Clinical trial NCT04408924
Conditions: Metastatic Castration-Resistant Prostate Cancer
Keywords: mCRPC CDK4 CDK6 CDK4/6 CDK4&6 inhibitor CDK4/6 inhibitor LY2835219 CYCLONE 1 CYCLONE1
Sponsor: Eli Lilly and Company
Start date: 2021-01-20; Completion date: 2023-06-02
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will evaluate how safe and effective abemaciclib is when given to participants whose metastatic prostate cancer progresses after they had received several previous treatments.

Detailed description:

Arms: arm 1: Participants received 200 mg abemaciclib administered orally twice daily on a continuous dosing schedule (28-day cycle) until symptomatic and/or radiographic progression, unacceptable toxicity, or until another discontinuation criterion is met.
Interventions: intervention 1: Abemaciclib
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol I3Y-MC-JPCY(b) 
CYCLONE 1: A Phase 2 Study of Abemaciclib in Metastatic Castration-Resistant 
Prostate Cancer Patients Previously Treated with a Novel Hormonal Agent and Taxane-
based Chemotherapy
NCT04408924   
Approval Date: 04-Mar-2021 


CONFIDENTIAL
I3Y-MC-JPCY(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: CYCLONE 1: A Phase 2 Study of Abemaciclib in Metastatic Castration-
Resistant Prostate Cancer Patients Previously Treated with a Novel Hormonal Agent and 
Taxane-based Chemotherapy
Protocol Number:  I3Y-MC-JPCY
Amendment: (b)
Compound: LY2835219
Study Phase: Phase 2
Short Title: Abemaciclib in Men with Heavily Treated Metastatic Castration-Resistant Prostate 
Cancer
Acronym: JPCY
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana, USA 46285
Regulatory Agency Identifier Number(s)
IND: 139694
EudraCT:  2020-000290-24
Approval Date: Protocol I3Y-MC-JPCY Electronically Signed and Approved by Lilly on 18-
Mar-2020
Protocol I3Y-MC-JPCY(a) Electronically Signed and Approved by Lilly on 24-Sep-2020
Protocol I3Y-MC-JPCY(b) Electronically Signed and Approved by Lilly on date provided below
Approval Date: 04-Mar-2021 GMT


CONFIDENTIAL
I3Y-MC-JPCY(b)
2
Medical Monitor Name and Contact Information will be provided separately.
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment (a)
24-Sep-2020
Protocol I3Y-MC-JPCY
18-Mar-2020
Amendment (b)
This amendment is considered to be 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:
Protocol amendment(b) for Study JPCY protocol was amended to update the dose modification 
guidance and safety monitoring. These updates are in alignment with changes made in the 
development core safety information of the Investigator’s Brochure (IB).
In addition, minor editorial changes have been made throughout the protocol to improve clarity 
and practicability of the protocol. 
Section # and Name
Description of Change
Brief Rationale
1.3. Schedule of Activities
Added clarification to vital signs that 
procedure does not repeated on Cycle 1 
Day 1 if assessed at baseline ≤3 days prior 
to initiating abemaciclib
Addition
1.3.1. Sampling Schedule for 
Pharmacokinetics and 
Biomarkers
Deleted text from footnote b to align with 
Inclusion Criterion 9
Deletion
5.3. Lifestyle Considerations
Added ‘affect prostate specific antigen 
levels’ for participants who must not take 
preparations or herbal products and 
removed ‘endocrine effects’
Addition
6.2.1. Selection and Timing of 
Doses
Added language to discuss with Lilly 
CRP/CRS prior to dispensing additional 
study treatment
Addition
6.5. Concomitant Therapy
Updated language for CYP3A modulators 
and transporter substrates
Update to align with current 
guidance
6.6.2. Toxicity Dose Adjustments 
and Delays of Abemaciclib
Formatted table for dose adjustments and 
delays of abemaciclib
Formatting; to align with IB 
update
6.6.2. Dose Adjustments and 
Delays Abemaciclib
Added AST to the dose modification table 
for increased transaminases
To align with IB update
Removed VTE specific guidance for dose 
modifications to follow non-hematologic 
dose adjustment guidance
To align with IB update


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I3Y-MC-JPCY(b)
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8.2.2.2. Guidance for Monitoring 
Renal Function
Updated renal function monitoring 
language
To align with IB update
8.2.2.3. Guidance for Venous 
Thromboembolic Events
Updated VTE safety monitoring language
To align with IB update
8.2.2.4. Guidance for Interstitial 
Lung Disease/Pneumonitis
Updated ILD/pneumonitis safety 
monitoring language 
To align with IB update
9.2. Sample Size Determination 
and 
Editorial changes to clarify study statistics
Editorial
9.4.2 Primary Analysis
10.7. Appendix 7
Added ALT and AST to the CTCAE 5.0 
table and updated Appendix title and 
summary text to reflect these additions
Addition


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I3Y-MC-JPCY(b)
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Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................10
1.3.
Schedule of Activities (SoA) ......................................................................................11
1.3.1.
Sampling Schedule for Pharmacokinetics and Biomarkers..........................................22
2.
Introduction..............................................................................................................24
2.1.
Study Rationale ..........................................................................................................24
2.2.
Background ................................................................................................................25
2.2.1.
Prostate Cancer...........................................................................................................25
2.2.2.
Abemaciclib ...............................................................................................................26
2.3.
Benefit/Risk Assessment ............................................................................................27
2.3.1.
Benefit Assessment.....................................................................................................27
2.3.2.
Overall Benefit:  Risk Conclusion...............................................................................28
3.
Objectives and Endpoints.........................................................................................29
4.
Study Design .............................................................................................................31
4.1.
Overall Design............................................................................................................31
4.2.
Scientific Rationale for Study Design .........................................................................31
4.3.
Justification for Dose..................................................................................................32
4.4.
End of Study Definition..............................................................................................32
5.
Study Population ......................................................................................................33
5.1.
Inclusion Criteria........................................................................................................33
5.2.
Exclusion Criteria.......................................................................................................35
5.3.
Lifestyle Considerations .............................................................................................37
5.4.
Screen Failures...........................................................................................................37
6.
Study Intervention....................................................................................................38
6.1.
Study Intervention(s) Administered ............................................................................38
6.2.
Preparation/Handling/Storage/Accountability.............................................................38
6.2.1.
Selection and Timing of Doses ...................................................................................39
6.3.
Measures to Minimize Bias:  Randomization and Blinding .........................................39
6.4.
Study Intervention Compliance...................................................................................39
6.5.
Concomitant Therapy .................................................................................................39
6.5.1.
Supportive Care..........................................................................................................41
6.6.
Dose Modification......................................................................................................42
6.6.1.
Dose Reductions for Abemaciclib...............................................................................42
6.6.2.
Dose Adjustments and Delays Abemaciclib................................................................43
6.7.
Intervention after the End of the Study........................................................................44
6.7.1.
Study Completion.......................................................................................................44
6.7.2.
Continued Access .......................................................................................................45
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................46
7.1.
Discontinuation of Study Intervention ........................................................................46


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I3Y-MC-JPCY(b)
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7.2.
Participant Discontinuation/Withdrawal from the Study .............................................47
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................47
7.3.
Lost to Follow up .......................................................................................................48
8.
Study Assessments and Procedures .........................................................................49
8.1.
Efficacy Assessments .................................................................................................49
8.1.1.
Definitions of Efficacy Measures................................................................................49
8.1.2.
Appropriateness of Assessments.................................................................................52
8.2.
Safety Assessments ....................................................................................................52
8.2.1.
Clinical Safety Laboratory Assessments .....................................................................52
8.2.2.
Safety Monitoring.......................................................................................................53
8.2.3.
Safety Surveillance.....................................................................................................55
8.3.
Adverse Events and Serious Adverse Events ..............................................................56
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................57
8.3.2.
Method of Detecting AE and SAEs.............................................................................57
8.3.3.
Follow-up of AEs and SAEs.......................................................................................58
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................59
8.3.5.
Pregnancy...................................................................................................................59
8.3.6.
Adverse Events of Special Interest..............................................................................59
8.3.7.
Complaint Handling ...................................................................................................59
8.4.
Treatment of Overdose ...............................................................................................59
8.5.
Pharmacokinetics........................................................................................................60
8.5.1.
Patient Diary...............................................................................................................60
8.6.
Pharmacodynamics.....................................................................................................60
8.7.
Genetics .....................................................................................................................60
8.7.1.
Whole Blood Sample for Pharmacogenetic Research..................................................60
8.8.
Biomarkers.................................................................................................................61
8.8.1.
Tissue Samples for Biomarker Research.....................................................................61
8.8.2.
Other Samples for Biomarker Research ......................................................................62
8.9.
Immunogenicity Assessments.....................................................................................63
8.10.
Health Economics.......................................................................................................63
8.10.1.
Patient reported outcomes...........................................................................................63
8.10.2.
Health Care Resource Utilization................................................................................64
9.
Statistical Considerations.........................................................................................65
9.1.
Statistical Hypotheses.................................................................................................65
9.2.
Sample Size Determination.........................................................................................65
9.3.
Populations for Analyses ............................................................................................65
9.4.
Statistical Analyses.....................................................................................................66
9.4.1.
General considerations................................................................................................66
9.4.2.
Primary analysis .........................................................................................................66
9.4.3.
Secondary endpoint(s) ................................................................................................67
9.4.4.
Exploratory endpoint(s) ..............................................................................................67
9.4.5.
Other Safety Analyses ................................................................................................67
9.4.6.
Other Analyses ...........................................................................................................67
9.5.
Interim Analyses.........................................................................................................69
9.6.
Data Monitoring Committee (DMC)...........................................................................69


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I3Y-MC-JPCY(b)
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10.
Supporting Documentation and Operational Considerations ................................70
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................70
10.1.1.
Regulatory and Ethical Considerations........................................................................70
10.1.2.
Financial Disclosure ...................................................................................................70
10.1.3.
Informed Consent Process ..........................................................................................71
10.1.4.
Data Protection...........................................................................................................71
10.1.5.
Committees Structure .................................................................................................71
10.1.6.
Data Quality Assurance ..............................................................................................72
10.1.7.
Source Documents......................................................................................................73
10.1.8.
Study and Site Start and Closure.................................................................................73
10.1.9.
Investigator Information .............................................................................................74
10.2.
Appendix 2:  Clinical Laboratory Tests.......................................................................75
10.3.
Appendix 3:  Adverse Events:  Definitions, and Procedures for 
Recording, Evaluating, Follow-up and Reporting........................................................77
10.3.1.
Definition of AE.........................................................................................................77
10.3.2.
Definition of SAE.......................................................................................................78
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................79
10.3.4.
Reporting of SAEs......................................................................................................80
10.4.
Appendix 4:  Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................82
10.5.
Appendix 5:  Liver Safety:  Suggested Actions and Follow-up 
Assessments ...............................................................................................................84
10.6.
Appendix 6:  Inducers and Strong Inhibitors of CYP3A..............................................86
10.7.
Appendix 7: CTCAE 5.0 Diarrhea/Pneumonitis/ALT and AST 
Increased Definitions..................................................................................................87
10.8.
Appendix 8:  Abbreviations ........................................................................................88
10.9.
Appendix 9:  Protocol Amendment History ................................................................93
11.
References.................................................................................................................96


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I3Y-MC-JPCY(b)
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: CYCLONE 1:  A Phase 2 Study of Abemaciclib in Metastatic Castration-
Resistant Prostate Cancer Patients Previously Treated with a Novel Hormonal Agent and 
Taxane-based Chemotherapy
Short Title: Abemaciclib in Men with Heavily Treated Metastatic Castration-Resistant Prostate 
Cancer
Rationale:
Prostate cancer is the second most common cancer in men and the fifth leading cause of cancer 
deaths among men worldwide.  Despite the initial sensitivity of advanced prostate cancer to 
androgen-deprivation therapy, most patients eventually develop castration-resistance. Persistent 
or reactivated androgen receptor (AR) signaling and/or activation of pathways involved in 
crosstalk with AR signaling are key drivers of progression to metastatic castration-resistant 
prostate cancer (mCRPC), an incurable and lethal stage of the disease.
The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma protein (pRb)-axis is a critical 
modulator of cell cycle entry and is commonly altered in cancers.  Evidence suggests that AR 
signaling promotes enhanced translation of the D-type cyclins resulting in CDK4 and CDK6
(CDK4&6) activation, pRb hyperphosphorylation and cell cycle progression.
Abemaciclib is an oral and potent ATP-competitive inhibitor of CDK4&6 that is administered on
a continuous dosing schedule. Abemaciclib is approved by major global regulatory authorities
for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth 
factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in combination with an 
aromatase inhibitor as initial endocrine-based therapy and with fulvestrant following endocrine 
therapy.  In addition, abemaciclib is also approved as monotherapy for heavily pre-treated
(following endocrine therapy and chemotherapy) HR+, HER2- MBC patients by the Food and 
Drug Administration.
Preclinical studies in cell cultures and mouse xenograft prostate cancer models showed that 
single agent abemaciclib induces cell cycle arrest and tumor growth inhibition (data on file). The 
clinical activity of abemaciclib in combination with abiraterone and prednisone is currently 
investigated in a randomized placebo-controlled Phase 2 study in patients with mCRPC 
(I3Y-MC-JPCM [CYCLONE 2], NCT03706365).
Treatment of advanced prostate cancer is palliative and therapeutic options are limited for 
mCRPC patients whose disease had progressed after life-prolonging therapies. Hence, there is 
an important unmet need for these patients that warrants the development of therapies with novel 
mechanisms of action.
This open-label single-arm Phase 2 study will assess the safety and efficacy of abemaciclib 
monotherapy in heavily pretreated mCRPC patients who received at least 1 novel hormonal 
agent and 2 taxane regimens.


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I3Y-MC-JPCY(b)
8
Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the efficacy of 
abemaciclib monotherapy.

Investigator-assessed ORR per 
RECIST 1.1.
Secondary

To further characterize the clinical 
activity of abemaciclib monotherapy.

rPFS

OS

DoR

DCR

PSA response rate

Time to PSA progression

Time to symptomatic progression

To characterize the safety profile of 
abemaciclib.

Assessment of safety including, but 
not limited to, the following:  AEs, 
SAEs, physical examination, and 
clinical laboratory abnormalities per 
CTCAE v5.0

To explore patient reported tolerability 
of abemaciclib monotherapy 
(including symptomatic AEs and 
overall side-effect burden), patient 
reported pain intensity, physical 
functioning, and overall health related 
quality 

PRO-CTCAE 

FACT-GP5

7-day Worst Pain Numeric Rating 
Scale

EORTC QLQ-C30 Physical 
Functioning Scale

EORTC QLQ-C30 Global Health 
Status/QoL Scale

To characterize the PK of abemaciclib 
and its metabolites.

Concentrations of abemaciclib and its 
metabolites.

To characterize Ki-67 baseline 
expression

% of cells expressing Ki-67 by IHC


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I3Y-MC-JPCY(b)
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Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events v5.0 (NCI 
2017); DCR = disease control rate; DoR = duration of response; EORTC-QLQ-C30 = European Organization for 
the Research and Treatment of Cancer Quality of Life Questionnaire; FACT-GP5 = Functional Assessment of 
Cancer Therapy- General; IHC = immunohistochemistry; Ki-67 = protein encoded by the MKI67 gene;
ORR = objective response rate; OS = overall survival; PK = pharmacokinetics; PSA = prostate specific antigen; 
PRO-CTCAE = Patient Reported Outcome-Common Terminology Criteria for Adverse Events v5.0 (NCI 2017); 
QoL = quality of life; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1 (Eisenhauer et al; 
2009); rPFS = radiographic progression-free survival; SAE = serious adverse event.
Overall Design
CYCLONE 1 is an open-label, single-arm, global multi-center, Phase 2 study to assess the safety 
and efficacy of abemaciclib monotherapy in patients with mCRPC. 
The study population consists of patients with progressive mCRPC (by prostate-specific antigen 
[PSA] and/or imaging) who have previously received, in the metastatic hormone-sensitive setting
and/or in the castration-resistant settings, at least 1 novel hormonal agent (abiraterone acetate, 
apalutamide, darolutamide or enzalutamide), and 2 taxane regimens (docetaxel and cabazitaxel).
Number of Participants:
Approximately 40 participants with mCRPC will be treated in this study.
Intervention Groups and Duration:
Eligible participants will receive abemaciclib 200 mg orally twice daily on a continuous 28-day 
dosing schedule. Abemaciclib can be taken with or without food, at approximately the same 
times each day, with at least 6 hours between doses.
Data Monitoring Committee: No


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I3Y-MC-JPCY(b)
10
1.2.
Schema
Abbreviations: mCRPC = metastatic castration resistant prostate cancer; n = number of participants; OS = overall 
survival; PK = pharmacokinetics; PRO = patient reported outcome; PSA = prostate specific antigen; RECIST 1.1
= Response Evaluation Criteria in Solid Tumors version 1.1.; rPFS = radiographic progression-free survival.


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I3Y-MC-JPCY(b)
11
1.3.
Schedule of Activities (SoA)
This section includes the following SoAs:

Screening, On-Treatment and Post-Treatment SoA

Continued Access SoA

Sampling Schedule for Pharmacokinetics and Biomarkers


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I3Y-MC-JPCY(b)
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Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
Documentation and Examination
Informed Consent
X
Written informed consent must be 
obtained within 28 days prior to Cycle 1 
Day 1 AND prior to conducting any 
protocol-specific tests/procedures.
Inclusion/
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
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 and throughout the study.
Physical Examination
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 Cycle 1 Day 1 if assessed 
at baseline ≤3 days prior to abemaciclib
initiation. Additional exams should be 


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I3Y-MC-JPCY(b)
13
Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
performed as clinically indicated.
Vital Signs
X
X
X
X
X
X
X
Perform prior to administering 
abemaciclib. Collect temperature, blood 
pressure, pulse oximetry, and pulse rate.
Repeat if clinically indicated.
Does not need to be repeated on Cycle 1 
Day 1 if assessed at baseline ≤3 days 
prior to abemaciclib initiation.
ECOG Performance 
Status
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
Single ECG performed locally. 
Participants must be supine for 
approximately 5 to 10 minutes before 
ECG collection and remain supine but 
awake during ECG collection. Repeat if 
clinically indicated.
AE Assessment
X
X
X
X
Collect continuously at every visit and 
throughout the study using CTCAE 
Version 5.0. 
See Section 8.3 for further details on AE 
and SAE reporting.


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I3Y-MC-JPCY(b)
14
Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
Laboratory Assessments
Hematology
X
X
X
X
X
X
X
See Section 10.2, Appendix 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.  
Chemistry
X
X
X
X
X
X
X
See Section 10.2, Appendix 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 Sections
8.2.2.1 and 10.5, Appendix 5, for hepatic 
monitoring.
PSA
X
X
X
X
X
See Section 10.2, Appendix 2.  
Testosterone
X
X
X
X
X
See Section 10.2, Appendix 2.  


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I3Y-MC-JPCY(b)
15
Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
Tumor Assessment
CT or MRI Scan of 
Chest, Abdomen, and 
Pelvis
X
Every 8 weeks, independent of treatment
delays,
(Day 1 of Cycle 3, 5, 7, 9, 11, etc…)
X
X
Perform within 7 days prior to scheduled 
calendar day (except in screening 
period).
Unscheduled assessments if signs of
disease progression are observed.
Perform within 14 days of symptomatic 
progression (if no radiographic 
progression yet) and prior to the start of 
new anticancer therapy, palliative 
radiotherapy or surgery.
Patients discontinuing abemaciclib prior 
to documented radiographic progression 
will continue to have scheduled disease 
assessments until documented 
radiographic progression, start of new 
anticancer therapy, withdrawal of
consent, death, or study completion, 
whichever occurs first.
Radionuclide Bone 
Scan
X
Every 8 weeks, independent of treatment
delays,
(Day 1 of Cycle 3, 5, 7, 9, 11, etc…)
X
X


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I3Y-MC-JPCY(b)
16
Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
MRI (preferred) or 
CT Scan of Brain 
X
Only required at screening for patients 
with suspicion and/or symptoms of CNS 
involvement to rule out CNS metastases.  
Unscheduled assessments if signs of 
CNS disease progression are observed.
Symptomatic 
Progression
X
X
X
X
X
Assess: 
Symptomatic skeletal event defined
as symptomatic fracture, surgery, or
radiation to bone or spinal cord 
compression
Pain progression or worsening of 
disease-related symptoms requiring 
initiation of a new systemic anti-
cancer therapy
Development of clinically significant 
symptoms due to loco-regional tumor 
progression requiring surgical 
intervention or radiation therapy
Perform until evidence of symptomatic 
disease progression, start of new 
anticancer therapy, withdrawal of 
consent, death, or study completion, 
whichever occurs first.
Study Treatment


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Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
Abemaciclib
Orally twice daily, on Days 1 through 28 of 
a 28-day cycle.
See Section 6.1
Study Drug 
Compliance 
Assessment
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
Review Patient Diary
X
X
X
X
Review patient diary at each study visit 
for completion of date and time for each 
dose taken on the day before PK 
sampling. After Cycle 3 Day 1, the diary 
is no longer required. 
Post-study Treatment Collections
Post-Discontinuation 
Anti-Cancer 
Therapies
X
X
Collect until death, withdrawal of 
consent, or study completion.
Survival Status
X
X
Although preferable to collect during a 
clinic visit, if no procedures are required, 
survival information may be collected by 
contacting the patient or family directly 
(e.g., via telephone.  This should be 
collected at minimum every 90 (±14) 
days if no other procedures are 
performed.


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Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
Pharmacogenomic, Biomarker and PD Assessment
Tumor Biopsy
See 
Section 
1.3.1
See Section 1.3.1
See Section 8.8
PK Sampling
PK
See Section 1.3.1
See Section 8.5
Patient Reported Outcomes
7-day Worst Pain 
NRS
X
X
X
X
X
See Section 8.10
PRO questionnaires should be 
administered in the following order: 
7-day Worst Pain NRS, then 
PRO-CTCAE, then FACT-GP5, and 
finally the EORTC QLQ-C30 Physical 
Functioning and Global Health 
Status/QoL scales.
PRO-CTCAE
X
X
X
X
X
See Section 8.10
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Screening, On-Treatment and Post-Treatment Schedule of Activities 
Study phases
Screening
On Treatment
Cycle duration = 28 days
Post-Treatment Follow-up
Instructions
Baseline
Cycle 1
Cycle 2
Cycle 3 and 
subsequent
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
Procedures and disease assessments ( 
tumor imaging) should be performed as 
per the schedule of activities, according 
to the calendar days, regardless of 
treatment delays.
Relative Day within 
Dosing Cycle & 
Visit Window 
(±n days)
≤28
≤14
D1
(±3)
D15
(±3)
D1
(±3)
D15
(±3)
D1
(±3)
V801
(30 days ±7)
V802-8XX
(90 days ±14)
FACT-GP5
X
X
X
X
X
See Section 8.10
EORTC QLQ-C30 
Physical Functioning 
Scale
X
X
X
X
X
See Section 8.10
EORTC QLQ-C30 
Global Health 
Status/QoL
X
X
X
X
X
See Section 8.10
Abbreviations: AE = adverse event; CNS = central nervous system; CT = computed tomography; CTC = circulating tumor cells; CTCAE = Common 
Terminology Criteria for Adverse Events (NCI 2017); D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); 
EORTC-QLQ-C30 = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; FACT-GP5 = Functional Assessment 
of Cancer Therapy- General; MRI = magnetic resonance imaging; n = number; NRS = numeric rating scale; PD = pharmacodynamics; PGx = 
pharmacogenomics; PK = pharmacokinetics; PRO = patient-reported outcome; PRO-CTCAE = Patient-reported outcome Common Terminology Criteria for 
Adverse Events;  PSA = prostate specific antigen; QoL = quality of life; SAE = serious adverse event; V = visit.
a
Short-term follow-up begins when the participant and investigator agree that the participant will no longer continue study treatment and lasts approximately 
30 days (±7 days).  
b
Long-term follow-up begins when the short-term follow-up period is completed and continues until the participant’s death, loss to follow-up, or study 
withdrawal.  
In all cases, no follow-up procedures will be performed for a participant who withdraws informed consent unless he has explicitly provided permission and 
consent.


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Mobile healthcare service may be leveraged to collect and process lab samples in conjunction with a patient’s visit, when deemed appropriate by the investigator
and allowed by local laws and regulations.


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Continued Access Schedule of Activities
Study phase
Continued Access Treatment
Follow-upa
Instructions
V501-V5XX
V901
Procedure
Abemaciclib
X
Orally twice daily on Days 1 through 28 of a 28-day cycle.
AE collection
X
X
Assessments to be conducted at a minimum with each collection 
and dispensing study drug (every 28 days) from Visits 501-5XX. 
After V801, only SAEs that are related to study intervention or 
protocol procedure will be collected. 
Frequency of evaluation, including efficacy assessments, is left to 
the judgement of the investigator based on standard of care. 
Abbreviation: AE = adverse event; SAE = serious adverse event; V = visit.
a
Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue abemaciclib in the continued access 
period and lasts approximately 30 days.


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1.3.1.
Sampling Schedule for Pharmacokinetics and Biomarkers 
Sampling Day
Tumor Biopsy
Plasma and blood 
microsample
(PK)a
Baseline (Day −28 to Day −1)
X
b (mandatory)
Cycle 1 Day 1 (Pre-dose)
Cycle 1 Day 1 (Post-dose)
Xd
Cycle 1 Day 15 (Pre-dose)
Xe
Cycle 2 Day 1 (Pre-dose)
Xe
Cycle 2 Day 15 (Pre-dose)
Xe
Cycle 3 Day 1 (Pre-dose)
Xe
Cycle 4 Day 1 (any time during visit)
End of treatment or Short-term follow-up (Visit 
801), prior to start of new anti-cancer therapy
X
g (optional)
Abbreviations:  eCRF = electronic case report form; CRP = clinical research physician; CRS = clinical research scientist; CTC = circulating tumor cells; 
PGx = pharmacogenomics; PK = pharmacokinetics.
a
The date/time of the first abemaciclib dose on Cycle 1 Day 1 should be recorded in the eCRF.  After Cycle 1 Day 1, the date and times (am/pm) of 
abemaciclib doses taken on the day prior to PK sampling should be recorded in the patient diary. 
b
Participants must have a metastatic lesion amenable to biopsy (core needle) for biomarker analysis.  Soft-tissue biopsy is preferred to bone biopsy whenever 
possible. Biopsy of newly emerged radiographic metastases preferred to biopsy of previously existing lesions whenever possible. Adequate archival 
metastatic tissue can be used in lieu of a new biopsy and if the biopsy was done within 12 weeks prior to enrollment and no treatment was initiated from 
biopsy to study entry.
c
d
For Cycle 1 Day 1, PK sampling should occur any time 30 minutes after first abemaciclib dose. The blood microsample should be taken within (+/-)
10 minutes of the plasma PK sample.  The date and times of all PK samples must be accurately recorded.
e
For Cycle 1 Day 15 and all subsequent PK samples, PK sampling should occur in the morning before the first abemaciclib dose of the day. The blood 
microsample should be taken within (+/-) 10 minutes of the plasma PK sample. The date and times of all PK samples must be accurately recorded.
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g
Optional biopsy of metastatic lesion at the time of radiographic progression will be considered only if participant has completed at least 4 cycles of 
abemaciclib. The biopsy of a newly emerged or a progressing metastasis is preferred.
h
Mobile healthcare service may be leveraged to collect and process PK and 
 in conjunction with a patient’s visit, when deemed 
appropriate by the investigator and allowed by local laws and regulations
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2.
Introduction
2.1.
Study Rationale
Cyclin-dependent kinases 4 and 6 (CDK4&6) inhibitors have recently emerged as a standard of 
care for the management of hormone receptor-positive (HR+), human epidermal growth factor 
receptor 2 negative (HER2-) metastatic breast cancer (MBC). Abemaciclib is an oral, selective, 
and potent adenosine triphosphate (ATP)-competitive inhibitor of CDK4&6 that is dosed on a
continuous schedule. Abemaciclib is approved by major global regulatory authorities for the 
treatment of patients with HR+, HER2- MBC in combination with an aromatase inhibitor (AI) as 
initial endocrine-based therapy and with fulvestrant following endocrine therapy. In addition, 
abemaciclib is also approved as monotherapy for heavily pre-treated (following endocrine 
therapy and chemotherapy) HR+, HER2- MBC patients by the Food and Drug Administration 
(FDA).
Persistent or reactivated androgen receptor (AR) signaling pathway through molecular 
adaptations (such as AR amplification, overexpression, mutations, or the expression of 
constitutively active variants) and/or activation of pathways involved in crosstalk with AR 
signaling are key drivers of castration-resistant prostate cancer (CRPC). Similar to the estrogen 
receptor signaling pathway in breast cancer, there is evidence that the AR signaling pathway 
interacts with the CDK4&6 and retinoblastoma protein (pRb) axis to sustain prostate cancer cell 
proliferation and survival (Knudsen et al. 1998; Xu et al. 2006).  It has been established that 
androgens induce cell-cycle progression, in part through mammalian target of rapamycin-
dependent translation of D-cyclins and subsequent activation of CDK4&6 and pRb 
hyperphosphorylation (Xu et al. 2006). It was also suggested that upregulation of cyclin D1 is a 
potential mechanism of resistance to novel anti-androgen agents (Pal et al. 2018). These findings 
suggest that CDK4&6 may play an important role in the development and/or progression of 
prostate cancer.
Preclinical studies in cell cultures and mouse xenograft prostate cancer models showed that 
single agent abemaciclib is effective in inducing cell cycle arrest and tumor growth inhibition
(data on file). The clinical activity of abemaciclib in combination with abiraterone and 
prednisone is currently being investigated in I3Y-MC-JPCM (CYCLONE 2), a randomized, 
double-blind, placebo-controlled Phase 2 study in men with metastatic castration-resistant 
prostate cancer (mCRPC [NCT03706365]).
There is a high unmet medical need for mCRPC patients whose disease progressed after novel 
hormonal agent(s) (NHAs) and chemotherapy; thus, the development of tolerable and effective 
treatments with novel mechanisms of action is warranted. Study I3Y-MC-JPCY (CYCLONE 1)
is an open-label single-arm, multi-center, Phase 2 study to evaluate the safety and efficacy of 
abemaciclib in this heavily pretreated mCRPC patient population.


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2.2.
Background
2.2.1.
Prostate Cancer
Prostate cancer (PCa) is a leading cause of mortality and morbidity globally, with more than 1.2 
million cases diagnosed and more than 359,000 deaths annually (Bray et al. 2018).  It is the 
second most commonly diagnosed malignancy, the fifth leading cause of cancer mortality in men 
and represents a substantial public health burden (Bray et al. 2018).  The majority of deaths from 
PCa are due to metastatic disease, identified either at diagnosis (de novo) or after relapse 
following local therapies.
Advanced PCa is an androgen-dependent disease and tumor cells are primarily dependent on AR 
activity for proliferation and survival.  Thus, a standard element in the treatment of patients with 
metastatic disease is androgen deprivation therapy (ADT), which consists of bilateral 
orchiectomy or initiating a gonadotropin-releasing hormone agonist or antagonist (GnRHa) as 
monotherapy or in combination with an anti-androgen, also known as combined androgen 
blockade (Lonergan and Tindall 2011).
Based on the findings from the Phase 3 studies CHAARTED (NCT00309985), STAMPEDE 
(NCT00268476), and LATITUDE (NCT01715285), all showing significant improvement in 
overall survival (OS), the addition of docetaxel or abiraterone acetate plus prednisone to ADT is 
now considered a standard of care for men with high-volume or high-risk forms of metastatic 
hormone-sensitive prostate cancer (mHSPC) (Sweeney et al. 2015; James et al. 2016, 2017; 
Fizazi et al. 2019b).  In addition, the ARCHES (NCT02677896) and ENZAMET 
(NCT02446405) studies with enzalutamide, and the TITAN (NCT02489318) study with 
apalutamide, recently demonstrated that addition of enzalutamide or apalutamide to ADT 
improves progression–free survival (PFS) in patients with mHSPC (Armstrong et al. 2019; Chi et 
al. 2018; Davis et al. 2019). Improvement of OS was also observed in ENZAMET and TITAN.
Advances in the management of non-metastatic castration-resistant prostate cancer (nmCRPC)
have also been recently reported. The SPARTAN (NCT01946204), PROSPER (NCT02003924),
and ARAMIS (NCT02200614) trials have demonstrated significant metastases-free survival 
benefit with apalutamide, enzalutamide or darolutamide, respectively, plus ADT in men with 
nmCRPC and whose prostate specific antigen (PSA) doubling time was 10 months or less
(Hussain et al. 2018; Smith et al. 2018; Fizazi et al. 2019a). 
Despite these significant advances, nearly all patients with mHSPC or nmCRPC experience 
disease progression to mCRPC and cancer-specific mortality. Overall, the median survival from 
mCRPC diagnosis is less than 2 years (Higano et al. 2019).
The therapies approved for the treatment of mCRPC (reviewed by Nuhn et al. 2019) include:

Novel hormonal agents with abiraterone acetate (with prednisone) or enzalutamide,

α-emitting radium isotope radium-223 (symptomatic bone metastases and no known 
visceral metastatic disease),

Autologous cellular immunotherapy sipuleucel-T (asymptomatic or minimally 
symptomatic disease), and 

Taxane-based chemotherapy (docetaxel or cabazitaxel, with prednisone).


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The optimum treatment sequence has not been established and the clinical activity of secondary
NHAs (e.g. abiraterone after enzalutamide or the opposite sequence) is modest, likely due to 
cross resistance mechanisms (Noonan et al. 2013; Schrader et al. 2014; Smith et al. 2017). 
While chemotherapy is a standard approach in this setting, it is often associated with treatment-
limiting toxicities.
Recently in the CARD study, treatment with cabazitaxel demonstrated statistically significant 
radiographic progression free survival (rPFS) benefit over anti-androgen therapy (abiraterone or 
enzalutamide) in participants with mCRPC who were previously treated with docetaxel and had 
progression within 12 months while receiving the alternative inhibitor (abiraterone or 
enzalutamide [de Wit et al. 2019]). The median rPFS was 8.0 months in the cabazitaxel group 
compared to 3.7 months in the anti-androgen group (hazard ratio 0.54; 95% confidence interval 
[CI], 0.40 to 0.73; p<.001). The median OS was 13.6 months in the cabazitaxel group compared 
to 11.0 months in the anti-androgen group (hazard ratio 0.64; 95% CI, 0.46 to 0.89; p=.008 [de 
Wit et al. 2019]).  While these results support the use of cabazitaxel over abiraterone or 
enzalutamide in this setting, limited data exists to guide treatment for patients progressing after a 
NHA and taxane-based chemotherapy.
Among the current unmet needs in prostate cancer, the lack of therapeutic options for mCRPC
patients who exhausted life prolonging therapies is one of the most pressing ones.
2.2.2.
Abemaciclib
During the cell cycle, the G1 restriction point controls entry into the S phase and is essential for
maintaining control of cell division (Sherr 1996; Ortega et al. 2002). The cyclin-dependent
kinases (CDKs), CDK4 and CDK6 (CDK4&6), participate in a complex with D-type cyclins to 
initiate the transition through the G1 restriction point by phosphorylating and inactivating the
tumor-suppressor retinoblastoma protein (pRb). Alterations in this pathway occur frequently in
human cancers and involve loss of CDK inhibitors by mutation or epigenetic silencing, 
mutation/overexpression of either CDK4 and CDK6 or cyclin D, or inactivation of Rb. These
alterations may render cells less dependent on mitogenic signaling for proliferation. From a 
therapeutic standpoint, the goal of inhibiting CDK4&6 with a small molecule inhibitor is to
prevent cell cycle progression through the G1 restriction point, thus arresting tumor growth.
Abemaciclib is an oral selective and potent ATP-competitive inhibitor of CDK4&6 that is 
administered on a continuous dosing schedule. The clinical activity of abemaciclib has been 
extensively studied in HR+, HER2− MBC. 
Monotherapy with abemaciclib (200 mg, twice daily on a continuous dosing schedule) 
demonstrated meaningful antitumor activity in heavily pretreated refractory HR+, HER2− MBC 
patients with response rates of 19.7% and 28.6% observed in the single-arm Phase 2 study 
MONARCH 1 (NCT02102490) and in the randomized Phase 2 study Next MONARCH 1 
(NCT02747004), respectively (Dickler et al. 2017; Hamilton et al. 2019). 
In the randomized, placebo-controlled MONARCH 2 Phase 3 study, the addition of abemaciclib 
to fulvestrant provided a significant improvement of progression-free survival (PFS) 
(16.9 months versus 9.3 months, hazard ratio 0.536; 95% CI: 0.445, 0.645; p<.0001), OS 
(46.7 months versus 37.3 months, hazard ratio 0.757; 95% CI, 0.606-0.945; p=.01) and objective 
response rate (ORR) (measurable disease: 48.1% versus 21.3%; 95% CI: 42.6% to 53.6%; 


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p<.001) compared to placebo plus fulvestrant in HR+, HER2− advanced or metastatic BC 
patients who progressed during prior endocrine therapy (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.
In the randomized, placebo-controlled MONARCH 3 Phase 3 study, the addition of abemaciclib 
to a nonsteroidal AI 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) and ORR (measurable disease: 61.0% versus 45.5%; p=.003) 
compared to placebo plus AI (Goetz et al. 2018; Johnston et al. 2019). The OS data, an 
important secondary end point of this study, are immature.
Abemaciclib is currently approved by major global regulatory authorities for the treatment of 
patients with HR+, HER2- advanced or MBC in combination with an AI as initial endocrine-
based therapy and with fulvestrant following endocrine therapy.  In addition, abemaciclib is also 
approved as monotherapy for heavily pre-treated (following endocrine therapy and 
chemotherapy) HR+, HER2- MBC patients by the FDA.
Using in vitro prostate cancer models, it has been shown that abemaciclib can inhibit pRb 
phosphorylation and arrest cells in G1 with evidence of subsequent senescence.  In AR+ 
xenograft models, single agent abemaciclib dosed daily demonstrated significant antitumor 
activity. 
 
  In these studies, single agent abemaciclib showed evidence of antitumor 
activity relative to the vehicle in each model and the abemaciclib plus enzalutamide arm 
demonstrated increased antitumor activity compared to both single-agent arms.  Altogether, 
preclinical data suggests that abemaciclib monotherapy could exhibit clinical antitumor activity
in prostate cancer. 
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits, risks, serious adverse events 
(SAEs), and reasonably anticipated adverse events (AEs) of abemaciclib is to be found in the 
Investigator’s Brochure (IB).  Information on AEs expected to be related to abemaciclib may be 
found in IB. Information on SAEs expected in the study population independent of drug 
exposure will be assessed by the sponsor in aggregate periodically during the course of the study 
and may be found in the IB.
More detailed information about the known and expected benefits and risks of standard of care 
endocrine therapies, such as GnRHa may be found in the respective Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics.
2.3.1.
Benefit Assessment
There is a pressing unmet need for novel therapeutic agents in the care of mCRPC patients who 
experience disease progression following novel hormonal agent(s) (androgen-synthesis or 
receptor inhibitor, such as abiraterone acetate, apalutamide, darolutamide or enzalutamide and
taxane-based chemotherapy with docetaxel and cabazitaxel. In this later-line setting, treatment 
options are limited and may include (where approved and if not previously given):
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
An alternate novel hormonal agent (abiraterone or enzalutamide) - with possible acquired 
resistance and a potential limited benefit that needs to be considered.

Radium-223 (for participants with symptomatic bone metastases, and no known visceral 
metastatic disease).

Poly (ADP-ribose) polymerase inhibitors, such as rucaparib or olaparib, for a selected 
population (patients with homologous recombination repair gene mutations), per the 
respective approved labels. 

Agents which have shown some modest palliative benefits (such as mitoxantrone, 
corticosteroids, or other secondary hormone therapy, such as ketoconazole,
diethylstilbesterol [DES], or other estrogens). 

Pembrolizumab in selected populations (patients with microsatellite instability ‐high or 
mismatch repair‐deficient tumors) per the approved label.

Clinical trials and best supportive care are additional options for these patients who have 
exhausted, or are not eligible to receive, life-prolonging therapies.
To the best of our knowledge, there are no historical control data for assessing treatment effects 
in this heavily pretreated patient population and clinical benefit obtained with treatment options 
mentioned above are likely to be of short duration.
In view of the potential antitumor activity of abemaciclib in the mCRPC population, 
CYCLONE 1 is designed to allow participants to continue therapy until disease progression.
However, participants may discontinue study intervention at any time if they choose to do so or 
if the investigator believes it is in the best interest of the participant. Additionally, in the event of 
unacceptable toxicity, directions for reducing and/or discontinuing abemaciclib are provided. 
The assessment of patient-reported outcomes (PROs) will provide information on participants’ 
experience of the treatment and will be part of the benefit-risk assessment.
This study is being performed to assess the safety and efficacy of abemaciclib monotherapy in 
participants with mCRPC whose disease progressed after at least 1 novel hormonal agent and 2 
taxane-based chemotherapy regimens.
2.3.2.
Overall Benefit: Risk Conclusion
Taking into account the safety profile of abemaciclib and the measures taken to minimize risk to 
participants participating in this study, the potential risks identified in association with
abemaciclib monotherapy are justified by the anticipated benefits that may be afforded to 
participants with heavily pre-treated mCRPC.
The benefit / risk assessment, therefore, currently favors the proposed abemaciclib study in 
participants who exhausted multiple or all life prolonging therapies for prostate cancer.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the efficacy of 
abemaciclib monotherapy.

Investigator-assessed ORR per 
RECIST 1.1.
Secondary

To further characterize the clinical 
activity of abemaciclib monotherapy.

rPFS

OS

DoR

DCR

PSA response rate

Time to PSA progression

Time to symptomatic progression

To characterize the safety profile of 
abemaciclib.

Assessment of safety including, but not 
limited to, the following: AEs, SAEs, 
physical examination, and clinical 
laboratory abnormalities per CTCAE 
v5.0

To explore patient reported 
tolerability of abemaciclib 
monotherapy (including symptomatic 
AEs and overall side-effect burden), 
patient reported pain intensity, 
physical functioning, and overall 
health related quality of life 

PRO-CTCAE

FACT-GP5

7-day Worst Pain Numeric Rating 
Scale

EORTC QLQ-C30 Physical 
Functioning Scale

EORTC QLQ-C30 Global Health 
Status/QoL Scale

To characterize the PK of 
abemaciclib and its metabolites.

Concentrations of abemaciclib and its 
metabolites.

To characterize Ki-67 baseline
expression

% of cells expressing Ki-67 by IHC
Exploratory
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Objectives
Endpoints
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events v5.0 (NCI 
2017); DCR = disease control rate; DoR = duration of response; EORTC-QLQ-C30 = European Organization for 
the Research and Treatment of Cancer Quality of Life Questionnaire; FACT-GP5 = Functional Assessment of 
Cancer Therapy- General; IHC = immunohistochemistry; Ki-67 = protein encoded by the MKI67 gene;
ORR= objective response rate; OS = overall survival; PK = pharmacokinetics; PSA = prostate specific antigen; 
PRO-CTCAE = Patient Reported Outcome-Common Terminology Criteria for Adverse Events v5.0 (NCI 2017); 
QoL = quality of life; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1 (Eisenhauer et al; 
2009); rPFS = radiographic progression-free survival; SAE = serious adverse event; SSE = symptomatic skeletal 
event.
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4.
Study Design
4.1.
Overall Design
CYCLONE 1 is a Phase 2 open-label, single-arm, multi-center study to assess the efficacy of 
abemaciclib monotherapy in participants with mCRPC whose disease progressed on or after at 
least 1 androgen-axis therapy (abiraterone acetate, apalutamide, darolutamide or enzalutamide) 
and 2 taxane-based chemotherapy regimens (docetaxel and cabazitaxel). Participants may have 
received up to 3 prior systemic treatments for mCRPC, must have measurable disease per 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and a metastatic lesion 
amenable to biopsy.  Androgen deprivation therapy with a GnRHa must be continued throughout 
the study for participants who have not undergone bilateral orchiectomy. Abemaciclib 200 mg
twice daily will be administered on a continuous dosing schedule until disease progression, 
unacceptable toxicity, or other discontinuation criteria are met. 
This study will initially treat approximately 40 participants.
4.2.
Scientific Rationale for Study Design
Patients whose mCRPC has progressed on or after prior NHA(s) and 2 taxane-based 
chemotherapy regimens represent a population with high unmet medical need.
In the recent CARD study (NCT02485691), treatment with cabazitaxel 25 mg/m2 (with 
prednisone 10 mg daily and primary prophylactic granulocyte-colony stimulating factor [G-CSF]
at every cycle) offered statistically significant rPFS benefit over anti-androgen therapy
(abiraterone or enzalutamide) in participants with mCRPC who were previously treated with 
docetaxel and progressed within 12 months while receiving the alternative inhibitor (abiraterone 
or enzalutamide [de Wit et al. 2019]). The median rPFS was 8.0 months in the cabazitaxel group
compared to 3.7 months in the anti-androgen group (hazard ratio 0.54; 95% CI, 0.40 to 0.73; 
p<.001). The principal reasons for the discontinuation of treatment with cabazitaxel or the anti-
androgen therapy were disease progression (in 43.7% and 71.0% of the patients, respectively) or 
an AE (in 19.8% and 8.9% of the patients, respectively). The median OS was 13.6 months in the 
cabazitaxel group compared to 11.0 months in the anti-androgen group (hazard ratio 0.64; 95% 
CI, 0.46 to 0.89; p=.008 [de Wit et al. 2019]). 
While these results support the use of cabazitaxel over a second NHA in this setting, as yet, there 
are limited data to guide treatment for mCRPC patients experiencing disease progression after 
receiving a NHA, docetaxel and cabazitaxel.  This represents a high unmet medical need, as 
there was no standard of care for these patients. Of interest, in CARD, only about half (53.5%) 
of the patients in the cabazitaxel group received a subsequent anticancer treatment, 23.2% 
crossed over to receive a second hormonal agent (abiraterone or enzalutamide), 14.7% received 
palliative radiation, 4.7% received radium-223, 4.7% were enrolled in clinical trials to receive an 
investigational drug and 1.6% received docetaxel as re-challenge (de Wit et al. 2019).
The single arm, open label design for this study is justified as currently there are limited standard 
therapies with demonstrated activity for the study population.


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Due to the nonoverlapping mechanism of action of abemaciclib when compared to currently 
approved therapies, and given its preclinical anti-proliferative effects on prostate cancer cell lines 
and xenograft models, the clinical activity and manageable safety profile as monotherapy 
observed in heavily treated HR+, HER2- MBC, abemaciclib may offer clinical benefit to the 
study population. This Phase 2 study will evaluate the safety and efficacy of abemaciclib
monotherapy in the post-NHA(s) and post-chemotherapy mCRPC setting.
4.3.
Justification for Dose
The maximum tolerated dose for abemaciclib monotherapy was defined in Phase 1 studies
I3Y-MC-JPBA and I3Y-MC-JPBC (Japanese participants) as 200 mg every 12 hours, which 
demonstrated acceptable safety and tolerability in participants with solid cancers (Patnaik et al. 
2016). Abemaciclib monotherapy is approved by the FDA for heavily pretreated HR+, HER2-
MBC.  The monotherapy indication is based on MONARCH 1 (NCT02102490) where 
abemaciclib 200 mg twice daily demonstrated a 19.7% (95% CI: 13.3, 27.5) ORR and median 
PFS of 6.0 months (Dickler et al. 2017).
, in CYCLONE 1, abemaciclib monotherapy will be administered 
orally at 200 mg twice daily on Days 1 through 28 of a 28-day cycle.
4.4.
End of Study Definition
This study will be considered complete (that is, scientific evaluation will be complete [study 
completion] following the evaluation of all primary and secondary endpoints, as determined by 
Lilly. Investigators will continue to follow the study schedule for all participants until notified 
by Lilly that study completion has occurred. “End of Study” refers to the date of the last visit or 
last scheduled procedure for the last participant.
CCI
CCI


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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 are met:
1. Adult male (age ≥18 years or country's legal age of majority), who must be, in the 
judgement of the investigator, an appropriate candidate for experimental therapy.
Participants must be capable of giving signed informed consent as described in Section 
10.1, Appendix 1, which includes compliance with the requirements and restrictions 
listed in the informed consent form (ICF) and in this protocol.
2. Histologically confirmed adenocarcinoma of the prostate. Well-differentiated 
neuroendocrine carcinoma, small cell or large cell neuroendocrine carcinoma, 
sarcomatoid, and carcinoid tumors are excluded.
3. Metastatic prostate cancer documented by positive bone scan and/or computed 
tomography (CT) or magnetic resonance imaging (MRI). Presence of at least 1 
measurable lesion per RECIST v1.1 (Eisenhauer et al. 2009). Previously irradiated 
lesions that did not show radiographic progression after radiation therapy, primary 
prostate lesion and bone lesions will be considered non-measurable disease. If lymph 
node metastasis is the only evidence of metastasis, it must be at least 1.5 cm in the short 
axis. 
4. Serum testosterone ≤1.73 nmol/L (≤50 ng/dL) at the screening visit. Participants who 
have not undergone bilateral orchiectomy are required to continue ADT with a GnRHa
throughout the study.
5. Progressive disease despite castrate level of serum testosterone based on at least 1 of the 
following criteria:

Prostate specific antigen (PSA) progression per Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3) criteria for trial eligibility: A sequence of at least 2 
rising PSA values at a minimum of 1-week intervals, with the last value being at 
least 1.0 ng/mL.

Radiographic progression per RECIST v1.1 for soft tissue and/or per PCWG3 for 
bone (appearance of ≥2 new bone lesions on bone scan), with or without PSA 
progression.


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6. Participants must have previously received in the metastatic hormone-sensitive setting 
and/or in the castration-resistant settings:

At least 1 novel androgen receptor-axis therapy with abiraterone acetate, 
apalutamide, darolutamide or enzalutamide
AND

2 taxane regimens. A taxane regimen is defined as at least 2 cycles of docetaxel 
or cabazitaxel. Re-challenge with docetaxel will not be considered a second 
taxane regimen.
If a participant has not received a second taxane regimen, the participant may still be 
eligible after discussion and approval by the Lilly clinical research physician/scientist 
(CRP/CRS) if:
o
Participant has history of hypersensitivity reactions or intolerance to docetaxel, 
cabazitaxel, drugs formulated with polysorbate 80 or to corticosteroids
or
o
Participant has any contraindication or preexisting condition not compatible 
with receiving an additional taxane therapy per local prescribing information
or
o
Participant experienced taxane-related AE requiring treatment discontinuation 
or did not yet resolve to Grade ≤1 (except alopecia).
The reason must be recorded in the participant’s medical notes and medical history in the 
electronic case report form (eCRF).  
7. Participants may have received up to 3 prior systemic therapy regimens in the metastatic 
castration-resistant setting.
NOTE:  GnRHa, first-generation antiandrogens (flutamide, nilutamide, or bicalutamide), 
DES (or other estrogens), corticosteroids, ketoconazole, and bone loss-prevention will 
not count as systemic therapy regimens.
8. Except for GnRHa and bone loss-prevention treatment, participants must have 
discontinued previous anti-cancer agents at least 21 days (or 5 half-lives, whichever is 
shorter) prior to treatment initiation. Participants must have recovered from acute toxic 
effects of prior therapy, palliative radiation or surgical procedure to Grade ≤1 or baseline 
(as per Common Terminology Criteria for Adverse Events [CTCAE] v 5.0), with the 
exception of alopecia or peripheral neuropathy.
9. Must be willing and amenable to undergo tumor biopsy of at least 1 metastatic site, 
which should be collected following determination of eligibility and before initiating 
study treatment.

Soft tissue biopsy is strongly preferred to bone biopsy whenever possible.


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
Biopsy of newly emerged radiographic metastases preferred to biopsy of 
previously existing lesions whenever possible.

Adequate archival metastatic tissue can be used if available in lieu of a new 
biopsy if the biopsy was done within 12 weeks prior to enrollment and no 
treatment was initiated from biopsy to study entry.
10. Have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (Oken et 
al. 1982) and adequate organ function, as defined below:
System
Laboratory Value
Hematologic
ANC
≥1.5×109/L
G-CSF should not be administered to meet ANC 
eligibility criteria.
Platelets
≥100×109/L
Hemoglobin
≥9 g/dL
Participants may receive erythrocyte transfusion to 
achieve this hemoglobin level at the discretion of the 
investigator. Initial treatment must not begin earlier than 
the day after the erythrocyte transfusion.
Hepatic
Total bilirubin
≤1.5 × ULN OR
<2.0 × ULN for participants with history of 
unconjugated hyperbilirubinemia (Gilbert’s syndrome)
ALT and AST
≤ 3 ×ULN 
Abbreviations:  ALT = alanine transaminase; ANC= absolute neutrophil count; AST = aspartate transaminase; 
dL = deciliter; G-CSF = granulocyte-colony-stimulating factor; g = gram; L= liter; ULN= upper limit of normal. 
11. Sexually active participants, with a female partner who is of child-bearing potential,
must agree to use a medically approved contraceptive method during the study and for at 
least 3 weeks following the last dose of abemaciclib (e.g., intrauterine device, 
nonhormonal birth control pills, or barrier method).  If condoms are used as a barrier 
contraceptive, a spermicidal agent should be added as double barrier protection. Please 
refer to Section 10.4, Appendix 4, for additional reproductive and contraceptive 
guidance.
5.2.
Exclusion Criteria 
Participants are excluded from the study if they meet ANY of the following criteria:
12. Prior treatment with abemaciclib or any CDK4 and/or CDK6 inhibitors.


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13. Currently enrolled in a clinical study involving an investigational product or any other 
type of medical research judged not to be scientifically or medically compatible with 
this study.  Have participated in any clinical trial for which treatment assignment is still 
blinded unless agreed by the Lilly CRP/CRS. If a participant is currently enrolled in a 
clinical trial involving non-approved use of a device, then agreement with the 
investigator and the Lilly CRP/CRS is required to establish eligibility.
14. Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-
situ of any origin), unless in complete remission with no therapy for a minimum of 
2 years.
15. Serious and/or uncontrolled preexisting medical condition(s) including but not limited 
to severe renal impairment (for example, estimated creatinine clearance <30 mL/min), 
severe hepatic impairment (Child-Pugh C), interstitial lung disease (ILD)/pneumonitis, 
severe dyspnea at rest or requiring oxygen therapy. Other serious preexisting medical 
condition(s) that, in the judgment of the investigator, would preclude participation in this 
study (such as history of major surgical resection involving the stomach or small bowel, 
or preexisting Crohn’s disease or ulcerative colitis, preexisting chronic condition 
resulting in Grade ≥2 diarrhea, gastrointestinal disorder affecting absorption or inability 
to swallow medication).
16. History of any of the following conditions within the last 12 months: syncope of 
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not 
limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.  
17. The participant has active systemic infections (for example, bacterial infection requiring 
intravenous [IV] antibiotics at time of initiating study treatment, fungal infection, or 
detectable viral infection requiring systemic therapy) or viral load (such as known 
human immunodeficiency virus positivity or with known active hepatitis B or C [for 
example, hepatitis B surface antigen positive]).  Screening is not required for 
enrollment.
18. Known or suspected central nervous system (CNS) metastatic disease (baseline 
screening for CNS metastases is not required unless there is presence of signs and/or 
symptoms of CNS involvement).
19. Untreated spinal cord compression or evidence of spinal metastases with risk of spinal
compression. Structurally unstable bone lesions suggesting impending fracture.
20. Estimated life expectancy < 4 months as assessed by the investigator.


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5.3.
Lifestyle Considerations

Participants should refrain from consuming grapefruits or grapefruit juice while on study 
intervention.

Participants must not take preparations or herbal products thought to affect PSA levels 
(such as, saw palmetto or pomegranate).

Participants must not donate blood or sperm during the study and for 3 months after the 
last study intervention dose.

Participants with known hypersensitivity or suspected intolerance to abemaciclib or any 
of its excipients (e.g., lactose) should not take abemaciclib unless deemed appropriate by 
the investigator.
See Section 6.5 for additional guidance on concomitant therapy.
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 
SAEs.
The following participants may be eligible for re-screening:

Participants who become eligible to enroll in the study as a result of a protocol 
amendment.

Participants whose status has changed such that the eligibility criterion that caused the 
participant to screen fail would no longer cause the participant to fail screening again 
(e.g., unexpected surgery during the screening period that is no longer relevant 
following recovery from surgery).

A patient who completes screening and meets all inclusion and exclusion requirements 
but is unable to be enrolled due to extenuating circumstances (such as severe weather, 
death in family, child illness).
The interval between rescreening should be ≥2 weeks.  Individuals may be rescreened a 
maximum of 2 times.  The individual must sign a new ICF and will be assigned a new 
identification number.  
Repeating 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 intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.  In CYCLONE 1, study intervention is defined as the administration of
abemaciclib.
6.1.
Study Intervention(s) Administered
Abemaciclib will be administered at a starting dose of 200 mg orally twice daily with a minimum 
of 6 hours between doses, at approximately the same time every day. Abemaciclib should be 
swallowed whole with a glass of water (do not chew, crush, split, dissolve in water, or alter in 
any way prior to swallowing). Abemaciclib may be taken with or without food.
If a participant misses a dose at the scheduled time for nonmedical reasons, the dose should be 
taken as soon as possible on the same day and then twice-daily administration should be resumed
(with at least 6 hours separating doses).  If a participant vomits after taking a dose, then the dose 
should not be retaken and the next dose should be taken at the usual scheduled time.
The investigator or his/her designee is responsible for the following:

Explaining the correct use of the drug and planned duration of each individual’s 
treatment to the participant/study-site personnel/legal representative.

Verifying the instructions are followed properly.

Maintaining accurate records of abemaciclib dispensing and collection.

Returning all unused medication to Lilly, or its designee at the end of the study, 
unless the site is authorized by Lilly or its designee to destroy unused medication, 
as allowed by local law.
Study Intervention
Dose
Treatment Schedule
Route of Administration
Abemaciclib
200 mg
Twice daily
Oral
6.2.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature/storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized study 
personnel may supply 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 study personnel. 
The investigator, or authorized study personnel, is responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and final 
disposition records). 


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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 
twice daily 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. In the event of a 
dose suspension due to toxicity immediately prior to the beginning of a cycle, the PK sampling 
schedule outlined in Section 1.3.1 may require adjustment and the sponsor should be notified. 
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 exceptional cases, such as planned delays 
(including but not limited to vacation or holidays), additional study treatment may be dispensed
after discussion with Lilly CRP/CRS.    
Participants may continue to receive study intervention until evidence of disease progression, or 
any discontinuation criteria are met (See Section 7). 
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a non-randomized, open-label study. 
6.4.
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each cycle.  Compliance will 
be assessed by counting returned tablets.  Study medication administration data will be recorded 
in the participant’s medical record and eCRF. Deviation(s) from the prescribed dosage regimen 
should be recorded in the eCRF.
Participants who are significantly noncompliant will be discontinued from the study after 
discussion with Lilly CRP/CRS. A participant will be considered significantly noncompliant if 
he missed more than 7 consecutive days of study medication (full dose) or more than 25% 
cumulative days of study medication (full dose). Similarly, a participant may be considered 
significantly noncompliant if he is judged by the investigator to have intentionally or repeatedly 
taken more than the prescribed amount of medication. Abemaciclib dose suspensions or delays 
related to toxicity may occur and will not result in a participant being considered noncompliant.
6.5.
Concomitant Therapy
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications including over-the-counter and analgesics use must be recorded in the eCRF. 
Concomitant medications and supportive care therapies must also be documented at time of 
discontinuations and at the short-term 30-day follow-up visit. The Lilly CRP/CRS should be 
contacted if there are any questions regarding concomitant or prior therapy.  Refer to the 
prescribing information of the concomitant medications for additional information. 


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Required:
Participants who have not undergone bilateral orchiectomy are required to continue ADT with a 
GnRHa throughout the study. The choice of the GnRHa will be at the investigator's discretion.
Permitted:
Bone loss prevention treatment with bisphosphonates or denosumab per their respective 
approved labels. Switching between bisphosphonates and denosumab is permitted during study
as long as it is in the absence of disease progression, and due to reasons including, but not 
limited to, tolerability.
Use with Caution:
Abemaciclib is extensively metabolized through oxidation by cytochrome P450 (CYP)3A. In 
clinical drug interaction studies, 

coadministration of clarithromycin, a strong CYP3A inhibitor, increased exposure to 
abemaciclib by 3.4-fold (Study I3Y-MC-JPBE), and 

coadministration of rifampin, a strong CYP3A inducer, decreased exposure to 
abemaciclib by 95% (Study I3Y-MC-JPBF).  
Strong inhibitors of CYP3A (given via non-topical routes of administration) should be 
substituted or avoided if possible (Section 10.6, Appendix 6). This includes grapefruit or 
grapefruit juice. In particular, avoid oral administration of the very strong CYP3A inhibitor,
ketoconazole. The information in Section 10.6, Appendix 6, is provided for guidance to 
investigators and does not preclude the use of these medications if clinically indicated.  
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should reduce 
the dose of abemaciclib by 50 mg at the start of CYP3A inhibitor treatment. That is, for patients 
receiving 200 mg twice daily, reduce the dose to 150 mg twice daily. For patients who have 
already dose reduced to 150 mg or 100 mg twice daily for tolerability, reduce the dose further to 
100 mg or 50 mg twice daily, respectively. Alternatively, the investigators may consider 
suspending abemaciclib for the duration of the CYP3A inhibitor medication. Dose suspensions 
≥28 days must be discussed with Lilly CRP/CRS.
Upon discontinuation of the strong CYP3A inhibitor, abemaciclib may be resumed at the same 
dose level or re-escalated to the dose that was used before starting the strong inhibitor after a 
sufficient washout period (at least 3 half-lives of the strong inhibitor). Re-escalation of the 
abemaciclib dose requires review and approval from Lilly CRP/CRS. Inducers of CYP3A should 
be substituted or avoided if possible (Section 10.6, Appendix 6). Coadministration with a 
CYP3A inducer ≥28 days must be discussed with Lilly CRP/CRS.
Transporter Substrates
At clinically relevant concentrations, abemaciclib inhibits the transporters P-glycoprotein, breast 
cancer resistance protein, organic cation transporter 2 (OCT2), multidrug and toxin extrusion 
protein 1 (MATE1), and MATE2-K. The observed serum creatinine increase in clinical studies 
with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, 


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and MATE2-K. In vivo interactions of abemaciclib with narrow therapeutic index substrates of 
these transporters, such as digoxin and dabigatran, may occur.
Prohibited: 
With the exception of a GnRHa, no other anticancer therapy will be permitted while participants 
are on study intervention (including, but not limited to [anti-]hormonal agents, other CDK4
and/or CDK6 inhibitors, biologics, other antineoplastic and investigational agents, 
chemotherapy, radiopharmaceuticals, immunotherapy, anti-cancer vaccines, ketoconazole).
Palliative radiation or surgical intervention to treat symptoms resulting from metastatic disease is 
not allowed.
Drugs, or herbal/non-herbal products (e.g., saw palmetto or pomegranate) that have known 
prostate cancer activity and/or are known to affect PSA levels, are not permitted while on study 
intervention. Megestrol acetate as an appetite stimulant is not permitted. 
6.5.1.
Supportive Care
Participants should receive full supportive care to maximize quality of life.  Participants will 
receive supportive care as judged by the treating physician.  If it is unclear whether a therapy 
should be regarded as supportive care, the investigator should consult with the Lilly CRP/CRS.  
Use of any supportive care should be recorded on the eCRF.
6.5.1.1.
Supportive Management for Diarrhea
When abemaciclib is initiated, the participant should receive instructions on the management of 
diarrhea.  In the event of diarrhea, supportive measures should be initiated as early as possible.  
These include:

At the first sign of loose stools, the participant should initiate anti-diarrheal therapy (e.g., 
loperamide) and notify the investigator/site for further instructions and appropriate 
follow-up.

Participants should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to either baseline 
or Grade 1, abemaciclib should be suspended until diarrhea is resolved to baseline or 
Grade 1.

When abemaciclib recommences dosing should be adjusted as outlined in Section 6.6.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics, such as fluoroquinolones must be prescribed.
Participants with severe diarrhea or any grade of diarrhea associated with severe nausea or 
vomiting should be carefully monitored and given IV fluid (IV hydration) and electrolyte 
replacement.
Refer to Section 6.6 for guidance on dose adjustments of abemaciclib for patients with diarrhea 
and see Section 10.7, Appendix 7, for diarrhea CTCAE grades.


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6.5.1.2.
Growth Factors
Growth factors should not be administered to a participant to satisfy study inclusion criteria.
While on study treatment, growth factors may be administered in accordance with American 
Society of Clinical Oncology guidelines (Smith et al. 2015).  Dosing of abemaciclib must be 
suspended if the administration of growth factors is required and must not be recommenced 
within 48 hours of the last dose of growth factors having been administered.  Following the 
administration of growth factors, the dose of abemaciclib must be reduced by 1 dose level on 
recommencement, if a dose reduction for the specific event necessitating the use of the growth 
factors has not already occurred.
6.6.
Dose Modification
Dose adjustments (suspensions and reductions) will be made based on the clinical assessment of 
hematologic and nonhematologic toxicities (defined as an AE possibly related to abemaciclib per 
investigator judgment).  The CTCAE v5.0 will be used to assess AEs.  Abemaciclib may be 
suspended for a maximum of 28 days to allow a participant sufficient time for recovery from 
abemaciclib-related toxicity. If a patient does not recover from the toxicity within 28 days from 
the time of last treatment, the patient should be considered for permanent discontinuation from 
abemaciclib. In exceptional circumstances, a delay >28 days is permitted upon agreement 
between the investigator and the Lilly CRP/CRS.
Participants undergoing non-tumor related surgical procedures should follow the guidelines 
below:

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 surgery 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 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 CRP/CRS. For participants requiring a dose reduction of study intervention, any re-
escalation to a prior dose level is permitted only after consultation with and approval by the Lilly 
CRP/CRS.
6.6.1.
Dose Reductions for Abemaciclib
Study Drug
Starting 
dose
Dose Reduction
First
Second
Third
Fourth
Abemaciclib
200 mg 
twice daily
150 mg 
twice daily
100 mg 
twice daily
50 mg 
twice daily
Discontinue


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6.6.2.
Dose Adjustments and Delays Abemaciclib
The toxicity dose adjustments and delays table below provides guidance for the management of 
treatment-emergent, related (i.e., with reasonable causal relationship with abemaciclib), and 
clinically significant AEs associated with abemaciclib. An investigator may suspend or reduce 
doses without meeting one of the criteria below and would not be considered a protocol 
deviation.
Toxicity Dose Adjustments and Delays of Abemaciclib
Toxicity Type
CTCAE Grade
Dose Modification
Hematologic Toxicity
Grade 1 or Grade 2
No dose modification is required
Grade 3
Suspend dose until toxicity resolves to 
≤Grade 2
Dose reduction is not required
Recurrent Grade 3, 
or Grade 4 
Suspend dose until toxicity resolves to 
≤Grade 2
Resume at next lower dose level
Hematologic Toxicity: If 
Patient Requires 
Administration of Blood Cell 
Growth Factors
Additional guidance for use of 
growth factors is in Section 
6.5.1.2
Regardless of severity
(Use of growth factors 
according to ASCO Guidelines)
Suspend dose for at least 48 hours after the 
last dose of blood cell growth factor and 
until toxicity resolves to ≤Grade 2
Resume at next lower dose unless the dose 
was already reduced for the toxicity that led 
to the use of the growth factor
Non-hematologic Toxicity
Excluding Diarrhea, ALT/AST 
Increased, and Interstitial Lung 
Disease/Pneumonitis (see 
below)
Additional guidance for renal 
monitoring is in Section 8.2.2.2
and for venous thromboembolic 
events is in Section 8.2.2.3
Grade 1 or Grade 2
No dose modification is required
Persistent or recurrent Grade 2 
that does not resolve with 
maximal supportive measures 
within 7 days to baseline or 
Grade 1.
Grade 3 or Grade 4
Suspend dose until toxicity resolves to 
baseline or Grade 1
Resume at next lower dose level
Diarrhea
Additional guidance for diarrhea 
management is in Section 6.5.1.1. 
See Section 10.7, Appendix 7, for 
CTCAE 5.0 grading
Grade 1
No dose modification is required
Grade 2 that does not resolve 
within 24 hours to ≤Grade 1
Suspend dose until toxicity resolves to 
≤Grade 1
Dose reduction is not 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 level


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Toxicity Type
CTCAE Grade
Dose Modification
Grade 3, or Grade 4, or requires 
hospitalization
ALT/AST Increased
See Section 8.2.2.1 for additional 
guidance for hepatic monitoring 
and Section 8.2.2.1.1 for special 
hepatic safety data collection. See 
Section 10.7, Appendix 7, for 
CTCAE 5.0 grading
Grade 1 or 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,
or Grade 4
Discontinue abemaciclib
Interstitial Lung 
Disease/Pneumonitis
Additional guidance for 
ILD/pneumonitis monitoring is in 
Section 8.2.2.4. See Section 10.7, 
Appendix 7, for CTCAE 5.0 
grading
Grade 1 or Grade 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 level
Grade 3 or Grade 4
Discontinue abemaciclib
Abbreviations: ALT = alanine aminotransferase; ASCO = American Society of Clinical Oncology; AST = aspartate 
aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2017); ILD = interstitial 
lung disease; ULN = upper limit of normal.
Note: Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the first event. As a general 
guidance, based on the risk/benefit balance assessment per the investigator, for a participant who experiences a new 
episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of the same Grade 3 
hematological toxicity, the investigator may consider resuming the participant on the same drug dose should the 
participant satisfy the following conditions:

The participant showed stable hematological counts (Grade ≤2) during that timeframe

In the absence of any infectious sign or risk factor

The participant is benefiting from study intervention.
6.7.
Intervention after the End of the Study
Please refer to the study schema (Section 1.2) for a depiction of study completion, continued 
access period, and the end of study.
6.7.1.
Study Completion
Study completion will occur following the final analysis of all primary and secondary objectives 
(Section 4.4), as determined by Lilly.  Investigators will continue to follow the SoA (Section 1.3)
for all participants until notified by Lilly that study completion has occurred.


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6.7.2.
Continued Access
Participants who are still on study intervention at the time of study completion may continue to 
receive study intervention if they are experiencing clinical benefit and no undue risks.
The continued access period will apply to this study only if at least 1 participant is still on study 
intervention when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
Participants are not required to sign a new ICF before treatment is provided during the continued 
access period; the initial ICF for this study includes continued access under this protocol.
The participant’s continued access to study intervention will end when a criterion for 
discontinuation is met (Section 7).  Continued access follow-up will begin when the participant 
and the investigator agree to discontinue study intervention and lasts approximately 30 days.  
Follow-up procedures will be performed as shown in the Continued Access SoA.
Participants who are in short-term follow-up when the continued access period begins will 
continue in short-term follow-up until the 30-day short-term follow-up visit is completed. Long-
term follow-up does not apply.
Participants who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
In all cases, no follow-up procedures will be performed for a participant who withdraws 
informed consent unless he or she has explicitly provided permission and consent.


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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. Investigators 
should try to find out the reason and document it on the corresponding CRF.
The reason and date of discontinuation will be collected for all participants.
Participants with PSA-only progression should continue study intervention until disease 
progression (radiographic and/or symptomatic progression), when participant safety is not 
compromised. 
Study intervention should be continued for as long as the participant consents and complies with 
study procedures and requirements, is tolerating the study intervention, until radiographic
progression according to RECIST 1.1 for soft tissue and/or PCWG3 for bone; and/or until 
symptomatic progression.
Symptomatic progression is defined as:
Symptomatic Skeletal Event (SSE), defined as symptomatic fracture, surgery 
or radiation to bone, or spinal cord compression
Pain progression or worsening of disease-related symptoms requiring 
initiation of a new systemic anti-cancer therapy.
Development of clinically significant symptoms due to loco-regional tumor 
progression requiring surgical intervention or radiation therapy.
When study intervention is discontinued due to symptomatic progression, the investigator should 
obtain CT/MRI and bone scan imaging within 14 days to assess for radiographic progression, 
prior to the participant initiating radiotherapy, surgery or subsequent anti-cancer therapy
(whichever comes first).
Patients discontinuing study intervention due to documented radiographic progression will be 
followed for the development of symptomatic progression until start of new anticancer therapy, 
withdrawal of consent, death, or study completion, whichever occurs first.
Participants discontinuing study intervention prior to documented radiographic progression will 
continue to have scheduled disease assessments until documented radiographic progression, start 
of new anticancer therapy, withdrawal of consent, death, or study completion, whichever occurs 
first.
All participants discontinuing study intervention will have procedures performed as shown in 
Section 1.3 and enter the short-and-long-term follow-up periods and will be followed for the 
initiation of subsequent anti-cancer therapies and survival status every 3 months until death, loss 
of follow-up, or withdrawal of consent, whichever comes first.  
Participants will be discontinued from study intervention in the following circumstances:


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
the participant or the participant’s designee (for example, parents or legal guardian) 
requests to be discontinued from study intervention

sponsor decision

investigator decision

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 discussed above 

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.

the participant experiences unacceptable toxicity

the participant is significantly noncompliant with study procedures and/or intervention.
In exceptional circumstances, a participant may continue study intervention beyond disease 
progression if there is no effective alternative therapy and the participant, in the opinion of the 
investigator, is receiving clinical benefit from the study drug.  In these rare cases, the investigator 
must obtain documented approval from the Lilly CRP/CRS to allow the patient to continue study 
intervention. Additionally, the patient must reconsent prior to continuing to receive study 
intervention.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant will be discontinued from the study in the following circumstances: 

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

at any time at the participant’s own request 

at the request of the participant’s designee (for example, parents or legal guardian)

at the discretion of the investigator 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Section 1.3). The participant will be permanently discontinued 
both from the study intervention and from the study at that time.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
The criteria for enrollment must be followed explicitly.  If an inadvertently enrolled participant is 
identified, the sponsor and investigator must be notified.  A discussion must occur between the 
Lilly CRP/CRS and the investigator to determine if the patient may continue in the study, with or 
without study drug. Inadvertently enrolled patients may continue in the study and on study drug 
when the Lilly CRP/CRS agrees with the investigator that it is medically appropriate for that 
patient to do so. The patient may not continue in the study with or without study drug if the Lilly 
CRP/CRS does not agree with the investigator’s determination that it is medically appropriate for 
the patient to continue. The investigator must obtain documented approval from the Lilly 
CRP/CRS to allow the inadvertently enrolled patient to continue in the study with or without 
study drug.  Patients who are discontinued from the study will have follow-up procedures 


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performed as outlined in Section 1.3 (Schedule of Activities), 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 he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel or designee 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.
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants who initiate treatment. Public 
sources may be searched for vital status information. If vital status is determined to be deceased, 
this will be documented, and the participant will not be considered lost to follow-up. Lilly 
personnel will not be involved in any attempts to collect vital status information.


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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3). 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 may maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Appendix 2 (Section 10.2) provides a list of laboratory tests that will be performed for this study.
The SoA (Section 1.3) provides the schedule for collection of samples in this study. Unless 
otherwise stated in the following subsections, all samples collected for specified laboratory tests 
will be destroyed within 60 days after receipt of confirmed test results. Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
8.1.
Efficacy Assessments
Baseline and on-study tumor assessments will be performed for each participant as per the SoA 
(Section 1.3), according to the calendar days, regardless of intervention delays.  During the
study, unscheduled tumor assessment and appropriate imaging should be considered if there are 
signs or symptoms suggestive of disease progression.
All applicable imaging will be done locally.  All CT/MRI and bone scan images will be collected 
and stored centrally. 
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). A PET scan alone or as part of a PET-CT may be 
performed for additional analyses but cannot be used to assess response according to 
RECIST 1.1.
The method of assessment used at baseline must be used consistently for serial tumor assessment 
throughout the study.
For participants continuing treatment during the Continued Access Period (after study 
completion), efficacy assessments (frequency and type of assessments) will be at the discretion 
of the investigator.
8.1.1.
Definitions of Efficacy Measures
Objective Response Rate is defined as the proportion of participants who have a soft tissue best 
overall response of complete response (CR) or partial response (PR) per RECIST 1.1, and do not 
have concurrent bone disease progression per PCWG3, as assessed by the investigator/local 


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radiologist. The primary analysis will require confirmation of responses, but interim analyses 
will consider both confirmed and unconfirmed responses.
Radiographic Progression Free Survival
The consensus guidelines of RECIST 1.1 and PCWG3 have been taken into consideration for the 
determination of radiographic disease progression.
For all participants, imaging studies (radionuclide bone scan and CT or MRI scan of the chest, 
abdomen, and pelvis) will be performed locally at baseline and repeated within 7 days prior to
Day 1 of every second cycle (every 8 weeks) beginning with Cycle 3 and continuing until 
radiographic progression, and within 14 days of symptomatic progression if no radiographic 
progression yet per the SoA (Section 1.3).
Radiographic PFS (rPFS) will be assessed by sequential imaging studies and is defined as the 
time from the date of treatment initiation to the earliest date of investigator-determined 
radiographic disease progression by objective radiographic CT/MRI disease assessment per 
RECIST 1.1 for soft tissue AND/OR radionuclide bone scan using the PCWG3 criteria for bone 
or death from any cause, in the absence of documented disease progression. Censoring rules are 
described in detail in the Statistical Analysis Plan (SAP).  Radiographic disease progression in 
soft tissue does not require a confirmatory scan.
The documentation required for the determination of radiographic disease progression in bone 
per PCWG3 is listed in the text below and in the following table.
Bone Progression per PCWG3
A participant is considered to have progressed by bone scan if:
1. For radiographic disease progression on bone observed on the first post-treatment bone 
scan
- Appearance of at least 2 new lesions on the first post-treatment scan (Week 9), with at 
least 2 additional lesions on the next scan (Week 17; 2+2 rule).
- The date of progression is the date of the first post-treatment scan, when the first 2 new 
lesions were documented.
OR
2. For radiographic disease progression in bone observed after the first post-treatment bone 
scan (Week 17 or later):
- Appearance of at least 2 new lesions relative to the first post-treatment scan (Week 9, 
new baseline) that are persisting on a confirmatory subsequent scan (at least 6 weeks 
later or at the next scheduled assessment).
- The date of progression is the date of the scan that first documents the second lesion.
Changes in intensity of uptake alone do not constitute either progression or regression.


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Date Progression 
Detected
Criteria for 
Progression
Criteria for 
Confirmation or 
Progression 
(Requirement and 
Timing)
Criteria for 
Documentation of 
Disease Progression 
on Subsequent Scan
Week 9 (C3D1)
(or earlier 
unscheduled visit)
Two or more new 
lesions compared to 
baseline bone scan
Requires confirmation 
at least 6 weeks after 
progression identified 
or at the Week 17 
assessment
Confirmatory scan:  
Two or more new 
bone lesions 
compared to Week 9 
scan
Week 17 or later
Two or more new 
lesions on bone scan 
compared to Week 9 
bone scan
Requires confirmation 
at least 6 weeks after 
progression identified 
or at the next 
scheduled assessment
Confirmatory scan:  
Two or more 
persisting (i.e., also 
present on the prior 
scan) new lesions 
relative to Week 9 
scan
Abbreviations:  C = cycle; D = day.
Source:  Scher et al. 2016.
Overall Survival is defined as the time from the date of treatment initiation to date of death due 
to any cause.  For participants not known to have died at the time of analysis, OS will be 
censored at the last known alive date.
Duration of Response is defined as the time from first documented evidence of soft tissue CR or 
PR until earliest date of disease progression by objective radiographic disease assessment per 
RECIST 1.1 for soft tissue AND/OR radionuclide bone scan using PCWG3 criteria for bone as 
assessed by the investigator/local radiologist, or death from any cause, whichever occurs first.
Disease Control Rate is defined as the proportion of patients who have a soft tissue best overall 
response of CR, PR, or stable disease (SD) per RECIST 1.1, and do not have concurrent bone 
disease progression per PCWG3.
Time to PSA progression is defined as the time from the date of treatment initiation to the date 
of first observation of PSA progression.  The PSA progression is defined as a ≥25% increase and 
an absolute increase of ≥2 ng/mL above the nadir (or baseline value if baseline is the smallest on 
study), which is confirmed by a second value obtained 3 or more weeks later.  Any post-baseline 
PSA measurements within 12 weeks since baseline will be ignored in determining PSA
progression (Scher et al. 2016).
Time to Symptomatic Progression is defined as the time from the date of treatment initiation to 
any of the following (whichever occurs earlier):

Symptomatic Skeletal Event (SSE), defined as symptomatic pathological fracture, tumor-
related orthopedic surgery, or external beam radiation to bone progression, or spinal cord 
compression.

Pain progression or worsening of disease-related symptoms requiring initiation of a new 
systemic anti-cancer therapy.


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
Development of clinically significant symptoms due to loco-regional tumor progression 
requiring surgical intervention or radiation therapy.
Prostate Specific Antigen Response Rate is defined as the proportion of participants with a 
reduction in PSA level of ≥50% from baseline (see Section 9.4.1), confirmed with a second 
assessment conducted at least 3 weeks later.
PSA Change from Baseline to 13 Weeks is defined as the individual proportion of rise or fall in 
PSA at 13 weeks relative to baseline (see Section 9.4.4).  Missing observations will not be 
imputed.
Maximum Decline in PSA is defined as the relative change in PSA from baseline (see Section 
9.4.1) to the lowest on-study value, occurring at any time point.
8.1.2.
Appropriateness of Assessments
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology studies. 
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3). For each 
participant, vital signs, laboratory tests, and other tests should be collected as shown in the SoA.
Any clinically significant findings that result in a diagnosis and that occur after the participant
receives the first dose of study intervention should be reported to Lilly or its designee as an AE 
via eCRF.
Additional information regarding guidance for monitoring of hepatic function, renal function, 
venous thromboembolic events (VTE), and interstitial lung disease (ILD)/pneumonitis can be 
found in Section 8.2.2.
8.2.1.
Clinical Safety Laboratory Assessments
Lilly or its designee will provide the investigator with the results of safety laboratory tests 
analyzed by a central vendor, if a central vendor is used for the clinical trial.   
See Section 10.2, Appendix 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 laboratory results, document this review, and report any clinically 
relevant changes occurring during the study as an AE. 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.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or until the completion of Visit 801 should be repeated until the values return to 
normal or baseline or are no longer considered clinically significant by the investigator or 
medical monitor.
o
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.


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o
All protocol-required laboratory assessments, as defined in Section 10.2, Appendix 2, 
must be conducted in accordance with the laboratory manual SoA.
o
If laboratory values from non-protocol-specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE, AE, or dose 
modification), then the results should be reported as a diagnosis of an AE (for example, 
hypertension, neutropenia, etc.).
8.2.2.
Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. 
8.2.2.1.
Hepatic Safety Monitoring
Liver testing (Section 10.5, Appendix 5), including alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin (TBL), direct bilirubin, gamma-
glutamyl transferase, and creatine phosphokinase, 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 ≥3× 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 (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-international normalized ratio; serological tests for viral hepatitis A, B, C, E, 
autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 
Based on the participant’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, cytomegalovirus, Epstein-Barr virus, 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 


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participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography, endoscopic retrograde cholangiopancreatography, cardiac 
echocardiogram, and/or a liver biopsy.  
8.2.2.1.1. Special Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur:
In participants 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 intervention due to a hepatic event or abnormality of liver 
tests

occurrence of a hepatic event considered to be an SAE
8.2.2.2.
Guidance for Monitoring Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
transporters without affecting glomerular function (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 (GFR) based on cystatin 
C.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function. Other 
measures of renal function, such as cystatin C GFR, should be used as an alternative to either 
creatinine or creatinine calculations of GFR. A serum cystatin C is collected with the central 
chemistry laboratory sample. If deterioration of renal function is suspected per the investigator’s 
clinical assessment, dose alteration should follow the protocol guidance for non-hematological 
toxicities in Section 6.6.2.
8.2.2.3.
Guidance for Venous Thromboembolic Events
In breast cancer, VTE has been identified as an adverse drug reaction for abemaciclib in 
combination with endocrine therapy (ET). In the randomized Phase 3 studies in participants with 
breast cancer who received abemaciclib in combination with ET, a greater number of participants
experienced VTEs in the abemaciclib plus ET arms than in the placebo plus ET arm or ET alone 
arm. The majority of participants who experienced VTEs were treated with anticoagulants. In 
studies with single-agent abemaciclib use in the metastatic breast cancer population or other 
tumor types, including non-small cell lung cancer, no increased rates of VTEs were observed as 


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compared to the incidence of VTEs for these particular patient populations who were treated 
with other anticancer agents. At this time, the mechanism underlying the association between 
abemaciclib and the occurrence of VTEs is not known.  
Monitor participants for signs and symptoms of deep vein thrombosis and pulmonary embolism 
and treat as medically appropriate. Dose modifications and management should follow the 
protocol guidance for non-hematological toxicities in Section 6.6.2.
8.2.2.4.
Guidance for Interstitial Lung Disease/Pneumonitis
Interstitial lung disease (ILD)/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. The majority of events observed in clinical trials were Grade 1 or Grade 2 with 
serious cases and fatal events reported. Additional information is available in the IB.
Ask your 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 CT, bronchoalveolar lavage, and biopsy as clinically indicated.
Refer to Section 6.6.2 for guidance on dose adjustments of abemaciclib for patients with 
ILD/pneumonitis (see Section 10.7, Appendix 7, for ILD/pneumonitis CTCAE grades).
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 (EMA)
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 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 pre-defined 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. 


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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 [IND] 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 6.6 of the protocol. 
Lilly Global Patient Safety has a robust process, for expedited communication of SAEs and 
suspected unexpected serious adverse reactions (SUSARs) 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 Sections 8.3 and 10.3, Appendix 3). 
8.3.
Adverse Events and Serious Adverse Events
Lilly standards for reporting AEs are to be followed regardless if country regulatory 
requirements are less stringent. A clinical study AE is any untoward medical event associated 
with the use of a drug in humans, irrespective if the AE is considered related to abemaciclib.
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 
caused the participant to discontinue the study intervention (see Section 7).
The investigator will use CTCAE version 5.0 (NCI 2017) to assign AE severity grades. 
Investigators are responsible for:

monitoring the safety of participants in this study and for alerting Lillyor its designee
to any event that seems unusual, even if this event may be considered an 
unanticipated benefit to the participant

the appropriate medical care of participants during the study

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study intervention or the study, or that caused 
the participant to discontinue study intervention before completing the study. The 
participant should be followed until the event resolves, stabilizes with appropriate 
diagnostic evaluation, or is reasonably explained.  Frequency of follow-up evaluation is 
left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
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After the ICF is signed, study site personnel will record via CRF/electronic data entry/designated 
data transmission methods the occurrence and nature of each participant’s preexisting conditions, 
including clinically significant signs and symptoms of the disease under treatment in the study.
In addition, study site personnel will record via CRF/electronic data entry/designated data 
transmission methods any change in the preexisting conditions and any new conditions as AEs. 
Investigators should record their assessment of the potential relatedness of each AE to study 
intervention via CRF/electronic data entry/designated data transmission methods.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study intervention or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies. A “reasonable possibility” means that there is a cause 
and effect relationship between the study intervention and/or study procedure and the AE.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuations that result 
from AEs to Lilly or its designee via CRF/electronic data entry/designated data transmission 
methods, clarifying, if possible, the circumstances leading to the dose modification or 
discontinuation of treatment
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 until the short-term 30-day follow-up visit. 
Adverse events that begin before the start of study intervention but after signing of the ICF will 
be recorded on the Adverse Event CRF.  Although all AEs after signing the ICF are recorded by 
the site in the CRF/electronic data entry, SAE reporting to the sponsor begins after the 
participant has signed the ICF and has received study drug. 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 Section 10.3, Appendix 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 intervention.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation (the participant summary CRF has been completed). 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.
8.3.2.
Method of Detecting AE 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 Section 10.3, Appendix 3. 


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.2.1.
Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatienthospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birthdefect

important medical events that may not be immediately life-threatening or result in death 
or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require intervention to
prevent one of the other outcomes listed in the definition above. 
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
participant’s medical history at the time of enrollment should not be considered SAEs.
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study intervention or other protocol-required procedure) 
should not be considered SAEs.
Pregnancy (during maternal or paternal exposure to study intervention) does not meet the 
definition of an AE but should be reported. However, to fulfill regulatory requirements any 
pregnancy should be reported following the SAE process to collect data on the outcome for both 
mother and fetus. See Section 10.4, Appendix 4, for details. 
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study intervention or study procedure. 
United States 21 CFR 312.32 and Regulation (EU) No 536/2014 and the associated detailed 
guidance or national regulatory requirements in participating countries require the reporting of 
SUSARs.  Lilly has procedures that will be followed for the recording and expedited reporting of 
SUSARs that are consistent with global regulations and associated detailed guidance. 
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 to baseline, stabilization, 
the event is otherwise explained, or the participant dies or is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is provided in Section 10.3, 
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8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 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 (e.g., 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
Details of all pregnancies in female partners of male participants will be collected after the start 
of study intervention and until 3 weeks following cessation of study intervention.
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 Section 10.3, Appendix 3.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Adverse Events of Special Interest
More information about the adverse events of special interest for abemaciclib can be found in the 
IB. 
8.3.7.
Complaint Handling
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.
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Participants will be instructed to contact the investigator as soon as possible if he 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 Sections 8.3.3 and 10.3, Appendix 10.3, of the protocol.
8.4.
Treatment of Overdose
In the event of an overdose, the investigator should: 

Contact the Lilly CRP/CRS immediately. 

Closely monitor the participant for any AE/SAE and laboratory abnormalities. 


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
Obtain a sample for PK analysis as soon as possible after the overdose has been 
identified, unless the Lilly CRP/CRS specifies otherwise. 

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 CRP/CRS based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
Pharmacokinetic samples will be collected to determine the concentrations of abemaciclib and its 
active metabolites, LSN3106726 (M20) and LSN2839567 (M2).  Blood samples for PK analysis 
will be collected by
1) venous puncture collection into a vacutainer, and 
2) capillary puncture collection into a volumetric absorptive microsampling device.
At the visits and times specified in the SoA (Section 1.3.1), both a venous blood sample and a 
blood microsample should be collected at approximately the same time (within [+/-] 10 minutes)
Pharmacokinetic samples will be analyzed at a laboratory approved by the sponsor and stored at 
a facility designated by the sponsor. Concentrations of abemaciclib and its metabolites, M2 and 
M20, will be determined using validated liquid chromatography with tandem mass spectrometry 
methods.
Pharmacokinetic samples will be retained for a maximum of 1 year following last subject visit 
for the study. 
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
time (24-hour clock time) of each sample will be recorded.
8.5.1.
Patient Diary
A diary will be provided to participants in order to help track date and time of each dose taken 
the day before planned PK sample collection.  Patient diary evaluations will occur through Cycle 
3 Day 1.  Refer to SoA (Section 1.3) for additional information.
8.6.
Pharmacodynamics
See Section 8.8. Samples collected will be identified by the participant number (coded) and 
retained at a facility selected by Lilly for a maximum of 15 years following the last participant
visit for the study. 
8.7.
Genetics
8.7.1.
Whole Blood Sample for Pharmacogenetic Research 
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8.8.
Biomarkers
8.8.1.
Tissue Samples for Biomarker Research
Tissue samples for biomarker research will be collected for the purposes described in Section
8.8. The following tissue samples for biomarker research will be collected according to 
Section 1.3.1, where local regulations allow.
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Collection of the following tumor tissue sample(s) is required for all participants in order to 
participate in this study:

Mandatory tumor biopsy of at least 1 metastatic site which will be collected following 
determination of eligibility and before initiating study intervention.
o
Biopsy of newly emerged radiographic metastases is preferable to the biopsy of 
previously existing lesions whenever possible.
o
Soft-tissue, as well as bony metastatic lesions will be considered acceptable.  
Soft-tissue biopsy is preferred to bone biopsy whenever possible.
At the time of tissue collection, it is highly recommended to confirm adequate tumor tissue (not a 
normal adjacent tissue sample or a tumor margin sample) has been sampled. 
Adequate archival metastatic tissue can be used if available in lieu of a new biopsy if the biopsy 
was done within 12 weeks prior to enrollment AND no treatment was initiated from biopsy to 
study entry. Sites should confirm availability of archival tissue with pathology laboratory prior 
to study entry.
An optional biopsy of metastatic lesion at the time of radiographic progression should only be 
considered if the participant has completed at least 4 cycles of study intervention. The biopsy of 
a newly emerged or a progressing metastasis is preferred over a pre-existing lesion that is not 
progressing, whenever possible.
The pathology report accompanying archival tissue may also be requested.  The pathology report 
must be coded with the patient number.  Personal identifiers, including the patient’s name and 
initials, must be removed from the institutional pathology report prior to submission. Lilly has a 
right to retain a portion of the submitted tissue.
Archival blocks will be sectioned and returned to study site upon request. Slides and tumor 
tissue samples collected as part of this study will not be returned.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and/or 
ERBs/IRBs impose shorter time limits.  This retention period enables the use of new 
technologies, response to questions from regulatory agencies, and investigation of variable 
response that may not be observed until later.
Technologies are expected to improve during the 15-year storage period, and therefore, cannot 
be specifically named.  Existing approaches, including mutation profiling, copy number 
variability analysis, gene expression assays, multiplex assays, and/or immunohistochemistry may 
be performed on these tissue samples to assess potential associations between these biomarkers 
and clinical outcomes.
8.8.2.
Other Samples for Biomarker Research
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8.9.
Immunogenicity Assessments
Not applicable.
8.10.
Health Economics
8.10.1.
Patient reported outcomes
The main objective of the patient reported outcome (PRO) measurement is to assess patient 
reported tolerability (i.e., assessment of symptomatic AEs).  In addition, the measurement of 
PROs will focus on the overall side effect impact, disease related symptoms, specifically pain, 
and well as physical functioning and global health related quality of life. 
Patient reported symptomatic AEs will be measured using The National Cancer Institute’s PRO 
version of the common terminology criteria for adverse events (PRO-CTCAE) 
(http://healthcaredelivery.cancer.gov/pro-ctcae/).  The choice of PRO-CTCAE symptoms items 
selected from the PRO-CTCAE item library is aligned with the recommendations published in 
Trask et al. 2018. 
 
 
 
 
 
 
Additionally, the GP5 item of the Functional Assessment of 
Cancer Therapy-General (FACT-G) instrument, which asks participants to report the extent to 
which “(they are) bothered by side-effects of treatment”, will be administered to assess overall 
side-effect burden.
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The impact of abemaciclib on pain will also be explored using the 7-day Worst Pain Numeric 
Rating Scale (NRS) data and analgesic use.  The 7-day Worst Pain NRS is a single-item 
questionnaire which measures worst pain over the last 7 days on a 0 to 10 point numeric rating 
scale, where 0 is ‘no pain’ and 10 is ‘pain as bad as you can imagine’. Data on over-the-counter 
and prescription analgesic medications including dose, unit, frequency, and route of 
administration will be collected by site personnel and recorded in the CRF. Analgesic use will 
be classified into categories, for example, according to the World Health Organization analgesic 
ladder or the Analgesic Quantification Algorithm scale.
Physical functioning and overall health-related quality of life will be measured using the 
Physical Functioning and Global Health Status/ Quality of Life (QoL) scales of the European 
Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC
QLC-C30).  Both the GP5 item and EORTC QLQ-C30 items are measured on a 5-point Likert 
scale, from ‘not at all’ to ‘very much’.
The PRO-CTCAE, FACT-GP5, 7-day Worst Pain NRS, and EORTC QLQ-C30 Physical 
Functioning and Global Health Status/QoL scales will be administered at baseline (screening), 
Day 1 of every cycle, treatment discontinuation, and short-term follow-up. Questionnaires 
should be completed by all participants where there is a validated language/cultural translation 
available in which the patient is fluent. The questionnaires should be completed before any 
extensive contact and consultation with the clinician/study investigator, as such encounters may 
thereafter bias patient responses. Questionnaires should be administered in the following order: 
7-day Worst Pain NRS, then PRO-CTCAE, then FACT-GP5, and finally the QLQ-C30 Physical 
Functioning and Global Health Status/QoL scales.
8.10.2.
Health Care Resource Utilization
Health care resources utilization data, associated with medical encounters, will be collected in 
the eCRF by the investigator or authorized study personnel for all participants throughout the 
study.  Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct economic analyses and will include hospitalizations 
and emergency room visits (reason and duration).


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The statistical hypothesis of this study is that there will be a clinically relevant rate of response to 
abemaciclib monotherapy administered to patients with mCRPC that have been previously 
treated with at least 1 novel androgen-axis therapy (androgen-synthesis or receptor inhibitor, 
such as abiraterone acetate, apalutamide, darolutamide or enzalutamide) and 2 taxane regimens 
(docetaxel, cabazitaxel).
9.2.
Sample Size Determination
Approximately 40 participants will be assigned to study intervention.  All treated patients will be 
included in the assessment of objective response, with patients lacking a complete disease 
assessment per RECIST 1.1 criteria at either baseline or at any time postbaseline being classified 
as non-responders.
An observed response rate of at least 12.5% in 40 participants will be considered as evidence of 
clinically relevant activity, which yields an adequate Type I error rate and power. As an 
illustration of Type I error control, assuming a true response rate of 5%, the probability of 
observing an ORR of at least 12.5% in a cohort of 40 participants is 4.8%. As an illustration of 
power, assuming a true response rate of 15%, the probability of observing an ORR of at least 
12.5% is 73.7%.  
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF
Treated/Safety
All participants who have initiated study intervention, regardless 
of how many doses of study intervention they receive or how 
many on-study research procedures are performed.
Biomarker Evaluable
All participants within the subset of participants from the Treated 
population from whom a valid pre-treatment tumor assay result has 
been obtained.
Pharmacokinetic Analysis
All treated participants who received at least 1 dose of abemaciclib
and have at least 1 evaluable PK sample.
Abbreviations: ICF = informed consent form; PK = pharmacokinetics.


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9.4.
Statistical Analyses
9.4.1.
General considerations
Statistical analysis of this study will be the responsibility of the sponsor or its designee.
This is an uncontrolled trial of abemaciclib, so in general, inferential statistical tests of treatment 
will not be performed.  All tests of effects between subgroups of participants will be conducted 
at a 2-sided alpha level of 0.05, unless otherwise stated, and all CIs will be given at a 2-sided 
95% level.
For all response-based evaluations of endpoint change from baseline, e.g., best overall response 
(BOR) by RECIST 1.1, PCWG3, or PSA value, the baseline value will be the last observation 
taken before treatment initiation that falls within the specified timeframe.  Participants without 
an observation in this timeframe will be considered non-evaluable for the associated response.
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 SAP and the clinical study report.  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
The SAP will be finalized prior to First Patient First 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.
9.4.2.
Primary analysis
The primary analysis of the primary endpoint of ORR will be performed approximately 6 months 
after the last patient enters treatment and/or investigator-assessed best response assessments have 
been completed for all participants.  All secondary endpoints will be evaluated at this time. 
Additional updated analyses of efficacy and safety may be conducted at later times if deemed 
appropriate by the sponsor.  
At each analysis, the ORR will be evaluated against a null hypothesis of 5%. For the interim 
analysis of efficacy, all participants who have initiated treatment more than approximately 
16 weeks prior to the data cut-off will be considered part of the at-risk population.  For the 
primary analysis, responders will consist of those participants with a BOR of confirmed PR or 
confirmed CR, per RECIST 1.1 criteria, and do not have concurrent bone progression per 
PCWG3 at the time of the analysis. If 5 or more responders are observed from 40 treated 
participants, the study will be considered positive. This is equivalent to evaluating the binomial 
exact test with a null hypothesis that the ORR is 5% against an alternative of an ORR greater 
than 5% at a one-sided α = 0.05.
Lilly or its designee will collect and store tumor assessment images, and an independent review 
of imaging scans may be performed by Lilly or its designee. Summaries of endpoints using 
independently reviewed BOR may be presented as sensitivity analyses, as described in the SAP.


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9.4.3.
Secondary endpoint(s)
Summaries of event rates, including radiologic ORR, and PSA-based response, will be defined as 
the proportion of all treated participants who achieve the specified response category.  
Participants with a non-evaluable or unknown response per specified criteria will be considered 
non-responders for the purpose of calculating the response rate.
Detailed censoring rules for time to event (TTE) endpoints are described in the SAP.  For all 
TTE endpoints, median event times and rates at various time points, with 95% CI, will be 
estimated using the Kaplan-Meier method (Kaplan and Meier 1958).  Sensitivity analyses for 
TTE will be described in the SAP.
9.4.4.
Exploratory endpoint(s)
9.4.5.
Other Safety Analyses
All safety analyses will be made on the Safety Population, defined as all participants who receive 
at least 1 dose of study drug will be evaluated for safety and toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA®) Version [21.0 (or higher)] will be 
used when reporting AEs by MedDRA terms. The MedDRA Lower Level Term (LLT) will be 
used in the treatment-emergent computation. Treatment-emergent adverse events (TEAEs) will 
be summarized by System Organ Class (SOC) and by decreasing frequency of Preferred Term 
(PT) within SOC.
Safety analyses will include summaries of the following:

TEAEs, including severity and possible relationship to study drug

Treatment-emergent SAEs, including possible relationship to study drug

AEs leading to dose adjustments

discontinuations from study intervention due to adverse events or death

treatment-emergent abnormal changes in laboratory values

treatment-emergent abnormal changes in vital signs
The number of participants with dose reductions, dose delays, or dose omissions will be 
summarized, as will the reasons for dose adjustments.
Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation.
9.4.6.
Other Analyses 
9.4.6.1.
Participant Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of participants enrolled in the study, and treated, as well as number and 
percentage of participants completing the study, as defined in the SAP, or discontinuing (overall 
and by reason for discontinuation).  A summary of all important protocol deviations will be 
provided.
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9.4.6.2.
Participant Characteristics
A summary of participant demographics, baseline participant and disease characteristics, 
historical diagnoses, preexisting conditions, and prior anti-cancer therapies will be reported using 
descriptive statistics.
Other participant characteristics will be summarized as deemed appropriate.
9.4.6.3.
Treatment Compliance
Treatment compliance will be summarized for all treated participants.
Compliance information for study drug will be collected by counting any remaining tablets at 
each cycle.  The estimate of percent compliance will be given by: 
Percent Compliance = 
Actual cumulative dose taken 
× 100
        Expected cumulative dose to be taken
The actual cumulative dose taken will be determined based on counting the number of tablets 
returned at each visit and subtracting that number from the number of 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.
9.4.6.4.
Extent of Exposure
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated participants.
9.4.6.5.
Post-Abemaciclib Therapy
The numbers and percentages of participants receiving post-study-treatment discontinuation 
anticancer therapies will be provided by type of therapy (surgery, radiotherapy, or systemic 
therapy), and by drug class and/or name, overall and by line of therapy.
9.4.6.6.
Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic analyses will be conducted on all participants who have received at least 1 dose 
of abemaciclib and have at least 1 evaluable PK sample.
Abemaciclib PK analyses may include, but are not limited to:
(1) Summary analyses of individual and/or mean concentrations of abemaciclib, M2 and 
M20, grouped by analyte, dose level, time point, etc.
(2) Population PK modeling analysis to evaluate population PK parameters and inter-
individual PK variability.
Relationships between exposure and measures of efficacy and safety may be explored.
9.4.6.7.
Patient Reported Outcomes
Patient Reported Outcomes will be analyzed using descriptive statistics will be calculated for 
patient-reported data for each instrument.  Further details will be described in the PRO SAP.


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9.4.6.8.
Biomarker Analysis
The percentage of cells expressing Ki-67 by immunohistochemistry (IHC) for each participant in 
the biomarker evaluable population will be summarized and listed. Additionally, Ki-67 
expression values will be classified into a series of binary variables (e.g., <10%, <25%, etc.; see 
SAP for details), and the proportion of participants in each group will be reported with 
corresponding exact 95% CIs. Given a sample size of 40 patients, corresponding exact 95% CIs
for a variety of observed prevalence rates are illustrated below.
Observed Prevalence Rate
95% Confidence Interval
0.05
(0.006, 0.169)
0.25
(0.127, 0.412)
0.5
(0.338, 0.662)
0.75
(0.588, 0.873)
0.95
(0.831, 0.994)
9.4.6.9.
Subgroup Analyses 
A prespecified list of subgroups will be identified in the SAP. The treatment effect within each 
subgroup will be summarized. Other subgroup analyses not specified in the SAP may be 
performed as deemed appropriate. These subgroups will be based on important characteristics, 
for example, prognostic significance.
9.5.
Interim Analyses 
A futility analysis will be conducted approximately 2 months after the 15th participant has 
entered treatment. Trial enrollment will continue while awaiting the results of the futility 
analysis. The study team will consider the totality of safety, efficacy, and PK data. As guidance, 
futility should be declared and trial enrollment stopped if 0 patients have achieved an 
unconfirmed PR or CR per RECIST 1.1 AND fewer than 5 participants have achieved a BOR of
SD per RECIST 1.1 at the time of the futility analysis.
One additional interim analysis of efficacy will be conducted approximately 2 months after all 
participants have entered treatment.  Endpoints using RECIST 1.1 will be analyzed considering 
both confirmed and unconfirmed responses. The interim analysis will be conducted to evaluate 
the initial evidence of antitumor activity. The sponsor has no intent to stop the study based on 
the interim analysis of antitumor activity and all participants will continue follow-up for all study 
objectives until study close.
Additional interim analysis may be conducted as deemed appropriate by the sponsor.
The SAP will describe the planned interim analyses in greater detail.
9.6.
Data Monitoring Committee (DMC)
Not applicable.


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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 with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines
o
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the 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:
o
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
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the study conduct for the participants under their responsibility
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.
o
Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement.
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.


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10.1.3.
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.

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 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.
10.1.4.
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 will contain 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.
10.1.5.
Committees Structure
Not applicable.


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10.1.6.
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 (e.g., 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 (e.g., 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 (e.g., 
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 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 the sponsor.

In addition, the 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 the 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. 
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 


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identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, electronic Clinical Outcome Assessment (eCOA) data (participant-focused 
outcome instrument) will be directly recorded by the participant into an instrument (for example, 
handheld smart phone or tablet, or by means of an interactive voice/web system).  The eCOA 
data will serve as the source documentation and the investigator does not maintain a separate, 
written or electronic record of these data.
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 the results will be provided to the investigator for 
review and retention.  Data will subsequently be transferred from the central vendor to the Lilly 
data warehouse.  Data from complaint forms submitted to sponsor will be encoded and stored in 
the global product complaint management system.
10.1.7.
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.
10.1.8.
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.


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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 should 
assure appropriate participant therapy and/or follow-up.
10.1.9.
Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.


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10.2.
Appendix 2: Clinical Laboratory Tests
The tests detailed below will be performed as indicated in the table.
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for inclusion/exclusion determination, study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample for central 
analysis is also obtained. If there is an abnormal laboratory value or abnormal value for any 
other diagnostic or screening test (for example, blood pressure increased, neutrophils decreased, 
etc.) and it is known to be related to a diagnosis (for example, hypertension, neutropenia, etc.) 
this should be reported in the CRF.  Do not enter the test abnormality, enter the diagnosis or 
categorical term.
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations and clinically significant findings should be reported 
in the CRF as an AE.
Enrollment and treatment decisions may be based on local laboratory results. A sample must 
still be sent to the central laboratory. Differences between these samples will not be considered a 
protocol deviation.


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Hematology –a, c
Leukocytes (WBC)
Basophils
Neutrophilsb
Erythrocytes (RBC)
Lymphocytes
Hemoglobin (HGB)
Monocytes
Hematocrit (HCT)
Eosinophils
Platelets (PLT)
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin concentration 
(MCHC)
Clinical chemistry –a, c
Serum concentrations of: 
Alanine aminotransferase (ALT)
Cystatin C
Albumin
Glucose (random)
Alkaline phosphatase
High-density lipoprotein (HDL)
Aspartate aminotransferase (AST)
Lactic acid dehydrogenase (LDH)
Bilirubin, direct
Low-density lipoprotein (LDL)
Bilirubin, total
Magnesium
Bicarbonate/CO2
Phosphate
Blood urea nitrogen (BUN) or blood urea
Potassium
Calcium
Protein
Chloride
Sodium
Cholesterol
Triglycerides
Creatinine
Urate
Creatinine kinase (CK)
Other Tests -a, c
PSA
Testosterone
Abbreviations:  CO2 = carbon dioxide; CRF = case report form; PSA = prostate specific antigen; RBC = red blood 
cells; WBC = white blood cells.
a
Central laboratory.  
b
Neutrophils reported by automated differential hematology instruments include both segmented and band forms. 
When a manual differential is needed to report the neutrophils, the segmented and band forms should be added 
together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Enrollment and treatment decisions may be based on local laboratory results. A sample must still be sent to the 
central laboratory. Differences between these samples will not be considered a protocol deviation. 


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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 participant 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.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e., not related to progression of underlying 
disease).

Exacerbation of a chronic or intermittent pre-existing 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 overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

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.


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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
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 (e.g., 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 pre-existing 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 (e.g., 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
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 


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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.
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 (e.g., 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 the 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 
the 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 the 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 use CTCAE v5.0 (NCI 2017) to assign AE severity grades.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
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 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 


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reviewed the AE/SAE and has provided an assessment of causality.

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 make an assessment of causality for 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 causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

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 completed CRF.

The investigator will submit any updated SAE data to Sponsor or designee within 
24 hours of receipt of the information.
10.3.4.
Reporting of SAEs
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 (see next section) or to 
the medical monitor by telephone.

Contacts for SAE reporting can be found in the SAE form.
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 


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telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SAE form.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Contraception Guidance:
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE (for study participants or their 
female partners if sexually active and if female partners are of childbearing age):
Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device

Intrauterine hormone-releasing systemc

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 90 
days.
Highly Effective Methodsb That Are User Dependent 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc

oral

intravaginal

transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc

oral

injectable

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 participant.
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.
c
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
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
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported including fetal status 
(presence or absence of anomalies) or indication for the procedure. 


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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 CRP/CRS.
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 immediate patient 
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
Hepatitis B core IgM antibody
Anti-nuclear antibody (ANA)


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Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA)a
HBV DNAd
Anti-actin antibodyb
Hepatitis 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; CRP = clinical research physician; CRS = clinical research scientist; 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; no Central Testing available.  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
Dexamethasone
a
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lesinurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
a Important note: All patients may receive supportive therapy with dexamethasone, preferably <=7 days, if clinically 
indicated.
Abbreviations:  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, and Investigations.
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 4-6 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 (e.g., 
tracheotomy or intubation)
Death
Definition:  A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Investigations
Alanine 
aminotransferase 
(ALT) increased 
>ULN - 3.0 x ULN if 
baseline was normal; 1.5 -
3.0 x baseline if baseline 
was abnormal
>3.0 - 5.0 x ULN if 
baseline was normal; >3.0 
- 5.0 x baseline if baseline 
was abnormal
>5.0 - 20.0 x ULN if 
baseline was normal; >5.0 -
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 a blood specimen.
Aspartate 
aminotransferase 
(AST) increased
>ULN - 3.0 x ULN if 
baseline was normal; 1.5 -
3.0 x baseline if baseline 
was abnormal
>3.0 - 5.0 x ULN if 
baseline was normal; >3.0 
- 5.0 x baseline if baseline 
was abnormal
>5.0 - 20.0 x ULN if 
baseline was normal; >5.0 -
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


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10.8.
Appendix 8: Abbreviations
Term
Definition
ADT
androgen deprivation therapy
AE
adverse event
AI
Aromatase inhibitor
ALT
alanine aminotransferase
AR
androgen receptor
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BOR
best overall response
CDK
cyclin-dependent kinase
CDK 4&6
cyclin-dependent kinases 4 & 6
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CNS
central nervous system
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.
CR
complete response
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.
CRPC
castration-resistant prostate cancer
CRS
clinical research scientist
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome p450
DES
diethylstilbestrol


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I3Y-MC-JPCY(b)
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Term
Definition
DMC
data monitoring committee
DSMT
Developmental Safety Management Team
DSST
Developmental Safety Surveillance Team
ECG
electrocardiogram
ECOG
eCOA
Eastern Cooperative Oncology Group
electronic Clinical Outcome Assessment
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medical Agency
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.
EORTC QLC-C30
European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire
ERB
Ethical review boards
FACT-G
Functional Assessment of Cancer Therapy-General
FACT-GP5
GP5 item of the Functional Assessment of Cancer Therapy-General instrument, which 
asks participants to report the extent to which “(they are) bothered by side-effects of 
treatment”
FDA
Food and Drug Administration
GCP
good clinical practice
GFR
glomerular filtration rate
GnRH
gonadotropin-releasing hormone
GnRHa
gonadotropin-releasing hormone agonist or antagonist
HER2-
human epidermal growth factor receptor 2 negative
HR+
hormone receptor positive
IB
Investigator’s Brochure
ICF
informed consent form


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I3Y-MC-JPCY(b)
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Term
Definition
ICH
International Council for Harmonisation
IEC
Independent Ethics Committees
IHC
immunohistochemistry
ILD
Interstitial lung disease
Informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate.  Informed consent is 
documented by means of a written, signed and dated informed consent form.
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.
IRB
Institutional Review Boards
IV
intravenous
MATE
multidrug and toxin extrusion
MBC
metastatic breast cancer
mCRPC
metastatic castration-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
mHSPC
metastatic hormone-sensitive prostate cancer
MRI
magnetic resonance imaging
NHA
Novel hormonal agent
nmCRPC
non-metastatic castration-resistant prostate cancer
NRS
Numeric Rating Scale
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
PCa
prostate caner


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I3Y-MC-JPCY(b)
91
Term
Definition
PCWG3
Prostate Cancer Clinical Trials Working Group 3
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PPS
per-protocol set:  The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PR
partial response
pRb
retinoblastoma protein
PRO
patient reported outcome
PRO-CTCAE
patient reported outcome- common terminology criteria for adverse events
PSA
prostate-specific antigen
PT
Preferred Term
QoL
Quality of Life
Rb
retinoblastoma gene
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
rPFS
radiographic progression free survival
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
SD
stable disease
SoA
Schedule of Activities
SOC
System Organ Class 
SSE
symptomatic skeletal event
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin


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I3Y-MC-JPCY(b)
92
Term
Definition
TEAE
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TTE
time to event
VTE
venous thromboembolic events


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10.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment a (24 September 2020) 
This amendment is considered to be 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 incorporates changes in response to regulators’ comments.  In addition, this 
amendment includes changes made to clarify information for sites and minor grammatical, 
formatting, or spelling edits.
Section # and Name
Description of Change
Brief Rationale
1.2 Schema
Clarification of Primary 
Endpoint
Administrative
1.3 Schedule of Activities
Added mobile healthcare 
service option to collect 
and process lab samples
Protocol flexibility
1.3.1 Sampling Schedule for 
Pharmacokinetics and Biomarkers
Added mobile healthcare 
service option to collect 
and process
pharmacokinetic (PK) 
and biomarker 
plasma/blood samples
Protocol flexibility
1.3.1 Sampling Schedule for 
Pharmacokinetics and Biomarkers
Added blood 
microsampling to PK 
sampling schedule 
Added blood microsampling
instructions  
2.3.1 Benefit Assessment
Updated new treatment 
options for metastatic 
castration-resistant 
prostate cancer (mCRPC) 
where approved
In response to regulators’ comments
5.1 Inclusion Criteria
Clarification of Inclusion
Criterion #1 to indicate 
participants’ suitability
for experimental therapy
In response to regulators’ comments
5.2 Exclusion Criteria
Clarification on prior 
Administrative 


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I3Y-MC-JPCY(b)
94
investigational agent
5.3 Lifestyle Considerations
Text was added to caution 
participants with known 
hypersensitivity or 
suspected intolerance to 
abemaciclib or any of its 
excipients
In response to regulators’ comments
6.1 Study Intervention(s) Administered
Clarification on missed or 
vomited doses
Administrative
6.2 
Preparation/Handling/Storage/Accountability
Clarification on study 
personnel responsibilities 
regarding study drug
Administrative 
6.2.1 Selection and Timing of Doses
Clarification to indicate
that additional study 
treatment may be 
dispensed for planned 
delays
Administrative
6.5 Concomitant Therapy
Clarification to refer to 
prescribing information 
for concomitant 
medications
In response to regulators’ comments
7.2.1 Discontinuation of Inadvertently 
Enrolled Patients
Clarification on 
discontinuation of 
inadvertently enrolled 
patients
Administrative
7.3 Lost to Follow up
Clarification on 
designated study 
personnel
Administrative
8.1.1 Definitions of Efficacy Measures
Clarification was 
provided on definition of 
“Objective Response 
Rate” and for 
consistency, “Disease 
Control Rate
In response to regulators’ comments
8.2.1 Clinical Safety Laboratory 
Assessments
Clarification on study 
personnel and 
responsibilities for 
designating local lab and 
Administrative


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I3Y-MC-JPCY(b)
95
reporting of AEs. 
8.5 Pharmacokinetics
Updated PK collection 
instructions
Added blood microsampling 
instructions 
8.8.1 Tissue Samples for Biomarker 
Research
Removed requirement of 
discussion with Lilly 
clinical research 
physician/scientist 
(CRP/CRS) for archival 
tissue 
Administrative
8.10.2 Health Care Resource Utilization
Clarification on 
authorized study 
personnel 
Administrative 
9.2 Sample Size Determination
Clarification on 
“Objective Response”
Editorial
9.4.2 Primary Analysis
Clarification was 
provided on definition of 
“Objective Response 
Rate”
Administrative
10.1.1 Regulatory and Ethical 
Considerations
Clarification on 
investigator study 
oversight and 
responsibilities 
Administrative
10.1.6 Data Quality Assurance
Updated instructions for 
data capture of eCOA
Administrative
10.2 Appendix 2:  Clinical Laboratory tests
Removed “recorded” typo
Editorial


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96
11.
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Leo Document ID = dfa00326-6bb9-406f-a51e-3b53a7e10a0d
Approver:
Approval Date & Time: 04-Mar-2021 15:43:17 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 04-Mar-2021 21:33:24 GMT
Signature meaning: Approved
PPD
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SAP_001.pdf: 
I3Y-MC-JPCY Statistical Analysis Plan
CYCLONE 1: A Phase 2 Study of Abemaciclib in Metastatic Castration-Resistant 
Prostate Cancer Patients Previously Treated with a Novel Hormonal Agent and Taxane-
based Chemotherapy
NCT04408924   
Approval Date: 10-Dec-2020 


I3Y-MC-JPCY Statistical Analysis Plan Version 1
Page 1
LY2835219
1.
Statistical Analysis Plan:
I3Y-MC-JPCY: CYCLONE 1: A Phase 2 Study of 
Abemaciclib in Metastatic Castration-Resistant Prostate 
Cancer Patients Previously Treated with a Novel 
Hormonal Agent and Taxane-based Chemotherapy
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities: This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Abemaciclib (LY2835219)
Study I3Y-MC-JPCY is an open-label, single-arm, Phase 2 study to assess the safety and 
efficacy of abemaciclib monotherapy in heavily pretreated mCRPC patients who received at 
least 1 novel hormonal agent and 2 taxane regimens.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I3Y-MC-JPCY
Phase 2
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 10-Dec-2020 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: I3Y-MC-JPCY: CYCLONE 1: A Phase 2 
Study of Abemaciclib in Metastatic Castration-Resistant Prostate 
Cancer Patients Previously Treated with a Novel Hormonal Agent 
and Taxane-based Chemotherapy........................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................8
6.
A Priori Statistical Methods ................................................................................................9
6.1.
General Considerations ..................................................................................................9
6.1.1.
Populations ............................................................................................................9
6.1.2.
Definitions and Conventions ..................................................................................9
6.2.
Handling of Dropouts or Missing Data.........................................................................10
6.3.
Patient Disposition .......................................................................................................10
6.4.
Patient/Subject Characteristics .....................................................................................10
6.4.1.
Demographics......................................................................................................10
6.4.2.
Baseline Disease Characteristics ..........................................................................10
6.4.3.
Historical Illnesses ...............................................................................................11
6.4.4.
Prior Therapies.....................................................................................................11
6.4.5.
Therapies After Study Treatment Discontinuation................................................12
6.5.
Treatment Compliance .................................................................................................12
6.6.
Concomitant Therapy...................................................................................................12
6.7.
Efficacy Analyses ........................................................................................................12
6.7.1.
Primary Outcome and Methodology.....................................................................12
6.7.2.
Secondary Efficacy Analyses ...............................................................................13
6.7.2.1.
Radiographic Progression-Free Survival.........................................................13
6.7.2.2.
Overall Survival .............................................................................................14
6.7.2.3.
Duration of Response .....................................................................................15
6.7.2.4.
Disease Control Rate ......................................................................................15
6.7.2.5.
Time to Prostate-Specific Antigen Progression ...............................................15
6.7.2.6.
Prostate-Specific Antigen Response Rate........................................................16
6.7.2.7.
Time to Symptomatic Progression ..................................................................16
6.7.3.
Sensitivity Analyses.............................................................................................16


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6.7.4.
Exploratory Analyses...........................................................................................17
6.8.
Health Outcomes/Quality-of-Life Analyses..................................................................17
6.9.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................17
6.10. Biomarker Analyses.....................................................................................................17
6.11. Safety Analyses............................................................................................................18
6.11.1.
Extent of Exposure...............................................................................................18
6.11.2.
Adverse Events ....................................................................................................18
6.11.3.
Deaths..................................................................................................................19
6.11.4.
Clinical Laboratory Evaluation.............................................................................19
6.11.5.
Vital Signs and Other Physical Findings...............................................................19
6.12. Subgroup Analyses.......................................................................................................20
6.13. Protocol Violations.......................................................................................................20
6.14. Interim Analyses and Data Monitoring.........................................................................20
6.15. Annual Report Analyses...............................................................................................20
6.16. Clinical Trial Registry Analyses...................................................................................20
7.
References ........................................................................................................................22


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Table of Contents
Table
Page
Table JPCY.4.1. Study Objectives and Endpoints.......................................................................6
Table JPCY.6.1. rPFS Event/Censoring Scheme ......................................................................14
Table JPCY.6.2. Time to PSA Progression Event/Censoring Scheme.......................................16


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first visit when a subject 
receives study treatment or any other protocol intervention.


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4.
Study Objectives
Table JPCY.4.1.
Study Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the efficacy of abemaciclib 
monotherapy

Investigator-assessed ORR per RECIST 1.1
Secondary

To further characterize the clinical activity of 
abemaciclib monotherapy

rPFS

OS

DoR

DCR

PSA response rate

Time to PSA progression

Time to symptomatic progression

To characterize the safety profile of 
abemaciclib

Assessment of safety including, but not limited 
to, the following: AEs, SAEs, physical 
examination, and clinical laboratory
abnormalities per CTCAE v5.0

To explore patient-reported tolerability of 
abemaciclib monotherapy (including 
symptomatic AEs and overall side-effect 
burden), patient-reported pain intensity, 
physical functioning, and overall 
health-related quality of life

PRO-CTCAE

FACT-GP5

7-day Worst Pain Numeric Rating Scale

EORTC QLQ-C30 Physical Functioning Scale

EORTC QLQ-C30 Global Health Status/QoL 
Scale

To characterize the PK of abemaciclib and its 
metabolites

Concentrations of abemaciclib and its 
metabolites

To characterize Ki-67 baseline expression

Percentage of cells expressing Ki-67 by IHC
ExploratoryCCI


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Study Objectives and Endpoints
Abbreviations: AE = adverse event; CTCAE v5.0 = Common Terminology Criteria for Adverse Events version 5.0 
(NCI 2017); DCR = disease control rate; DoR = duration of response; EORTC QLQ-C30 = European 
Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; FACT-GP5 = Functional 
Assessment of Cancer Therapy-General; IHC = immunohistochemistry; ORR= objective response rate; OS = 
overall survival; PK = pharmacokinetics; PRO-CTCAE = Patient-Reported Outcome Common Terminology 
Criteria for Adverse Events version 5.0 (NCI 2017); PSA = prostate-specific antigen; QoL = quality of life; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1 (Eisenhauer et al. 2009); rPFS = 
radiographic progression-free survival; SAE = serious adverse event; SSE = symptomatic skeletal event.


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5.
Study Design
5.1.
Summary of Study Design
I3Y-MC-JPCY (CYCLONE 1) is a Phase 2, open-label, single-arm, multicenter study to assess 
the efficacy of abemaciclib monotherapy in participants with metastatic castration-resistant 
prostate cancer (mCRPC) whose disease progressed on or after at least 1 androgen-axis therapy 
(abiraterone acetate, apalutamide, darolutamide or enzalutamide) and 2 taxane-based 
chemotherapy regimens (docetaxel and cabazitaxel). Participants may have received up to 3 prior 
systemic treatments for mCRPC, must have measurable disease per Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST 1.1), and a have metastatic lesion amenable to biopsy. 
Androgen deprivation therapy with a gonadotropin-releasing hormone agonist must be continued 
throughout the study for participants who have not undergone bilateral orchiectomy. 
Abemaciclib 200 mg twice daily will be administered on a continuous dosing schedule until 
disease progression, unacceptable toxicity, or other discontinuation criteria are met.
This study will initially treat approximately 40 participants.
5.2.
Determination of Sample Size
All treated patients will be included in the assessment of objective response.
An observed response rate of at least 12.5% will be considered as evidence of clinically relevant 
activity. Applying this rule to a 40-patient cohort yields an adequate Type I error rate and power. 
As an illustration of Type I error control, assuming a true response rate of 5%, the probability of 
observing an objective response rate (ORR) of at least 12.5% in a cohort of 40 participants is 
4.8%. As an illustration of power, assuming a true response rate of 15%, the probability of 
observing an ORR of at least 12.5% is 73.7%.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or its 
designee. The analyses for this study will be mostly descriptive, except for possible exploratory 
analysis as deemed appropriate. For continuous variables, summary statistics will include the 
number of patients, mean, median, standard deviation, minimum, and maximum. Categorical 
variables will be summarized using number of patients, frequency, and percentages. Missing data 
will not be imputed, except for missing date of birth for analysis purpose. If birth year and month 
are available and date is not available or missing, date will be imputed to the 15th of that month.
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
clinical research physician (CRP)/clinical research scientist (CRS), pharmacokineticist, and 
statistician. The Lilly CRP/CRS and statistician will also be responsible for the appropriate 
conduct of an internal review for both the final study report and any study-related material to be 
authorized by Lilly for publication.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR). Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
6.1.1. Populations
For the purpose of statistical analysis, following populations are defined:
Population
Description
Entered
All participants who sign the ICF
Treated/Safety
All participants who have initiated study intervention, regardless of how 
many doses of study intervention they receive or how many on-study research 
procedures are performed
Biomarker-Evaluable
All participants within the subset of participants from the treated population 
from whom a valid pretreatment tumor assay result has been obtained
Pharmacokinetic Analysis
All treated participants who received at least 1 dose of abemaciclib and have 
at least 1 evaluable PK sample
Abbreviations: ICF = informed consent form; PK = pharmacokinetics.
6.1.2. Definitions and Conventions
Study drug or study treatment refers to abemaciclib.
Date of first dose is the date of the first dose of study drug.
Study day will be calculated as


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
the difference between the date of the event or assessment and the date of first dose plus 
1 for all events or assessments occurring on or after the day of first dose (eg, if an event 
occurs on 08 January 2021 and the date of first dose was 06 January 2021, the study day 
of the event is 3)

the difference between the date of the event or assessment and the date of first dose for 
all events or assessments occurring before the day of first dose (eg, if an event occurs on 
05 January 2021 and the date of first dose was 06 January 2021, the study day of the 
event is -1).
One month is defined as 365/12 days.
Unless otherwise noted, summaries of continuous variables will include a mean, median, 
standard deviation, minimum, and maximum. 
Unless otherwise noted, summaries of categorical variables will include the frequency and 
percentage (relative to the population being analyzed) of each category. 
The assumptions for each statistical method will be evaluated. If there is violation of 
assumptions, alternative statistical methods may be used. Additional exploratory analyses of the 
data will be conducted as deemed appropriate. Unless otherwise stated, all tests of treatment 
effects will be conducted at a 1-sided alpha level of .025, and all confidence intervals (CIs) will 
be given at a 2-sided 95% level.
6.2.
Handling of Dropouts or Missing Data
With the exception of dates, missing data will not be imputed. The method of imputation for any 
dates that are imputed is described in the relevant section.
6.3.
Patient Disposition
A detailed description of patient disposition will be provided. It will include a summary of the 
number and percentage of patients entered into the study, treated in the study, reasons for 
discontinuation from study treatment, and reasons for discontinuation from study. Reason for 
discontinuation from both study treatment and the study will be summarized by predetermined 
categories. If the reason for discontinuation is an adverse event (AE), the associated AE term 
will be reported.
6.4.
Patient/Subject Characteristics
6.4.1. Demographics
Patient demographics will be summarized for all treated patients. Patient demographics will 
include sex, race, ethnicity, country, age, height, weight, and body mass index.
6.4.2. Baseline Disease Characteristics
Disease characteristics will be summarized. Disease characteristics will include the following:

initial pathological diagnosis


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
disease stage - TNM stage, Gleason score and prostate-specific antigen (PSA) at initial 
diagnosis

time from initial diagnosis to:
o
castration-resistant prostate cancer (CRPC)
o
study treatment start date

PSA doubling time prior to study treatment

type of progression at study entry (PSA progression and/or radiographic progression)

nature of disease (bone/nodal disease only, visceral metastases, or other)

number of organs involved (1, 2, or 3 or more)

metastatic site(s)

baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), and

baseline laboratory values (PSA, testosterone, lactate dehydrogenase [LDH], alkaline 
phosphatase [ALP], hemoglobin [Hb], albumin).
Disease stage (I-IV) at initial diagnosis will be derived based on TNM stage, Gleason score, and 
PSA.
Nature of disease and number of organs involved will be derived from the baseline electronic 
clinical (case) report forms: ‘Target Tumor: RECIST 1.1 (Tumor Assessment)’ and ‘Non-Target 
Tumor: RECIST 1.1 (Tumor Assessment)’ for soft tissue, and ‘Bone Lesion – Baseline (Tumor 
Assessment)’. The number of organs involved in soft tissue will be derived from the location 
codes of the target and non-target lesions.
6.4.3. Historical Illnesses
Historical illnesses are clinically relevant events in the past that ended before the screening visit. 
Historical illnesses (using Preferred Terms [PTs] from the most current version of the Medical 
Dictionary for Regulatory Activities [MedDRA]) will be summarized.
6.4.4. Prior Therapies
Prior radiotherapy, surgery, and systemic therapy will be summarized. Prior radiotherapy and 
surgery will be categorized by reason for regimen. Prior systemic therapies will be categorized 
by type of regimen (endocrine therapy, chemotherapy, targeted therapy, or other) and reason for 
regimen ([neo]adjuvant therapy or therapy for locally advanced, nonmetastatic 
castration-resistant, metastatic hormone-sensitive, or metastatic castration-resistant disease). 
Frequency of each specific therapy will be tabulated within each type of regimen and reason for 
regimen.


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6.4.5. Therapies After Study Treatment Discontinuation
The numbers and percentages of participants receiving anticancer therapies after study treatment 
discontinuation will be provided by type of therapy (surgery, radiotherapy, or systemic therapy) 
and by drug class and/or name, overall and by line of therapy.
Systemic therapies received following study treatment discontinuation will be summarized. 
Therapies will be summarized overall and by category:

endocrine therapy

chemotherapy

targeted therapy, or 

other.
6.5.
Treatment Compliance
Treatment compliance for abemaciclib will be measured by pill counts and summarized 
cumulatively. Compliance will be calculated as the ratio of total dose taken to the total assigned 
dose (plus or minus any dose adjustments and doses omitted/withheld). The total assigned dose 
for a patient with no adjustments or omissions is as follows:

200 mg per dose × 2 doses per day × number of days on study drug
6.6.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization (WHO) drug dictionary. All concomitant medications will be summarized 
by number and percentage of patients for the treated population using the base name (without 
esters or salts).
6.7.
Efficacy Analyses
Unless otherwise noted, all efficacy analyses will be performed on the treated population.
Patients with a nonevaluable or unknown response per each specified criteria will be considered 
nonresponders for the purpose of calculating response rates.
Unless otherwise stated, all tests of treatment effects will be conducted at a 1-sided alpha level of 
.025, and all CIs will be given at a 2-sided 95% level.
Objective response rate is the primary endpoint for this study. The study will be considered 
positive if ORR is positive at its primary analysis, as described below.
6.7.1. Primary Outcome and Methodology
The primary endpoint for this study is ORR, defined as the proportion of participants who have a 
soft tissue best overall response (BOR) of complete response (CR) or partial response (PR) per 
RECIST 1.1 and do not have concurrent bone disease progression per Prostate Cancer Working 
Group 3 (PCWG3) criteria, as assessed by the investigator/local radiologist. The primary 
analysis will require confirmation of responses, but, when appropriate, response rates including 


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both confirmed and unconfirmed responses may also be reported. Calculation of BOR will be 
done for each patient in the treated population and will include all response evaluations through 
the short-term follow-up visit and before the initiation of poststudy-treatment discontinuation 
therapy.
The primary analysis of the primary endpoint of ORR will be performed approximately 6 months 
after the last patient enters treatment. In certain circumstances, it may be appropriate to perform 
the primary analysis earlier (for instance, if all treated patients have experienced objective 
disease progression). All secondary endpoints will be evaluated at this time. Additional updated 
analyses of efficacy and safety may be conducted at later times if deemed appropriate by the 
sponsor.
The ORR will be evaluated against a null hypothesis of 5%. At the time of primary analysis, if 5 
or more responders are observed in the planned 40 patients, the study will be considered positive.
This is equivalent to a p-value ˂.05 for the exact test of a null hypothesis of an ORR of 5% 
against an alternative of ORR ˃5%.
Lilly or its designee will collect and store tumor assessment images, and an independent review 
of imaging scans may be performed by Lilly or its designee. Analyses of ORR may be repeated 
using independently reviewed BOR and presented as sensitivity analyses.
6.7.2. Secondary Efficacy Analyses
6.7.2.1.
Radiographic Progression-Free Survival
The radiographic progression-free survival (rPFS) time is measured from the date of first dose to 
the earliest date of investigator-determined radiographic disease progression (by objective 
radiographic disease assessment per RECIST 1.1 for soft tissue AND/OR radionuclide bone scan 
using PCWG3 criteria for bone) or death from any cause, whichever occurs first. Patients who 
have neither progressed nor died will be censored at the day of their last radiographic tumor 
assessment (if available) or date of first dose if no postinitiation (ie, postbaseline) radiographic 
assessment is available. The detailed censoring rules are described in Table JPCY.6.1.
Radiographic progression-free survival will be summarized and listed for all treated patients. The 
Kaplan-Meier (KM) method (Kaplan and Meier 1958) will be used to estimate the rPFS curve as 
well as rPFS rates at 3, 6, 9, and 12 months.


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Table JPCY.6.1.
rPFS Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Radiographic disease progression or death
Event
Earliest date of radiographic disease 
progression or deathb
No radiographic disease progression and no death
Censored
Date of last adequate radiographic 
assessment showing no evidence of 
disease progression or date of first dose
(whichever is later)c
Unless
No baseline radiographic tumor assessment available
Censored
Date of first dose
No adequate postbaseline radiographic tumor 
assessment available and death reported after 2 scan 
intervals following first dosec,d
Censored
Date of first dose
New anticancer treatment started and no radiographic 
disease progression or death within 14 days
Censored
Date of last adequate radiographic 
assessment showing no evidence of 
disease progression prior to (start of new 
therapy +14 days) or date of first dose 
(whichever is later)c
Radiographic disease progression or death documented 
after 2 or more scan intervals following last adequate 
radiographic tumor assessment or first dose (whichever 
is later)c,d
Censored
Date of last adequate radiographic 
assessment showing no evidence of 
disease progression or date of first dose
(whichever is later)c
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; rPFS = radiographic
progression-free survival; SD = stable disease.
a
Clinical/symptomatic deterioration that is not radiologically confirmed will not be considered as radiographic 
disease progression.
b
To be specific, once the radiographic disease progression is observed, especially for confirmed bone progression, 
the date of disease progression is the date at which initial bone progression (or soft tissue progression, whichever 
is earlier) is observed, not the date that the bone progression is confirmed by a subsequent assessment.
c
Adequate radiographic tumor assessment refers to an assessment of one of the following:
•
Soft tissue disease with one of the following responses: CR, PR, SD; and adequate bone scan showing no or 
initial evidence of disease progression.
•
Soft tissue disease with a response of PD.
•
Bone scan showing confirmed disease progression.
To be specific, “last adequate radiographic assessment showing no evidence of disease progression,” does not 
include the assessment showing initial/unconfirmed evidence of bone progression. If tumor scans for 1
assessment were performed on multiple days, use the earliest scan date for that visit as the date of assessment.
d
Two scan intervals refer to the time period of next 2 protocol-scheduled radiographic tumor assessments. Time is 
measured from the last adequate radiographic tumor assessment date. The window of the tumor assessment is 
also considered. For example, if the last adequate assessment occurs during Cycle 3, the next 2
protocol-mandated assessments are Cycle 5 and Cycle 7, and the window around each assessment is 7 days, then 
2 scan intervals will be considered as 2*(28*2 + 7) = 126 days.
6.7.2.2.
Overall Survival
The overall survival (OS) time is measured from the date of first dose to the date of death from 
any cause. If the patient is alive or lost to follow-up at the time of data analysis, OS data will be 
censored on the last date the patient is known to be alive. Overall survival will be summarized 


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and listed for all treated patients. The KM method (Kaplan and Meier 1958) will be used to 
estimate the OS curve as well as OS rates at 3, 6, 9, 12, and 18 months.
6.7.2.3.
Duration of Response
Duration of Response (DoR) is defined only for confirmed responders (patients with a soft tissue 
BOR of CR or PR). It is measured from the date of first evidence of soft tissue CR or PR to the 
earliest date of investigator-determined radiographic disease progression (by objective 
radiographic disease assessment per RECIST 1.1 for soft tissue AND/OR radionuclide bone scan 
using PCWG3 criteria for bone) or death from any cause, whichever is earlier. It is calculated as 
date of radiographic progression or death minus date of first soft tissue response evaluation of 
CR or PR plus 1. The DoR will be censored according to the same rules as rPFS.
Duration of response will be summarized and listed for all treated patients, and a KM analysis of 
DoR will be performed to estimate the DoR curve. Point estimates and CIs for DoR quartiles and 
DoR rates will be calculated every 3 months for the first 18 months.
6.7.2.4.
Disease Control Rate
The disease control rate (DCR) is the percentage of all treated patients with a best response of 
CR, PR, or stable disease (SD) that do not have concurrent bone disease progression per 
PCWG3. The DCR will be summarized for all treated patients.
6.7.2.5.
Time to Prostate-Specific Antigen Progression
Prostate-specific antigen progression is defined as a ≥25% increase and an absolute increase of 
≥2 ng/mL above the nadir (or baseline value if baseline is the smallest on study), which is 
confirmed by a second value obtained 3 or more weeks later. Any postbaseline PSA 
measurements within 12 weeks since baseline will be ignored in determining PSA progression. 
Time to PSA progression is measured from the date of first dose to the date of first observation 
of PSA progression. Patients who have not had PSA progression will be censored at the day of 
their last PSA assessment (if available) or date of first dose if no postinitiation (ie, postbaseline) 
PSA assessment is available. The detailed censoring rules are described in Table JPCY.6.2.
Time to PSA progression will be summarized and listed for all treated patients. The KM method 
(Kaplan and Meier 1958) will be used to estimate the time to PSA progression curve as well as 
landmark survival rates at 3, 6, 9, and 12 months.


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Table JPCY.6.2.
Time to PSA Progression Event/Censoring Scheme
Situation
Event/Censor
Date of Event or Censor
Confirmed PSA progression
Event
Date of first observation of PSA progressiona
Not known to have had confirmed PSA 
progression confirmed
Censored
Date of last PSA assessment showing no evidence 
of PSA progression or date of first dose (whichever 
is later)b
Unless
No baseline PSA assessment or no 
postbaseline PSA assessments available 
beyond 12 weeks since baseline
Censored
Date of first dose
Abbreviation: PSA = prostate-specific antigen.
a
To be specific, for confirmed PSA progression, the date of first observation of PSA progression is the date at 
which initial PSA progression is observed not the date that the PSA progression is later confirmed by a 
subsequent assessment.
b
To be specific, “last PSA assessment showing no evidence of PSA progression,” does not include the assessment 
showing initial/unconfirmed evidence of PSA progression.
6.7.2.6.
Prostate-Specific Antigen Response Rate
The PSA response rate is defined as the proportion of participants with a reduction in PSA level 
≥50% from baseline, confirmed with a second assessment conducted at least 3 weeks later. The 
PSA response rate will be listed and summarized for all treated patients. 
6.7.2.7.
Time to Symptomatic Progression
Time to symptomatic progression is defined as the time from first dose to any of the following 
(whichever occurs earlier):

symptomatic skeletal event, defined as symptomatic fracture, surgery or radiation to 
bone, or spinal cord compression

pain progression or worsening of disease-related symptoms requiring initiation of a new 
systemic anticancer therapy, and

development of clinically significant symptoms due to locoregional tumor progression 
requiring surgical intervention or radiation therapy.
For patients not known to have had symptomatic progression at the time of data analysis, data 
will be censored on the last date at which no symptomatic progression is indicated.
Time to symptomatic progression will be summarized and listed for all treated patients. A KM 
analysis will be performed to estimate the time to symptomatic progression survival curve as 
well as quartiles and rates at 3-month intervals. As appropriate, these analyses will be repeated 
for each of the individual components of time to symptomatic progression.
6.7.3. Sensitivity Analyses
Sensitivity analyses will be undertaken for calculation of the primary or key secondary endpoints 
in order to evaluate the robustness of the analysis. The following sensitivity analysis will be 
performed:


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
Blinded Independent Central Review - as appropriate, imaging-based endpoints 
(including ORR, DoR, and rPFS) will also be assessed by a blinded independent review 
of centrally stored imaging.
6.7.4. Exploratory Analyses
6.8.
Health Outcomes/Quality-of-Life Analyses
Patient-reported outcomes (PRO) are measured through the following:

single-item worst Pain Numerical Rating Scale (NRS)

the National Cancer Institute’s PRO version of the Common Terminology Criteria for 
Adverse Events version 5.0 (CTCAE) (PRO-CTCAE)

item GP5 of the Functional Assessment of Cancer Therapy-General (FACT-G), and

European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLC-C30).
Additionally, analgesic use will be classified into categories (eg, according to the WHO
analgesic ladder or the Analgesic Quantification Algorithm scale).
For each instrument, the compliance rate will be calculated by visit. Reasons for noncompliance 
will also be summarized.
6.9.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods 
Pharmacokinetic (PK) and pharmacodynamic analyses will be performed according to a separate 
PK analysis plan.
6.10. Biomarker Analyses
Protocol Section 8.8 describes the biomarker samples that will be collected during the course of 
the study and will be used to carry out biomarker-specific exploratory analyses. In addition to 
characterizing the biomarker data distribution, these analyses may include the assessment of 
prognostic or predictive relationships between the biomarker(s) being investigated and the 
clinical efficacy endpoints of the study.
In particular, the percentage of cells expressing Ki-67 by immunohistochemistry for each 
participant in the biomarker-evaluable population will be summarized and listed. Additionally, 
Ki-67 expression values will be classified into a series of binary variables (eg, <10%, <25%, 
etc.), and the proportion of participants in each group will be reported with corresponding exact 
95% CIs.
CCI
CCI


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If deemed necessary, further analysis of biomarkers may be described in a separate biomarker 
SAP.
6.11. Safety Analyses
Safety analyses will be completed on the safety population as specified below, unless COVID-19 
impact creates a situation requiring a change to an existing analysis or a need for additional 
analyses as outlined by Nilsson et al. (2020).
6.11.1. Extent of Exposure
Drug exposure, drug adjustments, and omissions for abemaciclib will be summarized for all 
treated patients. Drug exposure will include summaries of cycles received per patient, duration 
on therapy, and cumulative dose. The summary of dose adjustments and omissions will include 
the reason for adjustment or omission. Dose intensity will be summarized for all treated patients. 
Dose intensity will be calculated as the actual cumulative amount of drug taken divided by the 
duration of treatment. Relative dose intensity will be calculated as the actual amount of drug 
taken divided by the amount of drug assigned times 100% (ie, expressed as a percentage).
Extent of exposure will be measured by pill counts. Dose intensity will be expressed in mg/day. 
The assigned cumulative dose for abemaciclib while on study is

200 mg per dose × 2 doses per day × number of days on study drug.
6.11.2. Adverse Events
Adverse event verbatim text will be mapped by the sponsor or designee to corresponding 
terminology within the MedDRA. Severity grades will be assigned by the investigator using 
CTCAE version 5.0. Medical Dictionary for Regulatory Activities PTs, identified by Medical as 
clinically identical or synonymous, will be grouped together under a single, consolidated PT. For 
example, ‘Neutropenia’ and ‘Neutrophil count decreased’ will be reported as ‘Neutropenia’. 
Adverse events will be reported according to PTs resulting from this process. 
Preexisting conditions are defined as AEs that begin prior to the first dose of study drug. 
A treatment-emergent adverse event (TEAE) is defined as any AE that begins between the day of 
first dose and 30 days after treatment discontinuation (or up to any time if serious and related to 
study treatment) or any preexisting condition that increases in CTCAE version 5.0 grade between 
the day of first dose and 30 days after treatment discontinuation (or up to any time if serious and 
related to study treatment).
The MedDRA Lowest-Level Term will be used for comparisons of preexisting conditions to on-
treatment events in the treatment-emergent computation.
A serious adverse event (SAE) is any AE during this study that results in one of the following 
outcomes:

death

initial or prolonged inpatient hospitalization 


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
a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect, and

is considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
The following AE listings and summaries will be produced:

Overview of TEAEs

Summary of TEAEs by PT (all grade and Grade ≥3)

Summary of TEAEs by System Organ Class (SOC) and PT (all grade and Grade ≥3)

Summary of TEAEs by PT and maximum grade (1-5)

List of SAEs

Summary of SAEs by SOC and PT (all grade and grade ≥3), and

Summary of AEs as reason for study treatment discontinuation by PT.
The TEAE and SAE summaries will be produced for all TEAEs/SAEs and repeated for 
TEAEs/SAEs related to study treatment, where relationship of the AE to the study treatment will 
be assessed by the investigator (yes or no).
6.11.3. Deaths
All deaths on study not attributed to study disease by the investigator will be listed along with 
the reason for death, if known. For those deaths attributed to an AE, the listing will include the 
PT of the AE. A summary of deaths including reasons for death will be produced.
6.11.4. Clinical Laboratory Evaluation
All relevant hematology and chemistry laboratory values will be graded according to CTCAE 
version 5.0. These calculated grades will be summarized by cycle and maximum postbaseline 
grade over the entire study. Treatment-emergent changes will be summarized by the maximum 
postbaseline grade, and a shift table of baseline grade by maximum postbaseline grade will be 
produced.
6.11.5. Vital Signs and Other Physical Findings
Temperature, blood pressure, pulse rate, respiration rate, weight, and ECOG PS will be 
summarized by cycle.


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6.12. Subgroup Analyses
If results are suggestive of isolated efficacy or toxicity, subgroup analyses may be performed to 
identify hypotheses requiring further research.
6.13. Protocol Violations
Significant protocol violations that potentially compromise data integrity and patient safety will 
be summarized for all treated patients. These violations will include deviations that can be 
identified programmatically and those that can only be identified by the clinical research 
associate during monitoring. Significant protocol deviations are described in another document 
within the study Trial Master File.
6.14. Interim Analyses and Data Monitoring
There is 1 planned futility analysis and 1 planned interim analysis of efficacy for this study.
Interim analyses will be conducted by an assessment committee including, at a minimum, the 
study statistician, CRP/CRS, and Global Patient Safety physician.
The futility analysis will be conducted approximately 2 months after the 15th participant has 
entered treatment. Trial enrollment will continue while awaiting the results of the futility 
analysis. The study team will consider the totality of safety, efficacy, and PK data. As guidance, 
futility should be declared and trial enrollment stopped if 0 patients have achieved an 
unconfirmed PR or CR per RECIST 1.1 AND ˂5 participants have achieved a BOR of SD per 
RECIST 1.1 at the time of the futility analysis.
One additional interim analysis of efficacy will be conducted approximately 2 months after all 
participants have entered treatment. Endpoints using RECIST 1.1 will be analyzed considering 
both confirmed and unconfirmed responses. The interim analysis will be conducted to evaluate 
the initial evidence of antitumor activity but will not formally test for significance. The sponsor 
has no intent to stop the study based on the interim analysis of antitumor activity, and all 
participants will continue follow-up for all study objectives until study close. At a minimum, all
analyses described above of the primary efficacy endpoint, secondary efficacy endpoints, and 
safety will be conducted at this interim analysis.
Additional interim analyses may be conducted as deemed appropriate by the sponsor.
6.15. Annual Report Analyses
Annual report analyses, including Developmental Safety Update Report and Investigator’s 
Brochure analyses, are described in the LY2835219 Program SAP.
6.16. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling Clinical Trial Registry (CTR) 
requirements.
Analyses provided for CTR requirements include the following:


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
Summary of AEs, provided as a dataset which will be converted to an XML file; both 
SAEs and ‘Other’ AEs will be summarized by MedDRA PT
o
An AE is considered ‘Serious’ whether or not it is a TEAE.
o
An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious. For each SAE and ‘Other’ AE, for each term, the following are 
provided:

the number of participants at risk of an event

the number of participants who experienced each event term, and

the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in ˂5% of 
patients/subjects may not be included if a 5% threshold is chosen (5% is the minimum 
threshold).

Adverse event reporting is consistent with other document disclosures (eg, the CSR, 
manuscripts, etc.). 
In addition, a participant flow will be created that will describe how many enrolled patients 
completed the study and, for those who did not, the frequency of each reason for not completing. 
This analysis will be based on study discontinuation not treatment discontinuation. A patient will 
be identified as having completed the study if the patient dies while on the study or the patient 
had discontinued study treatment and is in follow-up at the time of the final OS analysis. Patients 
who withdraw consent before the final OS analysis or who are still on treatment at the time of the 
final OS analysis will be identified as not completing the study.


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7.
References
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
https://doi.org/10.1016/j.ejca.2008.10.026
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat 
Assoc. 1958(282);53:457-481. https://doi.org/10.2307/2281868
[NCI] National Cancer Institute. Common terminology criteria for adverse events (CTCAE) 
v5.0. Published November 27, 2017. Accessed October 7, 2019.
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50
Nilsson M, Crowe B, Anglin G, et al. Clinical trial drug safety assessment for studies and 
submissions impacted by COVID-19. Stat Biopharm Res. 2020;4:498-505.
https://doi.org/10.1080/19466315.2020.1804444


Leo Document ID = bbf28a95-1e8a-45c3-88f8-cfde53b81da1
Approver: Valerie Andre (EMA\YE76215)
Approval Date & Time: 10-Dec-2020 09:14:47 GMT
Signature meaning: Approved