Clinical trial NCT04707196
Conditions: Breast Neoplasms Neoplasm Metastasis
Sponsor: Eli Lilly and Company
Start date: 2021-02-22; Completion date: 2023-01-09
Enrollment: 200 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to learn more about the safety and tolerability of abemaciclib when given in combination with hormone therapy in Indian women with advanced breast cancer. Participants must have hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer and must live in India. For each participant, the study could last up to eight months and may include up to eight visits to the study center.

Detailed description:

Arms: arm 1: Participants received abemaciclib 150 milligram (mg) orally twice daily, on days 1 through 28 of a 28-day cycle, for up to 6 cycles or less in case of disease progression, or any other discontinuation criterion is met, plus either NSAI (nonsteroidal aromatase inhibitors - anastrozole or letrozole) administered orally as per standard of care or fulvestrant administered intramuscularly as per standard of care.
Interventions: intervention 1: Abemaciclib intervention 2: Nonsteroidal Aromatase Inhibitor (NSAI) intervention 3: Fulvestrant
Intervention descriptions: intervention 1: Administered orally intervention 2: Letrozole or anastrozole administered orally (physician choice) intervention 3: Administered intramuscularly

Protocol documents:
Prot_000.pdf: 
 
Protocol: I3Y-IN-JPEC(b) 
 
 
A Single-Arm, Phase 4 Study of Abemaciclib, a CDK4 and CDK6 
Inhibitor, in Combination With Endocrine Therapy 
(Anastrozole/Letrozole or Fulvestrant) in Participants With Hormone 
Receptor Positive, Human Epidermal Growth Factor Receptor 2 
Negative Locally Advanced and/or Metastatic Breast Cancer in India 
 
 
NCT04707196 
 
 
Approval Date: 29-Sep-2021 


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
1
Title Page
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 abemaciclib (LY2835219), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: A Single-Arm, Phase 4 Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, in 
combination with Endocrine Therapy (Anastrozole/Letrozole or Fulvestrant) in Participants with
Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Locally 
Advanced and/or Metastatic Breast Cancer in India
Protocol Number: I3Y-IN-JPEC
Amendment Number: b
Compound: LY2835219
Study Phase: Phase 4
Short Title: A Study of Abemaciclib in Combination with Endocrine Therapy 
(Anastrozole/Letrozole or Fulvestrant) in Participants with HR+, HER2- Locally 
Advanced and/or Metastatic Breast Cancer in India
Acronym: JPEC
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
CTRI Registration number: CTRI/2020/12/030021
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.
Medical Monitor Name and Contact Information will be provided separately. 
Approval Date: 29-Sep-2021 GMT


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Protocol I3Y-IN-JPEC(b)
2
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Protocol amendment (b)
See the protocol cover page
Original Protocol
17 June 2020
Amendment [b] 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
This amendment addresses.
Section # and Name
Description of Change
Brief Rationale
Synopsis
The participant number was updated from 
100 to 200.
As part of abemaciclib marketing 
authorization in India and related 
post-approval condition by the Indian 
MoH, Lilly was asked to do a Phase 4 
study on 200 patients. Lilly proposed a 
study on 100 patients along with the 
rationale of global Phase 3 data. The 
study was started basis conditional 
approval from the Indian MOH. Basis 
the additional safety data on Phase 3 
studies and Indian PSUR data, Lilly 
requested the Indian MoH to allow 
conducting the study with 100 enrolled 
patients; however, the MoH did not 
agree and recommended conducting the 
study in 200 patients. Hence, the 
protocol is being amended now to 
reflect 200 patients in the study. 
1.2 Schema
Study schema has been amended for total 
number of participants and number of 
participants in each cohort
As per MoH recommendation to 
conduct the study in 200 patients to 
generate additional safety data in Indian 
population. (as specified above).
4.2 Scientific Rationale 
for Study Design
The participant number was updated from 
100 to 200.
As per MoH recommendation to 
conduct the study in 200 patients to 
generate additional safety data in Indian 
population. (as specified above).
9.2 Sample Size 
Determination
The participant number was updated from 
100 to 200 and, accordingly, the cohort size 
was changed from 25 to 50.
The estimated incidence rate and 2-sided 
95% CI table were updated.
Statistical calculations updated as per 
the change in the number of 
participants.
Abbreviations: CI = confidence interval; MoH = Ministry of Health; PSUR = periodic safety update report.


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
3
Table of Contents
Title Page...................................................................................................................................1
Protocol Amendment Summary of Changes Table ......................................................................2
Table of Contents ......................................................................................................................3
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
Rationale:....................................................................................................................................7
Objectives and Endpoints............................................................................................................7
Overall Design:...........................................................................................................................7
Disclosure Statement:..................................................................................................................8
Number of Participants:...............................................................................................................8
Intervention Groups and Duration: ..............................................................................................8
Data Monitoring Committee:.......................................................................................................8
1.2.
Schema ........................................................................................................................9
1.3.
Schedule of Activities (SoA) .....................................................................................10
2.
Introduction..............................................................................................................18
2.1.
Study Rationale.........................................................................................................18
2.2.
Background...............................................................................................................18
2.2.1.
Metastatic Breast Cancer ............................................................................................18
2.2.2.
Abemaciclib ...............................................................................................................20
2.3.
Benefit/Risk Assessment...........................................................................................23
3.
Objectives and Endpoints.........................................................................................24
4.
Study Design .............................................................................................................25
4.1.
Overall Design ..........................................................................................................25
4.2.
Scientific Rationale for Study Design ......................................................................25
4.3.
Justification for Dose................................................................................................26
4.4.
End of Study Definition............................................................................................26
5.
Study Population ......................................................................................................27
5.1.
Inclusion Criteria......................................................................................................27
5.2.
Exclusion Criteria.....................................................................................................30
5.3.
Lifestyle Considerations ...........................................................................................31
5.4.
Screen Failures .........................................................................................................31
6.
Study Intervention....................................................................................................32
6.1.
Study Interventions Administered...........................................................................32
6.2.
Preparation/Handling/Storage/Accountability........................................................32
6.2.1.
Selection and Timing of Doses ...................................................................................32


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Protocol I3Y-IN-JPEC(b)
4
6.3.
Measures to Minimize Bias: Randomization and Blinding.....................................33
6.4.
Study Intervention Compliance ...............................................................................33
6.5.
Concomitant Therapy...............................................................................................33
6.6.
Palliative Medicine and Supportive Care ................................................................34
6.6.1.
Supportive Management for Diarrhea .........................................................................35
6.6.2.
Bisphosphonates and RANK-L Targeted Agents ........................................................36
6.6.3.
Growth Factors...........................................................................................................36
6.6.4.
Surgery.......................................................................................................................36
6.6.4.1. Surgery and/or Radiotherapy for Locoregionally Recurrent 
Breast Cancer..............................................................................................................36
6.7.
Dose Modification.....................................................................................................36
Abemaciclib dose modification for adverse reactions ................................................................37
Abemaciclib Dose Modification And Management- Hematologic 
Toxicities....................................................................................................................37
Abemaciclib Dose Modification and Management- Diarrhea.....................................................38
Abemaciclib Dose Modification and Management- Increased ALT/AST...................................38
Abemaciclib Dose Modification And Management– Interstitial Lung 
Disease/Pneumonitis...................................................................................................39
Abemaciclib Dose Modification And Management – Venous 
Thromboembolic Events.............................................................................................39
Abemaciclib Dose Modification And Management – Nonhematologic 
Toxicities  Excluding Diarrhea, ALT/AST Increased, 
ILD/pneumonitis, and Venous Thromboembolic Events .............................................39
6.7.1.
Dose Suspension and Cycle Delay..............................................................................39
6.7.2.
Anastrozole and Letrozole Dose Modification ............................................................40
6.7.3.
Fulvestrant Dose Modification....................................................................................40
6.8.
Intervention after the End of the Study...................................................................40
6.8.1.
Study Completion.......................................................................................................40
7.
Discontinuation of Study Intervention andParticipant 
Discontinuation/Withdrawal....................................................................................41
7.1.
Discontinuation of Study Intervention ....................................................................41
7.2.
Participant Discontinuation/Withdrawal from the Study.......................................41
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................42
7.3.
Lost to Follow up ......................................................................................................42
8.
Study Assessments and Procedures .........................................................................43
8.1.
Efficacy Assessments ................................................................................................43
8.2.
Safety Assessments ...................................................................................................43
8.2.1.
Clinical Safety LaboratoryAssessments......................................................................43
8.2.2.
Safety Monitoring.......................................................................................................44
8.2.2.1.
Hepatic Safety Monitoring..........................................................................................44
8.2.2.2.
Venous Thromboembolic Events (VTEs)....................................................................45


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Protocol I3Y-IN-JPEC(b)
5
8.2.2.3.
Serum Creatinine Increased ........................................................................................46
8.2.2.4.
Interstitial Lung Disease/Pneumonitis.........................................................................46
8.2.3.
Safety Surveillance.....................................................................................................46
8.3.
Adverse Events and Serious Adverse Events...........................................................47
8.3.1.
Time Period and Frequency for Collecting AE and SAE
Information.................................................................................................................48
8.3.1.1.
Participant Diary.........................................................................................................48
8.3.2.
Method of Detecting AEs and SAEs...........................................................................48
8.3.3.
Follow-up of AEs and SAEs.......................................................................................49
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................49
8.3.5.
Pregnancy...................................................................................................................49
8.3.6.
Adverse Events of Special Interest..............................................................................49
8.3.7.
Product Complaints ....................................................................................................49
8.4.
Treatment of Overdose.............................................................................................50
8.5.
Pharmacokinetics .....................................................................................................50
8.6.
Pharmacodynamics ..................................................................................................50
8.7.
Genetics.....................................................................................................................50
8.8.
Biomarkers ...............................................................................................................50
8.9.
Immunogenicity Assessments...................................................................................50
8.10.
Medical Resource Utilization and Health Economics .............................................50
9.
Statistical Considerations.........................................................................................51
9.1.
Statistical Hypotheses...............................................................................................51
9.2.
Sample Size Determination ......................................................................................51
9.3.
Populations for Analyses ..........................................................................................52
9.4.
Statistical Analyses ...................................................................................................52
9.4.1.
Primary and Secondary Endpoint(s)............................................................................52
9.4.2.
Other Analyses ...........................................................................................................53
9.4.2.1.
Patient Disposition .....................................................................................................53
9.4.2.2.
Patient Characteristics ................................................................................................53
9.4.2.3.
Concomitant Therapy .................................................................................................53
9.4.2.4.
Treatment Compliance................................................................................................53
9.5.
Interim Analyses.......................................................................................................53
10.
Supporting Documentation and Operational Considerations.................................54
10.1.
Appendix 1: Regulatory, Ethical, and StudyOversight 
Considerations ..........................................................................................................54
10.1.1.
Regulatory and Ethical Considerations........................................................................54
10.1.2.
Informed Consent Process ..........................................................................................54
10.1.3.
Data Protection...........................................................................................................55
10.1.4.
Committees Structure .................................................................................................55
10.1.5.
Dissemination of Clinical Study Data .........................................................................56


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Protocol I3Y-IN-JPEC(b)
6
10.1.6.
Source Documents......................................................................................................56
10.1.7.
Study and Site Start and Closure.................................................................................56
10.1.8.
Data Quality Assurance ..............................................................................................57
Data Capture System.................................................................................................................57
10.1.9.
Publication Policy.......................................................................................................58
10.1.10. Investigator Information .............................................................................................58
10.2.
Appendix 2: Clinical Laboratory Tests ...................................................................58
10.3.
Appendix 3: Adverse Events: Definitions and Proceduresfor 
Recording, Evaluating, Follow-up, and Reporting..................................................60
10.3.1.
Definition of AE.........................................................................................................60
10.3.2.
Definition of SAE.......................................................................................................62
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................64
10.3.4.
Reporting of SAEs......................................................................................................66
10.4.
Appendix 4: Contraceptive Guidance and Collection of
Pregnancy Information ............................................................................................67
Contraception Guidance:...........................................................................................................68
Collection of Pregnancy Information.........................................................................................69
10.5.
Appendix 5: Liver Safety: Suggested Actions andFollow-up 
Assessments...............................................................................................................70
10.6.
Appendix 6: Inducers and Strong Inhibitors of CYP3A.........................................72
10.7.
Appendix 7: CTCAE 5.0 Diarrhea/Pneumonitis/ALT and 
AST Increased Definitions........................................................................................73
10.8
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances.........................................................................................74
10.9
Appendix 9: Abbreviations ......................................................................................77
11.
References.................................................................................................................80


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Single-Arm, Phase 4 Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, 
in Combination with Endocrine Therapy (Anastrozole/Letrozole or Fulvestrant) in 
Participants with Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2-
Negative Locally Advanced and/or Metastatic Breast Cancer in India
Short Title: A Study of Abemaciclib in Combination with Endocrine Therapy 
(Anastrozole/Letrozole or Fulvestrant) in Participants with HR+, HER2- Locally Advanced 
and/or Metastatic Breast Cancer in India
Rationale:
Pivotal abemaciclib Phase 3 clinical trials I3Y-MC-JPBL (MONARCH 2) and I3Y-MC-
JPBM (MONARCH 3) demonstrated that abemaciclib, a cyclin-dependent kinase (CDK), 
CDK4 and CDK6 inhibitor (CDK4&6), when used in combination with endocrine therapy 
(ET) significantly improved progression-free survival (PFS) and objective response rate 
(ORR) in patients with hormone receptor positive (HR+), human epidermal growth factor 
receptor 2 negative (HER2-) advanced and/or metastatic breast cancer (MBC). While the 
safety of abemaciclib plus ET has been well characterized from these global Phase 3 studies, 
there is very limited information about the safety of abemaciclib in Indian breast cancer 
patients. This study will characterize the safety of abemaciclib in combination with ET in 
Indian patients with HR+, HER2- advanced and/or MBC.
Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the safety of 
abemaciclib in combination with ET 
(anastrozole/letrozole or fulvestrant)

TEAEs (including SAE and AESI) per CTCAE 
criteria version 5.0
Secondary

To evaluate incidence of treatment 
discontinuation of abemaciclib

Discontinuation of abemaciclib only due to an AE
Abbreviations: AE = adverse event; AES I= adverse events of special interest; CTCAE = Common Terminology 
Criteria for Adverse Events; ET = endocrine therapy; TEAE = treatment-emergent adverse events; SAEs = 
serious adverse events.
Overall Design:
This is a Phase 4, single-arm, cohort study of abemaciclib in combination with either an 
aromatase inhibitor (anastrozole or letrozole) or fulvestrant, in patients with HR+, HER 2-
locally advanced and/or metastatic breast cancer. This study is designed to characterize the 
safety and tolerability of abemaciclib plus ET in Indian participants.


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Protocol I3Y-IN-JPEC(b)
8
Disclosure Statement:
This is a single-group treatment study with 1 arm and no masking.
Number of Participants:
Approximately 200 participants will be enrolled in the study.
Intervention Groups and Duration:
There are two cohorts planned for the study.

Cohort A: abemaciclib 150 mg twice daily (BD) plus either anastrozole or letrozole

Cohort B: abemaciclib 150 mg BD plus fulvestrant
Participants will receive 6 cycles of study intervention (total duration ~6 months) or less if a 
criterion for discontinuation is met prior to the completion of 6 cycles. Participants who
completed the study after 6 cycles of treatment may continue to receive abemaciclib through a
patient support program as per investigator’s discretion.
Data Monitoring Committee:
No


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
9
1.2.
Schema
Abbreviations: AESI = adverse events of special interest; CTCAE = Common Terminology Criteria for 
Adverse Events; HER2- = human epidermal growth factor receptor 2-negative; HR+ = hormone receptor-
positive;
N = number of planned participants; TEAE= treatment emergent adverse events; SAEs= serious adverse events.
Note: Please refer to section 5.1 for a detailed information on inclusion criteria 2(a) and 2(b).


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Protocol I3Y-IN-JPEC(b)
10
1.3.
Schedule of Activities (SoA)
This section includes baseline, on- treatment, and post-discontinuation follow-up schedule of activities (SoAs)
Screening, On-Treatment and Post-Treatment Schedule of Activities
Study phases
Screening
On 
Treatment Cycle 
duration = 28 days
End of 
Study 
Visit a
Post-
Treatment
Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 to 
6
Cycle 
6
Short-
Term 
Follow-Up 
b
Relative Day within 
Dosing Cycle & 
Visit Window
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
D28 
(±3)
V801
(30 days +7)
Documentation 
and Examination
Informed consent
X
Written informed consent must be 
obtained prior to conducting any protocol-
specific tests/procedures.
Inclusion and 
exclusion 
criteria
X
See sections 5.1 and 5.2
Medical history
X
Including assessment of preexisting 
conditions, historical illnesses, prior 
anticancer therapies (including 
systemic, local, and surgical), and habits 
(such as
tobacco and alcohol use).
Prior and 
concomitant 
medication
X
X
X
X
At screening, record prior and concurrent 
medications. Record all premedications, 
supportive care, and concomitant 
medications including over-the-counter 
and analgesics use, continuously at every 
visit


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
11
and throughout the study.
Physical 
examination
X
X
X
X
X
X
X
X
Perform prior to administering 
abemaciclib. Includes height (only at 
screening) and
weight. Does not need to be repeated on


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
12
Screening, On-Treatment and Post-Treatment Schedule of Activities
Study phases
Screening
On Treatment 
Cycle duration = 28 
days
End of Study 
Visit a
Post-
Treatmen
t Follow-
up
Instructio
ns
Baseline
Cycle 1
Cycle 2
Cycle 3 to 
6
Cycle 
6
Short-
Term 
Follow-Up 
b
Relative Day within 
Dosing Cycle & Visit 
Window
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
D28 
(±3)
V801
(30 days 
+7)
Cycle 1 Day 1 if assessed at baseline ≤3
days prior to abemaciclib initiation. 
Additional exams should be performed 
as clinically indicated.
Vital signs
X
X
X
X
X
X
X
X
Perform prior to administering 
abemaciclib. Collect temperature, blood 
pressure, pulse, and pulse rate. Repeat if 
clinically
indicated.
ECOG 
performance status
X
X
X
X
X
X
Does not need to be repeated on Cycle 1
Day 1 if assessed at baseline ≤3 days 
prior to abemaciclib initiation.
Other Clinical 
Assessments
12-lead ECG
X
X
X
Single ECG performed locally. 
Participants should be supine for 
approximately 5 to 10 minutes before 
ECG collection and remain supine but 
awake during ECG collection. Repeat if 
clinically indicated.


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
13
AE assessment
X
X
X
X
At baseline determine the stool 
frequency for each participant to ensure 
increase from baseline can be assessed 
per CTCAE throughout the study (see 
appendix 7).
Collect continuously at every visit and 
throughout the study using CTCAE 
Version 5.0.


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
14
Screening, On-Treatment and Post-Treatment Schedule of Activities
Study phases
Screening
On Treatment 
Cycle duration = 28 days
End of Study 
Visit a
Post-
Treatment 
Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 to 6
Cycle 6
Short-Term 
Follow-Up b
Relative Day within 
Dosing Cycle & Visit 
Window
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
D28 
(±3)
V801
(30 days +7)
See Section 8.3 for further details on AE
and SAE reporting.
Laboratory Assessments
Hematology
X
X
X
X
X
X
X
X
See Appendix 2 (Section 10.2). Does not 
need to be repeated on Cycle 1 Day 1 if 
assessed at baseline ≤3 days prior to 
abemaciclib initiation. Repeat if clinically 
indicated.
Refer to Section 8.2.1.
Clinical chemistry
X
X
X
X
X
X
X
X
See Appendix 2 (Section 10.2). Does not 
need to be repeated on Cycle 1 Day 1 if 
assessed at baseline ≤3 days prior to 
abemaciclib initiation. Repeat if clinically 
indicated.
Refer to Section 8.2.1.
Pregnancy test
X
A serum pregnancy test is required at 
baseline only for participants receiving 
ovarian suppression with a GnRH agonist.
Pregnancy tests post baseline are per the 
investigator’s discretion.


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
15
Screening, On-Treatment and Post-Treatment Schedule of Activities
Study phases
Screening
On Treatment 
Cycle duration = 28 
days
End of Study 
Visit a
Post-
Treatmen
t Follow-
up
Instructio
ns
Baseline
Cycle 1
Cycle 2
Cycle 3 to 6
Cycle 6
Short-
Term 
Follow-Up 
b
Relative Day within 
Dosing Cycle & Visit 
Window
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
D28 
(±3)
V801
(30 days 
+7)
FSH and estradiol
X
Required only for women <55 years with
amenorrhea for at least 12 months 
to confirm post-menopausal 
status
Tumor imaging
X
Every 12 
weeks
Imaging at Screening:
Imaging performed previously as part 
of routine care may be used provided 
these were performed within 12 
weeks before Cycle 1 Day 1.
Imaging while On Treatment:
Imaging should be performed every 12 
weeks according to local standards and 
if clinically indicated as per the 
investigator’s judgment to determine 
disease progression.
More frequent imaging is allowed as part 
of routine medical care.


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
16
Screening, On-Treatment and Post-Treatment Schedule of Activities
Study phases
Screening
On Treatment 
Cycle duration = 28 days
End of Study 
Visit a
Post-
Treatment 
Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 to 6
Cycle 6
Short-Term 
Follow-Up b
Relative Day within 
Dosing Cycle & Visit 
Window
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
D28 
(±3)
V801
(30 days +7)
Bone nuclear 
imaging (such as 
bone scan, PET 
scan or PET/CT)
X
As per standard of care
Bone Imaging at Screening:
Imaging performed previously as part of 
routine care may be used provided these 
were performed within 12 weeks before 
Cycle 1 Day 1.
Bone Imaging while On Treatment:
Bone imaging should be performed 
according to local standards and if clinically 
indicated per the investigator’s judgment to 
determine disease progression.
Assessment of 
progression 
(symptomatic and 
radiological as per 
local practice)
X
X
X
X
Participants discontinuing either
abemaciclib or endocrine therapy prior to 
disease progression will continue to have 
scheduled assessments until documented
radiographic or symptomatic progression 
per investigator’s judgment.
Study Treatment
Abemaciclib
Orally twice daily, on Days 1 through 28 of a 
28-day cycle.
See Section 6.1.
Administer anastrozole 
or letrozole (Cohort A)
As per standard of care
See Section 6.1.
Administer 
fulvestrant (Cohort B)
As per standard of care
See Section 6.1.


CONFIDENTIAL
Protocol I3Y-IN-JPEC(b)
17
Screening, On-Treatment and Post-Treatment Schedule of Activities
Study phases
Screening
On Treatment 
Cycle duration = 28 days
End of Study 
Visit a
Post-
Treatment 
Follow-up
Instru
ctions
Baseline
Cycle 1
Cycle 2
Cycle 3 to 6
Cycle 6
Short-Term 
Follow-Up b
Relative Day within 
Dosing Cycle & Visit 
Window
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
D28 
(±3)
V801
(30 days +7)
Study intervention
compliance assessment
X
X
X
Abemaciclib bottle(s), including any 
unused
tablets, will be returned at the 
beginning of every cycle starting at 
Cycle 2 Day 1 and at abemaciclib 
discontinuation for drug 
accountability
Dispense and review 
patient diary
X
X
X
X
X
X
Review patient diary at each study 
visit for completion.
Abbreviations: AE = adverse events; D = day; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events;
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FSH = follicular stimulating hormone GnRH = gonadotropin-
releasing hormone; PET = positron emission tomography; SAEs = serious adverse events; V = visit.
a
The End of Study visit is not required for participants discontinuing study treatment prior to completion of 6 cycles or for participants who 
complete 6 cycles but do not continue to receive abemaciclib. These participants must complete the Short-Term Follow-Up instead.
b
Short-Term Follow-Up begins when the participant and investigator agree that the participant will no longer continue study treatment. 
The Short-Term Follow-Up is not required for participants who continue on abemaciclib (for example, in a patient support program) 
after the End of StudyVisit.


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2.
Introduction
2.1.
Study Rationale
Abemaciclib has been studied in combination with the nonsteroidal aromatase inhibitors 
(NSAIs) anastrozole or letrozole in hormone receptor positive (HR+), human epidermal 
growth factor receptor 2 negative (HER2-) breast cancer in study I3Y-MC-JPBM 
(MONARCH 3) and in combination with fulvestrant in I3Y-MC-JPBL (MONARCH 2). 
These 2 pivotal global studies showed a significant efficacy benefit and acceptable safety 
profile (Goetz et al. 2018; Sledge et al. 2017) and have led to the approval of abemaciclib by 
major global regulatory authorities for the treatment of patients with HR+, HER2- metastatic 
breast cancer (MBC) in combination with an NSAI as initial endocrine-based therapy and 
with fulvestrant following progression on endocrine therapy (ET).
In study I3Y-CR-JPBQ (JPBQ), a Phase 3 study of abemaciclib plus either NSAI or 
fulvestrant in HR+/HER2- locally locoregionally recurrent or MBC, patients were primarily
enrolled in China, with limited numbers from Brazil, South Africa, and India (N=32). The 
study showed that the efficacy and safety profile of abemaciclib was consistent with the 
results of MONARCH 2 and 3 (Jiang et al. 2019, Abstract presented in European Society for 
Medical Oncology Congress [ESMO], 2019). While the safety of abemaciclib in 
combination with endocrine therapies has been well characterized in these global Phase 3 
studies, there is only limited information from the JPBQ study about the safety of 
abemaciclib in MBC patients inIndia.
Study I3Y-IN-JPEC (hereafter referred to as Study JPEC) is a single-arm, open-label, cohort-
based, Phase 4 study that will prospectively assess the safety of abemaciclib in combination 
with either anastrozole/letrozole (enrolled in cohort A) or fulvestrant (cohort B) in Indian 
patients with HR+, HER2- locally advanced and/or MBC.
2.2.
Background
2.2.1.
Metastatic Breast Cancer
Breast cancer is the most common malignancy in women worldwide, impacting 2.1 
million women every year (Global Cancer Observatory [GCO], GLOBOCAN, 2018 
published in International Agency for Research on Cancer [IARC], 2020), and accounts 
for the second highest number of deaths among women globally (Centers for Disease 
Control and Prevention [CDC], 2019).
In India, approximately 162 468 new cases of breast cancer (14% of all cancer cases) 
emerge annually, making it the most common cancer in women in India (GLOBOCAN 
2018 published in International Agency for Research on Cancer [IARC]). Breast cancer 
cases are reported more in women from less developed countries than that of developed 
countries (883 000 vs 794 000 cases) (Ferlay et al. 2015). These findings can be 
corroborated with a significant rise in breast cancer related morbidities and mortalities in 
the Indian subcontinent (Malvia et al. 2017; Gupta et al. 2015; Babu et al. 2013; 
Balasubramaniam et al. 2013; Ali et al. 2011; Porter et al. 2009; Srinath et al. 2005).


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Breast cancers are the least reported cancers in India, per literature. Though the nature of 
the breast cancer may not differ entirely from its counterparts in Western countries, the 
proportion of breast cancer distribution is different in India (Rangarajan et al. 2016).
Well-equipped private hospitals observe 80% of Grade III breast cancer, but overall Grade II 
cancers dominate the proportion, with 9.5% to 20% of Grade I breast cancer (Rangarajan et 
al. 2016). Varying reference patterns and a wide economic gap in the patient population in 
India are some of the major underlying reasons for paucity of information in breast cancers 
in India and provides an insight into the trends of breast cancer in India (Rangarajan et al. 
2016).
While early-stage breast cancer is typically curable (Harbeck and Gnant, 2017), advanced 
breast cancer has a median overall survival rate of 2 to 3 years and a 5-year survival rate of 
approximately 25% (Cardoso et al. 2018). Metastatic breast cancer presents a poor 
prognosis in the Indian population, with a 5-year and 10-year overall survival rate of 22% 
and 5% (Gogia et al. 2019; Chopra, 2001). Approximately 1800 patients registered in the 
Indian breast cancer clinics from 2012 to 2018 were analyzed for the long-term outcome of 
MBC patients in India.
Hormone receptor positive status, oligometastasis, and good performance status, were 
associated with better outcomes in this study wherein most of the patients received 
chemotherapy followed by ET (Gogia et al. 2019).
Breast cancer treatment in India is highly varied in terms of health care standards. Despite 
major technological advancements in India, a large proportion of cancer patients either do 
not have access or cannot afford the treatment in India. It arises a need to develop safe and 
effective strategies that can be propagated on a country wide basis (Consensus Document for 
Management of Breast Cancer, Indian Council of Medical Research, 2016). The average 
population of breast cancer patients in India is a decade younger (48 to 53 years) than those 
in the Western countries (Kumar et al. 2018; Bustreo et al. 2016). This may be due to its 
population structure and its inherent bias against referral in India. The incidence of breast 
cancer increases with age and approximately 90% of sporadic breast cancers in India are 
associated with reproductive history, lifestyle, or environmental factors, primarily 
influencing their hormonal milieu (Consensus Document for Management of Breast Cancer, 
Indian Council of Medical Research, 2016).
More than 100 000 patients are treated for breast cancer every year in India (KhoKhar et al. 
2012), but, only about 11 to 23% of patients (1000 patients) opt for breast-conserving 
treatment (BCT) (Narendra et al. 2011). The lower rate of BCT in Indian patients is 
reflective of the late- stage at presentation and lack of well-equipped BCT centers, radiation 
therapy, and pathology (Vishwakarma et al. 2019; Agarwal et al. 2008; Dinshaw et al. 
2005; Raina et al. 2005). Indian women undergoing BCT are younger (<40 years), are 
higher grade, larger, HR negative tumors compared to the Western countries (Rangarajan et 
al. 2016). Low number of treatment facilities, lack of awareness, poor compliance to 
treatment, higher cost of treatment, and social stigma associated with the disease affects the 
effective management of breast cancer in India (Maurya and Brahmachari 2020). Resource 
constraints and limited availability of diagnostic tools (preoperative mammography etc.) 
has discouraged the use of effective breast cancer management in India (Rangarajan et al. 
2016).


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The Asian Society of Mastology (ASOMA), established in 2016 aims to improve the health 
care system in women with breast cancer in Asian countries. Sparsity of genetic counselling, 
molecular testing facilitates, and resource constraints are being considered for effective 
management of breast cancer in Asian countries (Srivastava et al. 2020).
Systemic treatment options for advanced breast cancer are largely determined by the 
presence (or absence) of HR and HER2. Recent advances in the treatment of HR+, HER2-
advanced breast cancer have contributed to improved patient outcomes (Cardoso et al. 
2018). Use of aromatase inhibitors in postmenopausal women is low and slowly increasing, 
however, ET is still the most widely used treatment for breast cancer in India (Agarwal et al. 
2008). The trend of use of ET therapy continues to dominate developing nations, with 
increased use of ET in 45.7% premenopausal women and 83.5% in postmenopausal women 
in Iraq (Abd-Alhussain et al. 2020; Jeon et al. 2017; Bujis et al. 2009). Penetration of 
generics in Indian markets (paclitaxel generic, docetaxel generic etc.) for MBC is also 
gaining popularity. Some investigators from India, conducted a retrospective analysis of 393 
patients who received generic versions of docetaxel, oxaliplatin, irinotecan, and 
gemcitabine. The median survival ranged to 47 months for patients with breast cancer (45% 
had metastatic disease) and 20% to 45% of patients reported serious adverse events (SAEs) 
(Lopes, 2013).
While NSAIs such as anastrozole and letrozole are the preferred initial treatment for the 
majority of patients with HR+, HER2- advanced breast cancer, ET resistance eventually 
develops, making patients unresponsive to standard ET approaches that target HR blockade 
(Flaum and Gradishar, 2018).  In HR+ breast cancer, estrogen induces overexpression of 
cyclin D1, which in association with cyclin-dependent kinase (CDK), CDK4 and CDK6 
(CDK4&6), promotes unregulated cell cycle progression. In breast cancer, cyclin D1/CDK4 
has been shown to promote phosphorylation of the retinoblastoma (Rb) protein, cell 
proliferation, and tumor growth (Sherr 1996; Ortega et al. 2002). CDK4&6 inhibitors (such 
as abemaciclib, palbociclib, or ribociclib) work by preventing Rb phosphorylation and 
blocking progression from G1 into S phase of the cell cycle, thus leading to suppression of 
tumor growth in preclinical models following short duration of target inhibition (Sherr 1996; 
Ortega et al. 2002). In estrogen receptor (ER) positive breast cancer cell lines, sustained 
target inhibition by CDK4&6 inhibitors prevents the rebound of Rb phosphorylation and cell 
cycle re-entry, resulting in senescence and apoptosis (Sherr 1996; Ortega et al. 2002). In the 
clinic, CDK4&6 inhibitors combined with ET (NSAI or fulvestrant) have demonstrated 
greater efficacy compared with ET alone in patients with HR+, HER2- advanced breast 
cancer (Finn et al. 2015; Hortobagyi et al. 2016; Goetz et al. 2017; Sledge et al. 2017; 
Slamon et al. 2018; Turner et al. 2018).
Due to the remarkable efficacy in progression-free survival (PFS) and objective response 
rate ORR and their manageable side-effect profile associated with the addition of CDK4&6 
inhibitors to ET, these agents have become the new standard of care for women with HR+, 
HER2- advanced breast cancer receiving first and subsequent lines of therapy (Flaum and 
Gradishar, 2018).
2.2.2. Abemaciclib


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Abemaciclib is an oral selective and potent adenosine triphosphate-competitive inhibitor of 
CDK4&6 that is administered on a continuous dosing schedule.
CDK4&6 inhibitors are known to interact with D-type cyclins and stimulate proliferation. 
CDK4&6 - D-cyclin complex, regulates the cell cycle checkpoints (G1/S), through 
phosphorylation and inactivation of the Rb tumor suppressor protein. Alterations in 
CDK4&6 or cyclin D commonly occur in human cancers and can be explored from a 
therapeutic standpoint.


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The inhibition of CDK4&6 (with a small molecule inhibitor) can prevent cell cycle 
progression (through G1 restriction point) thereby arresting tumor growth.
The clinical activity and safety of abemaciclib has been extensively studied in HR+, 
HER2- advanced breast cancer.
In the randomized, placebo-controlled MONARCH 2 Phase 3 study, the addition of 
abemaciclib to fulvestrant provided a significant improvement of PFS (16.9 months versus 
9.3 months, hazard ratio 0.536; 95% CI: 0.445, 0.645; p<.0001), overall survival (OS) (46.7 
months versus 37.3 months, hazard ratio 0.757; 95% CI, 0.606-0.945; p=.0137) and ORR 
(48.1% versus 21.3%; 95% CI: 42.6, 53.6; p<.001) compared to placebo plus fulvestrant in 
HR+, HER2- advanced or MBC patients who progressed during prior ET (Sledge et al. 
2017; Sledge et al. 2020). Of note, the OS benefit was consistent across subgroups 
including patients with a poorer prognosis with visceral metastases and primary endocrine 
resistance (Sledge et al. 2020).
In the randomized, placebo-controlled MONARCH 3 Phase 3 study, the addition of 
abemaciclib to a NSAI as initial treatment of HR+, HER2− advanced or MBC patients 
provided a significant improvement of PFS (28.2 months versus 14.8 months; hazard ratio 
0.540; 95% CI: 0.418 to 0.698; p=.000002) in the intent-to-treat population (N=493) and the 
ORR for patients with measurable disease (N=399, 80.9%) was 61.0% versus 45.5% (95% 
CI 37.0, 53.9; p=.003) compared to placebo plus NSAI (Johnston et al. 2019). The OS data, 
an important secondary end point of this study, are immature.
The most common adverse events of all grades for abemaciclib in the MONARCH 2 (plus 
fulvestrant) and MONARCH 3 (plus NSAI) were: diarrhea (86.4% and 82.3%), neutropenia 
(46.0% and 43.7%), nausea (45.1% and 41.3%), and fatigue (39.9% and 41.3%), 
respectively. Abemaciclib was discontinued for adverse events (AEs) in 15.9% of the cases 
in MONARCH 2 and 25.1% of patients in the abemaciclib arm discontinued any study 
intervention as the result of an AE in MONARCH 3 (Sledge et al. 2017; Johnston et al. 
2019). A comprehensive safety analysis of abemaciclib-associated AEs from MONARCH 2 
and 3 by Rugo et al. [Rugo et al., unpublished data] showed that the most common Grade ≥3 
AE was neutropenia (25.4%), typically occurring within the first 2 cycles of treatment, and 
resolving with dose adjustments.
The decreasing incidence in subsequent cycles following abemaciclib dose adjustment 
indicated low recurrence. Clinically significant diarrhea (Grade ≥2) was reported for 42.8% 
of patients taking abemaciclib with a median time to onset of 1 week, and duration ranging 
from 6 to 12 days. Clinically important laboratory abnormalities included increased alanine 
aminotransferase (ALT) Grade ≥3 (4 to 6%) and increased aspartate aminotransferase (AST) 
Grade ≥3 (2 to 4%). The median time to onset for Grade ≥3 increased ALT in the 
abemaciclib arms was approximately 60 days in both studies and 185 days and 71 days for 
AST in MONARCH 2 and 3, respectively. Effects were reversible in both studies, as 
demonstrated by short duration of Grade ≥3 increased ALT and AST, with a median time to 
resolution (for all patients regardless of dose adjustments) from onset of approximately 2 
weeks. Other clinically relevant AEs reported in these studies were any grade venous 
thromboembolic events (VTEs) (5 to 6%), and interstitial lung disease (ILD)/pneumonitis (2 
to 5%).


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Study JPBQ, where abemaciclib plus NSAI (cohort A) or fulvestrant (cohort B) was given in 
a predominantly Chinese HR+, HER2− locoregionally recurrent or MBC population, 
showed similar safety and tolerability results as in MONARCH2 and MONARCH3. 
However, the incidence of clinically significant diarrhea (Grade ≥2) was lower (28.8% 
reported for both
cohorts) likely due to the raised awareness and improved management in the JPBQ study 
[JPBQ Clinical Study Report, Zhang et al. unpublished data].
Abemaciclib is currently approved by major global regulatory authorities for the treatment of 
patients with HR+, HER2- advanced or MBC in combination with a NSAI as initial 
endocrine- based therapy and with fulvestrant following ET. In addition, abemaciclib is also 
approved as monotherapy for heavily pretreated (following ET and chemotherapy) HR+, 
HER2- MBC patients by the Food and Drug Administration (FDA) and other geographies 
including India.
While these results support the use of abemaciclib in combination with endocrine 
therapies for the treatment of advanced and/or MBC, the safety and tolerability has not 
been studied extensively in the Indian population. Study JPEC will assess the safety and 
tolerability of abemaciclib in combination with ET in Indian patients with HR+, HER2-
locally advanced and/or MBC.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits, risks, SAEs, AEs of 
special interest (AESI) and reasonably anticipated AEs of abemaciclib is to be found in the 
Investigator’s Brochure (IB).
More detailed information about the known and expected benefits and risks of standard of 
care endocrine therapies, may be found in the respective Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the safety of 
abemaciclib in combination with ET 
(anastrozole/letrozole or fulvestrant)

TEAEs (including SAEs and AESIs) by per 
CTCAE criteria version 5.0
Secondary

To evaluate incidence of treatment 
discontinuation of abemaciclib

Discontinuation of abemaciclib only, due to an AE
Abbreviations: AE = adverse event; AESI = adverse events of special interest; CTCAE = Common 
Terminology Criteria for Adverse Events; ET = endocrine therapy; TEAE = treatment-emergent adverse 
events; SAEs = serious adverse events.


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4.
Study Design
4.1.
Overall Design
Study JPEC is a Phase 4, single-arm, cohort study of abemaciclib in combination with either 
a NSAI (anastrozole or letrozole) or fulvestrant, in patients with HR+, HER2- locally 
advanced and/or MBC. This study is designed to characterize the safety of abemaciclib plus 
ET in Indian patients.
Participants receiving initial endocrine-based therapy for advanced/MBC will be assigned to 
cohort A to receive abemaciclib in combination with anastrozole/letrozole. Participants who 
have received prior ET in the advanced/metastatic setting or relapsed while on/or within 1 
year after ET in the adjuvant setting, will be assigned to cohort B to receive abemaciclib in 
combination with fulvestrant.
To evaluate the safety of abemaciclib in combination with anastrozole/letrozole or 
fulvestrant, AEs will be assessed throughout the study and the clinical safety laboratory will 
be assessed on day 1 and 14 in the first 2 cycles and then day 1 every 28 days in the 4 
subsequent cycles.
Participants will continue treatment for a total duration of 6 cycles or less in case of 
radiographic or clinical progression as per investigator’s judgment or another discontinuation
criterion has been met. Participants who complete the study after 6 cycles of treatment may 
continue to receive abemaciclib (for example, through a patient support program) as per 
investigators discretion.
4.2.
Scientific Rationale for Study Design
The primary objective of the Study JPEC is to characterize the safety of abemaciclib in 
combination with ET in HR+, HER2- advanced and/or MBC in Indian patients. The number 
and percentage of patients from the safety population (that is, having received at least one 
dose of abemaciclib) experiencing a treatment-emergent AE will be summarized per severity 
grade (as per CTCAE criteria version 5.0) and the number of participants with SAEs and or 
AESI will be described.
The study is designed to enroll approximately 200 patients in India targeting the same 
patient populations as were enrolled in the Phase 3 global studies of MONARCH 3 and 
MONARCH 2.

Cohort A: patients (similar to MONARCH 3), who are starting initial ET in the 
advanced/metastatic setting, will be assigned to abemaciclib + anastrozole or 
letrozole.

Cohorts B: patients (similar to MONARCH 2), who have received prior ET in the 
advanced/metastatic setting or relapsed while on or within 1 year after ET in the 
adjuvant setting, will be assigned to abemaciclib plus fulvestrant.
Patients will remain on study for a maximum of 6 cycles. The final analyses of primary and 
secondary objectives will be conducted when the last patient comes off study treatment, 
which is approximately 6 months after the last patient enrolls. This timeframe will enable to 


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26
gather sufficient data to characterize the safety of abemaciclib in combination with ET in 
HR+, HER2- advanced and/or MBC patients enrolled in India.
4.3.
Justification for Dose
Clinical trials MONARCH 2 and MONARCH 3 demonstrated efficacy with an acceptable 
risk- benefit profile when abemaciclib was dosed at 150 mg as combination therapy. Further 
justification for dose may be found in the IB, Patient Information Leaflet, and Prescribing 
Information.
Justification for the dosing of approved NSAIs, anastrozole and letrozole, and fulvestrant
may be found in the respective Patient Information Leaflet and Prescribing Information. 
Study JPEC will explore the safety of abemaciclib at a dose of 150 mg twice daily (BD) in 
combination with ET in Indian patients with HR+, HER2- advanced and/or MBC.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA (Section 1.3) for the last participant 
in the trial.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
have a diagnosis of HR+, HER2- breast cancer

to fulfill the requirement of HR+ disease, a breast cancer must 
express,by immunohistochemistry (IHC), at least 1 of the hormone 
receptors (ER or progesterone receptor) as defined in the relevant 
American Society of Clinical Oncology (ASCO)/College of 
American Pathologists (CAP) Guidelines (Hammond et al. 2010).

to fulfill the requirement of HER2- disease, a breast cancer must not 
demonstrate, at initial diagnosis or upon subsequent biopsy, 
overexpression of HER2 by either IHC or in-situ hybridization as
defined in the relevant ASCO/CAP Guidelines (Wolff et al. 2014). 
Although not required as a protocol procedure, a patient with a new 
metastatic lesion should be considered for biopsy whenever possible 
to reassess HER2 status prior to study entry if clinically indicated.
2.
meet either inclusion criterion (2a) or inclusion criterion (2b). Participants 
meeting inclusion criterion 2a will be enrolled in cohort A and participants 
meeting inclusion criterion 2b will be enrolled in cohort B.
(2a) have locoregionally recurrent disease not amenable to resection 
or radiation therapy with curative intent or metastatic disease

relapsed with radiologic evidence of progression more than 1
year from completion of/or with no adjuvant ET
and
have received no prior ET for locoregionally recurrent or metastatic 
disease
(Note: prior neoadjuvant or adjuvant ET for localized disease may 
have included, but is not limited to, anti-estrogens or aromatase 
inhibitors. In addition, a patient may be enrolled if she has 
received ≤2 weeks of NSAI in this disease setting immediately 
preceding screening and agrees to discontinue NSAI until study 
treatment initiation.)
OR
presented de novo MBC and not received any prior ET


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(2b) have locoregionally recurrent disease not amenable to 
resection or radiation therapy with curative intent or 
metastatic disease

relapsed with radiologic evidence of progression while 
receiving neoadjuvant or adjuvant ET, with nosubsequent ET 
received following progression
OR

relapsed with radiologic evidence of progression within 1 year 
from completion of adjuvant ET, with no subsequent ET received 
following progression
OR

relapsed with radiologic evidence of progression more than 1 year from 
completion of adjuvant ET and then subsequently relapsed with 
radiologic evidence of progression after receiving treatment with either 
an antiestrogen or an aromatase inhibitor as first-line ET for metastatic 
disease. Participants may not have received more than 1 line of ET or 
any prior chemotherapyfor metastatic disease
OR

presented de novo with metastatic disease and then relapsed with 
radiologic evidence of progression after receiving treatment with either 
an antiestrogen or an aromatase inhibitor as first-line ET for metastatic 
disease. Participants may not have received more than 1 line of ET or 
any prior chemotherapy for metastatic disease
3.
have postmenopausal status due to either surgical/natural menopause or ovarian 
suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a 
gonadotropin- releasing hormone (GnRH) agonist such as goserelin. 
Postmenopausal status due to surgical/natural menopause requires at least 1 of 
the following:

prior bilateral oophorectomy

age ≥55 years

age <55 years and amenorrhoeic for at least 12 months (in the 
absence of chemotherapy, tamoxifen, toremifene, or ovarian 
suppression) and follicle-stimulating hormone (FSH) and estradiol 
levels in the postmenopausal range
4.
if postmenopausal status is due to ovarian suppression with a GnRH agonist such as 
goserelin (initiated at least 28 days prior to Cycle 1 Day 1), participants must have a 
negative serum pregnancy test at baseline (within 14 days prior to enrollment) and
agree to use medically approved precautions to prevent pregnancy during the study 
and for 3 weeks following the last dose of abemaciclib.


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5.
sexually active participants, who are of child-bearing potential, must agree to use a 
medically approved contraceptive method during the study and for at least 3weeks
following the last dose of abemaciclib (for example, intrauterine device, 
nonhormonal birth control pills, or barrier method).
6.
Please refer to Appendix 4 (Section 10.4) for additional reproductive and
contraceptive guidance.
7.
are female and >18 years of age.
8.
have given signed informed consent as described in Appendix 1 (Section 10.1), 
which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol prior to any study-specific
procedures
9.
must have adequate organ function, as defined below:
Hematologic System
Parameter
Laboratory Value
ANC
1.5×109/L
Platelets
100×109/L
Hemoglobin
9 g/dL
Note: Transfusions to increase a participant’s hemoglobin level or initiation of erythropoietin or granulocyte-
colony stimulating factor (G-CSF) therapy to meet enrollment criteria is not allowed in the 14 days preceding the 
first dose of study intervention. If a participant receives transfusions, erythropoietin, or G-CSF therapy ≥14 days 
prior to the first dose of study intervention, the hematologic criteria listed above must be met following the 14-
day window and prior to the first dose of study intervention.
Hepatic System
Parameter
Laboratory Value
Total bilirubin
1.5×ULN
Except participants with a documented history of Gilbert 
Syndrome who must have a total bilirubin level <2.0×ULN
ALT and AST
≤3×ULN with no tumor involvement
OR
5×ULN if the liver has tumor involvement
Renal System
Parameter
Laboratory Value
Serum creatinine
<1.5×ULN
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = 
aspartate aminotransferase; G-CSF = granulocyte-colony stimulating factor; ULN = upper 
limit of normal.
10.
have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Oken et al. 1982).
11.
have discontinued previous therapies for cancer as listed:


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Previous Treatment
Length of Time Prior to First Dose of study 
intervention
Cytotoxic therapies or targeted agents that are small 
molecule inhibitors
21 days or 5 half-lives, whichever is shorter
Biologic agents that are large molecules including 
immunotherapy
28 days
Investigational agents
28 days. If the agent has a long half-life (for example,
>2 weeks), then 3 months or 5 half-lives (whichever is 
longer) should have passed
Radiotherapy
Limited-field radiotherapy with palliative intent
14 days
Other radiotherapy
28 days
Major surgery, excluding biopsy
28 days
12.
are willing to participate for the duration of the study and to follow studyprocedures.
13.
are able to swallow oral formulation of pharmaceutical product (for example, tablets).
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
14.
are currently receiving an investigational drug in a clinical trial or participating in 
any other type of medical research judged not to be scientifically or medically 
compatible with this study.
15.
have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. Visceral 
crisis is not the mere presence of visceral metastases but implies severe organ 
dysfunction as assessed by symptoms and signs, laboratory studies, and rapid
progression of the disease.
16.
have clinical evidence or history of central nervous system metastasis. Screening 
is not required for enrollment.
17.
have received prior treatment with chemotherapy (except for
neoadjuvant/adjuvant chemotherapy), fulvestrant, everolimus, or any 
CDK4&6 inhibitor.
18.
have received recent (within 28 days prior to study intervention) live vaccination 
(for example, yellow fever). Seasonal flu vaccinations that do not contain a live 
virusare permitted.
19.
have a personal history of any of the following conditions: presyncope or 
syncopeof either unexplained or cardiovascular etiology, ventricular 
tachycardia, ventricular fibrillation, or sudden cardiac arrest.
20.
have serious preexisting medical conditions that, in the judgment of the investigator, 
would preclude participation in this study such as severe renal impairment, [for 
example, estimated creatinine clearance <30 mL/min], ILD, severe dyspnea at rest or 
requiring oxygen therapy, history of major surgical resection involving the stomach 


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31
or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting 
chronic condition resulting in clinically significant diarrhea.
21.
have inflammatory breast cancer or a history of any other cancer (except
nonmelanoma skin cancer or carcinoma in-situ of the cervix), unless in complete 
remission with no therapy for a minimum of 3 years.
22.
have received an autologous or allogeneic stem-cell transplant
23.
have clinically relevant active bacterial or fungal infection, or detectable viral 
infection (for example, human immunodeficiency virus or viral hepatitis). 
Screening is not required for enrollment.
24.
are pregnant or breastfeeding.
5.3.
Lifestyle Considerations
Abemaciclib is a cytochrome P450 (CYP) 3A4 substrate. Participants should refrain from 
consuming grapefruit, grapefruit juice, and grapefruit-containing products while 
participating in the study due to the effect on CYP3A4.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened. Rescreened participants should be assigned a new participant number. The 
interval between rescreening should be weeks. Individuals may be rescreened a 
maximum of two times. Each time rescreening is performed, the individual must sign a new 
ICF and will be assigned a new identification number. Repeating of laboratory testing 
during the screening period or repeating screening tests to comply with the protocol-
designated screening period does not constitute rescreening.


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6.
Study Intervention
Study intervention is defined as any investigational interventions, marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Interventions Administered
Treatment Regimen
Treatment Period
Dose 
         Cohort A
Abemaciclib
28-day cycle
150 mg BD on Days 1-28
Anastrozole
or
Letrozole
28-day cycle
refer to local PI for dosing information
       Cohort B
Abemaciclib
28-day cycle
150 mg BD on Days 1-28
Fulvestrant
28-day cycle
refer to local PI for dosing information
Abbreviation: BD = twice daily; PI = prescribing information.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
recordmaintenance (that is, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study
interventions are provided in the Pharmacy Manual.
6.2.1.
Selection and Timing of Doses
A treatment cycle is defined as an interval of 28 days. Abemaciclib will be administered 
orally BD at approximately the same times each day on Days 1 through 28 of a 28-day cycle 
(±3 days). Details on treatment administration are described in Section 6.1.
A cycle delay or earlier start due to logistical reasons (for example, due to holiday, weekend, 
inclement weather, or other unforeseen circumstances), will be permitted for up to a 
maximum of 7 days (and not be considered a protocol violation). In the event of a visit 
delay, the participant should continue study intervention if she has adequate drug supply.


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Participants may continue to receive study intervention for a total duration of 6 cycles or less 
in case of disease progression, or any other discontinuation criterion is met (See Section 7).
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a non-randomized, open-label study.
Participants will be assigned to abemaciclib plus anastrozole/letrozole (Cohort A) or 
abemaciclib plus fulvestrant (Cohort B) (see section 5.1). Abemaciclib dispensing will be 
managed by using the interactive web response system (IWRS).
Site personnel will confirm that they have located the correct study medication packages by 
entering a confirmation number found on the packages into the IWRS.
6.4.
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
studyintervention.
The participant must take ≥75% of the planned doses for study intervention in a cycle to be 
deemed compliant. As outlined in Section 6.7, dose suspensions or delays may occur and 
will not result in a participant being considered as noncompliant. Participants may be
considered significantly noncompliant if they are judged by the investigator to have 
intentionally or repeatedly taken ≥125% of the planned doses of study intervention in a 
cycle.
6.5.
Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements, or other specific categories of interest) that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with:
●
Reason for use
●
Dates of administration including start and end dates
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.
Abemaciclib is extensively metabolized through oxidation by CYP3A. In clinical drug 
interaction studies, coadministration of clarithromycin, a strong CYP3A inhibitor, 
increased exposure to abemaciclib by 3.4-fold (Study I3Y-MC-JPBE) and coadministration 


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of rifampin, a strong CYP3A inducer, decreased exposure to abemaciclib by 95% (Study 
I3Y-MC-JPBF).
CYP3A4 inhibitors
Strong inhibitors of CYP3A (given via non-topical routes of administration) should be 
substituted or avoided if possible (Appendix 6 in Section 10.6). This includes grapefruit or 
grapefruit juice. If the planned duration of coadministration is <28 days, the investigator may 
consider suspending abemaciclib. Dose suspensions ≥28 days must be discussed with the Eli 
Lilly and Company (Lilly)-designated medical monitor.
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should reduce 
the dose of abemaciclib by 50 mg. That is, for patients receiving 150 mg twice daily, reduce 
the dose to 100 mg twice daily. For patients who have already dose reduced to 100 mg twice 
daily for tolerability, reduce the dose further to 50 mg twice daily.
Upon discontinuation of the strong CYP3A inhibitor, the dose of abemaciclib may be re-
escalated to the dose that was used before starting the strong inhibitor after a sufficient 
washout period (3 to 5 half-lives of the strong CYP3A inhibitor). Re-escalation of the 
abemaciclib dose requires review and approval from the Lilly-designated medical monitor.
CYP3A4 inducers
Inducers of CYP3A should be substituted or avoided if possible (Appendix 6, Section 10.6). 
Co-administration with a CYP3A inducer ≥28 days must be discussed with the Lilly-
designated medical monitor.
The information in Appendix 6 (Section 10.6) is provided for guidance to investigators and 
does not preclude the use of these medications if clinically indicated.
Abemaciclib and/or its major metabolites inhibit the efflux transporters P-glycoprotein and 
breast cancer resistance protein and renal transporters organic cation transporter 2, multidrug
and toxin extrusion protein 1 (MATE1), and MATE2-K at clinically relevant
concentrations.
Therefore, substrates of these transporters such as metformin and those with a narrow 
therapeutic index such as digoxin and dofetilide should be substituted or avoided if possible.
The Eli Lilly and Company (Lilly)-designated medical monitor should be contacted if there 
are any questions regarding concomitant or prior therapy. No other chemotherapy, 
immunotherapy, radiotherapy, herbal supplements and/or herbal drugs intended to treat 
cancer, or experimental drugs will be permitted while participants are receiving study 
intervention, except as described in Section 6.2.1 and Section 6.6.4.
6.6.
Palliative Medicine and Supportive Care
Palliative radiation therapy is permitted after discussion with and agreement of the
Lilly-designated medical monitor for irradiating small areas of painful metastases that 
cannot be managed adequately using systemic or local analgesics. Abemaciclib should be 
held while participants are receiving palliative radiation therapy and can be restarted after 
completion of the therapy as per clinical judgement of the investigator. Any symptomatic 


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deterioration or clinical disease progression requiring, in the opinion of the investigator, 
other forms of specific antitumor systemic therapy, will be cause for discontinuation of 
study intervention.
Appropriate documentation for all forms of premedications, supportive care, and 
concomitant medications must be captured on the electronic case report form (eCRF).
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008). Prophylactic 
antibiotic treatment should be consistent with ASCO guidelines (Flowers et al. 2013).
All concomitant medications should be recorded throughout the participant’s involvement 
in the study.
6.6.1. Supportive Management for Diarrhea
Participants must receive instructions on the management of diarrhea. Participants should be 
prescribed antidiarrheal therapy (for example, loperamide) at cycle 1 day 1. Sponsor will 
provide reimbursement for antidiarrheal therapy according to local laws. 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 participant should initiate antidiarrheal therapy 
(for example, loperamide) and notify the investigator for further instructions and 
appropriate follow-up.

Participants should also be encouraged to drink fluids (that is, 8 to 10 glasses ofclear
liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to at least 
Grade 1 (per CTCAE version 5.0), abemaciclib should be suspended until diarrhea 
is resolved to at least Grade 1.

When abemaciclib treatment recommences, dosing should be adjusted as outlinedin
Section 6.7.1. 
For severe cases of diarrhea, the measurement of neutrophil counts and body temperature 
and proactive management of diarrhea with antidiarrheal agents should be considered. If 
diarrhea is severe (requiring intravenous [IV] hydration) and/or associated with fever or 
severe neutropenia, broad-spectrum antibiotics such as fluoroquinolones should be 
considered.
Participants with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given IV fluid and electrolyte replacement as clinically 
indicated. Please refer to Section 6.7 for specific dose-related modifications for diarrhea.


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6.6.2.
Bisphosphonates and RANK-L Targeted Agents
Participants with bone metastases present on baseline imaging should be appropriately 
treated with approved bone-modifying agents per investigator’s discretion (e.g.,
bisphosphonates or RANK-L targeted agents) per respective approved labels.
6.6.3.
Growth Factors
Participants should receive full supportive care. The use of granulocyte-colony stimulating 
factor is permitted at the discretion of the investigator based on ASCO (Smith et al. 2015) 
and European Society for Medical Oncology (Crawford et al. 2009) guidelines. See Section
6.7.1.
6.6.4.
Surgery
Participants undergoing surgery:

For minor surgeries and procedures (for example, ambulatory), investigators should 
treat as clinically indicated and closely monitor any signs of infection or healing
complications.

For major surgeries, the recommendation is to suspend dosing of abemaciclib for at 
least 7 days before and may be resumed as clinically indicated.

Consider monitoring neutrophils and platelets before surgery and before resuming 
abemaciclib. The scars should be aseptic and healing process be reasonable before
resuming abemaciclib.

Dose suspensions ≥28 days must be discussed with Lilly-designated medical monitor.
6.6.4.1.Surgery and/or Radiotherapy for Locoregionally Recurrent Breast
Cancer
A participant with locoregionally recurrent breast cancer may receive surgery 
radiotherapy if study intervention renders the tumor operable. However, such a participant 
should not receive study intervention for the period beginning at least 7 days prior to 
surgery and continuing as clinically indicated after completion of surgery radiotherapy 
to allow for tissue healing and recovery. There is no restriction on the duration of this 
period without study intervention and, after this period ends, study intervention may 
resume. Importantly, a participant who receives surgery radiotherapy for locoregionally 
recurrent breast cancer is not considered noncompliant and does not incur a protocol 
deviation.
6.7.
Dose Modification
Dose reductions for abemaciclib should be performed as shown in the table below. 
Abemaciclib must be reduced sequentially by 1 dose level, unless an exception is granted in 
consultation with the Lilly-designated medical monitor. For participants requiring a dose 
reduction of study intervention, any reescalation to a prior dose level is permitted only after 


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consultation with and approval by the Lilly-designated medical monitor. If a patient 
receiving the 50-mg BD dose of abemaciclib requires further dose reduction, the patient 
must be discontinued from abemaciclib. In the event that abemaciclib must be discontinued, 
a patient may continue to receive ET in the absence of progression per the investigator’s 
clinical judgment.
Abemaciclib dose modification for adverse reactions
Dose Level
Abemaciclib dose
Starting dose
150 mg BID
First dose reduction
100 mg BID
Second dose reduction
50 mg BID
Third dose reduction
Not applicable
Abbreviation: BID = twice daily.
The toxicity dose adjustments and delays of abemaciclib in the tables below are guidance for 
management of treatment-emergent, related (that is, with reasonable causal relationship with 
abemaciclib), and clinically significant AEs of abemaciclib. Treatment-emergent laboratory 
abnormalities of neutrophil count decreased and/or ALT/AST increased, regardless of 
clinical significance, must follow the dose adjustment table below.
An investigator may suspend or reduce doses without 1 of the criteria below being met 
and would not be considered a protocol deviation.
Abemaciclib Dose Modification And Management- Hematologic Toxicities
CTCAE Grade
Abemaciclib dose modifications
Grade 1 or 2
No dose modification is required
Grade 3
Suspend dose until toxicity resolves to ≤Grade 2
Dose reduction is not required.
Grade 3 recurrent or Grade 4
Suspend dose until toxicity resolves to ≤Grade 2
Resume at next lower dose
Patient requires administration of a blood 
cell growth factor
Suspend abemaciclib dose for at least 48 hours 
after the last dose of blood cell growth factor and 
until toxicity resolves to ≤Grade 2
Resume abemaciclib at next lower dose unless 
the dose was already reduced for the toxicity that
led to the use of the growth factor
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.


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Abemaciclib Dose Modification and Management- Diarrhea
At the first sign of loose stools, start treatment with antidiarrheal agents (such as loperamide)
CTCAE Grade1
Abemaciclib dose modifications
Grade 1
No dose modification is required
Grade 2
If toxicity does not resolve within 24 hours to
< Grade 1, suspend dose until resolution
No dose reduction is required
Grade 2 that persists or recurs after resuming the 
same dose despite maximal supportive measures
Suspend dose until toxicity resolves to ≤Grade 1. 
Resume at next lower dose
Grade 3 or 4 or requires hospitalization
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
1 For grading of diarrhea events please refer to Appendix 7 (Section 10.7)
Abemaciclib Dose Modification and Management- Increased ALT/AST
Monitor ALT/AST prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly 
for the next 2 months, and as clinically indicated.
CTCAE Grade1
Abemaciclib dose modifications
Grade 1 Grade 2 
No dose modification is required
Persistent or Recurrent Grade 2, 
or Grade 3 
Suspend dose until toxicity resolves to baseline or
Grade 1. 
Resume at next lower dose
≥Grade 2 (with total bilirubin >2×ULN, in the 
absence of cholestasis
Discontinue abemaciclib
Grade 4 
Discontinue abemaciclib
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase, CTCAE = Common 
Terminology Criteria for Adverse Events; ULN = upper limit of normal.
1 For grading of ALT and AST increased please refer to Appendix 7 (Section 10.7)


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Abemaciclib Dose Modification And Management– Interstitial Lung 
Disease/Pneumonitis
CTCAE Grade1
Abemaciclib dose modifications
Grade 1 or 2
No dose modification is required
Grade 2 that persists or recurs despite maximal 
supportive measures and does not return to baseline 
or Grade 1 within 7 days
Suspend dose until toxicity resolves to baseline or 
Grade ≤1
Resume at next lower dose.
Grade 3 or 4
Discontinue abemaciclib
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events.
1 For grading of pneumonitis events please refer to Appendix 7 (Section 10.7)
Abemaciclib Dose Modification And Management – Venous 
Thromboembolic Events 
CTCAE Grade
Abemaciclib dose modifications
Grade 1 or 2
No dose modification is required
Grade 3 or 4
Suspend dose and treat as clinically indicated.
Abemaciclib may be resumed when the patient is
clinically stable.
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events.
Abemaciclib Dose Modification And Management – Nonhematologic 
Toxicities 
Excluding Diarrhea, ALT/AST Increased, ILD/pneumonitis, and Venous 
Thromboembolic Events 
CTCAE Grade
Abemaciclib dose modifications
Grade 1 or 2
No dose modification is required
Persistent or recurrent Grade 2 toxicity that does not 
resolve with maximal supportive measures within 
7 days to baseline or Grade 1
Suspend dose until toxicity resolves to baseline or 
Grade 1
Resume at next lower dose
Grade 3 or 4
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = 
Common Terminology Criteria for Adverse Events; ILD = interstitial lung disease.
6.7.1.
Dose Suspension and Cycle Delay
Study interventions may be suspended for a maximum of 28 days to allow a patient 
sufficient time for recovery from study treatment-related toxicity. In exceptional 
circumstances, a delay >28 days is permitted upon agreement between the investigator and 
the Lilly- designated medical monitor.


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For dose suspensions for abemaciclib related to surgery or palliative radiation see section 6.6.
A delay of a cycle due to holiday, weekend, bad weather, or other unforeseen circumstances 
will be permitted for a maximum of 7 days and not counted as a protocol deviation. In 
exceptional circumstances, a delay >7 days is permitted upon agreement between the 
investigator and the Lilly-designated medical monitor.
6.7.2.
Anastrozole and Letrozole Dose Modification
Dose adjustment for anastrozole and letrozole will be determined by the investigator in 
accordance with the local Prescribing information. Participants should remain on the same 
NSAI throughout the study. In exceptional cases, in the absence of evidence of progressive 
disease, the investigator may discuss a change in NSAI with the Lilly-designated medical 
monitor. In the event that anastrozole or letrozole are discontinued, the participant may 
continue abemaciclib alone in the absence of evidence of progression and per the 
investigator’s clinical judgement.
6.7.3.
Fulvestrant Dose Modification
Dose adjustment for fulvestrant will be determined by the investigator in accordance with 
the Prescribing Information. In the event that fulvestrant is discontinued, the participant 
may continue abemaciclib alone, in the absence of evidence of progression, and per the 
investigator’s clinical judgement.
6.8.
Intervention after the End of the Study
Please refer to the study schema (Section 1.2) for a depiction of study completion and the 
end of study.
6.8.1.
Study Completion
Study completion will occur following the final analysis of primary and secondary 
objectives, which will be conducted when the last patient completed 6 cycles of study 
intervention and comes off the study. This is expected approximately 6 months after the 
last patient entered treatment.
The end of study definition is defined in Section 4.4. Investigators will continue to follow 
the SoA provided in Section 1.3 until notified by Sponsor that end of study has occurred.


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7.
Discontinuation of Study Intervention and
Participant Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
Participants may discontinue the study intervention at any time for any reason.
The reason and date of discontinuation must be collected for all participants and 
documented on the corresponding CRF.
Participants will be discontinued from study intervention in the following circumstances:

participant completed 6 cycles of study intervention

participant decision
o
the participant or the participant’s designee (for example, parents or 
legal guardian) requests to be discontinued from study intervention

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)

investigator decision
o
the investigator decides that the patient should be discontinued from the 
study or study intervention
o
if the participant, for any reason, requires treatment from another 
therapeutic agent that has been demonstrated to be effective for 
treatment of the study indication. Discontinuation from study 
intervention will occur prior to introduction of the new agent.
o
the participant is significantly noncompliant with study procedures
and/or intervention.

the participant is enrolled in any other clinical trial involving an investigational 
product or other type of medical research judged not to be scientifically or medically
compatible with this study

radiographic or symptomatic disease progression as per investigator judgment

the participant experiences unacceptable toxicity

the patient becomes pregnant during the study
7.2.
Participant Discontinuation/Withdrawal from the Study
Participants will be discontinued from the study in the following circumstances

sponsor determines that participation in the study needs to be stopped for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and
GCP

the investigator decides that the patient should be discontinued from the study

the participant requests to be withdrawn from the study

the participant completed 6 cycles of study intervention and/or completed the short-
term follow-up visit

the study has been completed as defined in Section 6.8.1.


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7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria 
and was inadvertently enrolled, then the participant should be discontinued from study 
treatment unless there are extenuating circumstances that make it medically necessary for 
the participant to continue on study treatment.
If the investigator and the sponsor clinical research physician (CRP)/clinical research 
scientist (CRS) agree it is medically appropriate to continue, the investigator must obtain 
documented approval from the sponsor CRP/CRS to allow the inadvertently enrolled 
participant to continue in the study with or without treatment with investigational product. 
Safety follow up is as outlined in Section 1.3 (SoA), Section 8.2 (Safety Assessments), and 
Section 8.3 (Adverse Events and Serious Adverse Events) of the protocol.
7.3.
Lost to Follow up
A participant will be considered lost to follow-up if she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected 
to make diligent attempts to contact participants who fail to return for a scheduled visit or 
were otherwise unable to be followed up by the site.


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8.
Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. Protocol 
waivers or exemptions are not allowed.
●
Immediate safety concerns should be discussed with the sponsor immediately
upon occurrence or awareness to determine if the participant should continue 
or discontinue study intervention.
●
Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3). For 
each patient, vital signs, laboratory tests, and other tests should be collected as shown in the 
SoA (Section 1.3).
Results from any clinical laboratory test analyzed by a central laboratory (refer to Appendix 
2, Section 10.2) will be provided to investigator sites by Lilly or its designee.
Refer to Section 8.3 for details on the recording of AEs.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. Additional information regarding guidance for monitoring of hepatic function, renal 
function, VTE, and ILD/pneumonitis can be found in sections 8.2.2.
8.2.1.
Clinical Safety LaboratoryAssessments
Lilly or its designee will provide the investigator with the results of safety laboratory 
tests analyzed by a central vendor.
See Appendix 2 (Section 10.2), for the list of clinical laboratory tests to be performed 
and to the SoA (Section 1.3) for the timing and frequency.
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.


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All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within Visit 801 after the last dose of study 
intervention should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator.

If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified, and
the sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2 (Section
10.2),
must be conducted in accordance with the laboratory manual and the 
SoA (Section 1.3).

If laboratory values from non protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (for 
example, SAE, AE, or dose modification), then the results must be recorded in 
the CRF.
8.2.2.
Safety Monitoring
8.2.2.1.
Hepatic Safety Monitoring
Close Hepatic Monitoring And Evaluation
Liver testing (Section 10.5, Appendix 5), including ALT, AST, alkaline phosphatase (ALP), 
total bilirubin (TBL), direct bilirubin (D. Bil), gamma-glutamyl transferase (GGT), and 
creatine kinase (CK), should be repeated within 2 to 4 days to confirm the abnormality and 
to determine if it is increasing or decreasing, if one or more of these conditions occur:
If a participant with baseline results 
of …
develops the following elevations:
ALT or AST <1.5×ULN
ALT or AST ≥5×ULN or
ALT or AST ≥3x ULN concurrent with TBL ≥2×ULN
ALT or AST ≥1.5×ULN
ALT or AST ≥3×baseline or 
ALT or AST ≥2×baseline concurrent with TBL ≥2×ULN
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; 
ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation 
with the Lilly-designated medical monitor. At a minimum, this evaluation should include 
physical examination and a thorough medical history, including symptoms, recent illnesses 


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(for example, heart failure, systemic infection, hypotension, or seizures), history of 
concomitant medications (including over-the-counter, herbal and dietary supplements, 
history of alcohol drinking, and other substance abuse). In addition, the evaluation should 
include a blood test for prothrombin time (PT)-INR; serological tests for viral hepatitis A, B, 
C, E, autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or 
computed tomography [CT] scan).
Based on the patient’s history and initial evaluation results, further testing should be 
considered, in consultation with the Lilly-designated medical monitor, including tests for 
hepatitis D virus (HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), 
acetaminophen levels, acetaminophen protein adducts, urine toxicology screen, Wilson’s 
disease, blood alcohol levels, urinary ethyl glucuronide, and serum phosphatidylethanol. 
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for a hepatologist or 
gastroenterologist consultation, magnetic resonance cholangiopancreatography (MRCP), 
endoscopic retrograde cholangiopancreatography (ERCP), cardiac echocardiogram, and/or 
a liver biopsy.
Additional Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF, if 1 or more of the following 
conditions occur:
In participants enrolled with baseline ALT or AST<1.5 ULN

Elevation of serum ALT or AST to ≥5×ULN on 2 or more consecutive blood tests

The combination of elevated ALT or AST ≥3×ULN and elevated TBL ≥2×ULN
In participants enrolled with baseline ALT or AST ≥1.5×ULN

Elevated ALT or AST ≥3×baseline on 2 or more consecutive tests

The combination of elevated ALT or AST ≥2×baseline and elevated TBL ≥2×ULN
In all study participants

Discontinuation from study treatment due to a hepatic event or abnormality of livertests

Occurrence of a hepatic event considered to be a SAE
8.2.2.2.
Venous Thromboembolic Events (VTEs)
VTE has been identified as an adverse drug reaction for abemaciclib in 
combination with endocrine therapy. In the randomized Phase 3 studies in 
participants with breast cancer treated with abemaciclib in combination with ET, a
greater number of participants experienced VTEs in the abemaciclib plus ET arm
than in the placebo plus ET arm or ET alone arm. The majority of participants who 
experienced VTEs were treated with anticoagulants. 


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At this time, the mechanism underlying the association between abemaciclib and 
the occurrence of VTEs is not known. Participants should be monitored for signs 
and symptoms of deep vein thrombosis and pulmonary embolism and treated as 
medically appropriate. Additional information is available in the IB.
8.2.2.3.
Serum Creatinine Increased
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting glomerular filtration rate (as measured by iohexol
clearance). In clinical studies, increases in serum creatinine occurred within the first month 
of abemaciclib dosing (remained elevated but stable through the treatment period) were 
reversible upon treatment discontinuation, and were not accompanied by changes in markers 
of renal function, such as blood urea nitrogen, cystatin C, or calculated glomerular filtration 
rate based on cystatin C.
Dose adjustment (omission, reduction, or discontinuation) should not be based solely on 
interpretation of serum creatinine values because these may not reflect renal function. If
deterioration of renal function is suspected per the investigator’s clinical assessment, a 
cystatin C measurement may be performed to confirm renal status. Dose alteration should 
follow the protocol guidance for nonhematological toxicities (Section 6.7).
8.2.2.4.
Interstitial Lung Disease/Pneumonitis
Interstitial lung disease (ILD)/pneumonitis has been identified as an adverse drug 
reaction for abemaciclib. Additional information is available in the IB.
Ask your participants to report any new or worsening pulmonary symptoms such as dyspnea, 
cough, and fever, and investigate and treat as per your local clinical practice (including 
corticosteroids as appropriate). If ILD/pneumonitis is suspected, investigations may include 
imaging such as high-resolution computed tomography, bronchoalveolar lavage, and biopsy 
as clinically indicated.
Refer to Section 6.7 for guidance on dose adjustments of abemaciclib for participants with 
ILD/pneumonitis. Discontinue abemaciclib in cases of severe (Grade 3 or 4) 
ILD/pneumonitis.
8.2.3.
Safety Surveillance
The sponsor has robust safety surveillance processes based on recommendation made by 
Council for International Organizations of Medical Sciences (CIOMS) Working Group VI -
Management of Safety Information from Clinical Trials Report. These processes are in line 
with FDA’s expectations for Safety Assessment Committees and the European Medical 
Agency expectations for monitoring safety in clinical trials.
Each investigational drug has a Developmental Safety Surveillance Team (DSST) which is 
responsible for monitoring the safety of participants and overseeing the evolving safety 


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profile of investigational drugs. The DSST will review all available data including but not 
limited to clinical trial data (cumulative AE and SAE data and laboratory data), non-clinical 
data (toxicology studies), epidemiology studies and literature. The team will conduct real 
time review of all SAEs and other incoming expedited safety reports. The DSST is also 
responsible for review of accumulating safety data across all trials for the investigational 
drug. The DSST will meet in a timely manner at predefined intervals or on an ad-hoc basis 
as required.
The DSST is a multidisciplinary team which includes a physician/scientist who are well 
versed in Pharmacovigilance and with the therapeutic area for which the investigational 
drug is being developed. The roles and responsibilities of this team and the processes are 
clearly defined in Lilly’s internal Standard Operating Procedures.
Each investigational drug has a Developmental Safety Management Team (DSMT) which is 
a cross-functional, multidisciplinary team and includes DSST members, study team 
physicians and other members depending on the necessity such as epidemiologist, clinical 
pharmacologist, toxicologist, statistician. The DSST and DSMT work together to review 
clinical data from the clinical trial.
The DSST can make recommendations to the DSMT in order to minimize risk to 
participants in clinical trials. Such recommendations will include (but are not limited to) 
changes to conduct of the trial, determination of new adverse drug reactions and determining 
if event(s) meets the criteria for expedited reporting to regulators (such as investigational 
new drug safety reports) and investigators.
In addition, each individual clinical trial study team has clearly defined processes to review 
all relevant safety data at cohort level and trial level in order to monitor safety of participants 
in clinical trials and enable trial level decisions such as dose escalation. More information 
about these processes can be found in Section 6.7 of the protocol.
Lilly Global Patient Safety has a robust process, for expedited communication of SAEs and 
suspected unexpected serious adverse reactions per regulatory requirements and other 
important study information as needed. The protocol gives detailed information to study 
sites for collection and reporting of AEs and SAEs (see Section 8.3 and Appendix 3 [Section 
10.3]).
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study (see Section 7).


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8.3.1.
Time Period and Frequency for Collecting AE and SAE
Information
All SAEs will be collected from the signing of the ICF until participation in study has 
ended. All AEs will be collected from the signing of the ICF or until end of study visit.
Adverse events that begin before the start of study intervention but after signing of the ICF 
will be recorded on the AE CRF.
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data 
entry, SAE reporting to sponsor begins after the patient has signed the ICF and has received 
study intervention. However, if an SAE occurs after signing the ICF, but prior to receiving 
abemaciclib, it needs to be reported ONLY if it is considered reasonably possibly related to 
study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. Serious adverse events, including death, caused by disease progression 
should not be reported unless the investigator deems them to be possibly related to study 
treatment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1.
Participant Diary
A diary will be provided to participants in order to help track treatment compliance and 
for the participant to record possible side effects experienced during the treatment cycle. 
The investigator or designee should review the diary for completion and discuss any 
reported side effect with the patient.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrences.


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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Appendix 3 (Section 10.3).
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safetyof a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (for example, summary or listing of SAEs) from 
the sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy
The patient population in Study JPEC is restricted to post-menopausal women so 
pregnancies are therefore highly unlikely to occur in this study.
However, if a pregnancy is reported, the investigator should inform the sponsor within 24 
hours of learning of the pregnancy and should follow the procedures outlined in Appendix 
3 (Section 10.3).
Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6. Adverse Events of Special Interest
More information about the AESI for abemaciclib can be found in the IB.
8.3.7. Product Complaints
A product complaint is any written, electronic, or oral communication that alleges
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a trial intervention.
The Sponsor collects product complaints on investigational products and drug delivery 
systems used in clinical studies in order to ensure the safety of study participants, monitor 
quality, and to facilitate process and product improvements.


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Participants will be instructed to contact the investigator as soon as possible if he or she has 
a complaint or problem with the investigational product, so that the situation can be 
assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the 
processes outlined in Section 8.3.3 and Appendix 3 (Section 10.3) of the protocol.
8.4.
Treatment of Overdose
In the event of an overdose, the investigator should:
1. Contact the Lilly-designated medical monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratoryabnormalities
3. Document the quantity of the excess dose as well as the duration of the overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Lilly-designated medical monitor based on the clinical evaluation of 
the participant.
8.5.
Pharmacokinetics
Not applicable.
8.6.
Pharmacodynamics
Not applicable.
8.7.
Genetics
Not applicable.
8.8.
Biomarkers
Not applicable.
8.9.
Immunogenicity Assessments
Not applicable.
8.10.
Medical Resource Utilization and Health Economics
Not applicable.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
No formal statistical hypotheses exist, and no formal statistical hypothesis testing will be 
performed.
9.2.
Sample Size Determination
Approximately 200 participants with ER+, HER2- locally advanced or MBC will be enrolled 
in this study, with a minimum of at least 50 participants per cohort. The sample size has 
been selected to allow adequate assessment of study primary objective on safety. It can 
provide adequate precision for the estimated incidence rate of participants having a specified 
AE. With a total sample size of N = 200 for the study, example point estimates of incidence 
rates and corresponding 2-sided 95% CIs are summarized in the table below. The values are 
provided as a reference for estimation rather than a basis of any decision criteria.
Estimated Incidence Rate and 2-Sided 95% CI
N = 200
95% CIa
Number of 
Cases
Estimated Rate
Lower 
Limit
Upper Limit
10
0.05
0.02
0.09
20
0.10
0.06
0.15
40
0.20
0.15
0.26
60
0.30
0.24
0.37
80
120
140
160
180
0.40
0.60
0.70
0.80
0.90
0.33
0.53
0.63
0.74
0.85
0.47
0.67
0.76
0.85
0.94
Abbreviations: CI = confidence interval; N = number of participants.
a
95% Clopper-Pearson interval for binomial distribution.


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9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Entered
All participants who sign the informed consent form.
Safety
All participants assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the intervention 
they actually received.
9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of Sponsor or its designee.
Any change to the data analysis methods described in the protocol will require an 
amendment only if it changes a principal feature of the protocol. Any other change to the 
data analysis methods described in the protocol, and the justification for making the change, 
will be described in the statistical analysis plan and the clinical study report. Additional 
exploratory analyses of the data will be conducted as deemed appropriate.
The statistical analysis plan will be finalized prior to first patient visit and it will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
9.4.1.
Primary and Secondary Endpoint(s)
All participants who receive at least 1 dose of any study intervention will be evaluated for 
safety and toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA) Version (25.0x [or higher]) 
will be used when reporting AEs by MedDRA terms. The MedDRA lower level term will be 
used in the treatment-emergent computation. Treatment-emergent adverse events will be 
summarized by system organ class and by decreasing frequency of preferred term within the 
system organ class.
Safety analyses will include summaries of the following:

AEs, including severity in CTCAE grade and possible relationship to studyintervention

SAEs, including possible relationship to study intervention

Discontinuations from study treatment due to AEs
Time to treatment discontinuation is defined as the time from first dose until the date of 
treatment discontinuation.


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9.4.2.
Other Analyses
9.4.2.1.
Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of participants entered into the study, and treated in the study, or 
discontinuing (overall and by reason for discontinuation). A summary of all the important 
protocol deviations will be provided.
9.4.2.2.
Patient Characteristics
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics.
9.4.2.3.
Concomitant Therapy
A summary of prior and concomitant medications will be reported.
9.4.2.4.
Treatment Compliance
Fulvestrant will be administered at the investigator site; therefore, treatment compliance is 
assured.
Study treatment compliance for other study treatments will be assessed as the proportion of 
treatment that is actually taken, relative to what is expected, after accounting for protocol-
defined dose adjustments. Study treatment taken will be derived from the difference 
between the total number of pills dispensed and returned over the course of the patient’s 
treatment.
9.5.
Interim Analyses
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study
Oversight Considerations
10.1.1.
Regulatory and Ethical Considerations
●
This study will be conducted in accordance with the protocol and 
withthe following:
○
Consensus ethical principles derived from international guidelines
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical
Guidelines
○
Applicable ICH Good Clinical Practice (GCP) Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (for example, advertisements) must be submitted to an 
IRB/IEC bythe investigator and reviewed and approved by the IRB/IEC 
before the study is initiated.
●
Any amendments to the protocol will require IRB/IEC approval 
before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study
participants.
●
The investigator will be responsible for the following:
○
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, 
policies,and procedures established by the IRB/IEC
○
Notifying the IRB/IEC of SAEs [and/or UADEs] or other significant 
safety findings as required by IRB/IEC procedures
○
Providing oversight of the conduct of the study at the site and 
adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC,
European regulation 536/2014 for clinical studies (if applicable), and 
all other applicable local regulations
Investigator sites are compensated for participation in the study as detailed in the clinical 
trial agreement.
10.1.2.
Informed Consent Process
●
The investigator or his/her representative will explain the nature of the 
study, including the risks and benefits, to the participant or his/her legally
authorized representative and answer all questions regarding the study.


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●
Participants must be informed that their participation is voluntary. 
Participants or their legally authorized representative will be required to sign 
a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center.
●
The medical record must include a statement that written informed consent 
was obtained before the participant was entered in the study and the date the 
written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.
●
Participants must be re-consented to the most current version of the ICF(s)
during their participation in the study.
●
A copy of the ICF(s) must be provided to the participant or the 
participant’s legally authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.3.
Data Protection
●
Participants will be assigned a unique identifier by the sponsor. Any 
participant records, datasets or tissue samples that are transferred to the 
sponsor willcontain the identifier only; participant names or any 
information which would make the participant identifiable will not be
transferred.
●
The participant must be informed that his/her personal study-related data 
will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant who will 
be required to give consent for their data to be used as described in the 
informed consent.
●
The participant must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities.
●
The Sponsor has processes in place to ensure data protection, information 
security and data integrity. These processes include appropriate contingency 
plan(s) for appropriate and timely response in the event of a data security
breach.
10.1.4.
Committees Structure
Not applicable.


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10.1.5.
Dissemination of Clinical Study Data
Dissemination of study data will be performed according to all applicable Lilly policies.
10.1.6.
Source Documents
●
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed 
at the investigator’s site.
●
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request
previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
10.1.7.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for 
recruitment of participants.
The first act of recruitment is the first site open and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:
●
Failure of the investigator to comply with the protocol, the requirements of 
the IRB/IEC or local health authorities, the sponsor's procedures, or GCP
guidelines
●
Inadequate recruitment of participants by the investigator
●
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and assures appropriate participant therapy and/or follow-up.


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10.1.8.
Data Quality Assurance
●
All participant data relating to the study will be recorded on printed or 
electronic CRF unless transmitted to the sponsor or designee electronically 
(for example, laboratory data). The investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically 
signing the CRF.
●
The investigator must maintain accurate documentation (source data) 
that supports the information entered in the CRF.
●
The investigator must permit study-related monitoring, audits, IRB/IEC
review, and regulatory agency inspections and provide direct access to 
source data documents.
●
Monitoring details describing strategy (for example, risk-based initiatives 
in operations and quality such as Risk Management and Mitigation 
Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques are provided in the Monitoring Plan.
●
The sponsor or designee is responsible for the data management of this 
study including quality checking of the data.
●
The sponsor assumes accountability for actions delegated to other
individuals (fore example, Contract Research Organizations).
●
Study monitors will perform ongoing source data verification to confirm that
data entered into the CRF by authorized site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
●
Records and documents, including signed ICFs, pertaining to the conduct of 
this study must be retained by the investigator for the time period outlined in 
the Clinical Trial Agreement (CTA) unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written 
notification to thesponsor.
●
In addition, Sponsor or its representatives will periodically check a sample
of the participant data recorded against source documents at the study site. 
The study may be audited by Sponsor or its representatives, and/or 
regulatory agencies at any time. Investigators will be given notice before an 
audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor.


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An electronic data capture system (EDC) will be used in this study for the collection of 
CRF data. The investigator maintains a separate source for the data entered by the 
investigator or designee into the sponsor-provided EDC system. The investigator is 
responsible for the identification of any data to be considered source and for the 
confirmation that data reported are accurate and complete by signing the CRF.
Data collected via the sponsor-provided data capture system will be stored at third-party. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system. Prior to decommissioning, the investigator 
will receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored 
electronically in the central vendor’s database system and reports/electronic transfers will 
be provided to the investigator for review and retention. Data will subsequently be 
transferred from the central vendor to the Sponsor data warehouse.
Data from complaint forms submitted to Sponsor will be encoded and stored in the global 
product complaint management system.
10.1.9.
Publication Policy
In accordance with the sponsor’s publication policy the results of this study will be 
submitted for publication by a peer-reviewed journal.
10.1.10.
Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
10.2.
Appendix 2: Clinical Laboratory Tests
●
The tests detailed below will be performed as indicated in the table.
●
Protocol-specific requirements for inclusion or exclusion of 
participants are detailed in Section 5 of the protocol.
●
Additional tests may be performed at any time during the study as 
determined necessary by the investigator or required by local regulations. 
Refer to Section5.1 Inclusion Criteria for screening pregnancy criteria.
Investigators must document their review of each laboratory safety report. Laboratory results 
that could unblind the study will not be reported to investigative sites or other blinded 
personnel.


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Clinical Laboratory Tests
Basophils
Lymphocytes
Eosinophils
Mean cell hemoglobin concentration (MCHC)
Erythrocytes (RBC)
Mean cell volume (MCV)
Hemoglobin (HGB)
Monocytes
Hematocrit (HCT)
Neutrophils
Leukocytes (WBC)
Platelets (PLT)
Serum concentrations of:
Alanine aminotransferase (ALT)
Chloride
Albumin
Creatinine
Alkaline phosphatase (ALP)
Cystatin C
Aspartate aminotransferase (AST)
Potassium
Bilirubin, total
Protein, total
Bilirubin, direct
Sodium
Blood urea nitrogen (BUN) or 
blood urea Calcium
Pregnancy Test (Only for Participants Receiving Ovarian Suppression with a GnRH Agonist) – Local 
Laboratory
Serum pregnancy test
Postmenopausal Confirmation Testing (Required only for women <55 years with amenorrhea for at 
least 12 months to confirm post-menopausal status) - Local Laboratory
Follicle-stimulating hormone (FSH)
Estradiol
Note: Neutrophils reported by automated differential hematology instruments include both segmented and 
band forms. When a manual differential is needed to report the neutrophils, the segmented and band 
forms should be added together and reported on the CRF, unless the CRF specifically provides an entry 
field for bands.
Abbreviations: CRF = case report form; GnRH = gonadotropin-releasing hormone; RBC = red blood 
cells; WBC = white blood cells.
Hematology -Central Laboratory
Clinical Chemistry - Central Laboratory


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures
for Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.


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
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose, per se, will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdose should be reported regardless of sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy willbe
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE.
Events NOT Meeting the AE Definition
Events Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged bythe 
investigator to be more severe than expected for the participant’scondition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (for example, endoscopy, appendectomy): thecondition
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or
detected at the start of the study that do not worsen.


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10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (for example, hospitalization for signs/symptoms of the disease under 
study, death due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect


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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.


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10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested 
by Sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will assess the intensity of each AE and SAE reported during the study and 
assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event, and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.


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
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment ofcausality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Sponsor or designee. However, it 
is very important that the investigator always assess the causality of every event before 
the initial transmission of the SAE data to Sponsor or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causalityassessment.
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Assessment of Causality
Follow-up of AEs and SAEs

The investigator is obligated to assess the relationship between study interventionand 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

New or updated information will be recorded in the originally completedCRF.

The investigator will submit any updated SAE data to Sponsor or designee within 24 
hours of receipt of the information.


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10.3.4.
Reporting of SAEs
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Lilly-designated medical monitor.

Initial notification via telephone does not replace the need for the investigatorto
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SAE form.
SAE Reporting via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE will be the electronic data collection 
tool.

If the electronic system is unavailable, then the site will use the paper SAE data
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (seenext 
section) or to Lilly-designated medical monitor by telephone.

Contacts for SAE reporting can be found in SAE form.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of
Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (for example, amenorrhea in adolescents or athletes) and a menstrual 
cycle cannot be confirmed before first dose of study intervention, additional evaluation 
should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateralsalpingectomy

Documented bilateraloophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (for example, Mullerian agenesis, androgen insensitivity), 
investigator discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with:

12 months of amenorrhea for women >55, with no need for FSH

12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL 
and no other medical condition such as anorexia nervosa and not taking 
medications during the amenorrhea (for example oral contraceptives, 
hormones, gonadotropin releasing hormone, anti-estrogens, selective ER 
modulators (SERMs), or chemotherapy that induced amenorrhea)


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Contraception Guidance:
Please follow the contraceptive guidelines below.
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency

Intrauterine device

Bilateral tubal occlusion

Vasectomized partner

(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. Spermatogenesis cycle is approximately 90days.)
Highly Effective Methodsb That Are User Dependent

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the patient.)
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used 
consistently and correctly.
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method are not acceptable methods of contraception for this study. Male condom and 
female condom should not be used together (due to risk of failure with friction).


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Collection of Pregnancy Information
Female Participants who become pregnant
●
The investigator will collect pregnancy information on any female 
participant who becomes pregnant while participating in this study. The 
initial information will be recorded on the appropriate form and submitted
to the sponsor within 24 hours of learning of a participant's pregnancy.
●
The participant will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the sponsor. Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date. Any termination of pregnancy will be reported, 
including fetal status (presence or absence of anomalies) or indication for the
procedure.
●
While pregnancy itself is not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical 
reasons willbe reported as an AE or SAE.
●
A spontaneous abortion (occurring at <20 weeks gestational age) or still 
birth (occurring at >20 weeks gestational age) is always considered to be an
SAE and will be reported as such.
●
Any poststudy pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as 
described in Section 8.3.4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an 
SAE through spontaneous reporting.


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10.5.
Appendix 5: Liver Safety: Suggested Actions and
Follow-up Assessments
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and 
may be required in follow-up with participants in consultation with the Lilly-designated 
medical monitor.
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 8.2.2.1 for guidance on 
appropriate test selection.

For testing selected, analysis is required to be completed by the Lilly designated central laboratory 
except for microbiology.

Local testing may be performed in addition to central testing when required for immediatepatient 
management.

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells)
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
Lymphocytes
Creatine kinase (CK)
Monocytes
Other Chemistry
Basophils
Acetaminophen
Eosinophils
Acetaminophen Protein Adducts
Platelets
Alkaline Phosphatase Isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl Alcohol (EtOH)
Prothrombin Time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin A (IgA [Quantitative])
Hepatitis A Virus (HAV) Testing:
Immunoglobulin G (IgG [Quantitative])
HAV Total Antibody
Immunoglobulin M (IgM [Quantitative])
HAV IgM Antibody
Phosphatidylethanol (PEth)
Hepatis B Virus (HBV) Testing:
Urine Chemistry
Hepatitis B surface antigen (HBsAg)
Drug Screen
Hepatitis B surface antibody (Anti-HBs)
Ethyl glucuronide (EtG)
Hepatitis B core total antibody (Anti-HBc)
Other Serology


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Hepatitis B core IgM antibody
Anti-nuclear antibody (ANA)
Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA)a
HBV DNAd
Anti-actin antibodyb
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
HCV antibody
EBV antibody
HCV RNAd
EBV DNAd
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
HDV antibody
CMV antibody
Hepatitis E Virus (HEV) Testing:
CMV DNAd
HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
HEV IgM antibody
HSV (Type 1 and 2) antibody
HEV RNAd
HSV (Type 1 and 2) DNAd
Microbiologyc
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture:
Blood
Urine
Abbreviations: CRF = case report form; DNA = deoxyribonucleic acid; Ig = immunoglobulin; INR =
international normalized ratio; RNA = ribonucleic acid.
a
This is not required if Anti-Actin Antibody is tested.
b This is not required if Anti-smooth muscle antibody (ASMA) is tested.
c
Assayed by Investigator-designated local laboratory ONLY. For some abnormal lab values, only the 
related diagnosis will be reported in the CRF.
d Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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10.6.
Appendix 6: Inducers and Strong Inhibitors of CYP3A
The information in this table is provided for guidance to investigators and does not 
preclude the use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine 
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lesinurad
Modafinil
Primidone
Telotristatethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
a
Important note: All participants may receive supportive therapy with dexamethasone, preferably ≤7 days, if 
clinically indicated.
Abbreviation: CYP = cytochrome P450.


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10.7.
Appendix 7: CTCAE 5.0 Diarrhea/Pneumonitis/ALT and AST
Increased Definitions
Diarrhea/Pneumonitis/ALT and AST increased will be evaluated in this study using the 
criteria proposed by CTCAE v5.0 revised: Gastrointestinal disorders, Respiratory, Thoracic 
and Mediastinal Disorders.
Grade
Adverse Event
1
2
3
4
5
Gastrointestinal Disorders
Diarrhea
Increase of <4 
stools per day 
over baseline; 
mild increase 
in ostomy 
output 
compared to 
baseline
Increase of 4 to 6 
stools per day 
over baseline; 
moderate increase 
in ostomy output 
compared to 
baseline; limiting 
instrumental
ADL
Increase of ≥7 
stools per day over 
baseline; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting
self-care ADL
Life-threatening 
consequences; urgent 
intervention indicated
Death
Definition: a disorder characterized by an increase in frequency and/or loose watery bowel movements
Respiratory, Thoracic, and Mediastinal Disorders
Pneumonitis
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated
Symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL
Severe 
symptoms; 
limiting self-care 
ADL; oxygen 
indicated
Life-threatening 
respiratory 
compromise; 
urgent intervention 
indicated (for 
example, 
tracheotomy or
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Abbreviation: ADL = activities of daily living.
Investigations
Alanine 
aminotransferase 
(ALT) increased 
>ULN through
3.0 x ULN if 
baseline was 
normal; 1.5 
through 3.0 x 
baseline if 
baseline was 
abnormal
>3.0 through 5.0 x 
ULN if baseline 
was normal; >3.0 
through 5.0 x 
baseline if 
baseline was 
abnormal
>5.0 through 20.0 x 
ULN if baseline 
was normal; >5.0 
through 20.0 x 
baseline if baseline 
was abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Death
Definition:  a finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase 
(ALT or SGPT) in the blood specimen.


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Aspartate 
aminotransferase 
(AST) increased
>ULN through
3.0 x ULN if 
baseline was 
normal; 1.5 
through 3.0 x 
baseline if 
baseline was 
abnormal
>3.0 through 5.0 x 
ULN if baseline 
was normal; >3.0 
through 5.0 x 
baseline if 
baseline was 
abnormal
>5.0 through 20.0 x 
ULN if baseline 
was normal; >5.0 
through 20.0 x 
baseline if baseline 
was abnormal
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal
Death
Definition:  a finding based on laboratory test results that indicate an increase in the level of aspartate 
aminotransferase (AST or SGOT) in a blood specimen.
Abbreviation:  ADL = activities of daily living; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum
glutamic-pyruvic transaminase; ULN = upper limit of normal.
10.8
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances
Implementation of This Appendix
The changes to procedures described in this appendix are temporary measures intended to be used only 
during specific time periods as directed by the sponsor in partnership with the investigator.
Exceptional Circumstances
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures.
Implementing Changes Under Exceptional Circumstances
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may implement 
changes if permitted by local regulations. 
Ethical review boards, regulatory bodies, and any other relevant local authorities, as required, will be 
notified as early as possible to communicate implementation of changes in study conduct due to 
exceptional circumstances. To protect the safety of study participants, urgent changes may be 
implemented before such communications are made, but all changes will be reported as soon as possible 
following implementation. If approval of ERBs, regulatory bodies, or both is required per local 
regulations, confirmation of this approval will be retained in the study records.
In the event written approval is granted by the sponsor for changes in study conduct, additional written 
guidance, if needed, will be provided by the sponsor.
Considerations for Making a Change
The prevailing consideration for making a change is ensuring the safety of study participants. Additional 
important considerations for making a change are compliance with Good Clinical Practice, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed Consent


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Additional consent from the participant will be obtained, if required, for:

participation in remote visits, as defined in Section “Remote visits,”

dispensation of additional study intervention during an extended treatment period, 

alternate delivery of study intervention and ancillary supplies, and

provision of their personal or medical information required prior to implementation of these 
activities. 
Changes in Study Conduct During Exceptional circumstances
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed.
The following changes in study conduct will not be considered protocol deviations.
1.
Remote visits
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits.
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an exceptional 
circumstance if written approval is provided by the sponsor. Procedures on the SoA may be
performed at such visits.
Other alternative locations: Other procedures may be done at an alternate location in 
exceptional circumstances.
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. Furthermore, every effort should 
be made to enable participants to return to on-site visits as soon as reasonably possible, while 
ensuring the safety of both the participants and the site staff.
2.
Local laboratory testing option
Local laboratory testing may be conducted in lieu of central laboratory testing with sponsor approval. 
However, central laboratory testing must be retained whenever possible for all visits where central 
laboratory testing is required. The local laboratory must be qualified in accordance with applicable 
local regulations.
3.
Study intervention and ancillary supplies (including participant diaries)
When a participant is unable to go to the site to receive study supplies during normal on-site visits, 
the site should work with the sponsor to determine appropriate actions. These actions may include: 

asking the participant to go to the site and receive study supplies from site staff without 
completion of a full study visit, 

asking the participant’s designee to go to the site and receive study supplies on a participant’s 
behalf, and

arranging delivery of study supplies


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These requirements must be met before action is taken:

Alternate delivery of study intervention should be performed in a manner that ensures product 
integrity. The existing protocol requirements for product accountability remain unchanged, 
including verification of participant’s receipt of study supplies.

When delivering supplies to a location other than the study site (for example, participant’s 
home), the investigator, sponsor, or both should ensure oversight of the shipping process to 
ensure accountability and product quality (that is, storage conditions maintained and intact 
packaging upon receipt).

Instructions may be provided to the participant or designee on the final disposition of any 
unused or completed study supplies.
4.
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken at 
screening visit(s) are valid for a maximum of 28 days as outlined in the study protocol. The following 
rules will be applied for active, nonrandomized participants who have signed informed consent and 
are undergoing screening procedures but whose participation in the study must be paused due to 
exceptional circumstances:

If the screening period lasts for more than 42 days due to exceptional circumstances: The 
participant must be discontinued because of screening interruption due to an exceptional 
circumstance. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. The screening procedures per the usual SoA 
should be followed, starting at screening visit(s) to ensure participant eligibility by Cycle 1 
Day 1. 
5.
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should follow the visit windows described in the SoA. To maximize the possibility that these 
visits can be conducted as on-site visits, the windows for visits may be adjusted, upon further 
guidance and approval from the sponsor. This minimizes missing data and preserves the intended 
conduct of the study.
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.
Documentation
Changes to study conduct will be documented:

Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site 
study records.

Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and 
timely manner. 


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10.9
Appendix 9: Abbreviations
Term
Definition
AE
adverse event
AESI
adverse events of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BCT
breast conservation treatment
CAP
College of American Pathologists
CDK
cyclin-dependent kinase
CDK 4&6
cyclin-dependent kinases 4 & 6
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Complaint
A complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, purity, durability, reliability, safety or 
effectiveness, or performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable 
regulatory requirements.
CRP
clinical research physician: Individual responsible for the medical conduct of the 
study. Responsibilities of the CRP may be performed by a physician, clinical 
research scientist, global safety physician or other medical officer.
CRS
clinical research scientist
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome p450
DSMT
Developmental Safety Management Team
DSST
Developmental Safety Surveillance Team


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ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in 
the study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form 
directly or through their legally acceptable representatives.
ER
estrogen receptor
ET
endocrine therapy
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GnRH
gonadotropin-releasing hormone
HER2-
human epidermal growth factor receptor 2 negative
HR+
hormone receptor positive
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committees
IHC
immunohistochemistry
ILD
Interstitial lung disease
Interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment 
groups, that is conducted before the final reporting database is created/locked.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, 
or marketed products used for an unauthorized indication, or marketed products 
used to gain further information about the authorized form.


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IRB
Institutional Review Boards
IV
intravenous
IWRS
interactive web response system
MBC
metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
NSAIs
nonsteroidal aromatase inhibitors
ORR
objective response rate
OS
overall survival
Participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical 
trial, either as recipient of an investigational medicinal product or as a control
PFS
progression-free survival
Rb
retinoblastoma
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical study
SoA
schedule of activities
ULN
upper limit of normal
VTE
venous thromboembolic events


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11.
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experience from Southern India. Indian J Cancer. 2011;48(4):415-422.


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MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2-
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SAP_001.pdf: 
 
I3Y-IN-JPEC Statistical Analysis Plan (Version 1) 
 
 
A Single-Arm, Phase 4 Study of Abemaciclib, a CDK4 and CDK6 
Inhibitor, in Combination With Endocrine Therapy 
(Anastrozole/Letrozole or Fulvestrant) in Participants With Hormone 
Receptor Positive, Human Epidermal Growth Factor Receptor 2 
Negative Locally Advanced and/or Metastatic Breast Cancer in India 
 
 
NCT04707196 
 
 
Approval Date: 08-Feb-2021 


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STATISTICAL ANALYSIS PLAN 
 
Protocol title: A Single-Arm, Phase 4 Study of Abemaciclib, a CDK4 and CDK6 
Inhibitor, in combination with Endocrine Therapy (Anastrozole/Letrozole or 
Fulvestrant) in Participants with Hormone Receptor Positive, Human Epidermal 
Growth Factor Receptor 2 Negative Locally Advanced and/or Metastatic Breast 
Cancer in India 
Protocol number: I3Y-IN-JPEC 
Applicable Protocol Version: V1.0 
Author: 
Internal reviewer(s): 
Sponsor representative(s): 
 
Revision history: NA 
Date: NA 
 
The layout of this document is based on the Guideline on the International 
Conference on Harmonization (ICH E9). 
 
 
 
PPD
PPD
PPD


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TABLE OF CONTENTS 
Signature page ........................................................................................................ 5 
Glossary of abbreviations ...................................................................................... 6 
1. 
Overview ............................................................................................................ 7 
1.1 
Introduction ................................................................................................. 7 
2. 
Trial objectives ................................................................................................... 8 
2.1 
Primary objectives ....................................................................................... 8 
2.2 
Secondary objectives .................................................................................. 8 
3. 
Endpoints ........................................................................................................... 9 
3.1 
Primary endpoints ....................................................................................... 9 
3.2 
Secondary endpoints .................................................................................. 9 
4. 
Trial design ...................................................................................................... 10 
4.1 
Design overview ........................................................................................ 10 
4.2 
Schedule of events .................................................................................... 10 
5. 
Changes/deviations from the planned analysis................................................. 11 
6. 
Analysis populations ........................................................................................ 12 
6.1 
Entered Population .................................................................................... 12 
6.2 
Safety Population ...................................................................................... 12 
7. 
General considerations .................................................................................... 13 
7.1 
Visit and date conventions ........................................................................ 13 
7.2 
Baseline .................................................................................................... 13 
7.3 
Stratifications ............................................................................................ 13 
7.4 
Statistical tests .......................................................................................... 14 
7.5 
Common calculations ................................................................................ 14 
7.6 
Software .................................................................................................... 14 
8. 
Statistical considerations .................................................................................. 15 
8.1 
Multicentre studies .................................................................................... 15 
8.2 
Missing data .............................................................................................. 15 
9. 
Output presentations ........................................................................................ 16 


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10. 
Participant disposition and withdrawal .......................................................... 17 
10.1 
Variables and derivations .......................................................................... 17 
10.2 
Analysis .................................................................................................... 18 
11. 
Participant demographics and other baseline characteristics ........................ 19 
11.1 
Variables and derivations .......................................................................... 19 
11.2 
Analysis .................................................................................................... 19 
12. 
Exposure to Study Intervention ..................................................................... 20 
12.1 
Variables and derivations .......................................................................... 20 
12.2 
Analysis .................................................................................................... 20 
13. 
Study Intervention compliance ...................................................................... 21 
13.1 
Variables and derivations .......................................................................... 21 
13.2 
Analysis .................................................................................................... 21 
14. 
Extent of Exposure ....................................................................................... 22 
15. 
Medical and treatment history ....................................................................... 23 
15.1 
Variables and derivations .......................................................................... 23 
15.2 
Analysis .................................................................................................... 23 
16. 
Prior, concomitant and other medications ..................................................... 24 
16.1 
Variables and derivations .......................................................................... 24 
16.2 
Analysis .................................................................................................... 24 
17. 
Adverse events ............................................................................................. 25 
17.1 
Variables and derivations .......................................................................... 25 
17.2 
Analysis .................................................................................................... 27 
18. 
Safety laboratory tests .................................................................................. 28 
18.1 
Variables and derivations .......................................................................... 28 
18.2 
Analysis .................................................................................................... 28 
19. 
Vital signs ..................................................................................................... 29 
19.1 
Variables and derivations .......................................................................... 29 
19.2 
Analysis .................................................................................................... 29 


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20. 
Primary safety assessments ......................................................................... 30 
20.1 
Variables and derivations .......................................................................... 30 
20.2 
Analyses ................................................................................................... 30 
20.2.1 
Primary analysis ................................................................................. 30 
20.2.2 
Sensitivity analyses ............................................................................ 30 
21. 
Secondary safety assessments .................................................................... 31 
21.1 
Variables and derivations .......................................................................... 31 
21.2 
Analyses ................................................................................................... 31 
21.2.1 
Secondary analysis ............................................................................ 31 
22. 
Other assessments ....................................................................................... 32 
23. 
Revision history ............................................................................................ 33 
24. 
Appendix 1: Programming Conventions for Tables, Data Listings and Figures 
(TLFs) 34 
24.1 
Paper Size, Orientation and Margins ......................................................... 34 
24.2 
Fonts ......................................................................................................... 34 
24.3 
Header Information ................................................................................... 34 
24.4 
Table and Data Listing Table, Listing and Figure (TLF) Conventions ........ 35 
24.4.1 
General .............................................................................................. 35 
24.4.2 
Univariate statistics ............................................................................ 36 
24.4.3 
Frequencies and percentages [n, (m) and %] ..................................... 36 
24.4.4 
Confidence intervals (CIs) .................................................................. 37 
24.4.5 
Spacing .............................................................................................. 37 
24.4.6 
Missing values ................................................................................... 37 
24.5 
Figure output conventions ......................................................................... 37 
24.6 
Dates and times ........................................................................................ 37 
24.7 
Spelling format .......................................................................................... 37 
24.8 
Presentation of cohorts ............................................................................. 37 
24.9 
Presentation of visits ................................................................................. 38 
25. 
Appendix 2: Partial date conventions and TEAE derivation guidelines .......... 39 


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Signature page 
PPD


 
PPD


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Glossary of abbreviations 
 
ABBREVIATION 
DESCRIPTION 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
CDK  
Cyclin-Dependent Kinase 
CDK 4&6  
Cyclin-Dependent Kinases 4 & 6 
CI 
Confidence interval 
CV 
Coefficient of variation 
DBL 
Database lock 
eCRF 
Electronic case report form 
HER2-  
Human Epidermal Growth Factor Receptor 2 negative 
HR+  
Hormone Receptor Positive 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational product 
MedDRA 
Medical dictionary for regulatory activities 
N 
Sample size 
ODS 
Output delivery system 
Participant 
Equivalent to CDISC term “subject”: an individual who 
participates in a clinical trial, either as recipient of an 
investigational medicinal product or as a control 
PT 
Preferred term 
RTF 
Rich text format 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
TEAEs 
Treatment-emergent adverse events 
TLFs 
Tables, data listings and figures 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
 
 
 


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1. 
Overview 
1.1 
Introduction 
This document describes the rules and conventions to be used in the presentation 
and analysis of data from clinical trial I3Y-IN-JPEC titled “A Single-Arm, Phase 4 
Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, in combination with Endocrine 
Therapy (Anastrozole/Letrozole or Fulvestrant) in Participants with Hormone 
Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Locally 
Advanced and/or Metastatic Breast Cancer in India” 
This statistical analysis plan (SAP), is based on protocol I3Y-IN-JPEC, V1.0, dated 
20-Jan-21. 
 
 


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2. 
Trial objectives 
The following objectives are those stated in the protocol. 
2.1 
Primary objectives 
 
To characterize the safety of abemaciclib in combination with ET 
(anastrozole/letrozole or fulvestrant) 
2.2 
Secondary objectives 
 
To evaluate incidence of treatment discontinuation of abemaciclib 
 
 


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3. 
Endpoints 
The following endpoints are those stated in the protocol. 
3.1 
Primary endpoints 
 
TEAEs (including SAE and AESI) by per CTCAE criteria version 5.0 
3.2 
Secondary endpoints 
 
Discontinuation of abemaciclib only, due to an AE 
. 
 
 
 


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4. 
Trial design 
4.1 
Design overview 
This is a Phase 4, single-arm, cohort study of abemaciclib in combination with either 
a NSAI (anastrozole or letrozole) or fulvestrant, in patients with HR+, HER2- locally 
advanced and/or MBC. This study is designed to characterize the safety of 
abemaciclib plus ET in Indian patients. 
Participants receiving initial endocrine-based therapy for advanced/MBC will be 
assigned 
to 
cohort 
A 
to 
receive 
abemaciclib 
in 
combination 
with 
anastrozole/letrozole. 
Participants 
who 
have 
received 
prior 
ET 
in 
the 
advanced/metastatic setting or relapsed while on/or within 1 year after ET in the 
adjuvant setting, will be assigned to cohort B to receive abemaciclib in combination 
with fulvestrant. To evaluate the safety of abemaciclib in combination with 
anastrozole/letrozole or fulvestrant, AEs will be assessed throughout the study and 
the clinical safety laboratory will be assessed on day 1 and 14 in the first 2 cycles 
and then day 1 every 28 days in the 4 subsequent cycles. Participants will continue 
treatment for a total duration of 6 cycles or less in case of radiographic or clinical 
progression as per investigator’s judgment or another discontinuation criterion has 
been met. Participants who complete the study after 6 cycles of treatment may 
continue to receive abemaciclib (for example, through a patient support program) as 
per investigators discretion. 
 
4.2 
Schedule of events 
Please refer to section 1.3 of the study protocol. 
 
 


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5. 
Changes/deviations from the planned analysis 
Not applicable. 


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6. 
Analysis populations 
6.1 
Entered Population 
This analysis population will include all participants who sign the informed consent 
form.  
6.2 
Safety Population 
This analysis population will include all participants assigned to study intervention 
and who take at least 1 dose of study intervention. Participants will be analysed 
according to the intervention they actually received.  


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7. 
General considerations 
7.1 
Visit and date conventions 
No visit windowing (i.e., remapping of visits based on visit windows) will be 
performed for this trial. In the situation where the assessment/event date is partial or 
missing in any cycle, and any corresponding durations will appear missing in the data 
listings. Unscheduled measurements will not be included in cohort wise summaries. 
Data listings will include scheduled, unscheduled, retest and early discontinuation 
data. Trial visit will be assigned as delineated in Table 7.1: 
Table 7.1: Trial visit assignment schedule 
Study 
phases 
Screening 
On treatment cycle duration = 28 
days 
End 
of 
Visit 
Post-
Treatment 
follow up 
Baseline 
Cycle 1 
Cycle 2 
Cycle 
3 to 6 
Cycle 
6 
Short-Term 
Follow-Up b 
Relative 
Day within 
Dosing 
Cycle & 
Visit 
Window 
(±n days) 
≤28 
≤14 
D1 
(±3) 
D15 
(±3) 
D1 
(±3) 
D15 
(±3)  
D1 
(±3) 
D28 
(±3) 
V801 
 (30 days +7) 
 
7.2 
Baseline 
Baseline is defined as the last non-missing observation made prior to the first 
administration of study intervention. 
7.3 
Stratifications 
For analysis purposes, trial participants may be sub-classified into the following 
stratification levels, where applicable: 
 
Cohort 
o Cohort A: abemaciclib 150 mg twice daily (BD) plus either anastrozole 
or letrozole 
o Cohort B: abemaciclib 150 mg BD plus fulvestrant 
 
 


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7.4 
Statistical tests 
The default significance level for this trial is set at 5%. All 95% confidence intervals 
(CIs) and statistical tests will be two-sided. 
7.5 
Common calculations 
For quantitative measurements, change from baseline will be calculated as: (Test 
value at Visit Day X – Baseline value), where the baseline value is defined as the last 
non-missing observation taken prior to first exposure to study intervention. 
7.6 
Software 
All analyses will be conducted using SAS® Version 9.4. 
 
 


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8. 
Statistical considerations 
8.1 
Multicentre studies 
Not applicable. 
8.2 
Missing data 
Missing data is assumed to be missing and no imputation will be performed. Partial 
date imputation will be performed for the adverse events data.  
 


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9. 
Output presentations 
Summary tables will be stratified by cohorts. 
The templates provided in the separate output templates document describe the 
format and content for presentation of tables, listings and figures (TLFs). 
All percentages (%) for a summary are calculated using the total number of 
participants in the safety population as the denominator. 
Data listings will be based on safety population. 
Descriptive statistics for quantitative measurements will include the number of 
participants (n), mean, standard deviation (SD), minimum, median and maximum. 
 
 
 


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10. 
Participant disposition and withdrawal 
10.1 
Variables and derivations 
End of trial classifications are defined as follows: 
 
Screening failure:  
Screen failures are defined as participants who consent to participate in the 
clinical study but are not subsequently enrolled in the study.    
 
Study completer:  
The study completer is defined as the participant completed 6 cycles of study 
intervention. 
 
Lost to follow-up:  
A participant will be considered lost to follow-up if she repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site 
 
The following parameters will be summarised for the patient disposition table.  
 
No. of participants in entered population 
 
No. of participants in safety population 
 
No. of participants who completed the study 
 
No. of subjects who discontinued from the study 


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The following parameters will be summarised for the patient discontinuation table as 
per eCRF Patient’s primary reason for discontinuation (reasons mentioned in eCRF 
treatment discontinuation form) which are as follows: 
 
Progressive disease 
 
Adverse event 
 
Death 
 
Withdrawn by subject 
 
Physician decision 
 
Non-compliance with study drug 
 
Protocol deviation 
 
Study terminated by IRB or ERB 
 
Study terminated by sponsor 
 
Lost to follow-up 
 
Pregnancy  
10.2 
Analysis 
Participant disposition and withdrawals (obtained from the 143 page of eCRF) will be 
summarized and presented in data listings for the entered population. 
In participants’ disposition table, the entered participants and treated patients will be 
summarised (frequency) by total. Rest of the categories (e.g., completed patients, 
discontinued patients etc.) will be summarised (frequency and percentage) by 
stratification factor. The listing will be provided for the participant disposition status. 


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11. 
Participant demographics and other baseline characteristics 
11.1 
Variables and derivations 
The following demographic and other baseline characteristics will be summarized by 
cohort: 
 
Age (Years) (Calculated relative to date of informed consent) 
 
Sex 
 
Race 
 
Weight 
 
Height 
 
BMI 
 
ECOG status 
 
Disease duration in months 
 
Initial Pathological Diagnosis 
 
Disease Stage 
Age (Years) and BMI (kg/m2) will be calculated as follows: 
 
𝐴𝑔𝑒 (𝑌𝑒𝑎𝑟𝑠) = [
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑖𝑛𝑓𝑜𝑟𝑚𝑒𝑑 𝑐𝑜𝑛𝑠𝑒𝑛𝑡 – 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑏𝑖𝑟𝑡ℎ
365.25
] 
 
𝐵𝑀𝐼 (𝑘𝑔/𝑚2) = 
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
[ℎ𝑒𝑖𝑔ℎ𝑡 (𝑚)]2 
 
Age Categories: 
 
Age <65 years 
 
Age ≥ 65 years 
 
11.2 
Analysis 
Demographics and other baseline characteristics variables will be summarized by 
stratification factor. Overall summaries will include descriptive statistics for 
continuous measures (n, missing frequency, mean, standard deviation, median, 
minimum, and maximum…etc.) and for categorical measures (frequency, missing 
frequency and percent). Listing will be provided for safety population. 
 


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12. 
Exposure to Study Intervention 
12.1 
Variables and derivations  
The date of first study intervention administration will be derived as the first date of 
dosing from the study intervention administration eCRF page. The date of last study 
intervention administration will be derived as the date of last dose of study 
intervention from the subject disposition eCRF page. If this date is not available, then 
the date of last study intervention administration will be derived as the last date of 
dosing from the study intervention administration eCRF page. 
Interruptions, compliance, and dose changes will not be considered for calculating 
the duration of exposure, which will be derived as follows: 
Duration of exposure (weeks) for oral study drug = (Date of last study intervention 
administration- Date of first intervention administration +1)/7 
Duration of exposure (weeks) for Fulvestrant study drug = (Date of last study 
intervention administration + planned cycle length - Date of first intervention 
administration +1)/7 
 
 
12.2 
Analysis 
Exposure to study intervention will be summarized and listed for the safety 
population. 
 
 
 


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13. 
Study Intervention compliance 
13.1 
Variables and derivations  
The actual total number of tablets/capsules administered for each IMP will be 
obtained from the drug accountability eCRF page. 
The expected number of tablets/capsules administered for each study intervention is 
described in Section 9.4.2.4 of the protocol. The expected number of 
tablets/capsules administered for each study intervention only applies for days the 
participant was dosed (as per study intervention exposure eCRF page). the 
compliance will be done for oral drug only. 
The estimate of percent compliance for oral drug will be given by: 
Percent Compliance = (Actual cumulative dose taken / Expected cumulative dose to 
be taken) X 100 
The actual cumulative dose taken will be determined based on counting the number 
of capsules/tablets returned at each visit and subtracting that number from the 
number of capsules/tablets dispensed. The expected cumulative dose to be taken 
will be determined based on the assigned dose and taking into account any dose 
reductions or omissions. 
 
13.2 
Analysis 
Overall treatment compliance to study intervention will be summarized and listed for 
the safety population by each cohort.  


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14. 
Extent of Exposure 
For abemaciclib/letrozole or anastrozole, extent of exposure will be measured by pill 
counts and summarized by cumulatively. The summary will include total dosage 
taken, number of cycles taken and dose intensity. Dose intensity will be calculated as 
the ratio of total dose taken to the assigned cumulative dose. For example, the 
assigned cumulative dose for each patient during each cycle is 150 mg per dose × 2 
doses per day × 28 days = 8400 mg. The assigned cumulative dose while on study is 
150 mg per dose × 2 doses per day × number of days on treatment. 
For letrozole or anastrozole the cumulative dose will be calculated same way as per 
prescribing information. 
For fulvestrant, extent of exposure will be measured using the fulvestrant 
administration eCRF and summarized by cycle and cumulatively. The summary will 
include total dosage administered and dose intensity. Dose intensity will be 
calculated as the ratio of total dose administered to the assigned cumulative dose. 
The cumulative dose will be calculated same way as per prescribing information. 
Dose adjustments and omissions, along with the reason for adjustment or omission, 
will be summarized for abemaciclib/ letrozole or anastrozole and fulvestrant. 


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15. 
Medical and treatment history 
15.1 
Variables and derivations 
Medical history will be coded using the CTCAE grade, Version 5.0. 
The following grade categories will be summarised for the patient’s Medical history 
as mentioned in eCRF: 
 
Grade 1; Mild 
 
Grade 2; Moderate 
 
Grade 3; Severe 
 
Grade 4; Life threatening   
15.2 
Analysis 
Medical history will be summarized (frequency and percentage) for each cohort, by 
CTCAE grade for the safety population. Medical history will be presented as data 
listings for the safety population. 
 
 
 


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16. 
Prior, concomitant and other medications 
16.1 
Variables and derivations 
Prior medications are defined as medication taken prior to first administration of the 
study intervention. 
Concomitant medications are defined as any medication taken after or on the first 
administration of the study medication till the end of the trial or any medication taken 
prior to the first treatment administration and having “ONGOING” status at the first 
administration of the study medication.  
16.2 
Analysis 
Prior, concomitant medication will be summarized and listed for safety population.  


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17. 
Adverse events 
17.1 
Variables and derivations 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, 
Version 25.0x or higher. 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
An adverse event (AEs) is any undesirable sign, symptom or medical condition 
occurring after the patient signs the Informed Consent Form, even if the event is not 
considered to be treatment related. Each adverse event is to be recorded on the 
appropriate Adverse Event eCRF page. Adverse events will be graded. The severity 
grade will be estimated using a scale of mild (grade 1), moderate (grade 2), severe 
(grade 3), Life-threatening (grade 4) and Death related to AE (grade 5). 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (for example, hospitalization for signs/symptoms of the disease 
under study, death due to progression of disease). 
Treatment-emergent adverse events (TEAEs) are defined as AEs that started at the 
time of, or after the, first study medication administration as well as those events that 
started prior to the first study drug administration, but which worsened after the first 
study medication administration. 
Adverse Events will be assessed by Investigator for causal relationship to the study 
mediation. The relationship between an AE and the study medication will be 
determined by the Investigator on the basis or his/her medical/ pharmacological 
knowledge and clinical judgment and using the categories yes or no.  
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Life threatening  
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
4. Results in persistent disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Other 
 


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Imputations will only be performed where at least the year is provided. The 
imputations derived for partial dates will be as follows: 
 
Missing days will default to the first of the month for start dates and the last 
day of the month for stop dates. 
 
Missing months will default to the first month (January) for start dates and to 
the last month (December) for stop dates. 
 
There will be no default for a missing year field.   
In Appendix 2 the algorithm is given for calculation of partial date imputation for 
adverse events (AEs) and it will be used for partially missing adverse event start 
and end date imputation. 
The following parameters will be summarised for the patients overall adverse 
events as mentioned in eCRF  
 
Patients with at least one TEAEs  
 
Patients with at least one drug related TEAE  
 
Patients with at least one serious AEs 
 
Patients with at least one drug related serious AEs   
 
TEAEs/ related to study medication TEAEs by maximum CTCAE severity 
grade 
 
TEAEs by Causal Relationship to study medication  
 
TEAEs leading to death  
 
TEAEs /related to study medication TEAEs   
 
SAEs 
 
Drug-related TEAEs leading to death   
 
TEAEs leading to patient discontinuation from study 
 
Deaths on study 
 
Deaths within 30 days of treatment discontinuation or within 30 days of 
last dose. 
The following AEs are considered to be AESIs for abemaciclib: 
 
neutropenia 
 
infections 
 
diarrhoea 


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 
hepatic events, including increases in AST and ALT 
 
venous thromboembolic events (VTEs), and 
 
ILD/pneumonitis 
Note: All above parameters will be summarised as well for the patients 
overall adverse events of special interest. 
17.2 
Analysis 
 
All the Adverse events tables will be summarised as number of patients 
with an event as well as percentage (%) patients with an event. The 
overall TEAEs tables will be presented by cohort for safety population. 
Separate listing for AEs and SAEs will be provided with TEAEs flag 
variable by cohort and participant. A data listing with all TEAEs (including 
coding details [SOC and PT only]) will be presented. The TEAE listing 
may include details but not limited to AE outcome, start date, stop date, 
seriousness criteria for SAEs. 
  


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18. 
Safety laboratory tests 
All required variables for listing will be captured from the central lab (Clinical 
Laboratory Assessments (Haematology, Clinical chemistry, Pregnancy test, 
Postmenopausal Confirmation Testing)). 
18.1 
Variables and derivations 
For safety laboratory data, baseline will be defined as the last observation made prior 
to the first administration of study intervention.  
The following laboratory tests will be captured via central labs and to be included in 
the analysis: 
 
Haematology 
 
Clinical chemistry  
 
FSH and Estradiol (As applicable i.e. only required for women <55 years of 
age) 
Quantitative laboratory measurements reported as “< X”, i.e., below limit of 
quantitation, or “> X”, i.e., above the upper limit of quantification, will be converted to 
X for quantitative summaries, but will be presented as recorded, i.e., as “< X” or “> X” 
in the data listings. 
18.2 
Analysis 
The safety population alone will be used to analyse safety laboratory data. 
 
Grading for Safety laboratory results will be performed according to table 1.3 
of the protocol. Summaries of haematology, clinical chemistry and FSH and 
Estradiol testing for each cohort, by cycles, will include descriptive statistics of 
the following: 
 
Actual and change from baseline (for quantitative measurements) 
 
Frequencies and percentages (n and %) (for qualitative measurements) 
Listings will be provided for laboratory parameters by each cohort. Listing of 
abnormal lab values with upper and lower limit will be produced. 
 
 


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19. 
Vital signs 
All summaries for vital signs will be based on the safety population. Data listings for 
the vitals will be based on the safety population. 
19.1 
Variables and derivations 
For vital signs, baseline is defined as the last observation made prior to the first 
administration of study intervention. 
The following vital signs will be reported for this study: 
 
Systolic blood pressure (mmHg) 
 
Diastolic blood pressure (mmHg) 
 
Pulse rate 
19.2 
Analysis 
The following summaries will be provided for vital signs data for each cohort, by days 
(cycles): 
 
Actual and change from baseline by cycles. 
 
 


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20. 
Primary safety assessments 
The primary endpoint parameter is mention below. 
20.1 
Variables and derivations 
The following variables will be reported for this study: 
 
TEAEs, including severity in CTCAE grade and possible relationship to study 
intervention  
 
SAEs, including possible relationship to study intervention  
 
 Discontinuations from study treatment due to TEAEs 
20.2 
Analyses 
20.2.1 
Primary analysis 
Note: TEAEs including SAEs and AESIs related endpoint covered in Section 16 
(Adverse event). 
20.2.2 
Sensitivity analyses 
Not applicable 


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21. 
Secondary safety assessments 
To evaluate incidence of treatment discontinuation of abemaciclib 
21.1 
Variables and derivations 
The following variables will be reported for this study: 
 
Discontinuation of abemaciclib only due to an TEAE 
𝐼𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑅𝑎𝑡𝑒=
𝑁𝑜.𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠  𝑤𝑖𝑡ℎ 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑖𝑠𝑐𝑜𝑛𝑡𝑖𝑛𝑢𝑎𝑡𝑖𝑜𝑛 𝑜𝑛𝑙𝑦 𝑑𝑢𝑒 𝑡𝑜 𝑇𝐸𝐴𝐸
𝑁𝑜.𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡 𝑖𝑛 𝑠𝑎𝑓𝑒𝑡𝑦 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛
  
21.2 
Analyses 
21.2.1 
Secondary analysis  
Descriptive summary (frequency & percentage) will be provided by each cohort for 
discontinuation cases.  Data listings for these cases will be based on the safety 
population. 
 
 
 
 


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22. 
Other assessments 
The following assessments will only be presented in data listings for the safety 
population: 
 
Physical examination data 
 
Biopsy Assessment 
 
Hepatic Monitoring Procedures 
 
Hepatic Risk Factor Assessment 
 
Hospitalization Events 
 
Initial Pathological Diagnosis 
 
Liver Related Signs and Symptoms 
 
New Tumour Assessment 
 
Response Assessment 
 
Systemic and Loco regional Therapies 


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23. 
Revision history 
Version 
Date 
Change 
 
 
 
 
 
 


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24. 
Appendix 1: Programming Conventions for Tables, Data Listings and 
Figures (TLFs) 
24.1 
Paper Size, Orientation and Margins 
The margin, page size and line size specifications as stipulated in Table 23.1 will be 
used for the presentation of all TLFs. 
Table 23.1: Output margin, page size and line size specifications 
 
Landscape 
Portrait 
Margins (Inches): 
Top  
Bottom 
Left 
Right 
 
1.25 
1 
1 
1 
 
1 
1 
1.25 
1 
Header (Inches) 
0.5 
0.5 
Footer (Inches) 
0.5 
0.5 
SAS® specifications: 
PAGESIZE 
LINE SIZE 
 
46 
134 
 
67 
93 
24.2 
Fonts 
The font type “Courier New” should be used as default for tables and data listings, 
with a font size of 8. The font color should be black. No bolding, underlining and 
italics are permitted. 
Figures should have a default font of “Times Roman”, “Helvetica” or “Courier New”. 
24.3 
Header Information 
Headers should be defined as follows: 
 
The header should be placed at the top of the page (same place on each page). 
 
The sponsor name should appear in row 1, left-aligned. 
 
The word “CONFIDENTIAL” should appear in row 1, right-aligned. 
 
The protocol number should appear in row 2, left-aligned. 


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 
The page identification in the format Page X of Y (where Y is the total number of 
pages for the TLF) should appear in row 2, right-aligned. 
 
The TLF identification number should appear in row 3, centered. 
 
The TLF title should start in row 4, centered. 
 
The TLF population should appear in row 5, centered. The population should be 
spelled out in full, e.g. Safety analysis population in preference to Safety analysis 
population. 
 
Row 6 should be a continuous row of underscores (‘_’) (the number of 
underscores should equal the line size). 
 
Row 7 should be a blank line. 
 
Mixed case should be used for titles. 
 
Titles should not contain quotation marks or footnote references. 
 
The column headings should be underlined with a row of underscores (‘_’). 
 
Column headings spanning more than one column should be underlined and 
have underscores on either side of the title and should be centered. 
 
Column headings containing numbers should be centered. 
 
Column headings should be in mixed case. 
 
In general, the analysis population count should appear in the column header in 
the form “(N=XX)”. 
24.4 
Table and Data Listing Table, Listing and Figure (TLF) Conventions 
24.4.1 
General 
 
The first row in the body of the table or data listing should be blank. 
 
The left-hand column should start in Column 1. No indenting or centering of the 
TLF should occur. 
 
Rounding should be done with the SAS® function ROUND. 
 
Numerical values in tables should be rounded, not truncated. 
 
Numerical values should be decimal point aligned. 
 
Text values should be left aligned. 
 
The first letter of a text entry should be capitalized. 
 
The study drug should appear first in tables with treatment group as columns. 
 
All variables contained on the eCRF (which have data present) should appear in 
the data listings, along with all derived data appearing in the corresponding 
tables. 


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 
The width of the TLF should match the line size. 
24.4.2 
Univariate statistics 
 
Statistics should be presented in the same order across tables (i.e., n, mean, SD, 
minimum, median and maximum). 
 
If the original data has N decimal places, then the summary statistics should have 
the following decimal places: 
o Minimum, maximum and CV (%): N.= 2 
o Mean and median: N + =2. 
o SD: N + 2. 
 
24.4.3 
Frequencies and percentages [n, (m) and %] 
 
Mentions should be reported inside parentheses, with one space between the 
count and the left parenthesis of the mentions. An example is given below: 
o 124 (645) 
 
 
Percent values should be reported inside parentheses, with one space between 
the right parenthesis of the mention and the left parenthesis of the percentage. 
Parentheses should be justified to accept a maximum of 100.0 as a value and 
padded with blank space if the percent is less than 100.0. An example is given 
below: 
o 77 (156) (100.0) 
o 50 (56) (64.9) 
o 0 (0) (0.0) 
 
 
Percentages will be reported to one decimal place, except percentages <100.0 
but >99.9 will be presented as ‘>99.9’ (e.g., 99.99 is presented as >99.9); and 
percentages <0.1 will be presented as ‘<0.1’ (e.g., 0.08 is presented as <0.1). 
Rounding will be applied after the <0.1 and >99.9 rule. 
o (<0.1) 
o ( 6.8) 
o (>99.9) 
 


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Statistical Analysis Plan 
 08-Feb-21 
V1 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 37 of 40 
 
Percentages may be reported to 0 decimal places as appropriate (for example, 
where the denominator is relatively small). 
 
 
Where counts are zero, mentions of 0 and percentages of 0.0 should appear in 
the table. 
24.4.4 
Confidence intervals (CIs) 
 
CIs should be presented with one additional decimal place as that of the raw 
data, and SDs and standard errors (SEs) with two additional decimal places as 
that of the raw data. 
 
CIs should be justified so that parentheses displayed on consecutive lines of a 
table “line up”. 
24.4.5 
Spacing 
 
There should be a minimum of 1 blank space between columns (preferably 2). 
24.4.6 
Missing values 
 
A “0” should be used to indicate a zero frequency. 
 
A blank will be used to indicate missing data in data listings. 
24.5 
Figure output conventions 
Figures should be provided in RTF files using the SAS® Output Delivery System 
(ODS). 
24.6 
Dates and times 
Depending on data available, dates and times will take the form ddMMMyyyy and hh: 
mm. 
24.7 
Spelling format 
The spelling format to be used is English US.  
24.8 
Presentation of cohorts 
 
Abemaciclib+ anastrozole or letrozole 


I3Y-IN-JPEC  
Statistical Analysis Plan 
 08-Feb-21 
V1 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 38 of 40 
 
Abemaciclib+ fulvestrant 
24.9 
Presentation of visits 
 
Baseline 
 
Cycle 1- Day 1 
 
Cycle 1- Day 15 
 
Cycle 2- Day 1 
 
Cycle 2- Day 15 
 
Cycle 3 to 6- Day 1 
 
Cycle 6- Day 28 
 
Short-Term Follow-Up  


I3Y-IN-JPEC  
Statistical Analysis Plan 
 08-Feb-21 
V1 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 39 of 40 
25. 
Appendix 2: Partial date conventions and TEAE derivation guidelines 
No date imputations will be done for this study. Conventions pertaining to partial dates are 
presented in Table 24.1. 
Table 24.1: Algorithm for Treatment-emergent Adverse Events (TEAEs) 
START DATE 
STOP DATE 
ACTION 
Known 
Known, partial 
or missing 
If start date < Study drug start date, then not TEAE. 
If start date > Study drug start date, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“no”, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“yes”, then not TEAE. 
 
 
 
Partial, but known 
components show 
that it cannot be on 
or after study drug 
start date 
Known, partial 
or missing 
Not TEAE. 
 
 
 
Partial, could be on 
or after study drug 
start date 
Known 
If stop date < Study drug start date, then not TEAE. 
If stop date > Study drug start date, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“no”, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“yes”, then not TEAE. 
Partial 
Assume stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if day 
and month are unknown), then: 
If stop date < Study drug start date, then not TEAE. 
If stop date > Study drug start date, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“no”, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“yes”, then not TEAE. 
Missing 
Assumed TEAE. 
 
 
 
Missing 
Known 
If stop date < Study drug start date, then not TEAE. 


I3Y-IN-JPEC  
Statistical Analysis Plan 
 08-Feb-21 
V1 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 40 of 40 
If stop date > Study drug start date, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“no”, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“yes”, then not TEAE. 
Partial 
Assume stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if day 
and month are unknown), then: 
If stop date < Study drug start date, then not TEAE. 
If stop date > Study drug start date, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“no”, then TEAE. 
If start date = Study drug start date and the variable 
“prior to first dose of study intervention” is equal to 
“yes”, then not TEAE. 
Missing 
Assumed TEAE.