods 1 and 2
Screen
Period 1:  
Drug cocktail
Period 2 (Cycle 1, Days 1-12):  
Abemaciclib + drug cocktail  
Early
discharge/
follow upa
Study Day
≤ -30 
Baseline 
≤ -7
-1
1
2-7
1
2-7
8
9-12
Informed consent
Xq
Medical historym
X
Pregnancy test (if 
applicable)
X
Xb
Urinalysis
X
Xb
X 
(Day 7)
X
(Day 9)
X
Renal markers
Predosel
Predose
8 hr
24, 72 h 
(Days 9, 
11)
Hematology and 
serum chemistry
X
Xb
X 
(Day 7)
Predose, 
8hj,r
24, 72 h
(Days 9, 
11)
X
Physical exam & 
ECOG status
X
Xb,c
Predosec
24 h
(Day 9)c
Xc
Weight
X
X
X
X
Vital signsd
X
Xb
Predose, 2, 
8 h
24 h
(Day 2)
Predose, 
2, 8 h
24 h
(Day 2)
Predose, 
2, 8 h
24 h
(Day 9)
X
ABPMe
0-12 h
0-24 h
(Day 5-8)e
0-24 h
ECGf
X
X
Predose, 2, 
8 h
24 h
(Day 2)
Predose
Predose, 
2, 8 h
24 h
(Day 9)
X
INR (PD and 
safety)n
Predose, 
8 hr
24, 48, 
72, 96 h
Predose, 
8 hr
24, 48, 
72, 96 h
AEs & con medso
Throughout study
Bowel habit/dosing 
Patient diary
Daily from Baseline through the end of Cycle 2 (Period 4)
Bowel habit 
Patient outcomes
X
Predose
Predose
Day7
Abemaciclib Q12H
Day 1k
Day 2-7
Day 8k
Day 9-12
Drug cocktail 
administration
X
Xs
PK sampling 
abemaciclibg
Predose
(Day 7)
Predose
Predose 
(Day 9)
PK sampling 
caffeineg 
Predose, 
0.5, 1, 2, 3, 
4, 6, 8, 
12 h
24, 48 h
Predose, 
0.5, 1, 2, 
3, 4, 6, 8, 
12 h 
24, 48 h
PK sampling 
warfaring,p
Predose, 1, 
2, 4, 6, 8, 
10 h
24, 48, 
72, 96 h
Predose, 
1, 2, 4, 6, 
8, 10 h
24, 48, 
72, 96 h


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
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Abemaciclib (LY2835219)
Screen
Period 1:  
Drug cocktail
Period 2 (Cycle 1, Days 1-12):  
Abemaciclib + drug cocktail  
Early
discharge/
follow upa
Study Day
≤ -30 
Baseline 
≤ -7
-1
1
2-7
1
2-7
8
9-12
PK sampling 
dextromethorphang
Predose, 
1, 2, 4, 6, 
8, 10 h
24, 48, 
72 h
Predose, 
1, 2, 4, 6, 
8, 10 h
24, 48, 
72 h
PK sampling 
midazolamg
Predose, 
0.5, 1, 2, 3, 
4, 6, 8,12 h
24 h
Predose, 
0.5, 1, 2, 
3, 4, 6, 8, 
12 h 
24 h
Pharmacogenetic 
sample
Xh
CYP genotyping 
sample
Xh
Tumor assessment 
Xi
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; con meds = concomitant 
medications; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; exam = examination; 
INR = international normalized ratio; h = hour(s); PD = pharmacodynamic; PK = pharmacokinetic; 
Q12H = every 12 hours.
a
Patients who discontinue early from the study should return for a discharge visit after a washout period of at least 
10 days from the last abemaciclib dose to perform the same assessments as required at the follow-up visit.  If a 
patient completes Periods 1 and 2, it is expected that the patient will enter Period 3.  If patients do not enter 
Period 3 after completing required serial blood sampling in Period 2, patients will have a discharge visit after a 
washout period of at least 10 days from the last abemaciclib dose.
b
Serum pregnancy test should be repeated if >3 days from Day 1.
c
Directed physical examination.  Directed examination on Day 9 to include assessment for evidence of bleeding.
d
Vital signs will be collected before any blood samples at the specified time.  Supine or, semi-recumbent, or 
sitting blood pressure, heart rate, and body temperature will be obtained.  Vital signs can be omitted, if already 
taken as part of routine standard of care on the day informed consent is taken.
e
An ABPM device will be fitted for a 12-hour acclimation period between Days -7 to -2 in Period 1.  Following 
the acclimation period, baseline ABPM assessments will be performed over a 24-hour period between Day -2 
and dosing on Day 1 in Period 1.  In Period 2, ABPM assessments will be performed over a 24-hour period once 
between Days 5 to 8; no other procedures should be performed during this ABPM assessment.
f
Patients must be supine or semi-recumbent for approximately 5 to 10 minutes before ECG collection and remain 
supine or semi-recumbent but awake during ECG collection.  ECGs should be collected prior to any blood draws 
scheduled at the same time point, and ECGs should preferably be collected before (rather than just after) meals.  
ECGs may be obtained at additional times, when deemed clinically necessary.
g
All sample times are relative to the administration of the drug cocktail, except for the trough abemaciclib 
samples.  PK sample collection times are nominal; actual times should be recorded.  Separate blood samples, 
2 mL each, will be collected for the drug concentration measurements of abemaciclib, caffeine, 
dextromethorphan, midazolam, and warfarin.
h
Obtain only once after enrollment and eligibility is confirmed.  This sample can be taken during the baseline visit 
or at Predose Period 1, Day 1 once eligibility is confirmed.  
i
Radiological tumor assessment can be omitted if prior scan is within approximately 4 weeks.  See Section 8.3 for 
additional information.
j
Serum creatinine only.
k
The first dose of abemaciclib on Day 1 should take place at the study site.  Patients will report to the study site on 
Day 8 and will be coadministered abemaciclib and the drug cocktail in the morning.


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Abemaciclib (LY2835219)
l
Includes 2 blood samples collected for central laboratory assessment of renal markers in serum.
m To include the recording of the use of alcohol, tobacco, nicotine replacement therapy, and caffeine.
n
If warfarin is not dosed in Period 2 cocktail, the INR sampling throughout Period 2 is not required; however, the 
INR may be assessed at the investigator’s discretion for safety purposes.
o
Patients will be provided with a paper diary in which to record the start and stop times of all AEs, new 
concomitant medications and medications taken as needed from the baseline visit until the end of Period 2.
p
If warfarin is not dosed in Period 2 cocktail, the warfarin PK sampling throughout Period 2 is not required.
q
Date and time of informed consent will be recorded.
r
The 8-hour postdose sample may be drawn within ±2 hours (thus, at the 6 hour postdose or 10 hour postdose 
time point at the discretion of the site).  The actual time of collection must be recorded. 
s
Cocktail may be administered without warfarin in Period 2 if patient has an INR >2 after receiving warfarin in 
Period 1 (Section 7.2.1).


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Abemaciclib (LY2835219)
Study I3Y-MC-JPCB Study Schedule for Periods 3 and 4
Study Day
Period 3
Cycle 1, Days 13-28
Period 4 a
Cycle 2
Follow-upb
Directed physical exam & 
ECOG status
X
X
Vital signsc & weight
Xc
X
Renal biomarkers
Days 1, 14f, 28
Bowel habit/dosing 
Patient diary
X
(Daily)
Daily 
(Days 1 through 28)g
Bowel habit 
Patient outcomes
Days 14, 21
Days 1, 7, 14, 21, 28d
Hematology & serum 
chemistry
Days 1, 14f, 28
X
AEs & con meds
X
X
X
Abemaciclib Q12H
X
Daily
Tumor assessment 
Xe
X
Abbreviations:  AE = adverse event; con meds = concomitant medications; ECOG = Eastern Cooperative Oncology 
Group; exam = examination; Q12H = every 12 hours.
a
Patients will be required to return to the site on Day 1 of each 28-day cycle (±4 days).
b
For patients who will not participate in the safety extension, the follow-up assessment will occur approximately 
10 days after the end of the second cycle.
c
Vital signs will be collected before any blood samples at the specified time.  Supine, or semi-recumbent, or 
sitting blood pressure, heart rate, and temperature will be obtained.
d
Cycle 2, Day 28 patient outcomes may be completed before any procedures on Day 1 of Cycle 3.
e
Radiological tumor assessment should be performed on Day 28 (±14 days).
f
Cycle 2, Day 14 labs (+/- 2 days).
g
Patient diary will extend through the end of Period 4 if longer than 28 days.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
Page 84
Abemaciclib (LY2835219)
Study I3Y-MC-JPCB Study Schedule for Safety Extension Phase
Study Day
Safety extension: 
abemacicliba
Follow-upb
Directed physical exam & 
ECOG status
X
X
Vital signsc & weight
X
X
ECGe
X
Hematology, serum 
chemistry, & urinalysis
X
X
AEs & con meds
X
X
Abemaciclib 
administration 
X
Tumor assessment 
Xd
X
Abbreviations:  AE = adverse event; con meds = concomitant medications; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; exam = examination.
a
Patients will be required to return to the site on Day 1 of each 28-day cycle (±4 days).
b
For patients participating in the safety extension, the follow-up assessment will occur approximately 10 days 
after the planned end of the last cycle.
c
Vital signs will be collected before any blood samples at the specified time.  Supine, or semi-recumbent, or 
sitting blood pressure, heart rate, and temperature will be obtained.
d
Radiological tumor assessment should be performed on Day 28 (±14 days).  Imaging studies should be 
performed at the end of every 2 cycles (approximately every 4 to 8 weeks) up until 30 days after final 
abemaciclib dose, when another therapy is initiated, when there is disease progression, or when the patient dies
per standard of care until objective progression is observed based on the efficacy measurement criteria described 
in Section 8.3.  If a patient is discontinued from the study, repeat radiology may be omitted if progressive disease 
can be documented quantitatively with clinical measurements.
e
Patients must be supine or semi-recumbent for approximately 5 to 10 minutes before ECG collection and remain 
supine or semi-recumbent but awake during ECG collection.  ECGs should be collected prior to any blood draws 
scheduled at the same time point, and ECGs should preferably be collected before (rather than just after) meals.  
ECGs may be obtained at additional times, when deemed clinically necessary.


I3Y-MC-JPCB(d) Phase 1 Oncology Protocol
Page 85
Abemaciclib (LY2835219)
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total and direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils
Alanine aminotransferase 
Lymphocytes
Aspartate aminotransferase 
Monocytes
Gamma-glutamyl transpeptidase
Eosinophils
Blood urea nitrogen 
Basophils
Creatinine
Platelets
Uric acid
Calcium
Coagulation parametersa, f
Glucose, random
aPTT
Albumin
PT
Total protein
INR
Magnesium
Phosphorus
Chloride
Urinalysisa
Lactate dehydrogenase
Specific gravity
Osmolality
pH
Protein
Renal Biomarkersb
Glucose
Cystatin-C c
Ketones
NGAL c, d
Blood
KIM-1 d
Urine leukocyte esterase
Creatinine c, d
Serum Urine Pregnancy Test
(females of child bearing potential only)
CYP2C9, CYP2D6, CYP3A4, and CYP3A5 
genotypinge
Abbreviations:  RBC = red blood cells; WBC = white blood cells; aPTT = activated partial thromboplastin time, 
CYP = cytochrome P450; INR = international normalized ratio; KIM-1 = kidney injury molecule-1; 
NGAL = neutrophil gelatinase-associated lipocalin; PT = prothrombin time.
a
Performed by local laboratory for safety management and the central laboratory for reporting purposes at all 
timepoint, except screening when only a local laboratory will be used.
b
Performed by a central laboratory (not performed at screening).
c
Venous blood samples will be collected for serum tests.
d
Urine samples (at least 5 mL and up to 120 mL) will be collected and tested.
e
Performed at baseline only
f
Coagulation parameters need not be measured in Period 2 if warfarin is not included in the Period 2 drug 
cocktail.


Leo Document ID = 4281776f-5521-496b-a75e-7e6c59715252
Approver: 
Approval Date & Time: 22-Sep-2016 13:28:45 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Sep-2016 19:24:29 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
I3Y-MC-JPCB Statistical Analysis Plan 
 
Effects of Multiple Doses of Abemaciclib on the Pharmacokinetics of Cytochrome P450    
(CYP) 1A2, CYP2C9, CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients 
 
NCT02688088 
 
Approval Date: 04-Feb-2016 


Final, 03 Feb 2016
             Page 1 of 20
STATISTICAL ANALYSIS PLAN
Effects of Multiple Doses of Abemaciclib on the Pharmacokinetics of Cytochrome P450 
(CYP) 1A2, CYP2C9, CYP2D6, and CYP3A Substrates (Caffeine, Warfarin, 
Dextromethorphan, and Midazolam) in Cancer Patients
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  3rd February 2016
Study Drug: Abemaciclib (LY2835219)
Sponsor Reference:  I3Y-MC-JPCB
Covance CRU Study: 1000071-8325020
Clinical Phase I
Approval Date: 04-Feb-2016 GMT


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             Page 2 of 20
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary objective .................................................................................................... 6
4.2
Secondary objectives ............................................................................................... 6
4.3
Exploratory objectives ............................................................................................. 7
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS ............................................................................................................. 9
7.
SAMPLE SIZE JUSTIFICATION ............................................................................... 10
8.
DEFINITION OF ANALYSIS POPULATIONS.......................................................... 10
9.
STATISTICAL METHODOLOGY ............................................................................. 11
9.1
General.................................................................................................................. 11
9.2
Patient Characteristics ........................................................................................... 11
9.3
Pharmacokinetic Assessment................................................................................. 12
9.3.1
Pharmacokinetic Analysis............................................................................. 12
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 16
9.4
Pharmacodynamic Assessment .............................................................................. 16
9.4.1
Pharmacodynamic Analysis.......................................................................... 16
9.4.2
Pharmacodynamic Statistical Methodology .................................................. 16
9.5
Safety and Tolerability Assessments ...................................................................... 17
9.5.1
Adverse events ............................................................................................. 17
9.5.2
Concomitant medication............................................................................... 17
9.5.3
Clinical laboratory parameters ...................................................................... 17
9.5.4
Vital signs .................................................................................................... 18
9.5.5
Renal markers............................................................................................... 18
9.5.6
Ambulatory blood pressure monitoring (ABPM) .......................................... 18
9.5.7
Bowel habit data........................................................................................... 18
9.5.8
Eastern Cooperative Oncology Group (ECOG) Questionnaire ...................... 19
9.5.9
Tumor assessment ........................................................................................ 19
9.5.10
Genotyping sample....................................................................................... 19
9.5.11
Other assessments......................................................................................... 19
9.5.12
Safety and Tolerability Statistical Methodology ............................................ 19


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Statistical Analysis Plan 
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Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
10. INTERIM ANALYSES ............................................................................................... 19
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 19
12. REFERENCES ............................................................................................................ 20
13. DATA PRESENTATION ............................................................................................ 20
13.1 Derived Parameters ............................................................................................... 20
13.2 Missing Data ......................................................................................................... 20
13.3 Insufficient Data for Presentation .......................................................................... 20


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from zero to infinity
%AUC(tlast-)
Percentage of AUC(0-∞) extrapolated
AUCINR
Area under the INR curve
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL\F
Apparent total body clearance of drug calculated after extravascular 
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
e.g.
For example (Latin: exempli gratia)
ICH
International Conference on Harmonisation
INR
International normalized ratio
INRmax
Maximum observed INR response
KIM-1
Kidney injury molecule-1
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NGAL
Neutrophil gelatinase-associated lipocalin


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
PD
Pharmacodynamic
PK
Pharmacokinetic
PRO
Patient reported outcomes
Q12H
Every 12 hours
SAP
Statistical Analysis Plan
SD
Standard deviation 
SE
Safety extension
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
Vss\F
Apparent volume of distribution at steady state after extravascular 
administration
Vz\F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
06 October 2015) and Protocol Amendment (a) (final version dated 21 December 2015).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical, PD and PK analyses of data. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement between Eli Lilly and Company and Covance Early Clinical (EC)
Biometrics.
A limited amount of information concerning this study (e.g., objectives, study 
design) is given to help the reader’s interpret ation. This SAP must be signed off prior to first 
subject administration for this study.
When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR.
This SAP supersedes
the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified.
If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR.
Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR.
Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration o f the recommendations outlined in the Inte rnational 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary objective
The primary objective of this study is to assess the effect of abemaciclib on the PK of caffeine
(CYP1A2 substrate), warfarin (CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), and 
midazolam (CYP3A substrate) in cancer patients after multiple oral doses of abemaciclib.
4.2
Secondary objectives
The secondary objectives of this study are:

to characterize the tolerability of coadministration of abemaciclib with caffeine, 
warfarin, dextromethorphan, and midazolam following multiple doses of abemaciclib in 
cancer patients.

to assess the effect of abemaciclib on blood pressure and pulse rate following multiple 
doses of abemaciclib in cancer patients.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8325020
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4.3
Exploratory objectives
The exploratory objectives of this study are:

to determine the effect of abemaciclib on the PD of a single dose of warfarin as measured 
by international normalized ratio (INR).

to assess the effect of abemaciclib on markers of renal function, including creatinine, 
cystatin-C, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated 
lipocalin (NGAL).

to characterize bowel habits via a patient diary and a stool assessment tool (Bristol Stool 
Chart).

to characterize diarrhea experienced via patient reported outcome data based on selected 
individual items from existing patient reported outcomes (PRO) scales (FACIT-D) as 
well as custom-generated PRO items.
5. STUDY DESIGN
This will be an open-label, 4-period, fixed-sequence study, followed by a safety extension phase,
in patients with advanced and/or metastatic cancer.
The drug cocktail of 100 mg caffeine, 10 mg warfarin, 30 mg dextromethorphan, and 0.2 mg 
midazolam will be administered orally as a single dose on 2 occasions:  Day 1 in Period 1, and in 
combination with abemaciclib on Day 8 of Period 2, after 7 days of 200 mg abemaciclib
every 
12 hours (Q12H) dosing.  After completing Period 2, patients will continue to receive 
abemaciclib at a dose of 200 mg Q12H (or a modified dose) through the end of Periods 3 and 4, 
in 28-day cycles, and then may continue in a safety extension phase until discontinuation criteria 
are met.  Patients who do not complete dosing and PK sampling through Period 2 may be 
replaced.  
Patients will be provided with a diary from the baseline visit through the end of Cycle 2 to record 
the time and date of abemaciclib administration, any constipation or anti-diarrhea medications 
taken, and bowel habits and any changes.
The study design is illustrated in Figure JPCB.6.1.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
Figure JPCB.6.1. Study Design


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
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6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the safety TFLs.
Study Treatment Name
Abbreviation
Treatment 
order in TFLs
100 mg caffeine + 10 mg warfarin + 
30 mg dextromethorphan + 0.2 mg 
midazolam
Drug cocktail (Period 1)
1
200 mg Abemaciclib Q12H
200 mg Abemaciclib (Period 2)
2
200 mg Abemaciclib Q12H + 100 mg 
caffeine + 10 mg warfarin + 30 mg 
dextromethorphan + 0.2 mg midazolam
200 mg Abemaciclib + Drug 
cocktail (Period 2)
3
XX mg Abemaciclib Q12H (200 mg or a 
modified dose)
XX mg Abemaciclib (Periods 3 
and 4)
4
XX mg Abemaciclib Q12H (200 mg or a 
modified dose)
XX mg Abemaciclib (SE)
5
Drug cocktail = 100 mg caffeine + 10 mg warfarin + 30 mg dextromethorphan + 0.2 mg midazolam.
SE = Safety extension.
The following is a list of the study treatment abbreviations that will be used in the PK TFLs.
Study Treatment Name
Abbreviation
Treatment 
order in TFLs
100 mg caffeine + 10 mg warfarin + 
30 mg dextromethorphan + 0.2 mg 
midazolam
Drug cocktail (Period 1)
1
200 mg Abemaciclib Q12H
200 mg Abemaciclib (Period 2)
2
200 mg Abemaciclib Q12H + 100 mg 
caffeine
200 mg Abemaciclib + 100 mg 
caffeine (Period 2)
3
200 mg Abemaciclib Q12H + 10 mg 
warfarin
200 mg Abemaciclib + 10 mg 
warfarin (Period 2)
4
200 mg Abemaciclib Q12H + 30 mg 
dextromethorphan
200 mg Abemaciclib + 30 mg 
dextromethorphan (Period 2)
5
200 mg Abemaciclib Q12H + 0.2 mg 
midazolam
200 mg Abemaciclib + 0.2 mg 
midazolam (Period 2)
6


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
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7. SAMPLE SIZE JUSTIFICATION
Up to 48 patients may be enrolled in order that 22 patients complete Periods 1 and 2.
Caffeine
For caffeine area under the concentration time curve (AUC), the intra -subject variability
(coefficient of variation [CV]) was estimated to be 21.0% (Blanchard & Sawers 1983); 22 
patients will provide a precision of 0.13 on the log scale with 90% power.
Warfarin
For warfarin AUC, the intra-subject variability (coefficient of variation) was estimated to be 7%
(Steinijans et al. 1995); 22 patients will provide a precision of 0.04, with 9 0% power, which
corresponds to 4.4% on the log scale.
For warfarin Cmax, the intra-subject variability was
estimated to be 8% (Steinijans et al. 1995); 22 patients will provide a precision of 5.0% on the
log scale with 90% power.
Dextromethorphan
For dextromethorphan AUC, the intra-subject variability (coefficient of variation) was estimated
to be 33.7% (derived from a previous study); 22 patients will provide a precision of 0.20, with
90% power, which corresponds to 22.4% on the log scale. For dextromethorphan Cmax, the intra-
subject variability was estimated to be 32.1% (derived from a previous study); 22 patients will 
provide a precision of 21.3% on the log scale with 90% power.
Midazolam
For midazolam AUC, the intra-subject variability (coefficient of variation) was estimated to be
16.1% (derived from a previous study); 22 patients will provide a precision of 0.10, with 90%
power, which corresponds to 10.4% on the log scale. For midazolam Cmax, the intra-subject
variability was estimated to be 26.4% (derived from a previous study); 22 patients will provide a
precision of 17.3% on the log scale with 90% power.
ABPM
Using an intra-subject standard error of 9.48 mmHg in systolic blood pressure from Study JPBA,
a sample size of 22 completed patients will provide more than 90% coverage probability that the
half-width of the 90% confidence interval (CI) for the difference in means will be approximately
6 mmHg. The intra-subject standard error of diastolic blood pressure was estimated to be
6.78 mmHg and will provide more than 90% coverage probability that the half-width of the 90%
CI is in difference of means to be 4.3 mmHg.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug, 
and have at least one postdose safety assessment.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
The “Pharmacokinetic” population will consist of a ll subjects who received at least one dose of 
study drug and have evaluable PK data.  Subjects may be excluded from the PK summary 
statistics and statistical analysis if a subject has an adverse event (AE) of vomiting that occurs at 
or before 2 times median time to maximum concentration (tmax).
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PD data. Subjects may be excluded from the PD summary 
statistics and statistical analysis if a subject has an AE of vomiting that occurs at or before 2 
times median tmax. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP.  For continuous data, 
summary statistics will include the arithmetic mean, arithmetic SD, median, min, max and N; for 
log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric mean and geometric 
CV% will also be presented. For categorical data, frequency count and percentages will be 
presented. Data listings will be provided for all subjects up to the point of withdrawal, with any 
subjects excluded from the relevant population highlighted. Summary statistics and statistical 
analyses will generally only be performed for subjects included in the relevant analysis 
population. For the calculation of summary statistics and statistical analysis, unrounded data will 
be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline us ing a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.3 or greater.
9.2
Patient Characteristics
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, screening 
height and weight, and screening body mass index will be summar ized and listed.  All other 
demographic data will be listed only.
Baseline disease characteristics will be summarized and listed.  Furthermore, prior disease-
related therapies will be listed.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8325020
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9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.2.1 or later).
Plasma concentrations of caffeine, S-warfarin, dextromethorphan and midazolam will be used to 
determine the following PK parameters, when possible:  
Parameter
Units
Definition
AUC(0-tlast)
ng•h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
ng•h/mL 
area under the concentration versus time curve from zero to 
infinity
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
ng•h/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in non -
compartmental analysis
CL/F
L/h
Apparent total body clearance of drug calculated after 
extravascular administration
Vz/F
L
Apparent volume of distribution during the terminal phase after 
extravascular administration
Vss/F
L
Apparent volume of distribution at steady state after extravascular 
administration
Trough plasma concentrations of abemaciclib will be listed and summarised.
An alternative AUC measure, such as AUC to a common time point, may be calculated if 
AUC(0-∞) cannot be reliably calculated.
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR. Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus predose sampling times which will be set to zero.

The Cmax and tmax will be reported from observed values.  If Cmax occurs at more than 
one time point, tmax will be assigned to the first occurrence of Cmax. 

The AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification ( LLOQ), with 
at least one of these concentrations following C max. Any AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged. 
Any 
AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation fro m the log-linear decline in plasma
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log -
linear portion of the concentration-time curve.

The parameters based on predicted Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK Parameters with the 
exception of special handling of certain concentrations rep orted below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subje ct or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.


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Statistical Analysis Plan 
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
All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.

The average concentration profiles will be graphed using arithmetic
average 
concentrations.

The predose
average
concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the s ampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate.
This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.   The following 
methodology will not be used to exclude complete profiles from analysis.


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Statistical Analysis Plan 
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Data within an Individual Profile
A value within an individual profile may be exclude d from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the predose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a predose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log
transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not 
an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mea n ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.   Approval of the 
final report will connote approval of the exclusion.


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Statistical Analysis Plan 
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9.3.2
Pharmacokinetic Statistical Methodology
PK parameter estimates will be evaluated to delineate effects of drug interaction. 
Caffeine, 
warfarin, dextromethorphan, and midazolam administered in the absence of abemaciclib will 
represent the reference treatments and be analyzed separately.  Each drug administered with 
abemaciclib will represent the test treatments.  Log -transformed Cmax and AUC(0-∞) estimates 
will be evaluated in a linear mixed-effects analysis of variance model with a fixed effect for 
treatment and a random effect for subject.  The treatment differences will be back-transformed to 
present the ratios of geometric least squares (LS) means and the corresponding 90% CIs.
Example SAS code 1:
proc mixed data=pk;
    by parameter;
    class subject treatment;
    model log_pk = treatment / alpha=0.1 cl residual ddfm=kr;
    random subject;
    lsmeans treatment / alpha=0.1 cl pdiff;
    ods output lsmeans=lsmeans;
    ods output diffs=diffs;
run;
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs, and p -values from the Wilcoxon test will be 
calculated.
The inter- and intra-subject variability will be reported for each probe drug.
9.4
Pharmacodynamic Assessment
9.4.1
Pharmacodynamic Analysis
Area under the INR curve (AUC INR) and maximum observed INR response (INRmax) will be 
calculated to quantify the action of warfarin.
9.4.2
Pharmacodynamic Statistical Methodology
The PD parameters AUCINR and INRmax will be evaluated statistically to delineate the effect of 
INR response to warfarin dose.  A linear mixed-effects model with log-transformed PD 
parameter as a response variable, predose INR as a covariate, treatment as a fixed effect, and 
subject as a random effect.  For each of these PD parameters, the statistical inference will be 
made using the test treatment of warfarin + abemaciclib and the reference treatment of warfarin 
in the absence of abemaciclib.  The geometric LS means for the treatments and the ra tios of 
geometric LS means for AUCINR and INRmax, between the test (Abemaciclib) and reference
(Drug cocktail) treatments with 90% CIs will be established.
Example SAS code 2:


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Statistical Analysis Plan 
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Covance Clinical Study No. 8325020
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proc mixed data=pd;
    by parameter;
    class subject treatment;
    model log_pd = treatment pre_INR / alpha=0.1 cl residual ddfm=kr;
    random subject;
    lsmeans treatment / alpha=0.1 cl pdiff;
    ods output lsmeans=lsmeans;
    ods output diffs=diffs;
run;
Descriptive statistics will be presented for PD parameters by treatment. 
9.5
Safety and Tolerability Assessments
9.5.1
Adverse events
All AEs will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 
18 and graded according to the National Cancer Institute (NCI) Comm on Terminology Criteria 
for Adverse Events (CTCAE), Version 4.0.
Where changes in CTCAE grade are recorded in the Case Report Form (CRF), each separate 
grade of the AE will be reported in the listings , only the highest grade will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and its grade 
increases postdose.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, grading and 
relationship to the study dr ug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, CTCAE v 4.0 grade and code, and MedDRA system 
organ class and preferred term. The summary and frequency AE tables will be presented for all 
causalities and those considered related to the study drug. Any serious AEs will be tabulated and 
any deaths will be listed.
9.5.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version WhoDrug 
September 2015). Concomitant medication will be listed and ongoing concomitant medications 
will be summarized.
9.5.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be listed and summarized by parameter and 
treatment together with changes from baseline, where basline is defined as Period 1 Day 7 .
Urinalysis data will be listed.  Additionally clinical chemistry, hematology and urinalysis data 
outside the reference ranges will be listed.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8325020
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Furthermore, shift tables for clinical chemistry, hematology and urinalysis data will be presented 
to show the changes in CTCAE grade by parameter.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
Figures of absolute mean, mean changes from baseline, and mean percent changes from baseline 
will be presented for creatinine by treatment.  Furthermore, individual profiles of absolute 
values, change from baseline, and percent change from baseline will be presented for all renal 
biomarkers by parameter.
9.5.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Period 1 Day 1 predose. Figures of mean vital signs and mean changes 
from baseline profiles will be presented by treatment.   Furthermore, values for individual 
subjects will be listed.
9.5.5
Renal markers
Renal marker data will be listed and summarized by parameter and treatment together with 
changes from baseline, where baseline is defined as P eriod 1 Day 1 predose.  Data outside the 
reference ranges will be listed and values outside the reference ranges will be flagged on the 
individual subject data listings.
Figures of mean renal biomarkers, mean changes from baseline, and mean percent changes from 
baseline will be presented by parameter and treatment.  Furthermore, individual profiles of 
absolute values, change from baseline, and percent change from baseline will be presented for all 
renal biomarkers by parameter.
9.5.6
Ambulatory blood pressure monitoring (ABPM)
The mean ABPM data over 24 hours will be used for the secondary objective to assess the effect 
of abemaciclib on blood pressure and pulse rate .  The mean 6 hour and 24 hour data will be
summarized by treatment together with changes from baseline , where baseline is defined as 
Period 1 Day - 1.
Figures of mean ABPM data and mean changes from baseline will be 
presented by treatment.  Individual scatter plots over time will also be presented.  Furthermore, a 
time-matched APBM measurement versus concentration plot will be presented.
Mean values over 24 hours for individual subjects will be listed.
9.5.7
Bowel habit data
The bowel habit data will include patient diaries and patient reported outcomes.  The data will 
summarized and listed.  Additional analyses may be performed if required.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8325020
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9.5.8
Eastern Cooperative Oncology Group (ECOG) Questionnaire
The ECOG status data will be listed.
9.5.9
Tumor assessment
The tumour assessment data will be listed.
9.5.10
Genotyping sample
The genotyping sample data will be listed.   Patients with uncommon metabolic status such as 
CYP2C9 poor metabolizers will be excluded from the warfarin analysis.  CYP2D6 poor 
metabolizers will be excluded from dextromethorphan analysis.
9.5.11
Other assessments
All other safety assessments not detailed in this section will be listed but not sum marized or 
statistically analyzed. 
9.5.12
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
An interim analysis, which will serve as the final analysis for the primary objective, is planned 
for this study.  This interim analysis will be completed after the last patient has completed Period 
2.
Patients will be allowed to continue receiving abemaciclib during Period 3, 4, and the safety 
extension phase until discontinuation criteria are met (such as progressive disease or 
unacceptable toxicity).  A final analysis and final study report will be completed after t he last 
patient visit has occurred for this extension phase.
Two additional interim analyses may be conducted:  one analysis will be conducted after 
approximately half of the patients have completed Periods 1 and 2, as a preliminary assessment 
of the magnitude of any observed effect on blood pressure.  No changes to the study design are 
planned.  Another analysis will be conducted after the last patient has completed Period 4 and a 
preliminary study report will be written.  
Unplanned interims may be conducted if deemed necessary by Lilly study team.
This is an open-label study.  Data may be analyzed while the trial is ongoing.  An Assessment 
Committee will not be formed.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8325020
Sponsor Reference I3Y-MC-JPCB
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Blanchard J, Sawers SJ.  The absolute bioavailability of caffeine in man.  Eur J Clin 
Pharmacol. 1983;24(1):93-8.
4. Steinijans VW, Sauter R, Hauschke D, Diletti E, Schall R, Luus HG, Elze M, Blume H, 
Hoffman C, Franke G et al.  Reference tables for the intrasubject c oefficient of variation in 
bioequivalence studies.  Int J Clin Pharmacol Ther. 1995;33(8):427-430.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. t max, should be reported as received. N and percentage 
values should be reported as whole numbers.
Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 74c330f8-d8d6-479a-9147-a7a7c40f6998
Approver: 
Approval Date & Time: 03-Feb-2016 17:15:47 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 03-Feb-2016 17:16:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 03-Feb-2016 17:36:07 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Feb-2016 15:46:05 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD