Conditions: Advanced Cancer Metastatic Cancer
Keywords: CDK4/6 Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 26
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety of the study drug known as abemaciclib in native Chinese participants with advanced and/or metastatic cancers.

Detailed description:

Arms:
arm 1: Abemaciclib 150 milligram (mg) administered every 12 hours, orally, cycle 1 and then in cycle 2. Participants may continue to receive treatment until discontinuation criteria are met. One cycle is defined as 28 days. (Cycle 1: 32 days), with modifications during Cycle 1 to enable pharmacokinetic (PK) sampling following a single dose and repeated doses. arm 2: Abemaciclib 200 mg administered every 12 hours, orally, cycle 1 and then in cycle 2. Participants may continue to receive treatment until discontinuation criteria are met. One cycle is defined as 28 days. (Cycle 1: 32 days), with modifications during Cycle 1 to enable PK sampling following a single dose and repeated doses.

Interventions: intervention 1: Abemaciclib
Intervention descriptions: intervention 1: Administered orally

Protocol document:
Prot_001.pdf: 
Protocol I3Y-CR-JPBR (e)  
A Phase 1 Study of Abemaciclib in Native Chinese Patients with Advanced and/or Metastatic 
Cancers 
 
NCT02919696 
 
Approval Date: 12-Apr-2019 
 
 
 


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1. Protocol I3Y-CR-JPBR(e)
A Phase 1 Study of Abemaciclib in Native Chinese Patients 
with Advanced and/or Metastatic Cancers
Confidential Information
The information contained in this document 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 
CDK4/6 Dual Inhibitor (abemaciclib), 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 a multicenter, randomized, open-label study of oral abemaciclib in 
native Chinese patients with advanced and/or metastatic cancers.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  22 April 2016
Amendment (a) Electronically Signed and Approved by Lilly: 02 August 2016
Amendment (b) Electronically Signed and Approved by Lilly: 28 October 2016
Amendment (c) Electronically Signed and Approved by Lilly: 21 March 2017
Amendment (d) Electronically Signed and Approved by Lilly: 05 Jun 2018
Amendment (e) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 12-Apr-2019 GMT


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2. Synopsis
This Phase 1 study is a multicenter, randomized, open-label study of oral abemaciclib in Chinese 
patients with advanced and/or metastatic cancers.
Abemaciclib is a selective and potent small molecule cyclin-dependent kinase (CDK) 4/6 dual 
inhibitor with antitumor activity that is being developed for the treatment of cancers.  The 
objective of this study is to evaluate safety and tolerability of abemaciclib in Chinese patients 
with advanced and/or metastatic cancers.
Clinical Protocol Synopsis:  Study I3Y-CR-JPBR
Name of Investigational Product: abemaciclib
Title of Study:  A Phase 1 Study of Abemaciclib in Native Chinese Patients with Advanced and/or Metastatic 
Cancers
Number of Planned Patients:  20
Phase of Development:  1
Length of Study:
Planned first patient visit:  17 April 2017
Planned last patient visit:  4 May2018 (End of trial is defined as the last visit or last scheduled procedure shown in 
the Study Schedule for the last active patient in the study.)
Objectives:
The primary objective of this study is to evaluate the safety and tolerability of abemaciclib in Chinese patients with 
advanced and/or metastatic cancers.
The secondary objectives of this study are as follows:

To assess the pharmacokinetics (PK) of abemaciclib and its metabolites in Chinese patients with advanced 
and/or metastatic cancers

To assess the antitumor activity of abemaciclib
Study Design:
This study is a multicenter, open-label, Phase 1 trial of abemaciclib in Chinese patients with advanced and/or 
metastatic cancers.
The study will be focused on safety evaluation and PK data collection in patients with all advanced and/or 
metastatic cancers.  Patients will be randomized into 2 dose cohorts, and orally receive abemaciclib 150 mg or 
200 mg every 12 hours (Q12H).  One cycle is defined as 28 days (Cycle 1:  32 days), with modifications during 
Cycle 1 to enable PK sampling following a single dose and repeated doses.  The treatment of abemaciclib will 
continue until disease progression, development of unacceptable toxicity, or fulfillment of the other discontinuation 
criteria.  In case of patient discontinuation during Cycle 1, the enrollment will be extended until at least 10 patients 
with completed PK data are accrued in each cohort. Analysis on available PK and safety data will be conducted 
after study completion.
All patients in the study receive at least 2 cycles of abemaciclib unless one or more of the criteria for 
discontinuation are fulfilled; the short-term follow-up period for poststudy evaluation is 30 ±7 days after the 
decision to discontinue treatment.
Diagnosis and Criteria for Inclusion and Exclusions:
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 drug.
[1]
The patient must have histological or cytological evidence of cancer which is advanced and/or metastatic, and 
is an appropriate candidate for experimental therapy in the judgment of the investigator, after available 
standard therapies have ceased to provide clinical benefit.
[2]
Have the presence of measureable disease as defined by the Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1).  


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[3]
This criterion has been deleted.
[4]
This criterion has been deleted.
[5]
This criterion has been deleted.
[6]
Are native Chinese men or women≥18 years of age.
[7]
Have given written informed consent prior to any study-specific procedures.
[8]
Have adequate organ function, including:

Hematologic:  Absolute neutrophil count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L, and 
hemoglobin≥9 g/dL.  Patients may receive erythrocyte transfusions to achieve this hemoglobin level or 
platelet transfusions to achieve platelet levels at the discretion of the investigator; however, initial study 
drug treatment must not begin earlier than the day after transfusion.

Hepatic:  Bilirubin 1.5 times upper limits of normal (ULN), alanine aminotransferase (ALT), and 
aspartate aminotransferase (AST) 3.0 times ULN.

Renal:  Serum creatinine ≤1.2 mg/dL for males or ≤1.0 mg/dL for females.
[9]
Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale.
[10] Recovered from the acute effects of therapy (treatment- related toxicity resolved to baseline) except for 
residual alopecia.
[11] Are reliable and willing to make themselves available for the duration of the study and are willing to follow 
study procedures.
[12] Males and females with reproductive potential must agree to use medically approved precautions to avoid 
pregnancy during the trial and for 3 months following the last dose of study drug.
[9a] Are a man and agree to use a reliable method of birth control and to not donate sperm during the study 
and for at least 3 months following the last dose of study drug, OR
[9b] Are a woman of child-bearing potential with a negative serum pregnancy test at baseline (within 7 days 
prior to randomization and agree to use a reliable method of birth control during the study and for 3 months 
following the last dose of the study drug.
A woman of child-bearing potential is defined as a premenopausal female.  A postmenopausal female is 
defined as a woman:
1) at least 6 weeks after surgical bilateral oophorectomy that can be confirmed on medical history records, 
OR
2) with spontaneous amenorrhea for at least 12 months, not induced by a medical conditions such as anorexia 
nervosa nor induced by medication.
[13] Have an estimated life expectancy of ≥12 weeks.
[14] Are able to swallow capsules.
Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during screening.
[15] Have received previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and 
investigational therapy) within 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive 
agents prior to receiving study drug.
[16] Have a personal history of any of the following conditions:  presyncope or syncope of either unexplained or 
cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest, or have a
baseline ECG with any of the following abnormal findings: ventricular arrhythmia, evidence of acute 
myocardial ischemia, heart block (of any degree), or QTc prolongation (defined as QTcB ≥450 milliseconds).
[17] Have serious 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).
[18] Have an acute leukemia or other relevant cancers at the discretion of the investigator.
[19] Females who are pregnant or lactating.
[20] Have active bacterial, fungal, and/or known viral infection (for example, human immunodeficiency virus 
[HIV] antibodies, hepatitis B surface antigen [HBSAg], or hepatitis C antibodies).  Screening for active 
infections is not required for enrollment.


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[21] Patients consuming drugs or foods that are known to be inducers (for example, grapefruit juice, phenytoin, 
carbamazepine) or strong inhibitors of CYP3A4 should be excluded during Cycle 1.
[22] Patients receiving herbal regimens during Cycle 1 should be excluded.
[23] Have history or evidence of central nervous system (CNS) malignancy or metastasis.  Screening of 
asymptomatic patients without history of CNS metastases is not required for enrollment.
[24] This criterion has been deleted.
Investigational Product, Dosage, and Mode of Administration:
Oral abemaciclib will be administered Q12H, and at approximately the same time each day on a 28-day cycle
except Cycle 1.

The initial dose of study drug in Cycle 1 will be taken on Day 1 to enable PK sampling over 72 hours 
following a single dose; the remaining 55 doses will be taken every 12 hours on Days 4 to 31, with PK 
sampling on Day 18, Day 25 and over 24 hours following the single dose taken on Day 31.  Patients 
should be specifically instructed not to take a second dose of study drug on Day 31.

In Cycle 2 and beyond, study drug will be taken every 12 hours on Days 1 through 28 of a 28-day cycle.
Planned Duration of Treatment:
Patients will be on treatment until one of the discontinuation criteria is met.
Criteria for Evaluation:
Safety:
Hematology, chemistry, treatment-emergent adverse events (TEAEs) using Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 and the Medical Dictionary for Regulatory Activities (MedDRA), serious 
adverse events (SAEs), dose adjustments, electrocardiogram (ECG) and vital signs.
Efficacy:
Antitumor activity according to RECIST v. 1.1.
Bioanalytical:
Plasma concentrations of abemaciclib and its major metabolites LSN2839567 (M2) and LSN3106726 (M20) will 
be determined using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.
Pharmacokinetic:
Maximum plasma concentration (Cmax), area under the plasma concentration versus time curve (AUC0-tlast and 
AUC0-∞), and the time of maximal plasma concentration (tmax) following single and multiple dose.  In addition, 
half-life (t1/2), apparent volume of distribution (V/F), apparent systemic clearance (CL/F) and other relevant 
parameters.
Statistical Methods:
Safety:  Adverse events (AEs) including dose-limiting toxicity (DLT)-equivalent toxicities and TEAEs will be 
listed and summarized in frequency tables.  Severity of AE will be classified using CTCAE Version 4.0.  Other 
safety data such as laboratory tests and vital signs, will be summarized using summary statistics.
Efficacy:  Efficacy data will be listed by tumor type.
Pharmacokinetic:  The PK parameters of abemaciclib and its metabolites will be computed by standard 
noncompartmental methods of analysis using Phoenix WinNonlin.


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3. Table of Contents
A Phase 1 Study of Abemaciclib in Native Chinese Patients 
with Advanced and/or Metastatic Cancers
Section
Page
1.
Protocol I3Y-CR-JPBR(e) A Phase 1 Study of Abemaciclib in Native 
Chinese Patients with Advanced and/or Metastatic Cancers ................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................5
4.
Abbreviations and Definitions...........................................................................................11
5.
Introduction ......................................................................................................................16
5.1.
Rationale and Justification for the Study ......................................................................16
5.2.
Objectives ....................................................................................................................17
5.2.1.
Primary Objective ................................................................................................17
5.2.2.
Secondary Objectives...........................................................................................17
5.3.
General Introduction to Abemaciclib............................................................................17
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................18
5.3.2.
Nonclinical Pharmacokinetics ..............................................................................18
5.3.3.
Nonclinical Pharmacokinetic/Pharmacodynamic Modeling ..................................19
5.3.4.
Nonclinical Toxicology........................................................................................19
5.3.5.
Biomarkers...........................................................................................................23
5.3.6.
Clinical Experience..............................................................................................23
5.3.6.1.
Clinical Pharmacokinetics ..............................................................................24
5.3.6.2.
Safety.............................................................................................................24
5.4.
Rationale for Selection of Dose....................................................................................25
6.
Investigational Plan...........................................................................................................27
6.1.
Study Population..........................................................................................................27
6.1.1.
Inclusion Criteria .................................................................................................27
6.1.2.
Exclusion Criteria ................................................................................................28
6.2.
Summary of Study Design............................................................................................29
6.2.1.
Study Completion and End of Trial......................................................................29
6.2.1.1.
Study Period...................................................................................................29
6.2.1.2.
Continued Access Period................................................................................30
6.2.1.3.
End of Trial ....................................................................................................30
6.3.
Discontinuation............................................................................................................30
6.3.1.
Discontinuation of Patients...................................................................................30


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6.3.2.
Discontinuation of Study Sites .............................................................................31
6.3.3.
Discontinuation of the Study................................................................................32
7.
Treatment..........................................................................................................................33
7.1.
Materials and Supplies .................................................................................................33
7.2.
Study Drug Administration ..........................................................................................33
7.2.1.
Dosing Schedule ..................................................................................................33
7.2.2.
DLT-Equivalent Toxicity.....................................................................................34
7.2.3.
Dose Adjustments and Delays..............................................................................35
7.2.3.1.
Dose Adjustments...........................................................................................35
7.2.3.1.1.
Hematologic Toxicity ...............................................................................36
7.2.3.1.2.
Nonhematological Toxicity.......................................................................37
7.2.3.1.2.1.
Diarrhea..............................................................................................37
7.2.3.1.2.2.
Hepatic Toxicity .................................................................................38
7.2.3.2.
Dose Delays ...................................................................................................38
7.3.
Method of Assignment to Treatment ............................................................................38
7.4.
Blinding .......................................................................................................................39
7.5.
Concomitant Therapy...................................................................................................39
7.5.1.
Supportive Management for Diarrhea...................................................................39
7.6.
Treatment Compliance .................................................................................................40
8.
Safety, Pharmacokinetic, and Efficacy Data Collection .....................................................41
8.1.
Safety Evaluations........................................................................................................41
8.1.1.
Safety Data Collection and Review ......................................................................41
8.1.2.
Adverse Events ....................................................................................................41
8.1.2.1.
Serious Adverse Events ..................................................................................43
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................44
8.1.2.2.1.
Prior to Administration of Study Drug ......................................................44
8.1.2.2.2.
On Therapy...............................................................................................44
8.1.2.2.3.
Follow-Up Visit........................................................................................44
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................45
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................45
8.1.3.
Other Safety Measures .........................................................................................45
8.1.3.1.
Electrocardiograms.........................................................................................45
8.1.4.
Safety Monitoring ................................................................................................46
8.1.4.1.
Special Hepatic Safety Data Collection...........................................................46
8.1.4.2.
Renal Function ...............................................................................................47
8.1.4.3.
Venous Thromboembolic Events....................................................................47
8.1.5.
Complaint Handling.............................................................................................47
8.2.
Sample Collection and Testing.....................................................................................48


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8.2.1.
Samples for Study Qualification and Health Monitoring.......................................48
8.2.2.
Samples 
for 
Drug 
Concentration 
Measurements 
Pharmacokinetics .................................................................................................48
8.2.2.1.
Pharmacokinetic Samples...............................................................................48
8.2.3.
Biomarker Samples for Storage and Research ......................................................49
8.3.
Efficacy Evaluations ....................................................................................................49
8.4.
Procedure/Sampling Compliance..................................................................................49
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......................................................................................................51
10.
Data Analyses...................................................................................................................53
10.1. General Considerations ................................................................................................53
10.2. Determination of Sample Size ......................................................................................53
10.3. Patient Disposition .......................................................................................................53
10.4. Patient Characteristics ..................................................................................................53
10.5. Safety Analyses............................................................................................................53
10.6. Pharmacokinetic Analyses............................................................................................54
10.7. Efficacy........................................................................................................................54
10.8. Planned Analyses .........................................................................................................54
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................55
11.1. Informed Consent.........................................................................................................55
11.2. Ethical Review.............................................................................................................55
11.3. Regulatory Considerations ...........................................................................................55
11.3.1.
Investigator Information.......................................................................................56
11.3.2.
Protocol Signatures ..............................................................................................56
11.3.3.
Final Report Signature .........................................................................................56
12.
References ........................................................................................................................57


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List of Tables
Table
Page
Table JPBR.5.1. Exposure Multiples for Oral Administration of Abemaciclib Based on 
Administered Dose in Animals and Human Exposure in Study JPBA ............23
Table JPBR.7.1. Toxicity Dose Adjustments and Delays of Study Drug for Study JPBR .........35
Table JPBR.7.2. Dose Adjustments of Abemaciclib for Study I3Y-CR-JPBR ..........................38
Table JPBR.8.1. Adverse Event and Serious Adverse Event Reporting Guidelines for 
Study JPBR ...................................................................................................45


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List of Figures
Figure
Page
Figure JPBR.6.1. Study design for JPBR...................................................................................29
Figure JPBR.7.1. PK sampling and dosing schedule..................................................................34


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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JPBR Study Schedule ......................................................................58
Attachment 2.
Protocol JPBR Study Schedule – Continued Access Period............................61
Attachment 3.
Protocol JPBR Clinical Laboratory Tests.......................................................62
Attachment 4.
Protocol 
JPBR
Hepatic Monitoring Tests for Treatment Emergent Abnormality....................63
Attachment 5.
Protocol 
JPBR
Pharmacokinetic Sampling and ECG Schedule in Cycle 1 .............................64
Attachment 6.
Protocol 
JPBR
Example Inducers and Strong Inhibitors of CYP3A4 .....................................65
Attachment 7.
Protocol 
JPBR
Cytochrome P450 Substrates with Narrow Therapeutic Range.......................66
Attachment 8.
Protocol 
JPBR 
Recommendations 
for 
Reporting 
Serious Adverse Events .................................................................................67
Attachment 9.
Protocol JPBR ECOG Performance Status.....................................................68
Attachment 10.
Protocol JPBR RECIST Criteria 1.1...............................................................69
Attachment 11.
Protocol 
Amendment 
I3Y-CR-JPBR 
(e) 
Summary
A Phase 1 Study of Abemaciclib in Native Chinese Patients with 
Advanced and/or Metastatic Cancers .............................................................76


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4. Abbreviations and Definitions
Term
Definition
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
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration-time curve
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to last 
measurable plasma concentration
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
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
CDKI
cyclin-dependent kinase inhibitors
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL/F
apparent systemic clearance
CLRM
Clinical Laboratory Results Modernization
Cmax
maximum plasma 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 


I3Y-CR-JPBR(e) Phase 1 Oncology Protocol
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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.
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.
CR
complete response 
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.
CRP
clinical research physician
CRS
clinical research scientist
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DLT
dose-limiting toxicity
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.
FAS
full analysis set
FFPE
formalin-fixed paraffin-embedded


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FNA
fine needle aspirate
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factors
HBSAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
50% inhibition concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
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.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used 
as a reference in a clinical trial.
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.
IV
intravenous
IWRS
interactive web response system
LC/MS/MS
liquid chromatography with tandem mass spectrometry
mBC
metastatic breast cancer
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
monitor
A person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local SOPs (if any), and global Medical SOPs.  
Monitors are trained on the investigational product(s), the protocol, informed 
consent document, any other written information provided to subjects, relevant 
SOPs, International Conference on Harmonisation Good Clinical Practice 
guidelines (ICH-GCP), and all applicable laws (for example, privacy and data 
protection) and regulations.  
MRI
magnetic resonance imaging


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MTD
maximum tolerated dose
NCI
National Cancer Institute
NSAI
nonsteroidal aromatase inhibitors
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.
ORR
objective response rate
OS
overall survival
patient
A subject with a defined disease.
PD
progressive disease
PFS
progression-free survival
pHH3
phospho-histone H3
PK
pharmacokinetic
PR
partial response
pRb
phosphorylated retinoblastoma protein 
Q12H
every 12 hours
Q24H
every 24 hours
QTc
corrected QT interval
Rb
retinoblastoma protein
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
SAP
Statistical Analysis Plan
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.
screen failure
A patient who does not meet one or more criteria required for participation in a 


I3Y-CR-JPBR(e) Phase 1 Oncology Protocol
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trial
SD
stable disease
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
TEAE
treatment-emergent adverse event
TED70
threshold effective dose for 70% inhibition
TGI
tumor growth inhibition
tmax
time of maximal plasma concentration
topoII
topoisomerase II alpha
TPO
third-party organization
ULN
upper limit of normal
V/F
apparent volume of distribution
VPCs
ventricular premature complexes
VT
ventricular tachycardia
VTE
venous thromboembolic event
WBC
white blood cells


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A Phase 1 Study of Abemaciclib in Native Chinese Patients 
with Advanced and/or Metastatic Cancers
5. Introduction
5.1.
Rationale and Justification for the Study
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
maintaining control of cell division (Ortega et al. 2002; Sherr 1996).  The cyclin-dependent 
kinases, CDK4 and CDK6 (hereafter designated CDK4/6), participate in a complex with D-type 
cyclins to initiate the transition through the G1 restriction point.  A broad spectrum of human 
cancers have alterations in the CDK4/6-cyclinD-INK4-Rb pathway through either increased 
CDK4/6-cyclinD activity or mutations that attenuate function of the INK4 or Rb
(retinoblastoma) proteins (Malumbres and Barbacid 2001). These alterations render cells less 
dependent on mitogenic signaling for proliferation, one of the hallmarks of cancer cells.
The CDK4/6-cyclinD1 complex regulates the G1 restriction point through phosphorylation of the
Rb tumor suppressor protein.  Alterations in this pathway occur frequently in a broad spectrum 
of human cancers and involve 1) loss of cyclin-dependent kinase inhibitors (CDKI) by mutation 
or epigenetic silencing, 2) mutation/overexpression of either CDK4/6 or cyclin D, or 3) 
inactivation of Rb.  With the possible exception of those tumors with complete inactivation of 
Rb, which functions downstream of the CDK4/6-cyclinD1 complex, all these cancers are 
potentially sensitive to pharmacologic inhibition of CDK4/6.  From a therapeutic standpoint, the 
goal of inhibiting CDK4/6 with a small molecule inhibitor is to prevent cell cycle progression 
through the G1 restriction point, thus arresting tumor growth.  
Abemaciclib is a selective and potent small molecule CDK4/6 dual inhibitor with antitumor 
activity in preclinical pharmacology models, acceptable physical and pharmacokinetic (PK) 
properties, and an acceptable toxicity profile in nonclinical species.  This compound 
demonstrates significant inhibition of tumor growth in multiple human xenograft models 
including colorectal cancer, glioblastoma multiforme, acute myeloid leukemia, and non–small 
cell lung cancer (NSCLC).  Although characterized by a different constellation of genomic 
mutations, each of these 4 human xenografts has an intact, functional Rb protein.  Xenograft 
growth inhibition is generally dose dependent from 25 to 100 mg/kg following daily oral 
administration for 21 to 28 days.
The Phase 1 first-in-human study I3Y-MC-JPBA (Study JPBA) established a maximum tolerated 
dose (MTD:  200 mg every 12 hours on Days 1 through 28 of a 28-day cycle) and demonstrated 
acceptable safety and tolerability for abemaciclib in patients with advanced and/or metastatic 
cancers.  In this trial, abemaciclib demonstrated early single-agent clinical activity in cancers.  
Study I3Y-JE-JPBC (Study JPBC) was a 3-cohort dose-escalation Phase 1 trial in Japanese 
patients with advanced and/or metastatic cancers designed to confirm the safety and tolerability 
of abemaciclib up to the MTD which was established in Study JPBA. 


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Based on the Study JPBA expansion cohort of 68 patients with advanced and/or metastatic 
NSCLC, a global multicenter, open-label, randomized Phase 3 trial, I3Y-MC-JPBK (Study 
JPBK), is ongoing to compare the efficacy and safety of abemaciclib (200 mg Q12H) with 
erlotinib treatment for patients with Stage IV NSCLC whose tumors have a detectable KRAS 
mutation in either Codon 12 or 13 as detected by an investigational assay and who have 
progressed after platinum-based chemotherapy.  
Based on the other Study JPBA expansion cohort of 47 patients with metastatic breast cancer 
(mBC), a multicenter, randomized, Phase 3 study, Study I3Y-CR-JPBQ (JPBQ), is planned to 
compare the efficacy and safety to nonsteroidal aromatase inhibitors (NSAI) plus abemaciclib 
(150 mg Q12H) or plus placebo, and to compare fulvestrant plus abemaciclib (150 mg Q12H) or 
plus placebo in mainly east Asian postmenopausal women with hormone receptor-positive, 
HER2-negative locoregionally recurrent or metastatic breast cancer.
This Phase 1 trial, Study I3Y-CR-JPBR (hereafter Study JPBR), is designed to evaluate the 
safety and tolerability of abemaciclib monotherapy in Chinese patients with advanced and/or 
metastatic cancers to support Phase 3 studies to be conducted in China.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.
5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to evaluate the safety and tolerability of abemaciclib in 
Chinese patients with advanced and/or metastatic cancers.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to assess the PK of abemaciclib and its metabolites in Chinese patients with advanced 
and/or metastatic cancers

to assess the antitumor activity of abemaciclib
5.3.
General Introduction to Abemaciclib
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.


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5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
Abemaciclib represents a novel class of potent adenosine triphosphate (ATP) competitive and 
reversible CDK4/6 kinase inhibitor (50% inhibition concentration [IC50] for CDK4 = 
0.00196 M and IC50 for CDK6 = 0.0099 M).  This molecule displays a high level of 
selectivity over other related cyclin-dependent kinases at the enzyme and cellular level; for 
example, abemaciclib is approximately 3 orders of magnitude more selective for CDK4 
compared to CDK1.  In Colo-205 cells, the compound induces potent cellular inhibition of Rb 
phosphorylation (pSer780, IC50 = 0.121 M).  Other data has demonstrated that abemaciclib 
inhibits CDK4/6 to induce G1 arrest specifically in Rb+ tumors and is selective for G1 arrest at 
concentrations as high as 2.5 to 6 M.
This phenotypic selectivity is also demonstrated in vivo, where LSN2813542 (that is, 
abemaciclib mesylate) suppresses Rb phosphorylation and induces a G1 arrest as indicated by 
inhibition of topoisomerase II alpha and phospho-histone H3 (topoIIand pHH3 markers 
respectively, for cells in S phase and M phase), in a concerted fashion only consistent with arrest 
at the G1 restriction point in vivo.  Additionally, LSN2813542 showed excellent, sustained 
pharmacodynamic response in a mouse Colo-205 xenograft model (in vivo pRb inhibition ≥50% 
from 1 to 36 hours post oral dose of 50 mg/kg and potent suppression of topoIIand pHH3 at 
24 hours post oral dose of the same 50-mg/kg dose).  Dose response TED70 (threshold effective 
dose for 70% inhibition) values for pRb and topoIIinhibition (24 hours post oral dose time 
point) were 14.1 and 14.3 mg/kg, respectively.  This prolonged, robust target inhibition and G1 
arrest has resulted in the demonstration of statistically significant, dose-dependent antitumor 
activities (measured by tumor volume reduction) of LSN2813542 in 4 human subcutaneous 
xenograft models:  Colo-205 colorectal, H460 lung, U87 MG glioblastoma multiforme and 
MV4-11 acute myeloid leukemia.  For example, LSN2813542 can achieve statistically 
significant tumor growth inhibition when dosed orally at 25, 50, and 100 mg/kg for 21 days in 
the Colo-205 xenograft model.  Consistent with the mechanism of action of LSN2813542, the 
antitumor activity in Colo-205 was associated with a sustained inhibition of pRb, topoIIand 
pHH3 (30% to 50% inhibition of each marker on Days 14 and 21 of dosing at 100 mg/kg).
As a result of its brain exposure, treatment with this compound produces a statistically 
significant and dose-dependent improvement in survival in a rat orthotopic brain tumor model.  
Median survival was improved 8 and 12 days compared to vehicle following daily oral treatment 
at 40 mg/kg and 80 mg/kg for 21 days, respectively.
5.3.2. Nonclinical Pharmacokinetics
Studies evaluating absorption, distribution, metabolism, and excretion of abemaciclib were 
conducted in rats and dogs.  A single oral dose of radiolabeled abemaciclib was slowly absorbed 
(tmax ranged from 6.7 to 8 hours for abemaciclib and 8 hours for radioactivity), with parent drug 
accounting for approximately 79% and 41% of the plasma radioactivity in rats and dogs, 
respectively.  The radioactivity associated with [14C]abemaciclib was extensively distributed to 
tissues and organs in both pigmented (Long Evans) and nonpigmented (Sprague Dawley) rats
and was selectively associated with melanin-containing tissues.  Radioactivity in central nervous 


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system (CNS) tissues protected by the blood-brain barrier (cerebellum, cerebrum, medulla, and 
spinal cord) was measurable through 24 hours postdose.  Plasma protein binding of abemaciclib 
was high (mean ranged from approximately 95% to 99%) across species and its active 
metabolites in general had higher plasma free fraction than abemaciclib.  Metabolism in liver 
microsomes and cryopreserved hepatocytes in rats, dogs, and humans indicated formation of 
4 oxidative metabolites, including an active (based on in vitro binding data) N-desethyl 
metabolite (LSN2839567). In vivo in rats and dogs, parent was detected as the major component 
in plasma, and formation of the N-desethyl metabolite was observed as the major 
biotransformation pathway in these species.  Excretion studies in rats and dogs indicated that, 
following oral administration, the majority of the dose was excreted in the bile or feces. 
5.3.3. Nonclinical Pharmacokinetic/Pharmacodynamic Modeling
The primary objective of pharmacokinetic/pharmacodynamic modeling in preparation for the 
Phase 1 study was to estimate a pharmacologically effective and safe dose range in humans, 
based on preclinical data.
The nonclinical pharmacokinetic/pharmacodynamic analysis of abemaciclib activity for CDK4/6 
and tumor growth inhibition (TGI) was conducted on data generated using a Colo-205 xenograft 
model developed in the mouse.  A pharmacokinetic/pharmacodynamic model was developed to 
relate the predicted plasma concentrations to the observed level of in vivo CDK4/6 inhibition and 
tumor growth inhibition in the Colo-205 xenograft tumor model.  Abemaciclib plasma 
concentrations were connected to CDK4/6 inhibition and cell cycle arrest in Colo-205 human 
colorectal xenografts by incorporating the biomarkers, pRb, topoIIα, and pHH3, into a precursor-
dependent transit compartment model (Sharma et al. 1998; Sun and Jusko 1998; Mager and 
Jusko 2001; Hazra et al. 2006).  This biomarker model was then connected to TGI by i) relating 
the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent 
mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses.  Model 
validation was evaluated by predicting abemaciclib-mediated antitumor effect in A375 human 
melanoma xenografts.
The model successfully described abemaciclib-mediated CDK4/6 inhibition, cell cycle arrest, 
and TGI in Colo-205, and was successfully validated in A375 by effectively predicting CDK4/6, 
cell cycle, and TGI.  The model also demonstrated that a chronic dosing strategy achieving 
minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain 
durable cell cycle arrest.  High abemaciclib plasma concentrations led to quiescence and 
apoptosis.
5.3.4. 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 toxicity profile associated with abemaciclib administration in rat and dog was generally 


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similar to a cytotoxic chemotherapeutic agent, primarily including bone marrow suppression and 
gastrointestinal toxicity.  Clinical signs in animals included fecal changes (soft/liquid, mucoid, 
discolored – dogs), alopecia and dried/flaking/scabbed skin (rats), vomiting (dogs), decreased 
food consumption and body weight, dehydration, and decreased activity.
The following paragraphs provide a summary of the major findings in rats and dogs associated 
with administration of abemaciclib.  The repeat-dose 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) and also included a 28-day recovery period to assess reversibility.  The dosing 
schedule corresponds to 1 cycle of dosing in the Phase 1 clinical study.  Mortality attributed to 
abemaciclib was limited to the highest doses investigated, which were 50 mg/kg (300 mg/m2) in 
rats and 10 mg/kg (200 mg/m2) in dogs.  In rats, mortality occurred in 2 of 48 rats at 50 mg/kg 
on Days 14 and 20 and was associated with clinical signs of soft stools and/or reduced feces, 
dehydration, reduced food consumption, body weight loss, and decreased activity.  These 
mortalities, which were only observed in the toxicokinetic group, were attributed to both 
administration of abemaciclib and the weakened condition of the animals due to repeated blood 
sampling.
In dogs, declining clinical condition of animals given 10 mg/kg/day began on Day 9, leading to 
euthanasia of 2 dogs on Days 12 and 15 and early termination of the dose group on Day 16.  The 
dogs that were euthanized exhibited clinical signs including but not limited to:  red and/or liquid 
and/or soft feces, decreased activity and food consumption, body weight loss, dehydration, 
thinness, hypothermia, and paleness.  These animals also exhibited marked pancytopenia 
characterized by decreases in reticulocytes, leukocytes (neutrophils, monocytes, and 
lymphocytes), and platelets.  The cause of the mortality in dogs was attributed to gastrointestinal 
lesions in conjunction with marked myelosuppression.  A complete battery of safety 
pharmacology evaluations was also conducted.
The primary target organs in rats and dogs were identified as bone marrow, gastrointestinal tract, 
lymphoid tissues, and male reproductive tract.  Morphologic changes in these organs were 
consistent with cytotoxic effects in rapidly dividing cells.  Pancytopenia in the peripheral blood 
and bone marrow hypocellularity were observed at all doses, while effects on the gastrointestinal 
(crypt hyperplasia and villous atrophy) and lymphoid (depletion in the thymic cortex and lymph 
nodes) tissues mainly occurred at higher doses.  Cytotoxic effects on the male reproductive tract 
(hypospermatogenesis and atrophy of the testicular seminiferous epithelium, seminal vesicle, and 
prostate) were also observed in rats and dogs.  All of these changes demonstrated complete or 
partial reversibility within the 28-day recovery period.  In an embryo-fetal development study in 
which pregnant rats received abemaciclib, increased rates of skeletal and cardiac variations and 
malformations were observed at 4 mg/kg and above.  This increased rate of variations and 
malformations was accompanied by decreased fetal weights.  Based on embryo-fetal 
development studies, there is a risk of fetal toxicity, including teratogenicity, at clinically 
relevant exposure levels if a pregnant woman is exposed to abemaciclib.
In rats, the lung was also identified as a target organ for toxicity, characterized by multifocal 


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macrophage accumulation with or without bronchoalveolar inflammation.  Minimal-to-slight 
macrophage accumulation was observed at all doses, whereas minimal-to-moderate 
inflammation was seen at higher doses.  The inflammatory infiltrates were located primarily in 
the alveoli and composed of mixed cells (neutrophils, macrophages, lymphocytes); hyperplasia 
of the lining pneumocytes and/or fibrosis was sometimes associated with the inflammation.  
These changes could be compatible with infection.  The inflammation demonstrated complete 
reversibility within the 28-day recovery period.
Other morphologic changes seen in either rats or dogs were generally considered minor and not 
considered to be toxicologically important.  In rats, microscopic changes at higher doses 
included minimal-to-slight tubular vacuolar degeneration in the kidneys (without any evidence of 
renal functional impairment); minimal-to-slight diffuse vacuolation of acinar cells in the 
pancreas (without any evidence of cellular degeneration or functional impairment); minimal 
macrophage vacuolation in the spleen; a minor increased incidence of myofiber 
degeneration/necrosis; and minimal-to-slight hypercellularity of the thymic medulla.  In dogs, 
minimal-to-moderate cytoplasmic eosinophilia/decreased vacuolation and minimal-to-slight 
mononuclear cell infiltration were seen in the adrenal gland, which were not accompanied by a 
notable change in cell size or evidence of degeneration.
Abemaciclib was also investigated in a standard battery of safety pharmacology and genotoxicity 
studies.  No adverse findings associated with respiratory or CNS function were observed in rats 
at up to 50 mg/kg.  abemaciclib was negative in the bacterial mutation test (Ames) and in vitro
and in vivo mammalian tests (chromosome aberration and rat micronucleus, respectively), and is 
thus not considered to be a genotoxicant.
In the cardiovascular safety pharmacology study, dogs were given abemaciclib at doses of 
0.3, 1.0, and 10 mg/kg (6, 20, and 200 mg/m2).  Ventricular premature complexes (VPCs) and 
paroxysmal ventricular tachycardia (VT) occurred in 1 of 8 dogs given 10 mg/kg, a dose that 
exceeded the MTD in the 28-day repeat-dose toxicity study.  Although occasional VPC can be a 
normal variant in dogs, paroxysmal VT is not a normal finding.  These arrhythmias were 
observed at several time points between 22 and 48 hours postdose.  Although parent drug is 
detectable during this period, the occurrence of VT did not correlate with maximum plasma level 
of abemaciclib.  No waveform abnormalities or blood pressure changes were associated with this 
arrhythmia.  Based upon the incidence in a single animal and the delayed onset, the VT was 
likely due to ventricular irritation originating from the insertion site of the left ventricular 
pressure transducer and/or positive electrocardiogram electrode.  However, because the 
arrhythmia occurred only at the highest dose of abemaciclib, it cannot be ruled out as a potential 
compound-related effect.
In in vitro studies, abemaciclib did not demonstrate blockade of the current produced by the 
human ether-á-go-go-related gene potassium channel expressed in mammalian cells.  However, 
the 50% inhibition concentration (IC50) was not precisely determined due to incompatibility of 
the compound with the buffer system used in the assay; hence, the IC50 was determined to be 
>1.65 M.  Importantly, no corrected QT interval (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 


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to be low.
Abemaciclib was also evaluated in vitro for ocular irritation using the bovine corneal opacity and 
permeability test.  Based on the results, abemaciclib is considered to be a nonirritant.
Based on the light absorbing properties of abemaciclib and its distribution to the eye and skin in 
rats, there is the potential for phototoxicity if patients are exposed to sunlight or other sources of 
ultraviolet light.  Specific studies in animals or humans exposed to ultraviolet light have not been 
conducted yet; while taking abemaciclib, subjects should be advised to avoid the use of tanning 
beds and, if long exposure to sunlight is expected, to use sunscreen and wear sunglasses.
In conclusion, results from the nonclinical toxicology, safety pharmacology, and genetic
toxicology studies for abemaciclib demonstrate an acceptable safety profile with toxicities that
are generally considered to be monitorable and reversible.  Based on the safety profile of
abemaciclib in 28-day toxicology studies, dose/exposure multiples relative to relevant clinical
dose levels based on body surface area and mean plasma exposure obtained from patients in
Study JPBA are summarized in (Table JPBR.5.1).  Although the exposure multiples in animals 
relative to the clinical doses are low, the toxicology findings associated with abemaciclib in 
animals and humans are considered to be easily monitorable and have been demonstrated to be
reversible.  Therefore, collectively, the nonclinical toxicology studies support clinical
investigation of abemaciclib.


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Table JPBR.5.1.
Exposure Multiples for Oral Administration of Abemaciclib Based 
on Administered Dose in Animals and Human Exposure in Study 
JPBA
Dose per day
(mg/kg)
Dose per day
(mg/m2)
Dose
Multiplea
AUC0-24 hr
(ng·hr/mL)
Exposure 
Multipleb
Humanc
150 mg Q12H
(300 mg per day)
5
187.5
Rat:  1.6
Dog:  0.3
3,758d
Rat:  6.5
Dog:  0.2
200 mg Q12H
(400 mg per day)
6.7
250
Rat:  1.2
Dog:  0.2
5,886d
Rat:  4.3
Dog:  0.1
Rat NSTDe
50
300
-
23,800
-
Dog MinTDf
3
60
-
800
-
Abbreviations:  AUC0-24 hr = area under the concentration versus time curve from time 0-24 hours; 
MinTD = highest Minimally Toxic Dose; NSTD = highest Not Severely Toxic Dose; Q12H = every 12 hours.
a
Dose multiple is the dose in animals/dose in humans based on body surface area (mg/m2).
b Exposure multiple is the mean calculated AUC0-24 hr (males and females) on Day 1 in animals/AUC0-24 hr in 
humans at steady state.
c
Assumes body weight of 60 kg and body surface area of 1.6 m2.
d Human exposure (steady state) derived from clinical pharmacokinetic data collected in Study JPBA.
e
NSTD based on 28-day repeat-dose toxicity study in rats (803871).
f
MinTD based on 28-day repeat-dose toxicity study in dogs (803872).
More detailed information about the characteristics of abemaciclib can be found in the IB.
5.3.5. Biomarkers
Not applicable.
5.3.6. Clinical Experience
As of 22 September 2016, 12 clinical studies were completed (7 in healthy subjects and 5 in 
patients) and 19 clinical studies are ongoing (3 in healthy subjects and 16 in patients). Among 
them, Study JPBA was a multicenter, nonrandomized, open-label Phase 1 study of abemaciclib 
in patients with advanced and/or metastatic cancers.  In Part A (the dose-escalation phase), 
patients were treated on 2 different schedules:  either at 50, 100, 150, and 225 mg every 24 hours 
(Q24H), or at 75, 100, 150, 200, and 275 mg every 12 hours (Q12H).  In Parts B, C, D, E, F, and 
G (the tumor-specific cohorts), patients were treated on the twice-daily schedule at a dose no 
greater than the MTD with administration of abemaciclib on Days 1 through 28 of a 28-day cycle.  
The MTD was not reached for the once-daily schedule and for the twice-daily schedule was 
established at 200 mg Q12H. The Phase 2 study, JPBB, is a proof-of-concept trial for patients 
with mantle cell lymphoma (MCL). Abemaciclib is administered orally at 200 mg Q12H on 
Days 1 through 28 of a 28-day cycle.  Study JPBC, was a dose acceleration Phase 1 trial in 


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Japanese patients with advanced and/or metastatic cancers designed to confirm the safety and 
tolerability of abemaciclib up to the MTD which was established in Study JPBA. Study I3Y-
MC-JPBD (JPBD) is an open-label study to determine the disposition of labeled abemaciclib in 
healthy surgically sterile or postmenopausal females or sterile males following oral 
administration of a single 150-mg dose of abemaciclib containing approximately 5 Ci of [14C]-
abemaciclib.  A food-effect study (I3Y-MC-JPBG [JPBG]) involving administration of 
abemaciclib as a 50% w/w capsule to healthy volunteers with a high-fat meal indicated that the 
Cmax was increased 24% while the AUC remained unchanged, when compared to the fasted 
state. Results from a study (I3Y-MC-JPBU [JPBU]) of the effect of a high-fat meal using the 
proposed commercial formulation (25% w/w capsule) show an increase of approximately 30% in 
AUC and Cmax in the presence of food.  A high-fat meal did not change the interindividual 
variability in PK.  Although the change in AUC and Cmax in Study JPBU was statistically 
significant, it was small relative to the variability in exposure in the cancer patient population, 
and therefore not considered to be clinically relevant.  Based on currently available data, 
abemaciclib can be taken without regard to meals. 
5.3.6.1.
Clinical Pharmacokinetics
The PK profile of abemaciclib was studied using data available from a total of 222 patients 
enrolled in Study JPBA. 
A nonclinical PK/PD model has demonstrated that a chronic dosing strategy achieving minimum 
steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle 
arrest. 
Clinically, after a single oral dose administration, the time course of abemaciclib in plasma at the 
MTD of 200 mg is characterized by a median Tmax of 6 hours (cancer patients) and a mean t1/2
of approximately 21.3 hours. The mean Cmax and AUC0-tlast are 158 ng/mL and 4600 ng*hr/mL, 
respectively.  
At steady state after repeated oral Q12H dosing, the time course of abemaciclib concentration in 
plasma at the MTD is characterized by a mean Cmin,ss and Cmax,ss of approximately 197 and 
298 ng/mL, respectively.  The mean AUC0-τ,ss and AUC0-24,ss are approximately 3000 and 
5520 ng.hr/mL, respectively. 
5.3.6.2.
Safety
As of 22 September 2016, abemaciclib has been administered to 2087 cancer patients. There are 
16 ongoing and 5 completed clinical studies in cancer patients. Clinical study data are available 
for 870 patients from 5 completed studies (JPBA, JPBB, JPBC, JPBE, and JPBN and 3 ongoing 
studies (JPBH, JPBJ, and JPBY). LSS data are available from Studies JPBA, JPBB, JPBC, 
JPBE, JPBH, JPBJ, JPBK, JPBN, JPBO, JPBZ, JPBX, JPBY, and JPCB. 
Overall, the most common TEAEs (≥10%) possibly related to study drug for patients receiving 
abemaciclib as a single agent are diarrhea, nausea, fatigue, neutropenia, vomiting, decreased 
appetite, thrombocytopenia, anemia, leukopenia, abdominal pain, and blood creatinine increased. 
In Study JPBH, when abemaciclib was combined with endocrine therapy (anastrozole, letrozole, 


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tamoxifen, exemestane), diarrhea has been reported in 98.5% of the metastatic breast cancer 
patients; and in 86.0% of the metastatic breast cancer patients when combined with targeted 
agents (exemestane + everolimus, or trastuzumab). As a result of the higher incidence of 
diarrhea, the recommended abemaciclib dose is 150 mg Q12H when combined with these agents. 
Furthermore, it was noted in Study JPBY (abemaciclib 150 mg Q12H in combination with 
anastrozole), diarrhea was reduced at 52% when patients received loperamide prophylactically. 
The majority of deaths reported for patients in the presented studies with available safety data 
were due to disease progression.
Per LSS as of 22 September 2016, 167 patients in the ongoing and completed cancer patient 
studies experienced 264 SAEs that were reported as possibly related to study drug. SAEs that 
were possibly related to study drug and experienced by ≥5 patients receiving abemaciclib 
monotherapy included diarrhea (14 patients); nausea (9 patients); acute kidney injury and 
dehydration (7 patients each); anemia, pneumonia, and vomiting (6 patients each); and 
neutropenia and thrombocytopenia (5 patients each).
Two, unexpected hepatic SAEs (1 of liver failure and 1 of drug-induced liver injury) were 
identified in the open-label Phase 3 JUNIPER (I3Y-MC-JPBK) study comparing abemaciclib 
versus erlotinib in patients with Stage IV NSCLC. Both of these hepatic SAEs had confounding 
factors including prior treatment with nivolumab and baseline hepatic metastases.
SAEs that were possibly related to study drug and experienced by ≥5 patients receiving
abemaciclib combinations included neutropenia (5 patients; abemaciclib with pemetrexed) and
dehydration (5 patients; abemaciclib with endocrine therapy).
5.4.
Rationale for Selection of Dose
During dose escalation part in Study JPBA, the dosages of 50, 100, 150, and 225 mg every 
24 hours (Q24H), and 75, 100, 150, 200, and 275 mg Q12H were investigated.  None of the 
patients treated on the once-daily schedule and 3 of the 33 patients (9.1%) treated on the twice-
daily schedule experienced dose-limiting toxicities (DLTs).  At 275 mg Q12H, 2 of the 3 patients 
experienced DLTs of Grade 3 fatigue (1 of these patients also experienced a DLT-equivalent 
event of Grade 3 nausea on Day 6 of Cycle 2).  At the next lower dose level of 200 mg Q12H, 1 
of the 7 patients also experienced a DLT of Grade 3 fatigue.  Therefore, the MTD was 
established at 200 mg Q12H. Thus, a global multicenter, open-label, randomized Phase 3 trial, 
I3Y-MC-JPBK, is planned to compare the efficacy and safety of abemaciclib 200 mg orally 
administrated every 12 hours versus erlotinib treatment for patients with Stage IV NSCLC whose 
tumors have a detectable KRAS mutation and who have progressed after platinum-based 
chemotherapy.  Patients from China will be enrolled in this global Phase 3 study.
Preliminary safety data from Study JPBH, which is a Phase 1b study to evaluate safety and 
tolerability of abemaciclib in combination with endocrine therapies (including anastrozole and 
letrozole) in patients with advanced/metastastic breast cancer, demonstrates that the AE profile 
of 150-mg or 200-mg Q12H abemaciclib administered in combination with NSAIs is consistent 
with abemaciclib monotherapy, as the most common TEAEs possibly related to study drug were 


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diarrhea, nausea, fatigue, and neutrophil count decreased.  At the 200-mg dose, the incidence of 
treatment-emergent Grade 3 diarrhea was found to be greater when abemaciclib was 
administered in combination with an NSAI from a review of the preliminary safety data in Study 
JPBH, compared to abemaciclib administered alone in Part D of Study JPBA.  When the 
abemaciclib dose was reduced from 200 mg to 150 mg or lower for some patients in Study JPBH, 
either the severity of diarrhea decreased or the event resolved.  Therefore, a multicenter,
randomized Phase 3 study, Study JPBQ, is planned to compare the efficacy and safety to 
compare NSAI plus 150-mg abemaciclib or plus placebo, and to compare fulvestrant plus 150-
mg abemaciclib or plus placebo in mainly east Asian postmenopausal women with hormone 
receptor-positive, HER2-negative, locoregionally recurrent or metastatic breast cancer.
Since the objective of Study JPBR is to evaluate the safety and tolerability of abemaciclib 
monotherapy in Chinese patients with advanced and/or metastatic cancers and to support the 
subsequent Phase 3 studies in NSCLC and metastatic breast cancer (Studies JPBK and JPBQ) to 
be conducted in China, both doses of 150 mg and 200 mg Q12H will be evaluated in the study.


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6. Investigational Plan
6.1.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may, in 
principle, not be re-screened.  Individuals who previously failed screening due to minor 
abnormalities of clinical laboratory tests, may be re-tested by agreement between principal 
investigator and the sponsor.
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 first dose of study drug.
[1]
The patient must have histological or cytological evidence of cancer which is 
advanced and/or metastatic, and is an appropriate candidate for experimental 
therapy in the judgment of the investigator, after available standard therapies 
have ceased to provide clinical benefit.
[2]
Have the presence of measureable disease as defined by the Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1, Eisenhauer et al. 2009).
[3]
This criterion has been deleted.
[4]
This criterion has been deleted.
[5]
This criterion has been deleted.
[6]
Are native Chinese men or women≥18 years of age.
[7]
Have given written informed consent prior to any study-specific procedures.
[8]
Have adequate organ function, including:

Hematologic:  Absolute neutrophil count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L, 
and hemoglobin≥9 g/dL.  Patients may receive erythrocyte transfusions to achieve 
this hemoglobin level or receive platelet transfusion at the discretion of the 
investigator; however, initial study drug treatment must not begin earlier than the day 
after transfusion.

Hepatic:  Bilirubin 1.5 times upper limits of normal (ULN), alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST) 3.0 times ULN.

Renal:  Serum creatinine ≤1.2 mg/dL for males or ≤1.0 mg/dL for females.
[9]
Have a performance status ≤1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Oken et al. 1982).
[10] Recovered from the acute effects of therapy (treatment-related toxicity 
resolved to baseline) except for residual alopecia.
[11] Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[12] Males and females with reproductive potential must agree to use medically 
approved precautions to avoid pregnancy during the trial and for 3 months 
following the last dose of study drug.


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[12a] Are a man and agree to use a reliable method of birth control and to not 
donate sperm during the study and for at least 3 months following the last 
dose of study drug, OR  
[12b] Are a woman of child-bearing potential with a negative serum 
pregnancy test at baseline (within 7 days prior to randomization) and agree to 
use a reliable method of birth control during the study and for 3 months 
following the last dose of the study drug.
A woman of child-bearing potential is defined as a premenopausal female.  A 
postmenopausal female is defined as a woman:
1) at least 6 weeks after surgical bilateral oophorectomy that can be 
confirmed on medical history records, OR
2) with spontaneous amenorrhea for at least 12 months, not induced by a 
medical conditions such as anorexia nervosa nor induced by medication.
[13] Have an estimated life expectancy of ≥12 weeks.
[14] Are able to swallow capsules.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[15] Have received previous therapies for cancer (including chemotherapy, 
radiotherapy, immunotherapy, and investigational therapy) within 21 days for 
myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to 
receiving study drug.
[16] Have a personal history of any of the following conditions:  presyncope or 
syncope of either unexplained or cardiovascular etiology, ventricular 
tachycardia, ventricular fibrillation, or sudden cardiac arrest, or have a 
baseline ECG with any of the following abnormal findings: ventricular 
arrhythmia, evidence of acute myocardial ischemia, heart block (of any 
degree), or QTc prolongation (defined as QTcB ≥450 milliseconds).
[17] Have serious 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).
[18] Have an acute leukemia or other relevant cancers at the discretion of the 
investigator.
[19] Females who are pregnant or lactating.
[20] Have active bacterial, fungal, and/or known viral infection (for example, 
human immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen 
[HBSAg], or hepatitis C antibodies).  Screening for active infections is not
required for enrollment.
[21] Patients consuming drugs or foods that are known to be inducers (for 
example, grapefruit juice, phenytoin, carbamazepine) or strong inhibitors of 
CYP3A4 should be excluded during Cycle 1 (Attachment 6).
[22] Patients receiving herbal regimens during Cycle 1 should be excluded.


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[23] Have history or evidence of CNS malignancy or metastasis.  Screening of 
asymptomatic patients without history of CNS metastases is not required for 
enrollment.
[24] This criterion has been deleted.
6.2.
Summary of Study Design
This study is a multicenter, open-label, Phase 1 trial of abemaciclib in Chinese patients with 
advanced and/or metastatic cancers.
The study will be focused on safety evaluation and PK data collection in patients with all 
advanced and/or metastatic cancers.  Patients will be randomized into 2 dose cohorts, and orally 
receive abemaciclib 150 mg or 200 mg every 12 hours (Q12H).  One cycle is defined as 28 days 
(Cycle 1:  32 days), with modifications during Cycle 1 to enable PK sampling following a single 
dose and repeated doses.  The treatment of abemaciclib will continue until disease progression, 
development of unacceptable toxicity, or fulfillment of the other discontinuation criteria.  In case 
of patient discontinuation during Cycle 1, the enrollment will be extended until at least 
10 patients with completed PK data accrued in each cohort.  Analysis on available PK and safety 
data will be conducted after study completion.
All patients in the study receive at least 2 cycles of abemaciclib unless one or more of the criteria 
for discontinuation (refer to Section 6.3.1) are fulfilled; the short-term follow-up period for 
poststudy evaluation is 30 ±7 days after the decision to discontinue treatment.  Figure JPBR.6.1
shows the study design for Study JPBR.
Abbreviations:  Q12H = every 12 hours; R = randomization.
Figure JPBR.6.1.
Study design for JPBR.
Refer to Attachment 1 for the Study Schedule.
6.2.1. Study Completion and End of Trial
6.2.1.1.
Study Period
Study period begins at the first study treatment and ends at study completion.  The study period 
does not include the continued access period. Study completion will occur after all patients 
have been in study treatment for at least 6 cycles, or after all patients have discontinued study 
treatment and completed the short-term follow-up visit, whichever occurs earlier. Refer to 


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Attachment 2 for the Study Schedule for the continued access period.
Short-term follow-up will begin the day after the patient and the investigator agree to 
discontinue abemaciclib and lasts approximately 30 (±7) days.
Long-term follow-up will begin the day after short-term follow-up is completed and continues
to study completion.
6.2.1.2.
Continued Access Period
Continued access begins after study completion and ends at the end of trial. During the 
continued access period, patients on study treatment who continue to experience clinical benefit 
may continue to receive study treatment until one of the criteria for discontinuation is met. Lilly 
will notify investigators when the continued access period begins. Approximate visit duration of 
continued access is 28±2 days. Continued access follow-up will begin the day after the patient
and the investigator agree to discontinue abemaciclib and lasts approximately 30 (±7) days. All 
AE and SAE information will be collected in continued access. Efficacious measurement will be 
at the discretion of the investigator.
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed. Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
6.2.1.3.
End of Trial
End of trial is 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 the final follow-up visit (including the final follow-up visit for the continued access 
period, if applicable) or has been declared lost to follow-up.
6.3.
Discontinuation
6.3.1. Discontinuation of Patients
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 clinical research physician (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 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.


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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 drugs
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drugs 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 good clinical practice (GCP)

The patient has evidence of progressive disease.

The patient experiences unacceptable toxicity, including but not limited to the following 
circumstance (refer to Section 7.2.3.1.2.2).

Patients not recovering from toxicity within 14 days should be considered for 
discontinuation of the study.  A delay >14 days may be permitted before discontinuing 
the patient from treatment as long as the patient demonstrates clinical benefit without 
objective progression and is recovering from the toxicity. Such a decision should be 
discussed and documented with the Lilly CRP.
The patient is noncompliant with study procedures and/or treatment (Section 7.6).
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 
CRF.  Patients who discontinue will have follow-up procedures performed as shown in the Study 
Schedule (Attachment 1).
6.3.2. 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.


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6.3.3. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patients, judges it necessary for any scientific, medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.


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7. Treatment
7.1.
Materials and Supplies
Abemaciclib will be supplied as capsules for oral consumption. Abemaciclib capsules should be 
stored within the temperature range stated on the label.  Investigators should instruct patients to 
store the capsules at home in the original container and to keep out of the reach of children.  
Capsules should not be opened, crushed, or dissolved.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agent and planned duration of each 
individual’s treatment to the site personnel or patient,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensation, destruction, 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 so that the situation can be assessed.
7.2.1. Dosing Schedule
Oral abemaciclib will be administered every 12 hours (±3 hours) on 28-day cycles (Cycle 1:  
32 days).  Study drug should be taken at approximately the same times each day.
For Cycle 1, the initial dose of study drug will be taken on Day 1 to enable PK sampling over 
72 hours following a single dose; the remaining 55 doses will be taken every 12 hours on Days 4
to 31, with additional PK sampling on Day 18, Day 25, and over 24 hours following the single 
dose taken on Day 31 as scheduled in Attachment 5. For Cycle 1, patients should be specifically 
instructed not to take a second dose of study drug on Day 31; if such a dose is inadvertently 
taken on Day 31, it constitutes a protocol violation.  In principle, patients will be suggested to be 
hospitalized during PK sample collection especially for Day 1 and Day 31 in Cycle 1.
Figure JPBR.7.1 shows the PK sampling and dosing schedule for Study JPBR.


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Abbreviation:  PK = pharmacokinetic(s).
Figure JPBR.7.1.
PK sampling and dosing schedule.
From Cycle 2, patients will be administrated every 12 hours on Days 1 through 28 of a 28-day 
cycle.
A delay of ≤7 days in the initiation of a cycle (Day 1) for justifiable reasons (for example, 
inclement weather, holidays, or weekends) other than toxicity will be permitted.  Study treatment 
may be held up to 14 days within a cycle or at start of next cycle to permit sufficient time for 
recovery from the toxicity.  
Patients will receive at least 2 cycles of abemaciclib unless one or more of the criteria for 
discontinuation (refer to Section 6.3.1) are fulfilled; the short-term follow-up period for 
poststudy evaluation will be 30 ±7 days after the decision to discontinue treatment.
7.2.2. DLT-Equivalent Toxicity
The dose-limiting toxicity (DLT)-equivalent toxicity is defined as an AE occurring between 
1) Day 1 and Day 32 of Cycle 1; 2) Day 1 and Day 28 of Cycle 2 and beyond, that is possibly 
related to the study drug and fulfills any one of the following criterion using the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0:

Grade 3 or 4 nonhematological toxicity according to the NCI CTCAE Version 
4.0 except for nausea, vomiting, diarrhea, or electrolyte disturbance.

Grade 3 or 4 nausea, vomiting, diarrhea, or electrolyte disturbance that persists 
more than 2 days despite maximal supportive intervention.

Grade 4 hematological toxicity that persists more than 5 days.

Grade 3 or 4 thrombocytopenia with bleeding.

Grade 3 or 4 neutropenia with fever.


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7.2.3. Dose Adjustments and Delays
7.2.3.1.
Dose Adjustments
Dose adjustments are allowed both within a cycle and between cycles.
If a patient who, in the judgment of the investigator, is receiving clinical benefit from study 
therapy requires further dose reduction than is outlined in Table JPBR.7.2, then the investigator 
must discuss with the Lilly CRP prior to any further dose reduction.
Dose adjustments are allowed only one level at a time.  For patients requiring dose reduction(s), 
re-escalation to a prior dose level is permitted only after consultation with the Lilly CRP.
Dose adjustments and delays for the study are summarized in Table JPBR.7.1.
Table JPBR.7.1.
Toxicity Dose Adjustments and Delays of Study Drug for 
Study JPBR
Cause
Profile and Severity
Dose Suspension
Dose Reduction
Hematologic 
Toxicity
Section 7.2.3.1.1
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced by 
one dose level.
Hematologic 
Toxicity
Section 7.2.3.1.1
Recurrent Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced by 
one dose level.
Hematologic 
Toxicity
Section 7.2.3.1.1
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced by 
one dose level.
Hematologic 
Toxicity: If
patient requires 
administration of 
blood cell growth 
factors
Section 7.2.3.1.1
Regardless of severity
(Use of growth factors according 
to ASCO Guidelines)
Dose MUST be suspended 
for at least 48 hours after 
the last dose of blood cell 
growth factors was 
administered and until 
toxicity resolves to at least 
Grade 2.
Dose MUST be reduced by 
one dose level unless 
already performed for 
incidence of toxicity that 
led to the use of growth 
factor
Nonhematological 
Toxicityb
(except diarrhea
and ALT increased)
Section 7.2.3.1.2
Persistent or recurrent Grade 2 that 
does not resolve with maximal
supportive measures within 7 days 
to baseline or Grade 1
Dose MUST be suspended
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced by 
one dose level.
Nonhematological 
Toxicity
Section 7.2.3.1.2
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced by 
one dose level.
Diarrhea
Section 7.2.3.1.2.1
and 7.5.1
Grade 2 that does not resolve 
within 24 hours to at least Grade 1
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose reduction is NOT
required.
Diarrhea
Section 7.2.3.1.2.1
and 7.5.1
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures ,or any Grade 
of diarrhea that requires 
hospitalization.
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced by 
one dose level.


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Diarrhea
Section 7.2.3.1.2.1
and 7.5.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced by 
one dose level.
ALT Increased 
(Sections 
7.2.3.1.2.2. and 
8.1.4.1)
Persistent or recurrent
a Grade
2 (>3.0-5.0×ULN), or
Grade 3 (>5,0-20.0×ULN)c
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1.
Dose MUST be reduced by 
1 dose level.
ALT Increased 
(Sections 
7.2.3.1.2.2. and 
8.1.4.1)
Grade 4 (>20.0×ULN)
Study drug MUST be 
discontinued.
Study drug MUST be 
discontinued.
ALT 
Increased 
with increased total 
bilirubin, 
in 
the 
absence 
of 
cholestasis
(Sections 
7.2.3.1.2.2.)
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN
Study drug MUST be 
discontinued
Study drug MUST be 
discontinued
Abbreviation:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology.
Note:  MUST = mandatory.
a
Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:

shows stable hematological counts (Grade ≤2) during that timeframe

has absence of any signs or risk of infection

is benefiting from study treatment
b Additional guidance for renal and hepatic monitoring is in Sections 8.1.4.1 and 8.1.4.2.
c    Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section
8.1.4.1 for additional guidance for hepatic monitoring
7.2.3.1.1. Hematologic Toxicity
If a patient experiences Grade 4 hematologic toxicity, then study treatment must be suspended 
(until the toxicity resolves to either baseline or at least Grade 2) and the dose of abemaciclib 
must be reduced by one dose level as outlined in Table JPBR.7.2.
If a patient experiences Grade 3 hematologic toxicity, then study treatment must be suspended 
(until the toxicity resolves to either baseline or at least Grade 2) and the dose of abemaciclib may
be reduced by one dose level as outlined in Table JPBR.7.2 at the discretion of the investigator.
If the patient experiences a recurrent episode of Grade 3 hematologic toxicity, then dosing must
be suspended (until the toxicity resolves to at least Grade 2) and the dose of the study must be 
reduced by one dose level as outlined in Table JPBR.7.2.
Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from 
the stop date of the preceding event).  As a general guidance, based on the risk/benefit balance 
assessment per the investigator, for a patient who experiences a new episode of Grade 3 


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hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose 
should the patient satisfy the following conditions:
•
The patient showed stable hematological counts (Grade ≤2) during that timeframe
•
In the absence of any signs or risk of infection 
•
The patient is benefiting from study treatment
If a patient requires administration of blood cell growth factors, the dose of study drug must be 
suspended for at least 48 hours after the last dose of blood cell growth factors was administered
and until toxicity resolves to at least Grade 2, then reduced by one dose level as outlined in 
Table JPBR.7.2, if a dose reduction for the specific event necessitating the use of the growth 
factors has not already occurred.
7.2.3.1.2. Nonhematological Toxicity
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.  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 JPBR.7.2.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 7.2.3.1.2.1 or ALT increased, refer to Section 7.2.3.1.2.2) possibly related to 
abemaciclib that does not resolve with maximal supportive measures within 7 days to either 
baseline or Grade 1, then dosing 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 JPBR.7.2.
7.2.3.1.2.1.
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 either baseline or at least Grade 1) and must have 
abemaciclib dose reduced by one dose level as outlined in Table JPBR.7.2.
If a patient experiences persistent or recurrent diarrhea (Grade 2) that does not resolve with 
maximal supportive measures (refer to Section 7.5.1) within 24 hours to either baseline or at 
least Grade 1, then study treatment must be suspended (until the toxicity resolves to either 
baseline or at least Grade 1) and the dose of abemaciclib must be reduced by one dose level as 
outlined in Table JPBR.7.2.


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Table JPBR.7.2.
Dose Adjustments of Abemaciclib for Study I3Y-CR-JPBR
Dose 
Adjustment
Oral Dose
(For patients initiated with 
200 mg)
Oral Dose
(For patients initiated with 
150 mg)
Frequency
0
200 mg
150 mg
Every 12 hours
1
150 mg
100 mg
Every 12 hours
2
100 mg
50 mg
Every 12 hours
3
50 mg
-
Every 12 hours
7.2.3.1.2.2.
Hepatic Toxicity
Dose modifications and management for increased ALT are provided in Table JPBR.7.1. For 
persistent or recurrent Grade 2 ALT increased that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, or Grade 3 ALT increased, blinded study drug
must be suspended until the toxicity has resolved to at least Grade 1 and the dose must be 
reduced by 1 dose level. Discontinue blinded study drug for Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x ULN, in the absence of cholestasis. For Grade 4 ALT increased, 
the patient must be discontinued from blinded study drug.  Refer to Section 8.1.4.1 for additional 
hepatic monitoring guidance.
7.2.3.2.
Dose Delays
Before the start of each cycle, hematologic toxicity possibly related to abemaciclib must resolve 
to either baseline or at least Grade 2.
Before the start of each cycle, non-hematologic toxicity (except alopecia and fatigue) possibly 
related to abemaciclib must resolve to either baseline or at least Grade 1.
The start of a cycle may be delayed to allow sufficient time for recovery from toxicity possibly 
related to study drug.  Patients not recovering from such toxicity within 14 days should be 
considered for discontinuation from the study.
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive abemaciclib in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted at the 
investigational site to confirm that each patient meets all enrollment criteria.  Upon confirmation 
of eligibility, the sponsor will confirm the dose and identification number assignment for each 
patient using the interactive web response system (IWRS).
Upon obtaining informed consent, site personnel should access the IWRS, which will enter a 
patient number.  Patients who meet all criteria for enrollment will be randomly assigned to 
receive either 150-mg or 200-mg abemaciclib.  A simple randomization method will be adopted.  
Assignment to treatment groups will be determined by a computer-generated random sequence 
using the IWRS.  Site personnel will confirm that they have located the correct dosage by 
entering a confirmation number found on the packages into the IWRS.


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7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
No other chemotherapy, immunotherapy, or experimental medications will be permitted while 
the patients are on this study.  Due to the Phase 1 PK testing and possible unknown interactions, 
all herbal supplements will not be allowed while patients in Cycle 1, herbal therapies for cancer 
will not be permitted while patients are in Cycle 2 and beyond Cycle 2.  Palliative radiotherapy 
on a painful bone lesion, unless required due to progressive disease, is permitted during the 
study. 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 for each cycle 
on the electronic case report form (eCRF).  Concomitant medications and supportive care 
therapies must also be documented at the time of discontinuation and at the 30-day short-term 
follow-up visit.
The results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study 
indicate that oxidative metabolism of abemaciclib is primarily catalyzed by CYP3A4. 
Radiolabeled human disposition study indicates that abemaciclib is mostly cleared by oxidative 
metabolism. Based on these findings, grapefruit juice as well as inducers (for example, 
phenytoin, carbamazepine) and strong inhibitors of CYP3A4 should be excluded during PK 
phase (Cycle 1) of the study treatment, and should be avoided during other cycles of study 
treatment period (Attachment 6).
In addition, in vitro studies in primary cultures of human hepatocytes indicate that abemaciclib 
and its major metabolites LSN2839567 (M2) and LSN3106726 (M20) down regulate mRNA of 
1 or more CYPs, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A at 
clinically relevant concentrations.  The mechanism of down regulation and its clinical relevance 
are presently not understood.  Therefore, caution should be exercised when coadministering 
substrate drugs of the above CYPs with narrow therapeutic margin (Attachment 7).
Patients should receive full supportive care during the trial. Transfusion is permitted at the 
discretion of the investigator.  
Granulopoietic factor (G-CSF) may be used in accordance with ASCO guidelines (Smith et al. 
2015) and if they adhere to the dosage and administration described in the China Package Insert.  
7.5.1. Supportive Management for Diarrhea
In the event of diarrhea, supportive measures should be initiated as early as possible.  These 
include the following:

At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (for 
example, loperamide) and notify the investigator/site for further instructions and 
appropriate follow-up.

Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear 


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liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to either baseline 
or Grade 1, abemaciclib should be suspended until diarrhea is resolved to baseline or 
Grade 1.

When abemaciclib recommences, dosing should be adjusted as outlined in Section 7.2.3.1
and Table JPBR.7.2.
In severe cases of diarrhea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed. 
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given intravenous fluid (IV hydration) and electrolyte 
replacement.
7.6.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit by review of the patient 
diary, direct questioning, and counting of returned capsules.  Deviation(s) from the prescribed 
dosage regimen should be recorded on the CRF.
The patient must take 75% of the planned doses in a cycle to be deemed compliant with study 
drug administration.  Similarly, a patient may be considered noncompliant if he or she is judged 
by the investigator to have intentionally or repeatedly taken more than 125% of the prescribed 
amount of medication.  Any missed doses during a cycle 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 before making the final determination for 
discontinuation.  If a patient is discontinued due to study drug noncompliance, the patient may be 
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8. Safety, Pharmacokinetic, 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.
Study procedures and their timing, including tolerance limits for timing, are described in the 
Study Schedule (Attachment 1).
Blood samples, and ECGs will be collected at the times specified in the Study Schedule 
(Attachment 1).  Laboratory tests including hematology and chemistry will be performed.  A 
serum pregnancy test will be administered to females with child-bearing potential.  Attachment 3
lists the specific laboratory tests that will be performed for this study.  Enrollment and treatment 
decisions may be based upon results of tests performed.
If a patient’s dosage is reduced or treatment discontinued as a result of an AE, study-site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
All concomitant medications should be recorded throughout the patient’s participation in the 
study, until conclusion of the study follow-up period.
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 adverse event and serious adverse event 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 JPBR.8.1 presents a summary of AE and SAE reporting guidelines.  Refer to Attachment 8
for specific recommendations about reporting SAEs.
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 


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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.  All AEs 
observed will be graded using CTCAE v4.0.
The National Cancer Institute (NCI)-CTCAE v4.0 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 4.0X) 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 
NCI-CTCAE v4.0 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 (MedDRA) 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 CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.
The investigator will record all relevant AE/SAE information in the CRF. Investigators will be 
instructed to report to Lilly or its designee their assessment of the potential relatedness of each 
AE to protocol procedure, study drug via CRF.
The investigator decides whether he or she interprets the observed AEs as either related to 


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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.

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 therapy or other protocol-required procedure) should not 
be considered SAEs.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  An SAE is any adverse event 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 


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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.
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
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the informed consent form (ICF).
8.1.2.2.2. On Therapy
All AEs and SAEs, regardless of relatedness to study drug, 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 drugs or protocol procedures, occurring 
during the follow-up visit must be reported to Lilly or its designee.  The short-term follow-up 
visit starts following the discontinuation treatment.  At the end of the short-term follow-up visit, 
the patient will be required to have specific safety assessments (Attachment 1).  The timing of 
these safety assessments is 30 ± 7 days after the decision to stop study treatment.
Following the safety assessments, which mark the end of the short-term follow-up visit, the 
patient will enter the long-term follow-up visit period, 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 anti-cancer treatment prior to 
the scheduled end of the short-term follow-up visit, the follow-up visit duration may be 
shortened. In this case, the short-term follow-up assessments should be completed prior to the 
initiation of the new therapy.


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After the short-term follow-up visit, ongoing AEs possibly related to study drug should continue 
to be followed. If an investigator becomes aware of an SAE 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.
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 (DCSI) 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 AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JPBR.8.1.
Table JPBR.8.1.
Adverse Event and Serious Adverse Event Reporting Guidelines 
for Study JPBR
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
All SAEs regardless of relatedness
x
x
Study treatment period
All AEs 
x
All SAEs regardless of relatedness
x
x
30-day short-term follow-up 
All AEs 
x
All SAEs regardless of relatedness
x
x
Long-term follow-up 
All SAEs related to protocol procedures 
or study drug
x
x
Continued access period
All AEs
x
All SAEs regardless of relatedness
x
x
Continued access follow-up
All AEs
x
All SAEs regardless of relatedness
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study therapy and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study drug that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
8.1.3. Other Safety Measures
8.1.3.1.
Electrocardiograms
During Cycle 1, a 12-lead digital ECG will be collected according to the Study Schedule
(Attachment 1) and PK sampling and ECG Schedule (Attachment 5).  ECG test schedule will 
include:

Day 1:  pre-dosing test, 4 and 6 hours post-dosing test


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
Day 31:  pre-dosing test, 4 and 6 hours post-dosing test
On Day 28(±2) of Cycle 2 and beyond, ECG test will be conducted according to the Study 
Schedule (Attachment 1).
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.
ECGs 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.
ECGs 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 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 from at 
least 1 of the replicate ECGs from each time point.
8.1.4. Safety Monitoring
The Lilly CRP or 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:

trends in safety data,

laboratory analytes,

adverse events,
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C calculated glomerular filtration rate.
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period and were reversible upon treatment discontinuation. If deterioration 
of renal function is suspected, serum creatinine should not be the only measure used to assess a 
patient’s renal function. See Attachment 3. Dose alterations (omission, reduction and 
discontinuation) should not solely be based on interpretations of serum creatinine values because 
they may not reflect renal function.Special Hepatic Safety Data Collection
If a study patient experiences elevated ALT ≥5×ULN and elevated total bilirubin (TBL)≥2×ULN, 


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or ALT >8x ULN for patients with underlying baseline hepatic metastases, liver tests
(Attachment 4), including ALT, AST, TBL, direct bilirubin, gamma glutamyl transferase (GGT), 
and creatine phosphokinase (CPK), should be repeated within 3 to 5 days to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator, based on the 
hepatic monitoring tests (Attachment 4) and in consultation with the Lilly CRP.  Monitoring of 
ALT, AST, and TBL should continue until levels normalize or return to approximate baseline 
levels.  Additional diagnostic testing should be considered to rule out cause of increased liver 
enzymes per the investigator’s discretion.
Hepatic monitoring tests (Attachment 4) should be collected in the event that 1 or more of the 
following conditions is met for the patient during the course of the study:

ALT ≥5×ULN and TBL ≥2×ULN

ALT>8x ULN for patients with underlying hepatic metastasis

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
8.1.4.2.
Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration 
should 
follow 
the 
protocol 
guidance 
for 
non-hematological 
toxicities 
(Table JPBR.7.1).
8.1.4.3.
Venous Thromboembolic Events
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known.  For suspected or confirmed VTE (eg. deep vein thrombosis or pulmonary 
embolism), treatment should occur according to usual clinical practice.
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 


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study participants, monitor quality, and facilitate process and product improvements.
Complaints related to 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 3 lists the specific tests that will be performed for this study.
Attachment 4 lists the hepatic monitoring tests that will be performed for this study.
Attachment 5 lists the schedule for PK sample collections and ECGs in this study.
The information of sample disposal methods and blood volumes will be provided as other 
documents such as ICF.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood 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 
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 Measurements 
Pharmacokinetics
8.2.2.1.
Pharmacokinetic Samples
PK samples will be collected as specified in the Study Schedule (Attachment 1) and the PK
Sampling and ECG Schedule (Attachment 5).Venous blood samples of approximately 2 mL each 
will be collected to determine the plasma concentrations of abemaciclib and 2 major metabolites 
(LSN2839567 [M2], and LSN3106726 [M20]).  Instructions for the collection and handling of 


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blood samples will be provided by the sponsor.
These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemaciclib and its major metabolites, LSN2839567 (M2) and LSN3106726 
(M20), will be determined using a validated liquid chromatography/tandem mass spectrometry 
(LC/MS/MS) method.
The samples will be stored at a facility designated by the sponsor.
The remaining plasma from the samples collected for pharmacokinetics may be pooled and used 
for exploratory metabolism work as deemed appropriate.
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding, will be retained for a maximum of 1 year following last 
patient visit for the study.
8.2.3. Biomarker Samples for Storage and Research
Not applicable.
8.3.
Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1
for details regarding the timing of specific efficacy measures.
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement:

Computed tomography (CT) scan

Magnetic resonance imaging (MRI)
Each patient’s full extent of disease will also be assessed with:

Tumor measurement by RECIST 1.1 (Attachment 10, Eisenhauer et al. 2009),

Evaluation of tumor markers, if indicated,

Evaluation of performance status (Attachment 9, Oken et al. 1982).
To confirm objective responses, all lesions should be radiologically assessed, and the same 
radiologic method used for the initial response determination should be repeated at least 4 weeks 
following the initial observation of an objective response.  If a patient is discontinued from the 
study, repeat radiology assessments may be omitted if clear clinical signs of progressive disease 
are present.
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 


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minor alterations; however, the actual collection time must be correctly recorded on the eCRF or 
lab requisition form.
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 eCRFs, 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 eCRF 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 institutional 
review board (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.
For data handled by the sponsor internally, eCRF 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 laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
Clinical Laboratory Results Modernization (CLRM) and third-party organization (TPO)’s 
system.


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Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly CLRM and/or
TPO’s system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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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. 
The interpretation of the study results will be the responsibility of the investigator with the Lilly
CRP or CRS, pharmacokineticist, and statistician.  The CRP or CRS 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.
Safety analyses and all efficacy analyses will be conducted using the full analysis set (FAS), 
which will include the data from all patients who received at least one dose of any study drug.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
Detailed information regarding the planned statistical analyses will be described in the Statistical 
Analysis Plan (SAP).
10.2. Determination of Sample Size 
There are no formal sample size calculations.  Twenty or more patients may be enrolled to 
ensure 10 completers (that is, obtained the full set of PK samples for appropriate PK evaluation) 
in each dose cohort.
10.3. 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.
10.4. Patient Characteristics
Patient characteristics will include a summary of the following:

Patient demographics will be reported

Baseline disease characteristics

Prior disease-related therapies.
Other patient characteristics will be summarized as deemed appropriate.
10.5. Safety Analyses
Safety analyses will be conducted on all patients who have received at least one dose of the study 
drug.  Safety analyses will include summaries of the following data:

DLT-equivalent toxicity rate

TEAEs including seriousness, severity, and possible relationship to study drug


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
dose adjustments

laboratory measures

vital signs 

ECG

CTCAE Version 4.0 grades for laboratory and non-laboratory parameters.
10.6. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least one dose of 
the study drug and have had samples collected to allow the estimation of abemaciclib PK 
parameters.
Pharmacokinetic parameter estimates for abemaciclib will be calculated by standard 
noncompartmental methods of analysis using Phoenix WinNonlin on a computer that meets or 
exceeds the minimum system requirements for this program.  The primary parameters for 
analysis will be Cmax, AUC0-tlast and AUC0-∞of abemaciclib.  Other noncompartmental 
parameters, such as t1/2, CL/F, and V/F may be reported.  The PK profiles will be graphically 
presented and summary statistics of PK parameters will be obtained.
Additional exploratory analyses will be performed if warranted by data and other validated PK 
software programs (for example, NONMEM) may be used if appropriate and approved by 
Global Pharmacokinetic management.  The version of any software used for the analysis will be 
documented and the program will meet the Lilly requirements of software validation.
10.7. Efficacy
Tumor response and progression will be evaluated using the Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1.
Progression-free survival (PFS) time will be measured from the date of the first dose to the date 
of investigator-determined objective progression as defined by RECIST v1.1, or death from any 
cause.  Patients who have neither progressed nor died will be censored at the day of their last 
radiographic tumor assessment (if available) or date of the first dose if no post baseline 
radiographic assessment is available.  
Overall survival (OS) duration will be measured from the date of the first dose to the date of 
death from any cause.  For each patient who is not known to have died, OS will be censored at 
the date of last contact.
10.8. Planned Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least one dose of 
the study drug and have had samples collected to allow the estimation of abemaciclib PK 
parameters.
PK and safety analyses will be conducted after study completion.


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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 and dates on the ICF prior to the performance of any protocol procedures and prior to 
the administration of study drug.
In this protocol, the term "informed consent" includes all consent and assent given by patients or 
their legal representatives.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites. 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 sites.  The ERBs will review the protocol as required.
The study site’s ERBs should be provided with the following:

the current IB or Patient Information Leaflet, Package Insert, Protocol, 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 International Conference on Harmonisation (ICH) Good Clinical Practices (GCP) 
Guideline [E6]
3) applicable laws and regulations.


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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.
An identification code assigned 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 investigator with the most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
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.


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12. References
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.
Guan JL, Zhong WZ, An SJ, Yang JJ, Su J, Chen ZH, Yan HH, Chen ZY, Huang ZM, Zhang 
XC, Nie Q, Wu YL. KRAS mutation in patients with lung cancer:  a predictor for poor
prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol. 2013;20(4):1381-1388.
Hazra A, Krzyzanski W, Jusko WJ. Mathematical assessment of properties of precursor-
dependent indirect pharmacodynamic response models. J Pharmacokinet Phamacodyn. 
2006;33(6):683-717.
Mager DE, Jusko WJ. Pharmacodynamic modeling of time-dependent transduction systems. Clin 
Pharmacol Ther. 2001;70(3):210-216.
Malumbres M, Barbacid M. To cycle or not to cycle:  a critical decision in cancer. Nat Rev 
Cancer. 2001;1(3):222-231.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 
1982;5:649-655.
Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. 
Biochim Biophys Acta. 2002;1602(1):73-87.
Puyol M, Martín A, Dubus P, Mulero F, Pizcueta P, Khan G, Guerra C, Santamaría D, 
Barbacid M. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a 
therapeutic strategy for non-small cell lung carcinoma. Cancer Cell. 2010;18(1):63-73.
Sharma A, Ebling WF, Jusko WJ. Precursor-dependent indirect pharmacodynamic response 
model for tolerance and rebound phenomena. J Pharm Sci. 1998;87(12):1577-1584.
Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672-1677.
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; 
American Society of Clinical Oncology. Recommendations for the Use of WBC Growth Factors: 
American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 
2015;33(28):3199-21287-3205.
Sun YN, Jusko WJ. Transit compartments versus gamma distribution function to model signal 
transduction processes in pharmacodynamics. J Pharm Sci. 1998;87(6):732-737.


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Attachment 1. Protocol JPBR Study Schedule


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Study Schedule:  Protocol I3Y-CR-JPBR
Cycle/Visit
Screening/
Baseline/0
Cycle 1
Cycle 2
and 
Beyond/2-X
Short-term 
Follow-
up/801l
Long-term 
Follow-up
/802-8XXm
Day relative to Day 1 in Each Cycle 
-25
to
-1
-11
to
-1
-7
to
-1
1
2
3
4
11
±2
18
±2
25
±2
31
-1
32
-1
28±2
Day after Last Dose
30±7
Informed Consenta
X
Medical History (including initial 
history/preexisting conditions/previous 
treatment)
X
Pregnancy Test (if applicable)b
X
Physical Exam
X
X
X
X
X
Vital Signsc and Weight
X
X
X
X
X
X
X
Height
X
ECOG Performance Status
X
X
X
X
ECGd
X
X
X
X
Hematology/Serum chemistrye
X
X
X
X
X
X
X
X
Blood PK Samplingf
X
X
X
X
X
X
X
X
Tumor Measurement (Palpable and 
Visible)
X
X
X
X
Tumor Marker (if applicable) g
X
X
Radiological Tumor Assessmenth
X
X
X
Adverse Event Collection/CTCAE 
Gradingi
X
X
X
X
X
Concomitant Medications
X
X
X
X
Abemaciclib Therapyj
X
Xn
X
Patient Diary Dispense 
X
X
X
Patient Diary Collection
X
X
Survival informationk
X


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Study Schedule:  Protocol I3Y-CR-JPBR (concluded)
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
FFPE = Formalin-fixed paraffin-embedded; PD = progressive disease; PK = pharmacokinetic; Q12H = every 
12 hours; SAE = serious adverse event.
a
Informed consent form must be signed before performing any protocol procedure.  Data obtained before patient’s 
consent can be used as screening data if the relevant tests are conducted within the allowed time window.
b
Females with child-bearing potential must have a negative serum pregnancy test within 7 days of the first dose of 
study drug (i.e., Day -7 to Day -1).
c
Vital signs:  Temperature, Pulse, Blood Pressure, Respiratory Rate
d
ECGs of specified time point will be performed, collected, read/evaluated locally.  ECGs should be performed at 
baseline (-7 days to -1 day before Cycle 1 Day 1), and the planned timing of predose, 4 hours, and 6 hours after 
study drug administration:  Cycle 1, Day 1 and Day 31.  See Attachment 5 for detailed time points.
e
For baseline data, tests can be conducted within 3 days before the first dose of abemaciclib on Cycle 1, Day 1.  
The screening test results may be used as baseline data if the screening tests have been conducted within the 
allowed time window.  During cycle2, in addition to Day 28, the tests will also be conducted on Day 15 (±2
days).  
f
PK sampling should be performed during Cycle 1 (Attachment 5).
g
The frequency of tumor marker measurement is left to investigator.
h
Radiological assessment is performed at baseline (Day -25 to Day -1), then in the last 7 days of every other cycle 
beginning with Cycle 2.  For screening, scans performed prior to the date of consent may be used provided they 
are within 25 days of Cycle 1 Day 1.  For patients who discontinue study treatment without objectively measured 
PD, continue to evaluate tumor response every 56 days (±7 days) by the same method used at baseline and 
throughout the study until the patient has objective disease progression, or until the study’s final analysis.  After 
the patient has objective disease progression, radiologic assessments are no longer required and the patient will 
be followed up approximately every 56 days (±14 days) until the patient’s death or overall study completion.
i
For details, see Section 8.1.2.  Following the safety assessments in Visit 801, for patient with an AE 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.
j
For details, see Section 7.2.1.
k
Collection of survival data and subsequent antitumor therapies. Every 56 days (±14 days). Whenever possible, 
survival follow-up is conducted in person. If an in-person visit is not possible, the site may confirm survival by 
contacting the patient directly via phone.
l
Short-term follow-up starts just after the last dose of study drug and ends when final safety assessments are 
completed (30 ±7 days after last dose of study drug).
m For patients who discontinue study treatment without objectively measured PD, continue to evaluate tumor 
response every 56 days (±14 days) by the same method used at baseline and throughout the study until the patient
has objective disease progression, or until study completion.  After the patient has objective disease progression, 
radiologic tests are no longer required and the patient will be followed up approximately every 56 days 
(±14 days) until the patient’s death or overall study completion.
n For Cycle 1, single-dose abemaciclib will be given on Day 1 and Day 31, Q12H abemaciclib on Day 4, and then 
continuously until Day 30.


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Attachment 2. Protocol JPBR Study Schedule – Continued 
Access Period
Procedurea
Treatment during 
Continued Access Period
(every cycle)
30-Day Follow-Upb 
(+ 0-7d)
Visit
501-5XX
901
Toxicity 
Assessment/AEs
X
X
Abemaciclib Therapy
X
Abbreviations: AE = adverse event; d = days.
a
During continued access period, routine safety and efficacy monitoring, including radiographic evaluation of 
disease and laboratory testing, such as pregnancy testing, should be continued as necessary, and documentation 
retained within the source files, to confirm patient eligibility to continue on treatment or the 30-day short-term 
follow-up visit. The Sponsor will collect only data shown in this table for the continued access period.
b The short-term follow-up begins the day after the decision is made to discontinue study treatment and lasts 
approximately 30 days (no more than 37 days).


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Attachment 3. Protocol JPBR Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume (MCV)
Chloride
Mean cell hemoglobin concentration (MCHC)
Calcium
Leukocytes (WBC)
Albumin
Neutrophils
Total Protein
Lymphocytes
Blood Urea Nitrogen (BUN)
Monocytes
Creatinine 
Eosinophils
Alkaline Phosphatase
Basophils
Alanine Aminotransferase (ALT)
Platelets
Aspartate Aminotransferase (AST)
Total Bilirubin
Renal panel 
Cystatin-C
Serum Pregnancy Test (females with child-
bearing potential only)
All tests will be assayed by local laboratory.


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Attachment 4. Protocol JPBR
Hepatic Monitoring Tests for Treatment Emergent 
Abnormality
Selected tests may be obtained in the event of a treatment emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
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 Normalised Ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by local laboratory.
b Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 5. Protocol JPBR
Pharmacokinetic Sampling and ECG Schedule in Cycle 1
Pharmacokinetic Sampling and ECG Schedule in Cycle 1 
PK Sample 
Number
Day in 
Cycle 1
Abemaciclib 
Dosing
Sampling Time for PKa
ECGb
1
1
X
Pre-dose (0 h)
X
2
1 h ± 10 min post-dose
3
2 h ± 10 min post-dose
4
4 h ± 20 min post-dose
X
5
6 h ± 20 min post-dose
X
6
8 h ± 30 min post-dose
7
10 h ± 60 min post-dosec
8
2
No dose
24 h ± 2 h post-dose
9
3
No dose
48 h ± 2 h post-dose
10
4
X
Pre-dose
11
18 (2)
X
Pre-dose (0 h)
12
25 (2)
X
Pre-dose (0 h)
13
31 (-1)d
X
Pre-dose (0 h)
X
14
1 h ± 10 min post-dose
15
2 h ± 10 min post-dose
16
4 h ± 20 min post-dose
X
17
6 h ± 20 min post-dose
X
18
8 h ± 30 min post-dose
19
10 h ± 60 min post-dosec
20
32 (-1)d
No dose
24 h ± 2 h post-dose
Abbreviations:  CRFs = case report forms; ECG = electrocardiogram; PK = pharmacokinetic.
a
The dose and dosing date for 3 days prior to PK sampling will be recorded in the CRFs.
b Perform prior to blood sampling for PK if the ECG is matched with PK sampling point.  When ECGs and blood 
draws are obtained at the same time point, ECGs are completed first (within approximately 20 minutes prior to 
the PK sample).
c
If patient constraints preclude collection of this 10-hour PK sample, omission of this sample will not constitute a 
protocol deviation.
d If the PK sampling of Day 31 is preceded with -1 day allowance (Day 30), the evening dose on Day 30 and the 
morning dose on Day 31 should be omitted and 24-hour PK sample will be collected on Day 31.


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Attachment 6. Protocol JPBR
Example Inducers and Strong Inhibitors of CYP3A4
The information in this attachment is provided for guidance to investigators and 
does not preclude the use of these medications if clinically indicated.
Inducers of CYP3A4
Carbamazepine 
Dexamethasonea
Phenobarbital/phenobarbitone 
Phenytoin 
Rifapentine
Rifampin 
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A4
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Abbreviations: CYP = cytochrome P450; HIV = human immunodeficiency virus.
a
All patients may receive supportive therapy with dexamethasone, preferably 7 days, if clinically indicated.


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Attachment 7. Protocol JPBR
Cytochrome P450 Substrates with Narrow Therapeutic 
Range
Cytochrome
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenidine
Abbreviation:  CYP = cytochrome P450.
Important note: All patients may receive supportive therapy with dexamethasone, preferably ≤7 days, if clinically 
indicated.  Patients requiring more than 7 days of dexamethasone therapy will not incur a protocol deviation.


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Attachment 8. Protocol JPBR Recommendations for 
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report an 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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Attachment 9. Protocol JPBR ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out performance of a light or sedentary nature, for example, 
light housework, office work
2
Ambulatory and capable of all selfcare but unable to carry out any 
work activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally 
confined to bed or chair
5
Dead
Source:  Oken et al. 1982.


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Attachment 10. Protocol JPBR RECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST):  Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).  
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:  

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.


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


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


I3Y-CR-JPBR(e) Phase 1 Oncology Protocol
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lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease (PD).  
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment.  If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan.  
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected.  
Response Criteria
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of one or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response.
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).
Non-CR/non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.


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Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable:  When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.  
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline.
Table 1. Time Point Response: Patients with Target (Nontarget) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
Table 2 is to be used when patients have nonmeasurable disease only.


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Table 2. Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations:  CR = complete response; NE = inevaluable; PD = progressive disease.
a
non-CR/non-PD is preferred over SD for nontarget disease.
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment.  Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6-8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed.  The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur;  assessment of 
nontargets is not required.  
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required.  But, elimination of the requirement may 
increase the importance of central review to protect against bias, in particular of studies which 
are not blinded.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from first dose.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study).


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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD).
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.  


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Attachment 11. Protocol Amendment I3Y-CR-JPBR (e) 
Summary
A Phase 1 Study of Abemaciclib in Native Chinese 
Patients with Advanced and/or Metastatic Cancers
Overview
Protocol I3Y-CR-JPBR, a Phase 1 Study of Abemaciclib in Native Chinese Patients with 
Advanced and/or Metastatic Cancers, has been amended.  The new protocol is indicated by 
Amendment (e) and will be used to conduct the study in place of any preceding version of the 
protocol.
Study JPBR protocol was amended to update the safety language regarding hepatic monitoring, 
assessment of renal function, and venous thromboembolic events (VTEs) for ongoing patients.
The amendment (d) revised the wording of enrollment and randomization. When the amendment 
was approved, the enrollment has already completed. The amended sections was not effective
thus removed in this amendment (e).
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
The overall changes made to this protocol are as follows:.

Section 2 remove the enrollment and randomization restriction

Section 4 included VTE in abbreviations

Section 7.2.3.1, Table JPBR.7.1 modified along with Sections 7.2.3.1.1, 7.2.3.1.2 and 
7.2.3.1.2.1, and incorporated Section 7.2.3.1.2.2 for alignment with safety updates.

Sections 8.1.4, 8.1.4.1, 8.1.4.2 and 8.1.4.3 incorporated safety monitoring language for 
hepatic conditions, renal function and VTEs. 

Attachment 6 and 7 CYPs text updated to align with abemaciclib program information


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Revised Protocol Sections
Note:All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
Synopsis
Study Design:
Based on the enrollment status, the study team decided that from 17-May-2018 onwards, all 
patients who meet the enrollment criteria will be assigned to receive 150 mg abemaciclib and 
thus randomization will no longer be applied. Analysis on available PK and safety data will be 
conducted after study completion.
Section 4. Abbreviations…
VTE
venous thromboembolic event
6.2. Summary of Study Design
Based on the enrollment status, the study team decided that from 17-May-2018 onwards, all 
patients who meet the enrollment criteria will be assigned to receive 150 mg abemaciclib and 
thus randomization will no longer be applied. Analysis on available PK and safety data will be 
conducted after study completion.
7.2.3 Does Ajustments and Delays
Table JPBR.7.1.
Toxicity Dose Adjustments and Delays of Study Drug for 
Study JPBR
Cause
Profile and Severity
Dose Suspension
Dose Reduction
…
Hematologic 
Toxicity:If
pPatient requires 
administration of 
blood cell growth 
factors
Section 7.2.3.1.1
Regardless of severity
(Growth factors Uuse of growth 
factors according to ASCO 
Guidelines)
Dose MUST be suspended 
for at least 48 hours after 
the last dose of blood cell 
growth factors was 
administered and until 
toxicity resolves to at least 
Grade 2.
Dose MUST be reduced by 
one dose level unless 
already performed for 
incidence of toxicity that 
led to the use of growth 
factor
Nonhematological 
Toxicityb
(except diarrhea
and ALT increased)
Section 7.2.3.1.2
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures within 7 days 
to baseline or Grade 1
Dose MAYMUST be 
suspended. until toxicity 
resolves to either baseline 
or Grade 1.
Dose MAY MUST be 
reduced by one dose level.


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Nonhematological 
Toxicity
Section 7.2.3.1.2
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced by 
one dose level.
Diarrhea
Section 7.2.3.1.2.1
Requiring hospitalization or Grade 
3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced by 
one dose level.
Diarrhea
Section 7.2.3.1.2.1
and 7.5.1
Grade 2 that does not resolve with 
maximal supportive measures 
within 24 hours to at least Grade 1
Dose SHOULDMUST be 
suspended until toxicity 
resolves to at least Grade 1.
Dose MAY be reduced by 
one dose level. reduction is 
NOT required.
Diarrhea
Section 7.2.3.1.2.1
and 7.5.1
Persistent or recurrent Grade 2 that 
does not resolve with maximal 
supportive measures ,or any Grade 
of diarrhea that requires 
hospitalization 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 
one dose level.
Diarrhea
Section 7.2.3.1.2.1 
and 7.5.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced by 
one dose level.
ALT  Increased 
(Sections 
7.2.3.1.1.2. and 
8.1.2.1)
Persistent or recurrenta Grade2 
(>3.0-5.0×ULN), or Grade 3 (>5,0-
20.0×ULN)c
Dose MUST be suspended 
until toxicity resolves to 
baseline or Grade 1.
Dose MUST be reduced by 
1 dose level.
ALT  Increased 
(Sections 
7.2.3.1.1.2. and 
8.1.2.1)
Grade 4 (>20.0×ULN)
Study drug MUST be 
discontinued.
Study drug MUST be 
discontinued.
ALT Increased 
with increased total 
bilirubin, in the 
absence of 
cholestasis
(Sections 
7.2.3.1.2.2.)
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN
Study drug MUST be 
discontinued
Study drug MUST be 
discontinued
Abbreviation: ALT = alanine transaminase; ASCO = American Society of Clinical Oncology.
Note: MUST = mandatory.


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a
Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:

shows stable hematological counts (Grade ≤2) during that timeframe

has absence of any signs or risk of infection 

is benefiting from study treatment
b Additional guidance for renal and hepatic monitoring is in Sections 8.1.4.1 and 8.1.4.2.
c    Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section 
8.1.4.1 for additional guidance for hepatic monitoring
7.2.3.1.1 Hematologic Toxicity
If the patient experiences a recurrent episode of Grade 3 hematologic toxicity, then dosing must
be suspended (until the toxicity resolves to at least Grade 2) and the dose of the study must be 
reduced by one dose level as outlined in Table JPBR.7.2.
Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from 
the stop date of the preceding event).  As a general guidance, based on the risk/benefit balance 
assessment per the investigator, for a patient who experiences a new episode of Grade 3 
hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose 
should the patient satisfy the following conditions:
•
The patient showed stable hematological counts (Grade ≤2) during that timeframe
•
In the absence of any signs or risk of infection 
•
The patient is benefiting from study treatment
7.2.3.1.2. Nonhematological Toxicity
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 7.2.3.1.2.1 or ALT increased, refer to Section 7.2.3.1.2.2) possibly related to 
abemaciclib that does not resolve with maximal supportive measures within 7 days to either 
baseline or Grade 1, then dosing maymust be suspended (until the toxicity resolves to either 
baseline or at least Grade 1) and the dose of abemaciclib maymust be reduced as outlined in 
Table JPBR.7.2.
7.2.3.1.2.1.
Diarrhea
If a patient experiences persistent or recurrent diarrhea (Grade 2) that does not resolve with 
maximal supportive measures (refer to Section 7.5.1) within 24 hours to either baseline or at 


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least Grade 1, then study treatment shouldmust be suspended (until the toxicity resolves to either 
baseline or at least Grade 1) and the dose of abemaciclib maymust be reduced by one dose level 
as outlined in Table JPBR.7.2 at the discretion of the investigator. If the same dose level was 
resumed and diarrhea recurs despite maximal supportive measures, the dosing must be 
suspended (until the toxicity resolves to either baseline or at least Grade 1) and the dose of 
abemaciclib must be reduced again as outlined in Table JPBR.7.2.
7.2.3.1.2.2.
Hepatic Toxicity
Dose modifications and management for increased ALT are provided in Table JPBR.7.1. For 
persistent or recurrent Grade 2 ALT increased that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, or Grade 3 ALT increased, blinded study drug 
must be suspended until the toxicity has resolved to at least Grade 1 and the dose must be 
reduced by 1 dose level. Discontinue blinded study drug for Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x ULN, in the absence of cholestasis. For Grade 4 ALT increased, 
the patient must be discontinued from blinded study drug.  Refer to Section 8.1.4.1 for additional 
hepatic monitoring guidance.
7.3. Method of Assignment to Treatment
Based on the enrollment status, the study team decided that from 17-May-2018 onwards, all 
patients who meet the enrollment criteria will be assigned to receive 150 mg abemaciclib and 
thus randomization will no longer be applied.
8.1.2.
Adverse Events
The investigator will record all relevant AE/SAE information in the CRF. Investigators will be 
instructed to report to Lilly or its designee their assessment of the potential relatedness of each 
AE to protocol procedure, study drug via CRF.
8.1.2.1 Serious adverse Events
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria. An SAE is any adverse event during this study that results in one of the following 
outcomes:
8.1.4.
Safty Monitoring
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:

trends in safety data,

laboratory analytes,

adverse events,

If a study patient experiences elevated ALT ≥5X upper limit of normal (ULN) and 


I3Y-CR-JPBR(e) Phase 1 Oncology Protocol
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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/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 4).
8.1.4.1 Special Hepatic Safety Data Collection
If a study patient experiences elevated ALT ≥5×ULN and elevated total bilirubin (TBL)≥2×ULN, 
or ALT >8x ULN for patients with underlying baseline hepatic metastases, liver tests 
(Attachment 4), including ALT, AST, TBL, direct bilirubin, gamma glutamyl transferase (GGT), 
and creatine phosphokinase (CPK), should be repeated within 3 to 5 days to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator, based on the 
hepatic monitoring tests (Attachment 4) and in consultation with the Lilly CRP.  Monitoring of 
ALT, AST, and TBL should continue until levels normalize or return to approximate baseline 
levels.  Additional diagnostic testing should be considered to rule out cause of increased liver 
enzymes per the investigator’s discretion.
Hepatic monitoring tests (Attachment 4) should be collected in the event that 1 or more of the 
following conditions is met for the patient during the course of the study:

ALT ≥5×ULN and TBL ≥2×ULN

ALT>8x ULN for patients with underlying hepatic metastasis

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
8.1.4.2 Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration 
should 
follow 
the 
protocol 
guidance 
for 
non-hematological 
toxicities 
(Table JPBR.7.1).
8.1.4.3 Venous Thromboembolic Events
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 


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combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known.  For suspected or confirmed VTE (eg. deep vein thrombosis or pulmonary 
embolism), treatment should occur according to usual clinical practice.
Attachment 6 Protocol JPBR Example Inducers and Strong Inhibitors of CYP3A4
Strong inhibitors of CYP3A4
All HIV protease inhibitors
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Attachment 7 Protocol JPBR Cytochrome P450 Substrates with Narrow Therapeutic 
Range
Cytochrome
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel

SAP_000.pdf: 
I3Y-CR-JPBR Statistical Analysis Plan Version 2 
I3Y-CR-JPBR: A Phase 1 Study of Abemaciclib in Native Chinese Patients with Advanced 
and/or Metastatic Cancers 
 
NCT02919696 
 
Approval Date: 13-Dec-2018 
 
 
 


I3Y-CR-JPBR Statistical Analysis Plan Version 2
Page 1
LY2835219
1.
Statistical Analysis Plan:  
I3Y-CR-JPBR:  A Phase 1 Study of Abemaciclib in Native 
Chinese Patients with Advanced and/or Metastatic 
Cancers
Confidential Information
The information contained in this document 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 
CDK4/6 Dual Inhibitor (abemaciclib), 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 a multicenter, randomized, open-label study of oral abemaciclib in 
native Chinese patients with advanced and/or metastatic cancers.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I3Y-CR-JPBR
Phase 1
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly: 
05-Apr-2017
Statistical analysis Plan Version 2 electronically signed and approved by Lilly on the 
date below
Approval Date: 13-Dec-2018 GMT


I3Y-CR-JPBR Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I3Y-CR-JPBR:  A Phase 1 Study of 
Abemaciclib in Native Chinese Patients with Advanced and/or 
Metastatic Cancers..............................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
5.
Study Design.......................................................................................................................7
5.1.
Summary of Study Design..............................................................................................7
5.2.
Determination of Sample Size ........................................................................................7
5.3.
Method of Assignment to Treatment ..............................................................................7
6.
A Priori Statistical Methods ................................................................................................9
6.1.
General Considerations ..................................................................................................9
6.2.
Adjustments for Covariates ............................................................................................9
6.3.
Handling of Dropouts or Missing Data...........................................................................9
6.4.
Multiple Comparisons/Multiplicity.................................................................................9
6.5.
Use of an “Efficacy Subset” of Patients..........................................................................9
6.6.
Patient Disposition .........................................................................................................9
6.7.
Patient Characteristics ....................................................................................................9
6.8.
Treatment Compliance .................................................................................................10
6.9.
Concomitant Therapy...................................................................................................10
6.10. Efficacy Analyses ........................................................................................................10
6.11. Bioanalytical and Pharmacokinetic Methods ................................................................11
6.12. Safety Analyses............................................................................................................12
6.12.1.
Extent of Exposure...............................................................................................12
6.12.2.
Adverse Events ....................................................................................................12
6.12.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................14
6.12.4.
Clinical Laboratory Evaluation.............................................................................14
6.12.5.
Vital Signs and Other Physical Findings...............................................................14
6.12.6.
Electrocardiograms ..............................................................................................14
6.13. Protocol Violations.......................................................................................................14
6.14. Annual Report Analyses...............................................................................................14
6.15. Clinical Trial Registry Analyses...................................................................................14


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7.
References ........................................................................................................................16


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Table of Contents
Figure
Page
Figure JPBR 5.1 Study design for JPBR......................................................................................7


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to first patient visit.
Statistical Analysis Plan Version 2 was approved prior to the study completion lock. The SAP 
Version 2 clarified analysis population, analysis plan for treatment compliance, and details for 
efficacy analyses including censoring rules for PFS and OS.


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to evaluate the safety and tolerability of abemaciclib in 
Chinese patients with advanced and/or metastatic cancers.
4.2.
Secondary Objectives
The secondary objectives of this study are:

to assess the PK of abemaciclib and its metabolites in Chinese patients with advanced 
and/or metastatic cancers

to assess the antitumor activity of abemaciclib


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5.
Study Design 
5.1.
Summary of Study Design
This study is a multicenter, open-label, Phase 1 trial of abemaciclib in Chinese patients with
advanced and/or metastatic cancers.
The study will be focused on safety evaluation and PK data collection in patients with all
advanced and/or metastatic cancers. Patients will be randomized into 2 dose cohorts, and orally
receive abemaciclib 150 mg or 200 mg every 12 hours (Q12H). One cycle is defined as 28 days
(Cycle 1: 32 days), with modifications during Cycle 1 to enable PK sampling following a single
dose and repeated doses. The treatment of abemaciclib will continue until disease progression,
development of unacceptable toxicity, or fulfillment of the other discontinuation criteria. In case
of patient discontinuation during Cycle 1, the enrollment will be extended until at least 10 
patients with completed PK data accrued in each cohort. Analysis on available PK and safety
data will be conducted after study completion.
All patients in the study receive at least 2 cycles of abemaciclib unless one or more of the criteria
for discontinuation (refer to Protocal Section 6.3.1) are fulfilled; the short-term follow-up period 
for poststudy evaluation is 30 ±7 days after the decision to discontinue treatment. Figure JPBR 
5.1 shows the study design for Study JPBR.
Abbreviations: Q12H = every 12 hours; R = randomization.
Figure JPBR 5.1 Study design for JPBR.
5.2.
Determination of Sample Size
There are no formal sample size calculations. Twenty or more patients may be enrolled to ensure 
10 completers (that is, obtained the full set of PK samples for appropriate PK evaluation) in each 
dose cohort.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive abemaciclib in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted at the
investigational site to confirm that each patient meets all enrollment criteria. Upon confirmation


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of eligibility, the sponsor will confirm the dose and identification number assignment for each
patient using the interactive web response system (IWRS).
Upon obtaining informed consent, site personnel should access the IWRS, which will enter a
patient number. Patients who meet all criteria for enrollment will be randomly assigned to
receive either 150-mg or 200-mg abemaciclib. A simple randomization method will be adopted.
Assignment to treatment groups will be determined by a computer-generated random sequence
using the IWRS. Site personnel will confirm that they have located the correct dosage by
entering a confirmation number found on the packages into the IWRS.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company. The 
analyses for this study will be descriptive, except for possible efficacy analysis as deemed 
appropriate. Exploratory analyses of the data will be conducted as deemed appropriate.
Safety analyses and all efficacy analyses will be conducted using the treated analysis set , which 
will include the data from all patients who randomized and received at least one dose of any 
study drug.
Data analyses will be provided by cohort, and for all study patients combined wherever 
appropriate. For continuous variables, summary statistics will include number of patients, mean, 
median, standard deviation, minimum, and maximum. Categorical endpoints will be 
summarized using number of patients, frequency, and percentages.
6.2.
Adjustments for Covariates
No adjustments for covariates.
6.3.
Handling of Dropouts or Missing Data
Missing data will not be imputed.
6.4.
Multiple Comparisons/Multiplicity
No adjustments for multiplicity.
6.5.
Use of an “Efficacy Subset” of Patients
Not applicable.
6.6.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, reasons for 
discontinuation from study treatment, and reasons for discontinuation from the study.  Reason 
for discontinuation from both study treatment and the study will be listed by the pre-determined 
categories.  If the reason for discontinuation is adverse event (AE) or death, the associated AE or
cause of death will be reported.  All patients entered in the study will be included in the 
summary.
6.7.
Patient Characteristics
Patient characteristics will include the analysis of the following:

Patient demographics will be reported

Baseline disease characteristics

Prior disease-related therapies.


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Patient demographics and baseline disease characteristics will be listed for all patients on therapy
and summarized by cohort. Patient demographics will include sex, race, age, height, weight, and 
body mass index (BMI). Baseline disease characteristics will include initial pathological 
diagnosis and Eastern Cooperative Oncology Group (ECOG) performance status.
Prior systemic therapy, radiotherapy, and surgeries will be listed and summarized for all patients
on therapy.
Other patient characteristics will be analyzed as deemed appropriate.
6.8.
Treatment Compliance
Treatment compliance of abemaciclib will be measured by capsule counts and summarized over 
the whole treatment period. Compliance will be calculated as the ratio of total dose taken to the 
total assigned dose (minus any dose adjustments and doses omitted/withheld for medical or 
logistical reasons).  The total assigned dose for a patient with no adjustments, omissions,  or 
extensions for logistical reasons is 150 mg per dose × 2 doses per day × 28 days = 8400 mg for 
lower dose cohort and  200 mg per dose × 2 doses per day × 28 days = 11200 mg for higher dose 
cohort.
6.9.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World
Health Organization (WHO) drug dictionary.  All concomitant medications will be listed and 
summarized using the preferred name for all patients on therapy by cohort.  
6.10. Efficacy Analyses
The study was not designed to make an efficacy assessment. However, tumor response data,  
progression-free survival (PFS) data and overall survival (OS) data will be analyzed.  Tumor 
response and progression will be evaluated using the Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1, Eisenhauer et al. 2009).
Reported lesion data (target/ non-target or measurable/ nonmeasurable) will be listed for all 
enrolled patients.  Change from baseline in the sum of target lesion size will be listed by cycle 
and depicted as a waterfall plot.  The waterfall plot will depict each patient’s best change from 
baseline in the sum of target lesion size while on study. 
Investigator-determined response by cycle and best overall response for each patient will be 
listed. Response will be summarized using the Overall Response Rate (ORR) and Disease 
Control Rate (DCR).  Overall Response Rate will be defined as the percentage of enrolled 
patients with a best response of partial response (PR) or complete response (CR). Disease 
Control Rate will be defined as the percentage of enrolled patients with a best response of PR, 
CR, or stable disease (SD). Exact 95% confidence intervals (CIs) for each of these measures will 
be calculated.
Progression-free survival (PFS) time will be measured from the date of the first dose to the date 
of investigator-determined objective progression as defined by RECIST v1.1, or death from any 


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cause.  If a patient is not known to have progressed or died at the time of analysis,  PFS time will 
be censored at the last known progression-free assessment. The detailed censoring rules are desc 
ribed in the table below (Table JPBR.6.1). PFS for each patient will be calculated and listed. 
Swimmer plot will be applied to present the time to event for each patient.
Table JPBR.6.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Rule
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of first dose
Censored
2
No post baseline assessments and no 
death 
Date of first dose
Censored
3
No documented progression and no 
death (with a post-baseline tumor 
assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew 
consent from study participation) 
before documented progression or 
death 
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented 
progression 
Date of death 
Progressed
7
Documented progression or death 
after missing ≥2 consecutive post-
baseline tumor assessments
Date of last adequate tumor assessment 
before missed assessments or date of 
first dose, whichever is later
Censored
Note: Progression-free survival and associated outcome is determined by the earliest of the dates above, if more 
than 1 situation applies.
Overall survival (OS) duration will be measured from the date of the first dose to the date of 
death from any cause.  For each patient who is not known to have died, OS will be censored at 
the date of last day known alive.  
6.11. Bioanalytical and Pharmacokinetic Methods 
Pharmacokinetic analyses will be conducted on patients who have received at least one dose of 
the study drug and have had samples collected to allow the estimation of abemaciclib PK 
parameters.
Plasma concentrations of abemaciclib and its major metabolites, LSN2839567 (M2) and 
LSN3106726 (M20), will be determined using a validated liquid chromatography/tandem mass 
spectrometry (LC/MS/MS) method.


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Pharmacokinetic parameter estimates for abemaciclib and its major metabolites will be 
calculated by standard noncompartmental methods of analysis using Phoenix WinNonlin on a 
computer that meets or exceeds the minimum system requirements for this program. The primary 
parameters for analysis will be Cmax, AUC0-tlast and AUC0-∞Other noncompartmental parameters, 
such as t1/2, CL/F, and V/F may be reported. The PK profiles will be graphically presented and 
summary statistics of PK parameters will be obtained.
Additional exploratory analyses will be performed if warranted by data and other validated PK 
software programs (for example, NONMEM) may be used if appropriate and approved by 
Global Pharmacokinetic management. The version of any software used for the analysis will be 
documented and the program will meet the Lilly requirements of software validation.
6.12. Safety Analyses
6.12.1. Extent of Exposure
The number of cycles of treatment received, dose delays, and dose intensity will be summarized.
Extent of exposure will be measured by pill counts and summarized by cycle. The summary will 
include total dosage taken and dose intensity. Dose intensity will be calculated as the ratio of 
total dose taken to the assigned cumulative dose. The assigned cumulative dose for each patient 
during each cycle is 150 mg per dose × 2 doses per day × 28 days = 8400 mg for lower dose 
cohort and 200 mg per dose × 2 doses per day × 28 days = 11200 mg for the higher dose cohort. 
The assigned cumulative dose while on study for lower and higher dose cohort is 2 × 150 mg × 
number of days and 2 × 200 mg × number of days on treatment, accordingly.
Dose adjustments including the reasons for dose adjustment will also be listed and summarized.
6.12.2. Adverse Events
Adverse event (AE) terms and severity grades will be assigned by the investigator using 
Common Terminology Criteria for Adverse Events (CTCAE version 4.0, NCI 2009)  In addition, 
AE verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within MedDRA.  Adverse events will be reported using the following reporting process:

The CTCAE Version 4 term reported by the investigator will be mapped to the MedDRA 
PT and system organ class (SOC) of the corresponding MedDRA lower level term (LLT), 
unless the reported CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Pre-existing conditions are defined as AEs that begin prior to the first dose of study drug.
A treatment emergent adverse event (TEAE) is defined as any AE that begins between the day of
first dose and 30 days after treatment discontinuation (or up to any time if serious and related to 
study treatment), or any pre-existing condition that increases in CTCAE grade between the day 


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of first dose and 30 days after treatment discontinuation (or up to any time if serious and related 
to study treatment). Comparisons of pre-existing conditions to on-treatment events at the LLT 
level will be used in the treatment-emergent computation.
A serious adverse event (SAE) is any AE during this study that results in one of the following
outcomes:

death

initial or prolonged inpatient hospitalization

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.
To assess the relationship of the AE to the study treatment, the following terminologies are
defined (in Protocol Section 8.1.2):

Related: a direct cause and effect relationship between the study treatment and the AE is 
likely.

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 (SOPs), all “related” and “possibly related” AEs
and SAEs will be defined as related to study treatment.
The following TEAE/SAE listings and summaries will be produced:

List of pre-existing conditions and AEs

Overview of TEAEs

Summary of TEAEs by PT (all grade and grade ≥ 3)

Summary of TEAEs by SOC and PT (all grade and grade ≥ 3)

Summary of TEAEs by PT and maximum grade (1-5)

List of SAEs

Summary of SAEs by SOC and PT (all grade and grade ≥ 3)

List of DLT-equivalent toxicity.
The four summaries will be produced for all TEAEs/SAEs and repeated for TEAEs/SAEs related


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to study treatment.
6.12.3. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
All deaths on study will be listed along with the reason for death, if known. A summary of deaths 
will also be produced.
6.12.4. Clinical Laboratory Evaluation
Laboratory data will be listed and summarized by each cohort. Abnormal results will be listed 
separately. In addition to the investigator reported adverse events, all relevant hematology, 
chemistry laboratory values, and hepatic monitoring test results will be graded according to 
CTCAE version 4.0. These derived values will be included on the listings of laboratory data and 
summary tables will be produced in a similar manner to those created for the investigator 
reported adverse events.
6.12.5. Vital Signs and Other Physical Findings
Temperature, blood pressure, pulse rate, respiration rate, weight and ECOG performance status 
will be listed and summarized for all patients on therapy.
6.12.6. Electrocardiograms
All electrocardiogram (ECG) data will be listed.
6.13. Protocol Violations
Protocol violations that can be derived from the data and are related to inclusion/exclusion 
criteria or treatment will be listed.
6.14. Annual Report Analyses
Annual report analyses, including Developmental Safety Update Report (DSUR) and 
Investigational Brochure (IB) analyses, are described in the LY2835219 Program Safety 
Analysis Plan.
6.15. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by treatment 
group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE).


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
An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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7.
References 
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, v4.0, 
DCTD, NCI, NIH, DHHS. 2009. Publish date: 29 May 2009.
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.