A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate Plus Prednisone With or Without Abemaciclib in Patients With Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Eli Lilly and Company

Protocol I3Y-MC-JPCM (f)
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of 
Abiraterone Acetate Plus Prednisone With or Without Abemaciclib in Patients 
With Metastatic Castration-Resistant Prostate Cancer
NCT03706365
Approval Date: 30-Apr-2024

I3Y-MC-JPCM(f) Clinical Protocol 
Page 1 
LY2835219 
Protocol I3Y-MC-JPCM(f) 
CYCLONE 2: A Phase 2/3, Randomized, Double-Blind, 
Placebo-Controlled Study of Abiraterone Acetate plus 
Prednisone with or without Abemaciclib in Patients with 
Metastatic Castration-Resistant Prostate Cancer  
Confidential Information 
The information contained in this protocol is confidential and is intended for the use of clinical investigators. It 
is the property of Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to 
persons not involved in the clinical investigation of abemaciclib (LY2835219),unless such persons are bound 
by a confidentiality agreement with Eli Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially 
confidential information exempt from public disclosure. Eli Lilly and Company requests consultation regarding 
release/redaction prior to any public release. In the United States, this document is subject to Freedom of 
Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated without the 
written approval of Eli Lilly and Company or its subsidiaries. 
abemaciclib (LY2835219) 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Numbers: 
EudraCT Number: 2016-004276-21 
EU CT Number: 2023-506777-36-00 
Amendment (f) Electronically Signed and Approved by Lilly 
on approval date provided below. 
Document Number: VV-CLIN-151605 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 2 
LY2835219 
Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Amendment e 
08-Sep-2023 
Amendment d 
30-Aug-2023 
Amendment c 
11-Mar-2021 
Amendment b 
28-Feb-2020 
Amendment a 
10-Oct-2018 
Original Protocol 
10-Jul-2018 
Amendment [f] 
This amendment is considered to be nonsubstantial. 
Overall rationale for the Amendment f: 
The rationale for this amendment is to enable additional flexibility on visits, safety and efficacy 
assessments, and dispensing during the continued access period.  
Section # and Name 
Description of Change 
Brief Rationale 
2. Schedule of 
Activities (Table JPCM 
1 Baseline, Treatment, 
and Post-Treatment 
Schedule of Activities) 
In Chemistry row, the 
instructions text is updated to 
reflect that the Section 7.7.2.3 
was changed to Section 7.4.1.2 
Correction 
2. Schedule of 
Activities (Table JPCM 
2 Continued-Access 
Schedule of Activities) 
Updated the continued-access 
schedule of activities table  
Additional flexibility on visits, 
safety and efficacy assessments, and 
dispensing during the continued 
access period 
3.1.5 Rationale for 
Amendment (e) 
Added rationale for 
amendment (e) 
Addition 
 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 3 
LY2835219 
Table of Contents  
Section 
Page  
Protocol I3Y-MC-JPCM(f) CYCLONE 2: A Phase 2/3, Randomized, 
Double-Blind, Placebo-Controlled Study of Abiraterone Acetate plus 
Prednisone with or without Abemaciclib in Patients with Metastatic 
Castration-Resistant Prostate Cancer ......................................................................................1 
Protocol Amendment Summary of Changes Table .......................................................................2 
Table of Contents .............................................................................................................................3 
1. 
Synopsis .................................................................................................................................10 
2. 
Schedule of Activities ............................................................................................................14 
3. 
Introduction ...........................................................................................................................22 
3.1. 
Study Rationale ................................................................................................................22 
3.1.1. 
Rationale for Amendment a .....................................................................................22 
3.1.2. 
Rationale for Amendment b .....................................................................................23 
3.1.3. 
Rationale for Amendment c .....................................................................................23 
3.1.4. 
Rationale for Amendment d .....................................................................................23 
3.1.5. 
Rationale for Amendment e .....................................................................................24 
3.2. 
Background.......................................................................................................................24 
3.2.1. 
Metastatic Castration-Resistant Prostate Cancer .....................................................24 
3.2.2. 
Abemaciclib .............................................................................................................25 
3.2.3. 
Abiraterone Acetate .................................................................................................26 
3.3. 
Benefit/Risk Assessment ..................................................................................................26 
4. 
Objectives and Endpoints ......................................................................................................28 
5. 
Study Design .........................................................................................................................30 
5.1. 
Overall Design ..................................................................................................................30 
5.2. 
Number of Patients ...........................................................................................................32 
5.3. 
End of Study Definition....................................................................................................32 
5.4. 
Scientific Rationale for Study Design ..............................................................................33 
5.4.1. 
Study Design and Control Group .............................................................................33 
5.4.2. 
Population ................................................................................................................33 
5.4.3. 
Radiographic PFS as a Primary Efficacy Endpoint .................................................33 
5.5. 
Justification for Dose ........................................................................................................34 
6. 
Study Population ...................................................................................................................35 
6.1. 
Inclusion Criteria ..............................................................................................................35 
6.2. 
Exclusion Criteria .............................................................................................................37 
6.3. 
Lifestyle Restrictions ........................................................................................................38 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 4 
LY2835219 
6.4. 
Screen Failures .................................................................................................................38 
7. 
Treatments .............................................................................................................................40 
7.1. 
Treatments Administered .................................................................................................40 
7.1.1. 
Packaging and Labeling ...........................................................................................42 
7.2. 
Method of Treatment Assignment ....................................................................................42 
7.2.1. 
Selection and Timing of Doses ................................................................................42 
7.3. 
Blinding ............................................................................................................................42 
7.3.1. 
Unblinding at Interim Analyses ...............................................................................43 
7.3.2. 
Emergency Unblinding ............................................................................................43 
7.3.3. 
Inadvertent Unblinding ............................................................................................44 
7.4. 
Dose Modification ............................................................................................................44 
7.4.1. 
Special Treatment Considerations ...........................................................................45 
7.4.1.1. 
Abemaciclib/Placebo Dose Adjustments and Delays: 
Hematologic Toxicities, Nonhematologic Toxicities 
(excluding diarrhea, Interstitial Lung Disease 
(ILD)/Pneumonitis and ALT/AST increased), Diarrhea, 
Interstitial Lung Disease/Pneumonitis ...............................................................45 
7.4.1.2. 
Abemaciclib/Placebo and Abiraterone acetate and Dose 
Adjustments and Delays - Increased ALT or AST ............................................47 
7.5. 
Preparation/Handling/Storage/Accountability .................................................................49 
7.6. 
Treatment Compliance .....................................................................................................49 
7.7. 
Concomitant Therapy .......................................................................................................49 
7.7.1. 
Palliative Radiotherapy and/or Surgical Intervention for 
Prostate Cancer ........................................................................................................51 
7.7.2. 
Supportive Care ........................................................................................................51 
7.7.2.1. 
Supportive Management for Diarrhea ................................................................51 
7.7.2.2. 
Growth Factors ...................................................................................................51 
7.7.2.3. 
Transfusions .......................................................................................................52 
7.8. 
Treatment after the End of the Study ...............................................................................52 
7.8.1. 
Treatment after Study Completion ...........................................................................53 
7.8.1.1. 
Continued Access ...............................................................................................53 
8. 
Discontinuation Criteria ........................................................................................................54 
8.1. 
Discontinuation from Study Treatment ............................................................................54 
8.1.1. 
Discontinuation of Inadvertently Enrolled Patients .................................................55 
8.2. 
Discontinuation from the Study ........................................................................................55 
8.3. 
Lost to Follow-Up ............................................................................................................56 
9. 
Study Assessments and Procedures .......................................................................................57 
9.1. 
Efficacy Assessments .......................................................................................................57 
9.1.1. 
Appropriateness of Assessments ..............................................................................57 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 5 
LY2835219 
9.1.2. 
Definitions of Efficacy Measures ............................................................................57 
9.2. 
Adverse Events .................................................................................................................60 
9.2.1. 
Serious Adverse Events ...........................................................................................61 
9.2.2. 
Suspected Unexpected Serious Adverse Reactions .................................................62 
9.2.3. 
Complaint Handling .................................................................................................62 
9.3. 
Treatment of Overdose .....................................................................................................62 
9.4. 
Safety ................................................................................................................................62 
9.4.1. 
Safety Measures .......................................................................................................62 
9.4.2. 
Safety Monitoring ....................................................................................................62 
9.4.2.1. 
Hepatic Safety Monitoring .................................................................................63 
9.4.2.2. 
Special Hepatic Safety Data Collection .............................................................64 
9.4.2.3. 
Guidance for Monitoring Renal Function ..........................................................64 
9.4.2.4. 
Guidance for Venous Thromboembolic Events .................................................64 
9.4.2.5. 
Guidance for Interstitial Lung Disease/Pneumonitis .........................................65 
9.4.2.6. 
Guidance for Hypertension, Hypokalemia, Fluid 
Retention, and Cardiovascular Adverse Reactions Due to 
Mineralocorticoid Excess ...................................................................................65 
9.4.2.7. 
Guidance for Adrenocortical Insufficiency ........................................................66 
9.4.2.8. 
Guidance for Hypoglycemia ..............................................................................66 
9.5. 
Pharmacokinetics ..............................................................................................................66 
9.6. 
Pharmacodynamics ...........................................................................................................66 
9.7. 
Pharmacogenomics ...........................................................................................................67 
9.7.1. 
Whole Blood Sample for Pharmacogenetic Research .............................................67 
9.8. 
Biomarkers .......................................................................................................................67 
9.8.1. 
Tissue Samples for Biomarker Research .................................................................68 
9.8.2. 
Other Samples for Biomarker Research ...................................................................69 
9.9. 
Health Economics .............................................................................................................69 
9.9.1. 
Patient-Reported Outcomes .....................................................................................69 
9.9.2. 
Health Care Resource Utilization ............................................................................70 
10. Statistical Considerations ......................................................................................................71 
10.1. Sample Size Determination ..............................................................................................71 
10.2. Populations for Analyses ..................................................................................................71 
10.3. Statistical Analyses ...........................................................................................................72 
10.3.1. 
Efficacy Analyses ....................................................................................................72 
10.3.1.1. 
Radiographic Progression Free Survival ............................................................72 
10.3.1.2. 
Overall Survival .................................................................................................73 
10.3.1.3. 
Time to Prostate-Specific Antigen Progression .................................................73 
10.3.1.4. 
Objective Response Rate and Duration of Response .........................................74 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page6 
10.3.1.5. 
Time to Symptomatic Progression ..................................................................... 74 
-
10.3.2. 
Safety Analyses ........................................................................................................ 75 
10.3.3. 
Other Analyses ......................................................................................................... 75 
10.3.3.1. 
Patient Disposition ............................................................................................. 75 
10.3.3.2. 
10.3.3.3. 
10.3.3.4. 
10.3.3.5. 
10.3.3.6. 
10.3.3.7. 
10.3.3.8. 
10.3.3.9. 
Patient Characteristics ........................................................................................ 7 6 
Treatment Compliance ....................................................................................... 7 6 
Extent ofExposme ............................................................................................. 76 
Concomitant Therapy ......................................................................................... 7 6 
Post-Study-Treatment-Discontinuation Therapy ............................................... 7 6 
Pharmacokinetic/Phannacodynamic Analyses ................................................... 7 6 
Biomarker Analyses ........................................................................................... 77 
Health Outcome/Quality-of-Life Analyses ........................................................ 77 
10.3.4. 
Subgroup Analyses .................................................................................................. 77 
10.3.5. 
Interim Analyses ...................................................................................................... 77 
10.3.5.1. 
Safety Interim Analyses ..................................................................................... 78 
10.3.5.2. 
Futility/Adaptive Interim Analyses .................................................................... 78 
11. References ............................................................................................................................. 80 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page7 
Table 
Table JPCM. l. 
Table JPCM.2. 
Table JPCM.3. 
Table JPCM.4. 
Table JPCM.5. 
Table JPCM.6. 
Table JPCM. 7. 
Table JPCM.9. 
Table JPCM.10. 
LY2835219 
List of Tables 
Page 
Baseline, Treatment, and Post-Treatment Schedule of Activities ............. 14 
Continued-Access Schedule of Activities .................................................. 21 
Objectives and Endpoints .......................................................................... 28 
Planned Analyses ....................................................................................... 30 
Treatment Regimens .................................................................................. 41 
Dose Reductions for Abemaciclib/Placebo .............................................. .45 
Toxicity Dose Adjustments and Delays of Abemaciclib/Placebo: 
Hematologic Toxicities, Nonhematologic Toxicities, Dianhea, 
ILD/Pneumonitis ........................................................................................ 45 
Bone Progression per PCWG3 ................................................................... 58 
Soft Tissue Tumor Response Related Endpoints ....................................... 74 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 8 
LY2835219 
List of Figures 
Figure 
Page 
Figure JPCM.1. 
Illustration of study design.........................................................................32 
Figure JPCM.2. 
Continued access diagram..........................................................................52 
 
 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 9 
LY2835219 
List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...................................................................84 
Appendix 2. 
Clinical Laboratory Tests ...........................................................................90 
Appendix 3. 
Study Governance, Regulatory, and Ethical Considerations .....................93 
Appendix 4. 
Sampling Schedule for Pharmacokinetics/Pharmacodynamics .................98 
Appendix 5. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ...........100 
Appendix 6. 
Protocol JPCM ECOG Performance Status .............................................102 
Appendix 7. 
Protocol JPCM RECIST Criteria 1.1 .......................................................103 
Appendix 8. 
Protocol JPCM Strong and Moderate Inducers of CYP3A4, Strong 
Inhibitors of CYP3A4, Substrates of CYP2D6 with Narrow 
Therapeutic Range, and Transporter Substrates with Narrow 
Therapeutic Range ...................................................................................110 
Appendix 9. 
Protocol JPCM CTCAE 5.0 Diarrhea/Pneumonitis/ALT and AST 
Increased Definitions ...............................................................................112 
Appendix 10. 
Provisions for Changes in Study Conduct During Exceptional 
Circumstances ..........................................................................................114 
Appendix 11. 
Protocol Amendment History ..................................................................118 
 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 10 
1. Synopsis 
Protocol Title: 
CYCLONE 2: A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of 
Abiraterone Acetate Plus Prednisone with or without Abemaciclib in Patients with Metastatic 
Castration-Resistant Prostate Cancer 
Regulatory Agency Identifier Number(s): 
EudraCT Number: 2016-004276-21 
EU CT Number: 2023-506777-36-00 
Summary: 
Prostate cancer is the second most common cancer and the fifth most leading cause of death 
among men worldwide, with almost 70% of the cases occmTing in more developed 
regions (SEER 2017). 
Metastatic castration-resistant prostate cancer (mCRPC) emerges following 
androgen-deprivation therapy and is the most lethal phenotype of the disease. 
This Phase 2/3 study will be conducted in up to 3 pa1ts and is designed to detennine the 
recommended Phase 2 dose and assess the safety and efficacy of abemaciclib in combination 
with abiraterone acetate plus prednisone for the first-line treatment of patients with mCRPC. 
Objectives and Endpoints: 
Pali 1 
Prima1y objective: 
• 
Detemline the recommended Phase 2 dose (RP2D) of abemaciclib in combination with 
abiraterone acetate and prednisone 
Patts 1, 2, and 3 
Primaiy objective: 
• 
Radiographic progression-free survival (rPFS) 
Secondaiy objectives: 
• 
Safety and tolerability of the combination of abemaciclib and abiraterone acetate plus 
prednisone 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 11 
LY2835219 
 Objective response rate and duration of response 
 Overall survival 
 (If Part 3 is opened) rPFS by blinded, independent, central review (BICR) 
 Time to symptomatic progression 
 Time to prostate-specific antigen (PSA) progression 
 Time to worst pain progression  
 Pharmacokinetics (PK) of abemaciclib and abiraterone acetate when administered in 
combination 
Overall Design: 
This Phase 2/3, multicenter, multinational, randomized, double-blind, placebo-controlled study is 
designed to assess the safety and efficacy of abemaciclib when given in combination with 
abiraterone acetate plus prednisone as first-line therapy for patients with mCRPC. 
Patients who meet all of the inclusion criteria and none of the exclusion criteria will be centrally 
randomized to the abemaciclib or placebo group according to the following stratification factors: 
 Radiographic progression* at study entry (yes/no) 
 Measurable disease** (yes/no) 
 Prior docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) (yes/no) 
* 
Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) for soft tissue and/or per Prostate 
Cancer Working Group 3 (PCWG3) for bone. 
** Per RECIST 1.1. 
 
These stratification factors were chosen because they represent important prognostic factors 
and/or an imbalance may bias the results. 
The study will be conducted in up to 3 parts. Part 1 is a double-blind placebo-controlled safety 
lead-in portion that will randomize approximately 30 patients in a 2:2:1:1 ratio to explore 2 doses 
of abemaciclib (150 mg and 200 mg, twice daily or matching placebo) when given in 
combination with abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily. 
Part 1 is designed to determine the RP2D of abemaciclib. 
Part 2 is a double-blind placebo-controlled portion that will randomize approximately 
150 patients in a 1:1 ratio between abiraterone acetate 1000 mg once daily plus prednisone 5 mg 
twice daily and abemaciclib given at the RP2D or matching placebo. 
Part 3 may be opened if the prespecified expansion criteria in an adaptive interim analysis are 
met and will randomize approximately 170 additional patients. 
Study Population: 
This study will enroll patients with prostate cancer that has spread to other parts of the body and 
no longer responds to treatments to lower testosterone, a condition referred to as mCRPC.  
Eligible participants have progressive disease by PSA and/or imaging during continuous 
androgen-deprivation therapy (ADT)/post orchiectomy, adequate organ function, and an Eastern 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 12 
LY2835219 
Cooperative Oncology Group performance status of 0 or 1. Prior docetaxel for mHSPC is 
permitted. Prior treatments with abemaciclib or other CDK4 and 6 inhibitors, abiraterone, or 
other novel hormonal agents are not allowed. Medical conditions, such as clinically significant 
heart disease, active or chronic liver disease, and moderate/severe hepatic impairment (Child-
Pugh Class B and C), may preclude participation in the study.  
Patients who have not undergone bilateral orchiectomy are required to continue background 
ADT with an luteinizing hormone-releasing hormone agonist/antagonist throughout the study. 
The complete list of eligibility criteria is provided in the Section 6 of this protocol. 
Number of Patients: 
Up to approximately 350 patients with mCRPC will be enrolled. 
Planned enrollment for each study part is as follows: 
Part 1: approximately 30 patients 
Part 2: approximately 150 patients 
Part 3: approximately 170 patients 
Treatment Arms and Duration: 
Patients will have a screening period of up to 28 days prior to randomization. The first dose of 
study treatment (that is, abiraterone plus prednisone and abemaciclib/placebo) should be initiated 
no later than 7 days following randomization. Patients will be monitored for safety throughout 
the study as per the schedule of activities. Study treatment should be continued until radiographic 
and/or symptomatic progression or until other discontinuation criteria are met (see Section 8). 
Treatment decisions should not be based on PSA alone; study treatment should be continued in 
patients who have increasing PSA values in the absence of radiographic or symptomatic 
progression. 
Patients who discontinue the study will not be replaced. Patients will have a safety follow-up 
visit approximately 30 days after the decision to stop treatment or prior to initiation of a new 
therapy, whichever occurs first. All patients will be followed for survival. 
Dose, administration, and schedule: 
Study treatment is defined as blinded study drug (abemaciclib or placebo) and/or abiraterone 
acetate plus prednisone. Abemaciclib, abiraterone acetate, and prednisone are administered 
orally on Days 1 through 28 of a 28-day cycle. 
Where prednisone is not commercially available, prednisolone may be substituted. 
Part 1: 
 Experimental Arm A1: Abemaciclib 150 mg (3 tablets/capsules) orally twice daily  
 Experimental Arm A2: Abemaciclib 200 mg (4 tablets/capsules) orally twice daily 
 Control Arm B1: Placebo (3 tablets/capsules) orally twice daily 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 13 
• 
Control Alm B2: Placebo (4 tablets/capsules) orally twice daily 
• 
All aims: Abiraterone acetate 1000 mg orally once daily plus 5 mg prednisone orally 
twice daily 
Approximately 
patient has entered treatment, an internal 
assessment committee (AC), composed of Lilly members not involved in the day-to-day study 
conduct, will review safety and available PK data and deteimine the RP2D of abemaciclib. 
During the RP2D evaluation period, patients may still enroll in Pait 1. Once the RP2D has been 
selected, patients enrolled in Pait 1 will switch to the selected RP2D (abemaciclib or matching 
placebo) to continue the study. fu the situation where blinded study treatment has been dose 
reduced below the selected RP2D, dose escalation to RP2D will not be implemented and dose-
reduced patients will continue study at the same lower dose level. Subsequent patients will then 
stait to enroll in Pait 2 and will be randomized to receive abemaciclib at RP2D or matching 
placebo. 
Part 2 and Pait 3: 
• 
Experimental Alm A: Abemaciclib at RP2D orally twice daily 
• 
Control Alm B: Placebo (matching number of tablets/capsules) orally twice daily 
• 
Alms A and B: Abiraterone acetate 1000 mg orally once daily plus 5 mg prednisone 
orally twice daily 
An independent data monitoring committee (DMC) composed of members external to Lilly will 
perf01m a futility analysis after approximately I radiographic progression-free survival (rPFS) 
events and will perf 01m up to 2 adaptive interim analyses, 
-
. Should the prespecified adaptive expansion criteria be met at either interim analysis, 
enrollment to Part 3 will open. 
Short-teim follow-up (post discontinuation): Patients will be followed 30 days after study 
treatment discontinuation. 
Long-teim follow-up: After the sh01t-teim follow-up visit, ALL patients will enter the long-teim 
follow-up period. Patients will be followed for survival and initiation of subsequent anticancer 
therapies eveiy 3 months. fu addition, patients discontinuing treatment prior to documented 
radiographic progression will continue to have scheduled disease assessments until documented 
radiographic progression and will be followed for the development of symptomatic progression. 
Patients discontinuing treatment due to documented radiographic progression will be followed 
for the development of symptomatic progression. 
Ethical Considerations of Benefit/Risk: 
The potential risks of abemaciclib in combination with standard of care abiraterone plus 
prednisone are justified in consideration of the measures to minimize risks and the anticipated 
benefit of improved response to therapy, as measured by radiographic progression-free survival 
in participants with mCRPC. A favorable benefit/risk balance is anticipated for the studied 
combination. 
Data Monitoring Committee: Yes, an independent DMC has been commissioned for this study. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 14 
LY2835219 
2. Schedule of Activities  
Table JPCM.1. 
Baseline, Treatment, and Post-Treatment Schedule of Activities  
 
Study Period 
 
 
Baseline 
(Days Prior 
to 
Randomization) 
On Treatment 
Cycle = 28 days (4 weeks) 
Post-Treatment Follow-
up 
Instructions 
Activities and 
Forms to be 
Completed 
≤28 
≤14 
Day 1 of 
Every 
Cycle 
(±3 Days) 
Day 15 
of Cycle 1 
and 
Cycle 2 
(±3 Days) 
Day 15 
of Cycle 3 
(±3 Days) 
Short-
Term 
Follow-
Upa 
Visit 801 
(±3 Days) 
Long-
Term 
Follow-Up 
Visit 
802-8XX 
(Every 
90±7 Days) 
Procedures and disease assessments (including tumor 
imaging) should be performed according to the calendar 
days, regardless of treatment delays. 
Baseline Documentation 
Informed Consent 
X 
 
 
 
 
 
Written informed consent must be obtained within 28 days 
prior to randomization AND prior to conducting any 
protocol-specific tests/procedures. 
Inclusion/Exclusion 
Evaluation 
X 
 
 
 
 
 
 
Medical History 
Preexisting 
Conditions 
X 
 
 
 
 
 
Including assessment of preexisting conditions, historical 
illnesses that resolved, and habits (such as tobacco and 
alcohol use). 
Prior and 
Concomitant 
Medication Review 
X 
X 
X 
 
Collect throughout the study; includes information on 
over-the-counter and prescription analgesics use. 
Physical 
Examination 
 
X 
X 
X 
 
X 
 
Including height (only at screening), weight, and vital 
signs (temperature, blood pressure, pulse rate, respiration 
rate). Perform prior to administering study drug(s). 
ECOG Performance 
Status 
 
X 
X 
 
 
X 
 
Does not need to be repeated on Cycle 1 Day 1 if assessed 
at baseline ≤3 days prior to treatment initiation. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 15 
LY2835219 
 
Study Period 
 
 
Baseline 
(Days Prior 
to 
Randomization) 
On Treatment 
Cycle = 28 days (4 weeks) 
Post-Treatment Follow-
up 
Instructions 
Activities and 
Forms to be 
Completed 
≤28 
≤14 
Day 1 of 
Every 
Cycle 
(±3 Days) 
Day 15 
of Cycle 1 
and 
Cycle 2 
(±3 Days) 
Day 15 
of Cycle 3 
(±3 Days) 
Short-
Term 
Follow-
Upa 
Visit 801 
(±3 Days) 
Long-
Term 
Follow-Up 
Visit 
802-8XX 
(Every 
90±7 Days) 
Procedures and disease assessments (including tumor 
imaging) should be performed according to the calendar 
days, regardless of treatment delays. 
 
Laboratory Assessments 
 
Hematology 
 
X 
X 
X 
 
X 
See Appendix 2. Perform ≤3 days prior to administration 
of study treatment. Does not need to be repeated on Cycle 
1 Day 1 if assessed at baseline ≤3 days prior to treatment 
initiation. Repeat if clinically indicated. 
Chemistry 
 
X 
X  
X  
X  
X 
 
Includes liver function. See Appendix 2. Perform ≤3 days 
prior to administration of study treatment. Does not need 
to be repeated on Cycle 1 Day 1 if assessed at baseline ≤3 
days prior to treatment initiation. Repeat if clinically 
indicated and refer to Section 7.4.1.2 for more frequent 
hepatic monitoring. 
Coagulation 
 
X 
 
 
 
X 
See Appendix 2. Repeat if clinically indicated. 
Urinalysis 
 
X 
 
 
 
X 
See Appendix 2. Perform ≤3 days prior to administration 
of study treatment. Does not need to be repeated on Cycle 
1 Day 1 if assessed at baseline ≤3 days prior to treatment 
initiation. Repeat if clinically indicated.  
PSA 
 
X 
X 
 
 
X 
See Appendix 2. Perform ≤3 days prior to administration 
of study treatment. Repeat if clinically indicated. 
Testosterone 
 
X 
X 
 
X 
See Appendix 2. Perform ≤3 days prior to administration 
of study treatment. Repeat if clinically indicated.  
Other Clinical Assessments 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 16 
LY2835219 
 
Study Period 
 
 
Baseline 
(Days Prior 
to 
Randomization) 
On Treatment 
Cycle = 28 days (4 weeks) 
Post-Treatment Follow-
up 
Instructions 
Activities and 
Forms to be 
Completed 
≤28 
≤14 
Day 1 of 
Every 
Cycle 
(±3 Days) 
Day 15 
of Cycle 1 
and 
Cycle 2 
(±3 Days) 
Day 15 
of Cycle 3 
(±3 Days) 
Short-
Term 
Follow-
Upa 
Visit 801 
(±3 Days) 
Long-
Term 
Follow-Up 
Visit 
802-8XX 
(Every 
90±7 Days) 
Procedures and disease assessments (including tumor 
imaging) should be performed according to the calendar 
days, regardless of treatment delays. 
12-Lead ECG 
 
X 
Every 8 weeks for the first 24 weeks, 
every 12 weeks thereafter 
(Day 1 of Cycles 3, 5, 7, 10, 13, 16, 
…) 
X 
Single ECG performed locally. Hypokalemia should be 
corrected (and normalization confirmed) prior to ECG 
collection. Patients must be supine for approximately 5 to 
10 minutes before ECG collection and remain supine but 
awake during ECG collection. 
Repeat if clinically indicated. 
MUGA Scan or 
Cardiac ECHO 
X 
 
 
 
 
 
Repeat if clinically indicated. 
Adverse Event 
Assessment 
Continuous from time of Informed Consent Form 
signature until 30 days after last study drug dose. 
X 
Grading via CTCAE version 5.0 (NCI 2017). 
After V801, only SAEs that are related to study regimen or 
protocol procedure will be collected. 
All drug- or procedure-related AEs and SAEs should be 
followed until they resolve, are no longer considered to be 
drug- or procedure-related, become stable or return to 
baseline, the patient starts a new therapy, the patient dies, 
or the patient becomes lost to follow-up. Frequency of 
evaluation is left to the judgment of the investigator. 
Study Drug 
Compliance 
Assessment 
 
X 
 
 
Post-
Discontinuation 
Anti-Cancer 
Therapies 
 
 
X 
X 
  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 17 
LY2835219 
 
Study Period 
 
 
Baseline 
(Days Prior 
to 
Randomization) 
On Treatment 
Cycle = 28 days (4 weeks) 
Post-Treatment Follow-
up 
Instructions 
Activities and 
Forms to be 
Completed 
≤28 
≤14 
Day 1 of 
Every 
Cycle 
(±3 Days) 
Day 15 
of Cycle 1 
and 
Cycle 2 
(±3 Days) 
Day 15 
of Cycle 3 
(±3 Days) 
Short-
Term 
Follow-
Upa 
Visit 801 
(±3 Days) 
Long-
Term 
Follow-Up 
Visit 
802-8XX 
(Every 
90±7 Days) 
Procedures and disease assessments (including tumor 
imaging) should be performed according to the calendar 
days, regardless of treatment delays. 
Survival 
Assessment 
 
 
X 
X 
Although preferable to collect during a clinic visit, 
survival information may be collected by contacting the 
patient or family directly (e.g., via telephone) if no 
procedures are required. This should be collected at 
minimum every 90 (±14) days if no other procedures are 
performed. 
Tumor Assessment 
CT or MRI Scan of 
Chest, Abdomen, 
and Pelvis 
X 
Every 8 weeks for the first 24 weeks, 
every 12 weeks thereafter, 
independent of treatment delays 
(e.g. Day 1 of Cycles 3, 5, 7, 10, 13, 
16, …), and within 14 days of 
symptomatic progression if no 
radiographic progression yet. 
X 
X 
Within 7 days prior to the scheduled calendar day (except 
in screening period).  
Unscheduled assessments if signs of disease progression 
are observed.  
Radiographic disease assessment per RECIST 1.1 for soft 
tissue and radionuclide bone scan using PCWG3 criteria 
for bone, assessed by the investigator/local radiologist. 
 
Patients discontinuing treatment prior to documented 
radiographic progression will continue to have scheduled 
disease assessments (i.e. per the ‘on treatment’ period) 
until documented radiographic progression and will be 
followed for the development of symptomatic progression.  
 
Patients discontinuing treatment due to documented 
radiographic progression will be followed for the 
development of symptomatic progression. 
Radionuclide Bone 
Scan 
X 
X 
X 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 18 
LY2835219 
 
Study Period 
 
 
Baseline 
(Days Prior 
to 
Randomization) 
On Treatment 
Cycle = 28 days (4 weeks) 
Post-Treatment Follow-
up 
Instructions 
Activities and 
Forms to be 
Completed 
≤28 
≤14 
Day 1 of 
Every 
Cycle 
(±3 Days) 
Day 15 
of Cycle 1 
and 
Cycle 2 
(±3 Days) 
Day 15 
of Cycle 3 
(±3 Days) 
Short-
Term 
Follow-
Upa 
Visit 801 
(±3 Days) 
Long-
Term 
Follow-Up 
Visit 
802-8XX 
(Every 
90±7 Days) 
Procedures and disease assessments (including tumor 
imaging) should be performed according to the calendar 
days, regardless of treatment delays. 
Brain MRI/CT 
X 
 
Only required at screening for patients with evidence of 
neurological changes 14 days prior to receiving study drug 
to rule out CNS metastases. Unscheduled assessments if 
signs of CNS disease progression are observed. 
Symptomatic 
progression 
 
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 
locoregional tumor progression requiring surgical 
intervention or radiation therapy. 
Biomarker Assessment 
Blood Sample: 
Genetics 
See Appendix 4. 
Tumor Biopsy 
PK/PD Sampling 
Pharmacodynamics 
See Appendix 4. 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Activities and 
Forms to be 
Completed 
Phannacokinetics 
Baseline 
{Days Prior 
to 
Randomization 
~28 
~14 
Study Period 
On Treatment 
Cycle = 28 days (4 weeks) 
Day 1 of 
Day 15 
Day 15 
Every 
of Cycle 1 
of Cycle 3 
Cycle 
and 
(±3 Days) 
(±3 Days) 
Cycle2 
(±3 Days) 
Post-Treatment Follow-
up 
Short-
Long-
Te1·m 
Te1·m 
Follow-
Follow-Up 
Upa 
Visit 
Visit 801 
802--8:XX 
(±3 Days) 
(Every 
90±7 Da s 
Patient Reported Outcomes 
Page 19 
Instructions 
Procedures and disease assessments (including tumor 
imaging) should be pe1fonned according to the calendar 
days, regardless of treatment delays. 
The PRO questionnaires must be completed before 
1---------------------+------+----------,----------t1 significant interaction with site personnel and administered 
WorstPain NRS 
X 
X 
X 
-
Abemaciclib/ 
Placebo 
Abiraterone Acetate 
Prednisone 
LY2835219 
X 
X 
X 
X 
X 
X 
Study Treatment 
Take prescribed dose BID on Days I 
through 28 of a 28-day cycle. 
Take prescribed dose QD on Days I 
throu 
28 of a 28-da c cle. 
Take presc1ibed dose BID on Days I 
throu 
28 of a 28-da c cle. 
Approved on 30 Apr 2024 GMT 
in the following order: Worst Pain NRS first, 
Where prednisone is not commercially available, 
rednisolone ma be substin1ted. 

13Y-MC-JPCM(f) Clinical Protocol 
Page 20 
Abbreviations: AE = adverse event; BID = twice daily; CNS = central nervous system; CTCAE = Common Terminology Criteria for Adverse Events (NCI 
2017); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); 
MUGA = multigated acquisition scan; NRS = numeric rating scale; PCWG3 
= Prostate Cancer Working Group 3; PRO = patient-repo11ed outcome; PSA = prostate-specific antigen; QD = once daily; RECIST 1.1 = Response Evaluation 
Crite1ia in Solid Tumors, Version 1.1 (Eisenhauer et al. 2009); wk = week. 
A Sh011-te1m follow-up begins when the patient and the investigator agree that the patient will no longer continue study treatment and lasts approximately 30 
days. In all cases, no follow-up procedures will be pe1fonned for a patient who withdraws informed consent unless he has explicitly provided pennission and 
consent. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 21 
LY2835219 
Table JPCM.2. 
Continued-Access Schedule of Activities  
Visit 
Study Treatment 
Follow-Upa 
Instructions 
501-5XX 
901 
Procedures 
 
 
Frequency of visits (in clinic or remote), AE assessments and follow-up, 
efficacy assessments, and dispensing (for up to 3 cycles) are at the 
investigator’s discretion based on the standard of care and local 
regulations. 
Adverse Events Collection 
X 
X 
Grading via CTCAE, Version 5.0.  
 
After V901, only SAEs that are related to study regimen or protocol 
procedure will be collected.  
 
All drug- or procedure-related AEs and SAEs should be followed until 
they resolve, are no longer considered to be drug- or procedure-related, 
become stable or return to baseline, the patient starts a new therapy, the 
patient dies, or the patient becomes lost to follow-up.  
Administer Abemaciclib 
X 
 
Take prescribed dose BID on Days 1 through 28 of a 28-day cycle. 
Administer Abiraterone 
Acetate 
X 
 
Take prescribed dose QD on Days 1 through 28 of a 28-day cycle. 
Administer Prednisone 
X 
 
Take prescribed dose BID on Days 1 through 28 of a 28-day cycle. 
Abbreviations: AE = adverse event; BID = twice daily; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2017); QD = once daily; 
SAE = serious adverse event. 
a Continued-access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued-access 
period and lasts approximately 30 days. In all cases, no follow-up procedures will be performed for a patient who withdraws informed consent unless he has 
explicitly provided permission and consent. 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 22 
3. Introduction 
3.1. Study Rationale 
Study I3Y-MC-JPCM (JPCM) is a Phase 2/3, multicenter, multinational, randomized, 
double-blind, placebo-controlled study with a lead-in safety evaluation that is designed to 
dete1mine the safety and efficacy of abemaciclib when combined with abiraterone acetate plus 
prednisone (hereinafter implies prednisone or prednisolone) for the first-line treatment of 
patients with metastatic castration-resistant prostate cancer (mCRPC). 
Abiraterone acetate was selected over other approved diu gs for this study in combination with 
abemaciclib because: 
• 
abiraterone acetate plus prednisone is commonly used as first-line treatment for mCRPC 
throughout the world 
• 
abiraterone acetate and abemaciclib have toxicities that are only pa1tially overlapping 
• 
the combination of abiraterone acetate and abemaciclib is not anticipated to result in 
diug-drng interaction. 
3. 1. 1. Rationale for Amendment a 
Protocol Amendment (a) for Study JPCM protocol was amended to allow the use of prednisolone 
where prednisone is not commercially available, to adjust wording on inadve1tently emolled 
patients based on regulator's feedback, and to adjust the list for strong and moderate inducers of 
CYP3A, strong inhibitors of CYP3A, or substrates of CYP2D6s, or transp011ers with na1rnw 
therapeutic range. 
fu addition, minor editorial changes were made throughout the protocol to improve clarity and 
practicability of the protocol, secure alignment with the intended study design, and update 
inf01mation available for study drngs. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 23 
3.1.2. Rationale for Amendment b 
Protocol Amendment (b) for Study JPCM protocol was amended to add a DMC, update the dose 
modification guidance and the safety language for ILD/pneumonitis, (these updates are in 
alignment with changes made in the development core safety information of the Investigator's 
Brochure), implement collection and storage of radiographic images, and update special hepatic 
data collection guidance to further improve a comprehensive evaluation of patients with 
treatment emergent abno1mal liver tests. 
In addition, minor editorial changes have been made throughout the protocol to improve cla1ity 
and practicability of the protocol, secure alignment with the intended study design, and update 
info1mation available for study dmgs. 
3.1.3. Rationale for Amendment c 
Protocol Amendment ( c) for Study JPCM protocol was amended to implement an adaptive 
Phase 2/3 study design by adding Part 3 that will be triggered based on prespecified expansion 
criteria. If triggered, Pait 3 will randomize approximately 170 additional patients. The statistical 
analysis plan was updated accordingly, including specifying an overall I-sided type I enor rate 
of 0.025. 
Radiographic Progression Free smvival is considered to be an appropriate regulato1y endpoint in 
the first line mCRPC setting. Time to prostate-specific antigen (PSA) progression is not 
considered an appropriately validated smTogate efficacy endpoint and was therefore removed as 
a co-prima1y endpoint and changed to a seconda1y endpoint. 
Additionally, rPFS by BICR was added as a seconda1y endpoint. Time to worst pain progression 
was added as a secondaiy endpoint. 
Baseline tumor biopsy will be optional in Part 3. 
Added and updated safety monitoring guidance on abiraterone acetate related adverse reactions 
in alignment with prescribing info1mation revised 10/2020. Added and updated safety 
monitoring guidance on abemaciclib related adverse reactions in alignment with changes made in 
the development core safety info1mation of the Investigator's Brochure (IB) revised 12/2020. 
To ensure appropriate safety monitoring of study participants, maintain data integrity, and 
minimize dismptions to the conduct of the study, provisions for changes in study conduct during 
exceptional circumstances ( such as pandemics or natural disasters) were added in Appendix IO. 
In addition, minor editorial changes have been made throughout the protocol. 
3. 1.4. Rationale for Amendment d 
Protocol Amendment ( d) for Study JPCM protocol was amended to comply with the new 
Emopean Union Clinical Trial Regulation (EU-CTR). Moreover, updated strong and moderate 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 24 
LY2835219 
inducers of CYP3A4, strong inhibitors of CYP3A4, substrates of CYP2D6 with narrow 
therapeutic range, and transporter substrates with narrow therapeutic range. 
In addition, minor editorial changes have been made throughout the protocol. 
3.1.5. Rationale for Amendment e  
Protocol Amendment (e) for Study JPCM protocol was amended to correct the EudraCT 
Number. 
3.2. Background  
3.2.1. Metastatic Castration-Resistant Prostate Cancer  
Prostate cancer is a leading cause of mortality and morbidity globally, with more than 1 million 
cases diagnosed and more than 300,000 deaths annually. Prostate cancer is the second most 
common diagnosed malignancy, the fifth leading cause of cancer mortality in men, and 
represents a substantial public health burden. In 2014, there were an estimated 3 million men 
living with PCa in the United States (SEER 2017). 
Advanced or metastatic PCa is an androgen-dependent disease and PCa cells are primarily 
dependent on AR activity for proliferation and survival. The key element in the control of 
prostate tumor growth is androgen-deprivation therapy (ADT), which consists of initiating a 
luteinizing hormone-releasing hormone (LHRH) agonist/antagonist (medical castration) or, less 
commonly, bilateral orchiectomy (surgical castration) with or without concurrent anti-androgens 
(Lonergan and Tindall 2011). 
Based on the recent findings from the CHAARTED (NCT00309985), STAMPEDE 
(NCT00268476), and LATITUDE (NCT01715285) trials, all showing significant improvement 
in overall survival (OS), a combination approach of docetaxel, or abiraterone acetate plus 
prednisone, with ADT is now also considered a treatment option for men with high-risk forms of 
metastatic hormone-sensitive prostate cancer (mHSPC; Sweeney et al. 2015; James et al. 2016, 
2017; Fizazi et al. 2017). 
Although most patients with advanced metastatic disease initially respond to conventional ADT 
with or without docetaxel or abiraterone acetate, inevitably and despite effective suppression of 
serum testosterone, disease progresses to mCRPC. The treatment of mCRPC has changed 
significantly over the last years as a result of the introduction of multiple new systemic therapies 
that have had a positive impact on treatment outcomes, including OS. Therapies that have been 
approved for use in mCRPC include novel anti-hormonal agents (abiraterone acetate and 
enzalutamide), the α-emitting radium isotope radium-223 (bone metastases and no known 
visceral metastatic disease), the autologous cellular immunotherapy sipuleucel-T (asymptomatic 
or minimally symptomatic disease), and cytotoxic chemotherapies (mitoxantrone, docetaxel, and 
cabazitaxel; Sartor and de Bono 2018). 
Despite the recent advances in the therapy for mCRPC, median OS remains approximately 18 to 
36 months. In addition, the optimal treatment sequencing pathway remains unknown. In practice, 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 25 
LY2835219 
sequencing decisions are made in the light of the distribution, extent, and pace of disease, co-
morbidities, patient preferences, and drug availability (Pal et al. 2018). As treating metastatic 
PCa is becoming increasingly complex, the current focus must be to continue improving 
outcomes for patients with aggressive disease and explore innovative combinations capable of 
controlling and delaying tumor progression. 
This Phase 2/3, randomized, double-blind, placebo-controlled study will evaluate the clinical 
benefit of adding abemaciclib to abiraterone acetate plus prednisone in patients with mCRPC. 
3.2.2. Abemaciclib  
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
maintaining control of cell division (Sherr 1996; Ortega et al. 2002). The CDKs 4 and 6 
participate in a complex with D-type cyclins to initiate the transition through the G1 restriction 
point by phosphorylating and inactivating the retinoblastoma (Rb) tumor-suppressor protein. 
Alterations in this pathway occur frequently in human cancers and involve (1) loss of CDK 
inhibitors by mutation or epigenetic silencing, (2) mutation/overexpression of either CDK4 and 
CDK6 or cyclin D, or (3) inactivation of Rb. These alterations render cells less dependent on 
mitogenic signaling for proliferation. With the possible exception of those tumors with complete 
inactivation of Rb, which functions downstream of the CDK4 and CDK6–cyclin D complex, all 
of these cancers are potentially sensitive to pharmacologic inhibition of CDK4 and CDK6. From 
a therapeutic standpoint, the goal of inhibiting CDK4 and CDK6 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 adenosine triphosphate (ATP)-competitive inhibitor 
of CDK4 and CDK6. In cancer cells, continuous exposure to abemaciclib inhibited Rb 
phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in 
senescence and apoptosis. Abemaciclib showed antitumor activity in multiple preclinical 
pharmacology models and an acceptable toxicity profile in nonclinical species. Abemaciclib has 
been shown to significantly inhibit tumor growth in multiple murine xenograft models for human 
cancer. 
The clinical activity of abemaciclib has been extensively studied in hormone receptor–
positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast 
cancer (MBC). The demonstration of a robust single-agent activity of abemaciclib was shown in 
both the JPBA Phase 1b study with a response rate of 33.3% across dose levels and the 
MONARCH 1 Phase 2 study with a response rate of 19.7% (at 200-mg dose twice daily), in 
heavily pretreated patients with refractory HR+/HER2− MBC (Patnaik et al. 2016; Dickler et al. 
2017). Importantly, the safety profile of abemaciclib allowed for dosing on a continuous 
schedule. 
Two large, randomized, double-blind, placebo-controlled Phase 3 clinical trials have 
demonstrated the effectiveness of abemaciclib when combined with endocrine therapy (ET) for 
HR+/HER2− MBC. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 26 
LY2835219 
In the MONARCH 2 study (NCT02107703), abemaciclib was evaluated in combination with 
fulvestrant in HR+/HER2− MBC patients receiving prior ET. Abemaciclib plus fulvestrant 
significantly extended progression-free survival (PFS) versus fulvestrant alone (median, 16.4 vs 
9.3 months; hazard ratio, 0.553; 95% confidence interval [CI], 0.449 to 0.681; p<.001). In 
patients with measurable disease, abemaciclib plus fulvestrant achieved an objective response 
rate (ORR) of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 
27.6%) in the control arm (Sledge et al. 2017). 
The MONARCH 3 study (NCT 02246621) evaluated abemaciclib in combination with 
nonsteroidal aromatase inhibitor (NSAI) letrozole or anastrozole in HR+/HER2− MBC patients 
who had not received prior systemic therapy for metastatic disease. Median PFS was 
significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.418 to 0.698; 
p<.000121; median PFS: 28.2 months in the abemaciclib arm, 14.8 months in the placebo arm). 
In patients with measurable disease, the confirmed ORR was 55.4% in the abemaciclib arm and 
40.2% in the placebo arm (Goetz et al. 2018). 
The most common adverse reactions (incidence ≥20%) were diarrhea, neutropenia, nausea, 
abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, 
alopecia, and thrombocytopenia. 
Abemaciclib (VERZENIO) is currently approved by major global regulatory authorities for the 
treatment of HR+, HER2− advanced or MBC: 
 in combination with an aromatase inhibitor for postmenopausal women as initial 
endocrine-based therapy; 
 in combination with fulvestrant for women with disease progression following ET; and 
 as a single agent for adult patients with disease progression following ET and prior 
chemotherapy in the metastatic setting (approved in the US). 
Details on the safety profile of monotherapy abemaciclib as well in combination with other 
agents is available in the IB. 
3.2.3. Abiraterone Acetate  
Abiraterone, the active metabolite of abiraterone acetate, irreversibly inhibits cytochrome 
P450 (CYP)17 (17α-hydroxylase/C17, 20-lyase), an essential enzyme in androgen biosynthesis 
that is expressed in testicular, adrenal and prostatic tumor tissues. Abiraterone acetate is 
approved in combination with prednisone for the treatment of patients with high risk mHSPC 
and mCRPC (abiraterone acetate PI, 2018).  
For more information, refer to abiraterone acetate prescribing information. 
3.3. Benefit/Risk Assessment  
More 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 IB. 
Information on AEs expected to be related to abemaciclib may be found in Section 6 (Summary 
of Data, Guidance for the Investigator, and Developmental Core Safety Information [DCSI]) of 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 27 
LY2835219 
the IB. Information on SAEs expected in the study population independent of drug exposure and 
that will be assessed by the sponsor in aggregate periodically during the course of the study may 
be found in Section 6 (Effects in Humans) of the IB. 
More detailed information about the known and expected benefits and risks of abiraterone 
acetate or prednisone may be found in the following: Patient Information Leaflet, Package Insert, 
or Summary of Product Characteristics. 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 28 
4. Objectives and Endpoints 
Table JPCM.3 shows the objectives and endpoints of the study. 
Table JPCM.3. 
Objectives and Endpoints 
Ob· ectives Part 1 
Primary 
To detennine the RP2D of abemaciclib that may be 
safely administered to patients with mCRPC in 
combination with abiraterone acetate and prednisone. 
Ob"ectives Part 1, 2, and 3: Combined Po ulations 
P1·ima1 
To compare the rPFS of patients receiving abiraterone 
acetate plus prednisone with or without abemaciclib. 
Seconda1 
To characterize further the safety profile of the 
combination of abemaciclib and abiraterone acetate plus 
prednisone. 
To compare the efficacy in patients receiving abiraterone 
acetate plus prednisone with or without abemaciclib. 
Time to symptomatic progression. 
To chai·acterize the PK of abemaciclib and abiraterone 
acetate when admit:tistered in combination. 
To assess patient-reported pain. 
LY2835219 
End oints 
Safety (including, but not limited to): TEAEs, SAEs, 
deaths, and clinical laboratory abnonnalities. 
End oint.s 
rPFS 
The safety endpoints evaluated will include, but are not 
limited to, the following: AEs, TEAEs, SAEs, clinical 
laborat01y tests, ECGs, vital signs, and physical 
examinations. 
• 
ORRandDoR 
• 
OS 
• 
Time to PSA progression 
• 
(If Pait 3 is opened) rPFS by blinded, 
inde endent, central review 
ICR 
Time from randomization to any of the following 
(whichever occurs earlier): 
Symptomatic Skeletal Event: symptomatic 
fracture, surge1y 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 requiting surgical intervention or 
radiation thera . 
Abemaciclib and abit·aterone acetate steady-state plasma 
concentrations. 
Time to worst pait1 progression, using the Worst Pait1 
NRS score and the WHO-AL. 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Abbreviations: AEs = adverse events; DoR = duration of response; ECG = electrocardiogram; 
NRS = numerical rating scale; 
ORR = objective response rate; OS = overall survival; PK = phannacokinetics; PR = pru.tial response; 
Page 29 
PSA = prostate-specific antigen; RECIST 1.1 = Response Evaluation Criteria in Solid Tmnors, Version 1.1 
(Eisenhauer et al. 2009); RP2D = recommended Phase 2 Dose; rPFS = radiographic progression free survival; 
SAE = serious adverse event; TEAE = treatment-emergent adverse event; 
WHO-AL = World Health Organization - Analgesic Ladder. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 30 
5. Study Design 
5.1. Overall Design 
Study JPCM is a Phase 2/3, multicenter, multinational, randomized, double-blind, 
placebo-controlled study designed to evaluate the clinical benefit of abiraterone acetate plus 
prednisone with or without abemaciclib in patients with mCRPC. Planned analyses with detailed 
descliptions are listed below. 
Table JPCM.4. 
Anal sis 
RP2D 
Selection 
Futility 
Adaptive 
InteriJn 1 
Adaptive 
Intel'im 2 
PriJna1-y 
Analysis of 
rPFS 
Final Analysis 
of OS 
Planned Analyses 
Tonio 
Approximatelyl 
rPFS events 
Approximately.
rPFS events 
Approximatelyl 
rPFS events 
Approximately.
rPFS events if Pait 3 
not opened 
rPFS events is Pait 3 
is o ened for enrollment 
See SAP 
Details 
AC review of safety and PK data only to select 
RP2D (Section 10.3.5.1). 
Performed by independent DMC to assess if 
stopping mle for fotility has been met (Section 
10.3.5.2 . 
Perfoimed by independent DMC to assess if criteria 
for opening emollment to Pait 3 have been met 
Section 10.3.5.2 . 
(If applicable) Perfmmed by independent DMC to 
assess if criteria for opening enrollment to Pait 3 
have been met (Section 10.3.5.2). 
Final analysis ofprima1y endpoint 
(Section 10.3.1.1). 
See SAP for details. 
Abbreviations: AC = assessment committee; DMC = data monitoring committee; OS = overall survival; 
PK = pha1macokinetics; RP2D = recommended Phase 2 dose; rPFS = radiographic progression-free survival; 
SAP = statistical analysis plan. 
This study will include a lead-in portion (Pait 1) to evaluate safety and tolerability, and to 
dete1mine the recommended Phase 2 dose (RP2D) of abemaciclib in combination with 
abiraterone acetate plus prednisone. 
Pa1i 1 is a double-blind placebo-controlled safety lead-in period that will randomize 
approximately 30 patients to explore 2 doses of abemaciclib, 150 mg (Ann Al; 
3 tablets/capsules twice daily) and 200 mg (Ann A2; 4 tablets/capsules twice daily), in 
combination with abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily. Both 
Alm s Al and A2 will be placebo-controlled (Alm Bl and B2; patients will receive 3 or 
4 placebo tablets/capsules twice daily and abiraterone acetate 1000 mg once daily plus 
prednisone 5 mg twice daily). Thus, there will be 4 aims in Pait 1 and randomization will be 
based on a 2:2:1:1 ratio. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 31 
Approximately 
patient has entered treatment, an internal 
assessment committee (AC) will review safety and available phaimacokinetic (PK) data and 
deteimine the RP2D. The AC will, at a minimum, be composed of Lilly members not involved in 
the day-to-day study conduct (the medical director, a Global Patient Safety physician, a 
PK/phaimacodynamics scientist, and a statistician). In the case of unacceptable and/or 
unmanageable toxicity of the combination, the AC may decide to discontinue the study upon 
completion of Pait 1. During the evaluation period, patients may still emoll in Pait 1. Once 
RP2D has been selected, patients emolled in Part 1 will switch to the selected RP2D ( or 
matching placebo) to continue the study. In the situation where blinded study treatment has been 
dose reduced below the selected RP2D, dose escalation to RP2D will not be implemented and 
dose-reduced patients will continue study at the same lower dose level. Subsequent patients will 
then stait to emoll in Part 2 and will be randomized to receive abemaciclib at RP2D* or 
matching placebo. 
Part 2 will randomize approximately 150 patients in a. 1:1 ratio between 2 aims: 
* 
• 
Alm A (experimental aim): Abiraterone acetate 1000 mg once daily plus prednisone 
5 mg twice daily and abemaciclib at RP2D* twice daily 
• 
Alm B (control rum): Abiraterone acetate 1000 mg once daily, prednisone 5 mg twice 
daily, and placebo (matching number of tablets/capsules twice daily). 
After approximately I rPFS events, an independent DMC will perf01m a futility analysis. As 
described in the DMC Chaiter, the DMC will consist of at least 3 members external to Lilly, 
none of whom are involved as study investigators, including at least 1 clinician and 1 statistician. 
After approximately I rPFS events, the DMC will perform an interim adaptive analysis. If the 
prespecified adaptive expansion criteiia are met, Pait 3 will be opened for emollment. If the 
expansion criteria ru·e not met, the DMC will perfoim another interim adaptive analysis after 
approximately I rPFS events. If the prespecified adaptive expansion criteria ru·e met, Pait 3 will 
be opened for emollment. If opened for emollment, Prut 3 will randomize approximately 170 
additional patients in a 1: 1 ratio. If the expansion criteria ru·e not met in either interim adaptive 
analysis, Pait 3 will not be opened for emollment, and scientific evaluation will continue until 
study completion (Section 7.8). 
Abemaciclib, matching placebo, and abiraterone acetate plus prednisone will be administered 
orally. 
Patients (emolled in Pait 1, Part 2, or Pait 3) will be centrally randomized to the abemaciclib 
group(s) and the placebo group(s) according to the following stratification factors: 
-
Radiographic progression* at study entry (yes/no) 
-
Measurable disease** (yes/no) 
-
Prior docetaxel for mHSPC (yes/no). 
* Per RECIST 1.1 for soft tissue and/or per PCWG3 for bone. 
** Per RECIST 1.1. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 32 
These stratification factors were chosen because they represent impo1tant prognostic factors 
and/or an imbalance may bias the results. Patients emolled in Pait 1, Part 2, and Pait 3 will be 
combined to fo1m the experimental group (abemaciclib and abiraterone acetate plus prednisone) 
and control group (placebo and abiraterone acetate plus prednisone); see Section 10.2. 
Figure JPCM. l illustrates the study design. 
Al 
Abiraterone Acetate 1000mg QD 
Prednisone 5mg BID 
Abemaciclib 150mg Bl D 
A2 
Abiraterone Acetate 1000mg QD 
Prednisone 5mg BID 
Abemaciclib 200mg Bl D 
Bl Abiraterone Acetate 1000mg QD 
2:2:1 :1 
Prednisone 5mg BID 
Placebo 150mg BID 
N=5 
B2 
Abiraterone Acetate 1000mg QD 
Prednisone 5mg BID 
Placebo 200mg BID 
N=5 
Safety/PK analysis condueted by AC al'P'"OXlmately 28 days ofter the 
30• pMlent has entered tre:nment to determine the RP20*. 
Note: Pait I: N=30, 
PK = pha1macokinetic; 
Phase 2 dose. 
ice daily; mg = milligram; N =number of patients; 
; QD = daily; R = Randomization; RP2D = recommended 
Figure JPCM.1. 
Illustration of study design. 
5.2. Number of Patients 
Planned emollment for each study pait is as follows: 
Part 1: will randomize approximately 30 patients in a 2:2:1:1 ratio 
Part 2: will randomize approximately 150 patients in a 1:1 ratio 
Pait 3: will randomize approximately 170 patients in a 1: 1 ratio 
5.3. End of Study Definition 
End of the study is the date of the last visit or last scheduled procedure for the last patient, as 
shown in the Schedule of Activities, Section 2. 
Refer to Figure JPCM.2 for a depiction of study completion, the continued-access period, and 
end of study. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 33 
LY2835219 
5.4. Scientific Rationale for Study Design  
5.4.1. Study Design and Control Group  
Abiraterone acetate 1000 mg once daily in combination with prednisone (or prednisolone) 5 mg 
twice daily is indicated for the treatment of mCRPC patients, prior to or after docetaxel-based 
chemotherapy regimen, based on the results of 2 randomized placebo-controlled, multicenter 
Phase 3 clinical trials: COU-AA-302 and COU-AA-301, respectively (de Bono et al. 2011; Ryan 
et al. 2013). 
In this study, all patients will receive abiraterone acetate 1000 mg once daily plus prednisone (or 
prednisolone) 5 mg twice daily as per approved posology in this mCRPC population.  
The experimental group will receive abemaciclib and the control group will receive matching 
placebo.  
5.4.2. Population  
The primary objective is to determine whether abemaciclib in combination with abiraterone 
acetate plus prednisone improves rPFS. Since optimal sequencing of current mCRPC treatments 
has not been prospectively/formally established and given that response rates to abiraterone 
therapy after treatment with enzalutamide (or reverse sequence) are relatively low (15% to 30%; 
Noonan et al. 2013; Schrader et al. 2014; Smith et al. 2017), the study population will consist of 
treatment-naïve mCRPC patients. Prior treatment with abiraterone acetate, enzalutamide, 
apalutamide, darolutamide, radiopharmaceuticals, and sipuleucel-T is not allowed. Prior 
docetaxel for mHSPC, but not for mCRPC, is permitted. 
5.4.3. Radiographic PFS as a Primary Efficacy Endpoint  
Metastatic PCa is a heterogeneous disease that progresses through multiple clinical steps with a 
high prevalence of bone metastases. For mCRPC patients, progression of metastatic bone disease 
is of paramount clinical importance since it is responsible for the severe morbidity of skeletal-
related events such as symptomatic fractures, pain, surgery or palliative radiation to bone, and 
spinal cord compression. Delaying the emergence or the progression of radiographically 
detectable distant metastases is a clinically relevant endpoint for the determination of the benefit 
of the study treatment that is not impacted by posttreatment anticancer therapies. Drug 
development for PCa has been limited due to the lack of an objective definition for cancer 
progression and the use of composite time-to-event endpoints that include combinations of 
radiographic progression, PSA progression, skeletal-related events, development of symptoms, 
initiation of other anticancer treatment, and death to assess progression-free survival. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) designates numerous 
lesions as nonmeasurable. These include bone metastases without a soft tissue component 
measuring ≥10 mm (the large majority of bone metastases). Conventional RECIST also lacks 
provisions to differentiate true progression of bone metastasis from the flare, a paradoxical 
worsening of the bone scan attributed to bone healing as a result of a favorable antitumor effect.  
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 34 
To ensme consistent and reproducible assessment of rPFS and control for tumor flare, the 
Prostate Cancer Working Group 2 (PCWG2) definition, later refmed by Prostate Cancer 
Working Group 3 (PCWG3), establishes progression in bone as: 
1) the appearance of at least 2 new lesions on the first post-treatment scan, with at least 
2 additional lesions on the next scan (2+2 rnle), or 
2) for radiographic disease progression in bone obse1ved aBer the first post-treatment scan, 
at least 2 new lesions (relative to the first post-treatment scan) that are persisting on a 
confumat01y subsequent scan. 
The date of progression is the date of the first post-treatment scan when the first 2 new lesions 
were documented. 
fu study COU-AA-302, which randomly assigned chemotherapy-naive patients with mCRPC to 
receive abiraterone acetate plus prednisone or placebo plus prednisone, rPFS (per RECIST and 
PCWG2) assessed by independent radiologists and investigators was highly consistent and 
highly associated with overall survival, providing initial prospective evidence on further 
developing rPFS as an inte1mediate endpoint in mCRPC trials. fu this study, the consensus 
guidelines of the RECIST 1.1 for soft tissue and the PCWG3 for bone have been taken into 
consideration for the dete1mination of rPFS. The rPFS (which also includes death from any 
cause) will be assessed by the investigator/local radiologist for the prima1y endpoint, and rPFS 
by BICR will be evaluated as a seconda1y endpoint if Part 3 is opened for emollment. 
Overall survival is an important seconda1y endpoint for this study and is defined as the time from 
random assignment to the date of death resulting from any cause. 
5.5. Justification for Dose 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 35 
LY2835219 
6. Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1. Inclusion Criteria  
Patients are eligible to be included in the study only if they meet ALL of the following criteria: 
[1] 
Male patients, 18 years of age or older; willing and able to provide written informed 
consent. 
[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 measurable soft 
tissue metastatic lesions by computed tomography (CT) or magnetic resonance imaging 
(MRI). If lymph node metastasis is the only evidence of metastasis, it must be ≥1.5 cm in 
the short axis. Visceral metastasis, including to liver, is allowed. 
[4] 
Serum testosterone level ≤1.73 nmol/L (50 ng/dL) at the screening visit. Patients who 
have not undergone bilateral orchiectomy are required to continue ADT (LHRH 
agonists/antagonists) throughout the study. 
[5] 
Progressive disease at study entry demonstrated during continuous ADT/post 
orchiectomy defined as one or more of the following criteria: 
 Sequence of at least 2 rising PSA values at a minimum of 1-week intervals with 
the last result being at least 1.0 ng/mL if confirmed PSA rise is the only indication 
of progression. Patients who received an anti-androgen must have PSA progression 
after withdrawal (≥4 weeks since last flutamide or ≥6 weeks since last 
bicalutamide or nilutamide). 
 Radiographic progression per RECIST 1.1 for soft tissue and/or per PCWG3 for 
bone (i.e., appearance of ≥2 new bone lesions), with or without PSA progression. 
[6] 
Patient must have discontinued all previous treatments for cancer (except ADT and bone 
loss-prevention treatment), must have recovered from of all acute toxic effects of prior 
therapy or surgical procedure to Grade ≤1 or baseline (as per Common Terminology 
Criteria for Adverse Events version 5.0 [CTCAE v 5.0]) prior to randomization, with the 
exception of alopecia or peripheral neuropathy AND have a washout period from last 
dose of prior systemic or radiation therapy as follows: 
 Patients must discontinue flutamide at least 4 weeks, bicalutamide and nilutamide 
at least 6 weeks, prior to randomization. 
 At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors (e.g., 
dutasteride, finasteride), estrogens, and cyproterone to randomization. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 36 
LY2835219 
 At least 4 weeks must have elapsed from the use of chemotherapy (i.e., docetaxel, 
for mHSPC) to randomization. 
 At least 4 weeks must have elapsed from major surgery or radiation therapy prior 
to randomization. 
[7] 
Mandatory for Part 1 and Part 2; optional for Part 3:  
Able and willing to undergo tumor biopsy of at least 1 metastatic site, which should be 
collected following determination of eligibility and before initiating study treatment.  
 Biopsy of newly emerged radiographic metastases is desired and preferable to the 
biopsy of previously existing lesions whenever possible. 
 Soft-tissue as well as bony metastatic lesions will be considered acceptable. Soft-
tissue biopsy is preferred to bone biopsy 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 randomization and no 
treatment was initiated from biopsy to study entry. 
Optional for Part 1, Part 2, and Part 3: 
Biopsy of metastatic tissue at the time of on-study radiographic progression, prior to start 
of new anti-cancer therapy.  
 Biopsy of a progressing metastatic lesion is preferred whenever possible.  
 If patient discontinues study for reasons other than radiographic progression, the 
biopsy should be considered only if the patient has completed at least 6 cycles of 
study treatment. 
[8] 
Have adequate organ function, as defined below: 
System 
Laboratory Value 
Cardiac 
LVEF 
≥50% 
Clinical Chemistry 
Serum albumin 
≥3 g/dL 
Serum potassium 
≥3.5 mM 
Hematologic 
ANC 
1.5×109/L 
Platelets 
100×109/L 
Hemoglobin 
9 g/dL (≥90 g/L) independent of transfusions 
Hepatic 
Total bilirubin 
1.5×ULN 
ALT and AST 
2.5×ULN 
Renal 
Serum creatinine 
1.5×ULN 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ANC = absolute neutrophil 
count; LVEF = left ventricular ejection fraction; ULN = upper limit of normal. 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 37 
LY2835219 
[9] 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. 
[10] 
Willing to comply with study procedures. Patients with reproductive potential must agree 
to use effective contraception and to not donate sperm during the study and for at least 3 
months following the last dose of study treatment. 
6.2. Exclusion Criteria  
Patients will be excluded from the study if they meet ANY of the following criteria: 
[11] 
Prior therapy with CYP17 inhibitors (including abiraterone acetate, TAK-700, TOK-001, 
and ketoconazole). 
[12] 
Prior treatment with abemaciclib or any CDK4 and 6 inhibitors. 
[13] 
Known or suspected contraindications or hypersensitivity to abiraterone acetate, 
prednisone, or abemaciclib or to any of the excipients. 
[14] 
Prior cytotoxic chemotherapy for metastatic castration resistant prostate cancer (patients 
treated with docetaxel in the mHSPC are eligible). Prior radiopharmaceuticals for 
prostate cancer, or prior enzalutamide, apalutamide, darolutamide, or sipuleucel-T. 
Patients who had prior radiation or surgery to all target lesions. 
[15] 
Are 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. If patient has participated in a clinical study involving an investigational 
product, 3 months or 5 half-lives (whichever is shorter) should have passed. If a patient is 
currently enrolled in a clinical trial involving non-approved use of a device, then 
agreement with the investigator and the Lilly Clinical Research Physician/Clinical 
Research Scientist (CRP/CRS) is required to establish eligibility. 
[16] 
Gastrointestinal disorder affecting absorption or inability to swallow large pills. 
[17] 
Have prior malignancies or active concurrent malignancy (with the exception of 
non-melanomatous skin cancer). Patients with carcinoma in situ of any origin and 
patients with prior malignancies who are in remission and whose likelihood of recurrence 
is very low per investigator’s judgment are eligible for this study. The Lilly CRP/CRS 
will approve enrollment of patients with prior malignancies in remission before these 
patients are enrolled. 
[18] 
The patient has serious preexisting medical condition(s) that, in the judgment of the 
investigator, would preclude participation in this study (e.g., interstitial lung disease, 
severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection 
involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis 
or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea). 
[19] 
The patient has a history of any of the following conditions: syncope of cardiovascular 
etiology, ventricular arrhythmia of pathological origin (including, but not limited to, 
ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Atrial 
fibrillation or other cardiac arrhythmia requiring medical therapy.  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 38 
LY2835219 
[20] 
Clinically significant heart disease as evidenced by myocardial infarction, arterial 
thrombotic events in the past 6 months, severe or unstable angina, or New York Heart 
Association (NYHA) Class II to IV heart failure or cardiac ejection fraction measurement 
of <50% at baseline. 
[21] 
Patients with clinically active or chronic liver disease, moderate/severe hepatic 
impairment (Child-Pugh Class B and C), ascites, or bleeding disorders secondary to 
hepatic dysfunction. 
[22] 
History of adrenal dysfunction. 
[23] 
The patient 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. 
[24] 
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 
involvement). 
[25] 
Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg or diastolic 
BP≥95 mmHg). Patients with a history of hypertension are allowed provided BP is 
controlled by anti-hypertensive treatment. 
[26] 
Life expectancy <6 months. 
[27] 
Patient treated with drugs known to be strong inhibitors or strong or moderate inducers of 
cytochrome P450 3A4 (CYP3A4) and the treatment cannot be discontinued or switched 
to a different medication at least 5 half-lives prior to starting study drug. 
[28] 
Have received recent (within 4 weeks prior to randomization) live vaccination. Seasonal 
flu vaccines that do not contain a live virus are permitted. 
[29] 
Untreated spinal cord compression or evidence of spinal metastases with risk of spinal 
compression. Structurally unstable bone lesions suggesting impending fracture. 
6.3. Lifestyle Restrictions  
The following lifestyle restrictions are applicable to all patients on all arms: 
 While on study, patients should refrain from consuming grapefruit and pomegranate 
fruits and/or juice, saw palmetto, and other herbal/nonherbal products known to be strong 
inhibitors of CYP3A, have prostate cancer activity, or affect PSA levels. 
 Patients must use effective contraception and not donate blood or sperm during the study 
and for 3 months after the last dose. 
6.4. Screen Failures  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only after discussion with and permission from the Lilly CRP/CRS. Individuals may 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 39 
LY2835219 
be rescreened a maximum of 1 time. The interval between rescreenings should be at least 
2 weeks. Each time rescreening is performed, the individual must sign a new informed consent 
form (ICF) and will be assigned a new identification number. 
Repeating of laboratory tests during the 28-day screening period does not constitute rescreening. 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
7. Treatments 
7.1. Treatments Administered 
The following treatments will be administered in this study: 
Pa1i 1: 
Page 40 
• 
Experimental Alm Al: Abemaciclib 150 mg (3 tablets/capsules) orally twice daily 
• 
Experimental Alm A2: Abemaciclib 200 mg (4 tablets/capsules) orally twice daily 
• 
Control Alm Bl: Placebo (3 tablets/capsules) orally twice daily 
• 
Control Alm B2: Placebo (4 tablets/capsules) orally twice daily 
• 
Alms Al, A2, Bl, and B2: Abiraterone acetate 1000 mg orally once daily plus 5 mg 
prednisone orally twice daily. 
Pali 2 and Pait 3: 
• 
Experimental Alm A: Abemaciclib at RP2D* orally twice daily 
• 
Control (Placebo) Alm B: Placebo (matching number of tablets/capsules) orally twice 
daily 
• 
Alms A and B: Abiraterone acetate 1000 mg orally once daily plus 5 mg prednisone 
orally twice daily. 
Treatment Name • 
Abemaciclib 
Placebo 
Abiraterone acetate 
Prednisone 
Authorized as 
Authorized and not 
Not authorized 
Authorized and not 
Authorized and used 
defined by EU 
used according to 
used according to 
according to EU 
Clinical Trial 
EU authorization 
EU authorization 
authorization 
Regulation 
a 
Study treatment is defined as any medicinal product(s) or medical device(s) intended to be administered to 
or used by a study participant according to the study protocol. 
Blinded study mug (abemaciclib or placebo) tablets/capsules are 50 mg. Dosing is twice daily. 
Ideally, doses should be spaced 12 hours apa1t, with a Ininimum of 6 hours between doses. 
Instruct patients to take the doses at approximately the same times eve1y day and to swallow 
tablets/capsules whole with a glass of water (do not chew, crush, split, dissolve in water, or alter 
tablets/capsules in any way prior to swallowing). Blinded study drugs may be taken with or 
without food. If the patient volnits or misses a dose, advice the patient to take the next prescribed 
dose at the usual time. Instruct patients not to ingest tablets/capsules if broken, cracked, or 
otherwise not intact. Placebo will be provided as a tablets/capsules fmmulation and will be 
matched in size, color, and shape to abemaciclib tablets/capsules to maintain the study blind. 
Abiraterone acetate and prednisone should be administered according to the respective 
prescribing inf mmation. 
Where prednisone is not commercially available, prednisolone may be substituted. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 41 
Patients will continue to receive study treatment until a discontinuation criterion is met (see 
Section 8). See Section 7.8.1 for inf01mation about continued access to study treatment. 
Table JPCM.5 shows the treatment regimens. 
Table JPCM.5. 
Treatment Regimens 
StudyDmg 
Dose 
Route 
Timing 
Part 1 
Abemaciclib 
Ann Al 
150mg 
PO 
Twice daily 
Lead-in 
AnnA2 
200mg 
Placebo 
3 
PO 
Twice daily 
Alm Bl 
tablets/capsules 
4 
AlmB2 
tablets/capsules 
Abiraterone 
Alms Al, A2, 
1000 mg 
PO 
Once daily 
acetate 
Bl , andB2 
Prednisone 
Alms Al, A2, 
5mg 
PO 
Twice daily 
Bl , and B2 
Part 2 and 
Abemaciclib 
RP2D* 
Twice daily 
Part 3 
AimA 
PO 
Placebo 
AimB 
RP2D* 
PO 
Twice daily 
Abiraterone 
acetate 
AimsAandB 
1000 mg 
PO 
Once daily 
Prednisone 
AimsAandB 
5mg 
PO 
Twice daily 
Abbreviations: mg = milligram; PO = by mouth; RP2D = recommended Phase 2 dose. 
fuvestigator Responsibilities 
The investigator or his/her designee is responsible for the following: 
• 
following the protocol at all times 
• 
explaining the conect use of the chugs and planned duration of each individual's 
treatment to the patient/study site personnel/legal representative 
• 
verifying that instructions are followed properly 
• 
maintaining accurate records of study treatment dispensing and collection 
• 
at the end of the study returning all unused medication to Lilly, or its designee, 
unless Lilly and sites have agreed all unused medication is to be destroyed by the 
site, as allowed by local law. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 42 
LY2835219 
7.1.1. Packaging and Labeling  
Abemaciclib and matching placebo will be supplied by Lilly or its designee in accordance with 
current Good Manufacturing Practice. Study treatments and clinical study materials will be 
labeled as appropriate according to the country’s regulatory requirements. 
7.2. Method of Treatment Assignment  
Patients who meet all criteria for enrollment will be randomly assigned to receive abiraterone 
acetate and prednisone in combination with abemaciclib or placebo. 
In Part 1, approximately 30 patients will be randomized in a 2:2:1:1 ratio into Arm A1, Arm A2, 
Arm B1, or Arm B2. In Part 2, approximately 150 patients will be randomized in a 1:1 ratio into 
Arm A or Arm B. In Part 3, approximately 170 additional patients will be randomized in a 
1:1 ratio into Arm A or Arm B. 
Randomization will be stratified by the following factors: 
 Radiographic progression* at study entry (yes/no) 
 Measurable disease** (yes/no) 
 Prior docetaxel for mHSPC (yes/no) 
* Per RECIST1.1 for soft tissue and/or per PCWG3 for bone.  
** Per RECIST1.1 
The interactive Web response system (IWRS) will use randomization stratification factors to 
assign double-blind study treatment to each patient. 
7.2.1. Selection and Timing of Doses  
A cycle is defined as an interval of 28 days. Abemaciclib or placebo will be administered orally 
twice daily at approximately the same times each day on Days 1 through 28 of a 28-day cycle. 
Ideally, doses should be spaced 12 hours apart, with a minimum of 6 hours between doses. 
Details on treatment administration for combination therapy are described in the study design; 
Section 5.1. In the event of a dose suspension due to toxicity immediately prior to the beginning 
of a cycle, the PK sampling schedule outlined in Appendix 4 may require adjustment and the 
sponsor should be notified. 
A delay or earlier start of a cycle due to holiday, weekend, bad weather, or other unforeseen 
circumstances will be permitted for a maximum of 7 days and not counted as a protocol 
deviation. In exceptional cases, such as planned cycle delays (including but not limited to 
vacation or holidays), additional study treatment may be dispensed after discussion with Lilly 
CRP/CRS.  
A patient may continue to receive study treatment until discontinuation criteria are met (as 
described in Section 8). 
7.3. Blinding  
This is a double-blind study. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 43 
LY2835219 
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is completed. Access to 
unblinded data/documents will be controlled by restricting access to the data/documents in 
Lilly’s data and statistical warehouse. Any changes to this unblinding plan may be described in a 
protocol amendment, the statistical analysis plan (SAP), and/or a separate unblinding plan 
document. 
Efficacy information will not be shared between sites until the study is completed. Upon study 
completion (see Section 7.8.1), investigators may unblind patients to study treatment assignment. 
Unblinding of the investigator and the patient at the time of documented objective disease 
progression is permitted to ensure optimal patient management and/or facilitate selection of 
subsequent treatment. The investigator must consult with the Lilly CRP/CRS prior to unblinding. 
Unblinding must be performed through the IWRS. 
If the investigator or patient becomes unblinded, that patient will be discontinued from study 
treatment and will undergo post-discontinuation follow-up. Long-term follow up procedures will 
be followed until death, loss of follow-up, withdrawal of consent, or study completion. 
7.3.1. Unblinding at Interim Analyses  
See Section 10.3.5 for details on the conduct of interim analyses. The AC will, at a minimum, be 
composed of Lilly members not involved in the day-to-day study conduct (the medical director, a 
Global Patient Safety physician, a PK/pharmacodynamics scientist, and a statistician). The AC 
will conduct only 1 unblinded analysis, of safety and PK data only, to facilitate abemaciclib dose 
selection prior to Part 2. Thereafter, only the DMC is authorized to evaluate unblinded futility 
and adaptive interim analyses (see Section 10.3.5). The DMC will be independent and consist of 
at least 3 members external to Lilly, none of whom are involved as study investigators, including 
at least 1 clinician and 1 statistician. The DMC will communicate any recommendations based 
on the interim analyses to the Lilly Senior Management Designee. Further details are included in 
the DMC Charter. For those analyses assigned to the DMC, only the designated Statistical 
Analysis Center, which is independent of the sponsor, will perform analyses on unblinded data. 
Study sites will receive information about interim results only if they need to know for the safety 
of their patients. Further details are included in the study unblinding plan. 
7.3.2. Emergency Unblinding  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted. Patient safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP/CRS prior to 
unblinding a patient’s treatment assignment unless this could delay emergency treatment of the 
patient. If a patient’s treatment assignment is unblinded, Lilly must be notified immediately. 
Emergency unblinding for AEs must be performed through the IWRS. This option must be used 
when the patient’s acute well-being requires knowledge of the patient’s treatment assignment.  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 44 
LY2835219 
All calls resulting in an unblinding event are recorded and reported by the IWRS. If the 
investigator or patient becomes unblinded, that patient will be discontinued from study treatment 
and will undergo post-discontinuation follow-up. Long-term follow up procedures will be 
followed until death, loss of follow-up, or withdrawal of consent, or study completion. 
7.3.3. Inadvertent Unblinding  
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur. If an investigator, site 
personnel, or patient is inadvertently unblinded, the unblinding will not be sufficient cause for 
the patient to be discontinued from study treatment or excluded from study analyses. 
In cases in which there are ethical reasons for the patient to remain on the study treatment in the 
event of unblinding, the investigator must obtain specific approval from a Lilly CRP/CRS for the 
patient to continue in the study. 
7.4. 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 study treatment 
per investigator judgment). The CTCAE v 5.0 will be used to assess AEs. Study treatment may 
be suspended for a maximum of 28 days to allow a patient sufficient time for recovery from 
study treatment-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 study treatment. In exceptional circumstances, a delay >28 days is permitted upon 
agreement between the investigator and the Lilly CRP/CRS. 
For more information about abemaciclib/placebo dose modifications for AEs and adverse events 
of special interest (AESIs), see Section 7.4.1. 
Dose reductions for abemaciclib/placebo should be as shown in Table JPCM.6. 
Abemaciclib/placebo must be reduced sequentially by 1 dose level, unless an exception is 
granted in consultation with the Lilly CRP/CRS. Mid-cycle dose reductions for 
abemaciclib/placebo may be implemented by informing patients to reduce the number of 50-mg 
tablets/capsules taken for each dose (with dose reductions appropriately documented in the 
electronic case report form [eCRF]). If 1 study treatment (abiraterone acetate or 
abemaciclib/placebo) has been discontinued or maximally dose reduced due to toxicity and the 
toxicity has not resolved, patients may continue to receive the other study treatment at the current 
dose if it is apparent that the toxicity is not related to the other study treatment and the patient 
continues to receive clinical benefit. 
 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 45 
LY2835219 
Table JPCM.6. 
Dose Reductions for Abemaciclib/Placebo  
 
 
Abbreviation: BID = twice daily; mg = milligrams. 
Dose adjustments for abiraterone acetate and prednisone should follow prescribing information. 
See Section 7.4.1.2. for guidance on dose modification for abnormal liver function test. 
For patients requiring a dose reduction of study treatments (abemaciclib/placebo or abiraterone 
acetate), any re-escalation to a prior dose level is permitted only after consultation with the Lilly 
CRP/CRS. 
7.4.1. Special Treatment Considerations  
7.4.1.1. Abemaciclib/Placebo Dose Adjustments and Delays: Hematologic 
Toxicities, Nonhematologic Toxicities (excluding diarrhea, Interstitial 
Lung Disease (ILD)/Pneumonitis and ALT/AST increased), Diarrhea, 
Interstitial Lung Disease/Pneumonitis  
 
Table JPCM.7 is a guidance for management of treatment-emergent, related, and clinically 
significant AEs of abemaciclib/placebo. An investigator may suspend or reduce doses without 
1 of the criteria below being met and would not be considered a protocol deviation. 
Table JPCM.7. 
Toxicity Dose Adjustments and Delays of Abemaciclib/Placebo: 
Hematologic Toxicities, Nonhematologic Toxicities, Diarrhea, 
ILD/Pneumonitis  
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. 
 
Blinded Study Drug Dose (Abemaciclib/Placebo) 
Starting dose  
150 mg BID 
200 mg BID 
First dose reduction 
100 mg BID 
150 mg BID 
Second dose reduction 
50 mg BID 
100 mg BID 
Third dose reduction 
Discontinue 
50 mg BID 
Fourth dose reduction 
 
Discontinue 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 46 
LY2835219 
Toxicity Type 
CTCAE Grade 
Dose Modification 
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 
7.7.2.2 
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. 
Nonhematologic Toxicity 
Excluding Diarrhea, Interstitial 
Lung Disease /Pneumonitis, 
and ALT/AST increased (see 
Section 7.4.1.2 for ALT/AST) 
 
Additional guidance for 
monitoring renal function is in 
Section 9.4.2.3.  
Additional guidance for 
venous thromboembolic 
events is in Section 9.4.2.4. 
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, or 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 7.7.2.1. 
See Appendix 9 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, 
 
or Grade 3, or Grade 4, or 
requires hospitalization 
Suspend dose until toxicity resolves to ≤Grade 
1. 
Resume at next lower dose level. 
Interstitial Lung 
Disease/Pneumonitis 
Additional guidance for 
Interstitial Lung 
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 
Suspend dose until toxicity resolves to 
baseline or Grade ≤1.  
Resume at next lower dose level. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 47 
Toxicity Tvoe 
CTCAEGrade 
Dose Modification 
Disease/Pneumonitis 
days 
management is in 
Section 9.4.2.5. 
Grade 3 or Grade 4 
Discontinue abemaciclib/placebo. 
Abbreviations: ALT = alanine aminotransferase; ASCO = Ame1ican Society of Clinical Oncology; AST = aspartate 
aminotransferase. 
Detennination of persistent events will be at the discretion of the investigator. 
Recurrent toxicity refers to the same event occmTing within the next 8 weeks (as measured from the stop 
date of the preceding event). As a general guidance, based on the risk/benefit balance assessment per the 
investigator, for a patient who experiences a new episode of Grade 3 hematological toxicity after more than 
8 weeks following the last episode of same Grade 3 hematological toxicity, the investigator may consider 
resuming the patient on the same drug dose should the patient satisfy the following conditions: 
• 
The patient showed stable hematological counts (Grade :Si) during that time frame; 
• 
In the absence of any infectious sign or risk factor; 
• 
The patient is benefiting from study treatment. 
7.4.1.2. Abemaciclib/Placebo and Abiraterone acetate and Dose Adjustments 
and Delays - Increased ALT or AST 
Measure sernm aminotransferases (alanine aminotransferase [ALT] and aspa1tate 
aminotransferase [AST]) and bilirnbin levels prior to starting study treatment and eve1y 2 weeks 
for the first 3 months and monthly thereafter. 
Promptly measure ALT, AST, alkaline phosphatase (ALP), total bilirnbin (TBL), direct bilirnbin 
(DBL), gamma-glutamyl transferase (GGT), and creatine kinase (CK) if clinical symptoms or 
signs suggestive ofhepatotoxicity develop. 
Review concomitant medications that are potentially hepatotoxic if patients develop liver 
function test abnmm alities 
An investigator 
may suspend or reduce doses without 1 of the below criteria being met. This would not be 
considered a protocol deviation. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 48 
a If at any time, a patient develops a Grade 23 elevation of ALT or AST at the reduced dose of 
500 mg once daily, pe1manently discontinue abiraterone. 
hlfrecunent Grade 3 (i.e., within 8 weeks as measured from the resta1ting date of the study 
diug) is only obse1ved for AST, the investigator may consult with the Lilly CRP/CRS prior to 
pe1manently discontinuing study treatment. 
Hepatic monitoring should be initiated for patients who develop liver function test abnmmalities. 
Refer to Section 9.4.2.1 for Hepatic Safety Monitoring. 
Additional safety data should be collected for patients who develop liver function test 
abno1malities. Refer to Section 9.4.2.2 for Special Hepatic Safety Data Collection. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 49 
LY2835219 
7.5. Preparation/Handling/Storage/Accountability  
Abemaciclib and placebo will be supplied by Lilly and labeled according to country regulation 
requirements. All study treatment should be stored according to their associated product label 
and taken as indicated. Patients should store all study treatment in the original package provided 
and according to the product label (where applicable) and be instructed to keep all medications 
out of reach from children. 
7.6. Treatment Compliance  
Patient compliance will be assessed by counting returned tablets/capsules. Study medication 
administration data will be recorded in the patient’s medical record and eCRF. Deviations from 
the prescribed dosage regimen should be recorded on the eCRF. 
Patients who are significantly noncompliant will be discontinued from the study. A patient will 
be considered significantly noncompliant if he misses more than 7 consecutive days of study 
medication (full doses) or more than 25% cumulative days of study medication (full doses) 
during the study. Similarly, a patient will 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 patient being considered noncompliant. 
7.7. Concomitant Therapy  
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications must be captured on the eCRF. Concomitant medications and supportive care 
therapies must also be documented at time of discontinuation and at the 30-day follow up visit. 
With the exception of standard LHRH agonists/antagonists, no other anticancer therapy will be 
permitted while patients are on study treatment (including, but not limited to, hormonal 
anticancer therapies, CYP17 inhibitors [TAK-700, TOK-001 and ketoconazole], other CDK4 
and 6 inhibitors, chemotherapy, radiotherapy, radiopharmaceuticals, and 
immunotherapy/vaccines). 
Drugs or herbal/nonherbal products (e.g., saw palmetto, pomegranate) that have known prostate 
cancer activity and/or are known to affect PSA levels will be not permitted while the patients are 
on study treatment. Spironolactone is not permitted. Megestrol acetate as an appetite stimulant is 
not permitted. Premedication with antiemetics is allowed according to standard practice 
guidelines. 
Patients with bone metastases present on baseline imaging should be appropriately treated with 
bisphosphonates or RANK-L targeted agents (e.g., denosumab), per respective approved labels. 
Patients receiving bisphosphonates or RANK-L targeted agents are permitted to switch after 
initiation of study treatment as long as it is in the absence of disease progression, and due to 
reasons including, but not limited to, tolerability.  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 50 
LY2835219 
Modulators of CYP3A 
Abemaciclib is extensively metabolized through oxidation by CYP3A. In clinical drug 
interaction studies:  
 coadministration of clarithromycin, a strong CYP3A inhibitor, increased exposure (area 
under the concentration-versus-time curve [AUC]) to abemaciclib by 3.4-fold (Study 
I3Y-MC-JPBE), and  
 coadministration of rifampin, a strong CYP3A inducer, decreased exposure to 
abemaciclib by 95% (Study I3Y-MC-JPBF).  
Strong inhibitors of CYP3A (given via nontopical routes of administration) should be substituted 
or avoided if possible (Appendix 8). This includes grapefruit or grapefruit juice. In particular, 
avoid oral administration of the very strong CYP3A inhibitor, ketoconazole.  
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should reduce 
the dose of abemaciclib/placebo 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 investigator may consider 
suspending abemaciclib/placebo 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/placebo 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/placebo dose requires review and approval from Lilly CRP/CRS. 
Inducers of CYP3A should be substituted or avoided if possible (Appendix 8). 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, 
and MATE2-K. In vivo interactions of abemaciclib with narrow therapeutic index substrates of 
these transporters, such as digoxin and dabigatran, may occur. 
Abiraterone 
Abiraterone is a substrate of CYP3A4, and as such it is recommended to avoid concomitant 
strong CYP3A4 inducers. Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes 
CYP2D6 and CYP2C8. For further information regarding the potential for abiraterone and/or 
prednisone to affect the exposures of other medicinal products, or for the potential for medicinal 
products to affect the exposures of abiraterone and/or prednisone refer to prescribing 
information. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 51 
LY2835219 
7.7.1. Palliative Radiotherapy and/or Surgical Intervention for 
Prostate Cancer  
Palliative radiation or surgical intervention to treat symptoms resulting from metastatic disease 
are not allowed. Patients with symptomatic disease progression requiring radiation therapy or 
surgical intervention (no longer clinically benefiting, see section 8.1) will be discontinued from 
study treatment and have a tumor assessment before receiving radiotherapy or surgery. The 
reason and date of discontinuation will be collected for all patients. 
7.7.2. Supportive Care  
Patients should receive full supportive care to maximize quality of life. Patients 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. 
7.7.2.1. Supportive Management for Diarrhea  
When study treatment is initiated, the patient should receive instructions on the management of 
diarrhea. In the event of diarrhea (see Appendix 9), supportive measures should be initiated as 
early as possible. These include: 
 At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (e.g., 
loperamide) and notify the investigator/site for further instructions and appropriate 
follow-up. 
 Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear liquids 
per day). 
 Site personnel should assess response within 24 hours. 
 If diarrhea does not resolve with antidiarrheal therapy within 24 hours to either baseline 
or Grade 1, blinded study drug should be suspended until diarrhea is resolved to baseline 
or Grade 1. 
 When blinded study drug recommences dosing should be adjusted as outlined in 
Section 7.4.1.1. 
In severe cases of diarrhea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered. 
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed. 
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given IV fluid (IV hydration) and electrolyte replacement. 
7.7.2.2. Growth Factors  
Growth factors should not be administered to enable a patient to satisfy study inclusion criteria. 
Granulocyte colony-stimulating factor (G-CSF) or similar agents are not permitted as primary 
prophylaxis. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 52 
LY2835219 
The use of G-CSF is permitted at the discretion of the investigator based on American Society of 
Clinical Oncology (ASCO; Smith et al. 2015) and European Society for Medical Oncology 
(Crawford et al. 2009) guidelines. If the administration of growth factors is clinically indicated, 
dosing of abemaciclib/placebo must be suspended and must not be recommenced within 
48 hours of the last dose of growth factors being administered. The dose of abemaciclib/placebo 
must be reduced by 1 dose level following the administration of growth factors. 
7.7.2.3. Transfusions  
Transfusion therapy is permitted during the study if clinically indicated at any time during the 
study, but should not be administered to enable a patient to satisfy study inclusion criteria. 
Erythropoiesis-stimulating agents (ESAs; including erythropoietin and darbepoetin) may be used 
in accordance with the ASCO/ASH guidelines (Rizzo et al. 2010). 
7.8. Treatment after the End of the Study  
Study completion will occur after the final primary analysis of the last study part has been 
conducted. Investigators will continue to follow the schedule of activities provided in Section 2 
until notified by Lilly that study completion has occurred. 
Refer to Figure JPCM.2 for a depiction of these concepts for the study: study completion, the 
continued access period, and end of study. 
 
Abbreviations: OS= overall survival; rPFS= radiographic progression free survival. 
Figure JPCM.2. 
Continued access diagram.  
 
Approved on 30 Apr 2024 GMT
Study Treatment 
Period 
Study b 
Continued Access 
Period8 
End of 
Trialc 
I 
Complet,ion 
A 
--------------'!\'-· ----------------------''----------
( 
y 
\ 
A 
A 
A 
' 
Patient 
' ' 
Discontinues 
Short-Term f-o Long-Tenn ri-
Long-Tenn 
Study 
Follow-Up 
Follow-Up 
Follow-Up 
Treatment 
Short-Tenn 
Follow-Up 
Patients 
On 
& 
Treatment 
Patient 
Discontinues 
Study 
Treatment 
& 
Patient OD 
Patient on 
4 
--
Paient OD Study treatment 
Study 
t-o 
Study 
Treatment 
Treatment 
6. 
6. 
P!imar}· 
Fi:,aJ A"3lysu 
..:\:n:a!y5.is o! 
of 
rPFS 
01.'erall Sur\.i n l 
Lilly l\ill notify sites w b.H the coatiaued access puiod be:gim aad e:ods. 
" riul ualysi:s of OS. Lilly will o.otify sites l"llu shldy comple.tioa occurs.. 
• Eiad of study occ:un at dte last visit or last scheduled procedure for tile la.st p•tient. 
Patient 
Discontinues 
... 
Study 
.. 
Treatment 
Extension 
Period 
Follow-Up 
Lastri5.it1 
sdwdlll,d 
procedure :for 
bstpatiem 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 53 
LY2835219 
7.8.1. Treatment after Study Completion  
Study completion will occur following the final analysis of OS, as determined by Lilly (i.e., the 
scientific evaluation will be complete). Investigators will continue to follow the Schedule of 
Activities (Section 2) for all patients until notified by Lilly that study completion has occurred. 
Refer to Section 7.3 for unblinding that occurs after study completion. 
7.8.1.1. Continued Access  
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks. Placebo will no 
longer be administered and crossover will not be permitted. 
The continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs. Lilly will notify investigators when the continued 
access period begins. 
Patients 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 patient’s continued access to study treatment will end when a criterion for discontinuation is 
met (Section 8). Continued access follow-up will begin when the patient and the investigator 
agree to discontinue study treatment and lasts approximately 30 days. Follow-up procedures will 
be performed as shown in the Continued Access Schedule of Activities (Section 2). 
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed. Long-term 
follow-up does not apply. 
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up. 
In all cases, no follow-up procedures will be performed for a patient who withdraws informed 
consent unless he or she has explicitly provided permission and consent. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 54 
LY2835219 
8. Discontinuation Criteria  
8.1. Discontinuation from Study Treatment  
Study treatment should be continued as long as the patient consents and complies with study 
procedures and requirements, is tolerating the study treatment, and until radiographic and/or 
symptomatic progression. 
If the patient had radiographic progression, but no symptomatic progression, and alternate 
treatment is not initiated, the patient may continue on study treatment at the Investigator’s 
discretion. 
Patients with PSA-only progression should continue study treatment until disease progression 
(radiographic and/or symptomatic progression) where patient safety is not compromised. 
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. 
The reason and date of discontinuation will be collected for all patients. 
When study treatment is discontinued due to symptomatic progression, the investigator should 
obtain imaging studies within 14 days to assess for radiographic progression, including a 
confirmatory bone scan, as appropriate. 
All patients discontinuing study treatment will have procedures performed as shown in the 
Schedule of Activities (Section 2) and enter the short- and long-term follow-up periods and will 
be followed for the initiation of subsequent anti-cancer therapies every 3 months until death, loss 
of follow-up, or withdrawal of consent, whichever comes first. In addition, patients discontinuing 
treatment prior to documented radiographic progression will continue to have scheduled disease 
assessments until documented radiographic progression and will be followed for the 
development of symptomatic progression. Patients discontinuing treatment due to documented 
radiographic progression will be followed for the development of symptomatic progression. 
Patients will be discontinued from study treatment in the following circumstances: 
 the patient is enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study 
 the patient is significantly noncompliant with study procedures and/or treatment 
 disease progression, radiographic or clinical, as discussed above 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 55 
LY2835219 
 unacceptable toxicity 
 the patient has had maximum dose reductions allowed per protocol 
(Table JPCM.6) and experiences an AE that would cause an additional dose 
reduction 
 the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication. 
Discontinuation from study treatment will occur prior to introduction of the new 
agent 
 the investigator decides that the patient should be discontinued from study 
treatment 
 the patient requests to be discontinued from study treatment 
 the patient’s designee (legal representative) requests that the patient be 
discontinued from study treatment. 
Patients who are discontinued from all study treatment will have follow-up procedures 
performed as shown in the Schedule of Activities (Section 2). 
8.1.1. Discontinuation of Inadvertently Enrolled Patients  
The criteria for enrollment must be followed explicitly. If the investigator or site identifies a 
patient who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor 
must be notified. If the sponsor identifies a patient who did not meet enrollment criteria and who 
was inadvertently enrolled, the investigator site will be notified. A discussion must occur 
between the 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 performed as shown in the Schedule of Activities (Section 2). 
8.2. Discontinuation from the Study  
Patients will be discontinued from the study in the following circumstances: 
 participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP) 
 the investigator decides that the patient should be discontinued from the study 
 the patient requests to be discontinued from the study 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 56 
LY2835219 
 the patient’s designee (legal representative) requests that the patient be 
discontinued from the study. 
Patients who are discontinued from the study will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2). 
8.3. Lost to Follow-Up  
A patient will be considered lost to follow-up if he repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Study site personnel are expected to make diligent 
attempts to contact patients who fail to return for a scheduled visit or who the site is otherwise 
unable to follow-up. 
Study site personnel, or an independent third party, will attempt to collect the survival status for 
all randomized patients who are lost to follow-up, including randomized patients who do not 
receive study treatment, within legal and ethical boundaries. Public sources may be searched for 
survival status information. If the patient’s survival status is determined, the survival status will 
be documented and the patient will not be considered lost to follow-up. 
Lilly personnel will not be involved in any attempts to collect survival status information. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 57 
LY2835219 
9. Study Assessments and Procedures  
Section 2 provides the Schedule of Activities for this study. 
Appendix 2 provides a list of the laboratory tests that will be performed for this study. 
Appendix 4 provides the schedule for collection of samples in this study. 
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after receipt of confirmed test results. Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards. 
9.1. Efficacy Assessments  
Baseline and on-study tumor assessments will be performed for each patient as per the Schedule 
of Activities (Section 2). During 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 scans will be collected and stored 
centrally. The method of assessment used at baseline must be used consistently for serial tumor 
assessment throughout the study. 
See Section 9.1.2 for definitions of the efficacy endpoints. 
9.1.1. Appropriateness of Assessments  
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology studies. 
9.1.2. Definitions of Efficacy Measures  
Primary Objective 
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 patients, imaging studies (radionuclide bone scan and CT or MRI scan of the chest, 
abdomen, and pelvis) will be performed locally at baseline and repeated every 8 weeks for the 
first 24 weeks and every 12 weeks thereafter, independent of treatment delay. Imaging may be 
performed within 7 days prior to the scheduled calendar day (e.g. Day 1 of every second cycle 
beginning with Cycle 3 and continuing through Cycle 7 (inclusive), and Day 1 of every third 
cycle after Cycle 7), and within 14 days of symptomatic progression if no radiographic 
progression yet per the Schedule of Activities. 
rPFS will be assessed by sequential imaging studies and is defined as the time from the date of 
randomization 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.  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 58 
LY2835219 
The documentation required for the determination of radiographic disease progression in bone is 
listed in Table JPCM.9. 
Disease Progression on Bone Scan as per PCWG3 
Progression of disease by bone per PCWG3 is defined as the 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), OR for radiographic disease progression in bone observed after the first 
post-treatment scan (Week 17 or later), at least 2 new lesions relative to the first post-treatment 
scan (Week 9) 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 first scan when the first 2 (or more) new lesions are 
documented. 
Changes in intensity of uptake alone do not constitute either progression or regression. 
Table JPCM.9. 
Bone Progression per PCWG3  
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 
Source: Scher et al. (2016). 
 
Objective Radiographic Disease Assessment per RECIST 1.1 for Soft Tissue 
See Appendix 7. Radiographic disease progression in soft tissue does not require a confirmatory 
scan. 
Secondary Objectives 
Radiographic Progression-Free Survival by Blinded, Independent Central Review (BICR) 
In addition to the primary endpoint of rPFS by investigator-determined radiographic disease 
progression or death, rPFS by BICR will be assessed if Part 3 is opened for enrollment. 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 59 
Time to PSA Progression 
Time to PSA progression is defined as the time from the date of randomization to the date of first 
obse1vation of PSA progression. The PSA progression is defined as a 225% increase and an 
absolute increase of22 ng/mL above the nadir (or baseline value if baseline is the smallest on 
study), which is confilmed by a second value obtained 3 or more weeks later. Any postbaseline 
PSA measurements within 12 weeks since baseline will be ignored in dete1mining PSA 
progress10n. 
Duration of Response is defined as the time from first documented evidence of soft tissue 
complete response (CR) or partial response (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. 
Objective Response Rate is defined as the prop01tion of paiticipants who have a soft tissue best 
overall response of CR or PR per RECIST 1.1 as assessed by the investigator/local radiologist. 
Only patients with measurable soft tissue disease at baseline ( defined as having at least 1 tai·get 
lesion on CT or MRI scans) will be included in the analysis. 
Overall Survival is defined as the time from the date of randomization to date of death due to 
any cause. 
Time to Symptomatic Progression is defined as the time from randomization to any of the 
following (whichever occurs earlier): 
• 
Symptomatic Skeletal Event (SSE, defined as symptomatic fracture, surge1y, 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 inte1vention or radiation therapy. 
Exploratory Objectives 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 60 
LY2835219 
9.2. 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 study treatment. 
Additional events meeting the AE definition are medication error, misuse, or abuse of IMP, 
including subsequent signs, symptoms, or clinical sequelae.  
The investigator will use CTCAE, v 5.0 (NCI 2017) to assign AE terms and severity grades. 
Investigators are responsible for: 
 monitoring the safety of patients in this study and for alerting Lilly or its designee 
to any event that seems unusual, even if this event may be considered an 
unanticipated benefit to the patient 
 the appropriate medical care of patients during the study 
 documenting their review of each laboratory safety report 
 following, through an appropriate health care option, AEs that are serious or 
otherwise medically important, considered related to study treatment or the study, 
or that caused the patient to discontinue study treatment before completing the 
study. The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained. Frequency of 
follow-up evaluation is left to the discretion of the investigator. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. 
After the ICF is signed, study site personnel will record via CRF/electronic data entry/designated 
data transmission methods the occurrence and nature of each patient’s preexisting conditions, 
including clinically significant signs and symptoms of the disease under treatment in the study. 
In addition, study site personnel will record via 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 
treatment 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 treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies. A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
Study site personnel must report any dose modifications 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. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 61 
LY2835219 
9.2.1. Serious Adverse Events  
An SAE is any AE from this study that results in one of the following outcomes: 
 death 
 initial or prolonged inpatient hospitalization 
 a life-threatening experience (that is, immediate risk of dying) 
 persistent or significant disability/incapacity 
 congenital anomaly/birth defect 
 important medical events that may not be immediately life-threatening or result in 
death or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data 
entry/designated data transmission methods, SAE reporting to Lilly begins after the patient has 
signed the ICF and has received study treatment. However, if an SAE occurs after signing the 
ICF, but prior to receiving study treatment, it needs to be reported ONLY if it is considered 
reasonably possibly related to study procedure. 
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly-approved method. If alerts are issued via telephone, they are to 
be immediately followed with official notification on study-specific SAE forms. This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information. 
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported. However, to fulfill regulatory requirements any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus. 
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient summary CRF has been completed). 
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of enrollment should not be considered SAEs. 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs. 
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 62 
LY2835219 
SAE regulatory reporting 
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 evaluate the reported SAEs, including confirmation of relatedness and assessment 
of expectedness. The sponsor has processes for safety reports for identification, recording, and 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs) according to 
local regulatory requirements. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, institutional review board 
(IRB)/independent ethics committee (IEC), and investigators. 
9.2.2. Suspected Unexpected Serious Adverse Reactions  
SUSARs are serious events that are not listed in the IB and that the investigator identifies as 
related to study treatment or study procedure. United States 21 CFR 312.32 and Regulation (EU) 
No 536/2014 and the associated detailed guidance’s 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’s. 
9.2.3. Complaint Handling  
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements. 
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed. 
9.3. Treatment of Overdose  
Refer to the specific IB Section 7.3.9 and/or Product Label for the applicable targeted agent(s) 
with marketed approval. 
9.4. Safety  
9.4.1. Safety Measures  
For each patient, ECGs, vital signs, laboratory tests, or other tests should be collected as shown 
in the Schedule of Activities (Section 2). 
Results from any clinical laboratory test analyzed by a central laboratory (refer to Appendix 2) 
will be provided to investigative sites by Lilly or its designee. 
Refer to Section 9.1.2 for details on the recording of AEs. 
9.4.2. Safety Monitoring  
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 63 
LY2835219 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring committee (DMC; an advisory group for 
this study formed to protect the integrity of data; refer to Section 10.3.5) can conduct additional 
analyses of the safety data. 
Refer to Section 7.4.1.2 for Guidance for Abnormal Liver Function Test.  
Refer to Section 9.4.2.2 for details regarding hepatic safety data collection in the event of 
particular circumstances. 
9.4.2.1. Hepatic Safety Monitoring  
Liver testing (Appendix 5), including ALT, AST, ALP, TBL, DBL, GGT, and creatine kinase 
(CK), should be repeated within 2 to 4 days to confirm the abnormality and to determine if it is 
increasing or decreasing, if 1 or more of these conditions occur: 
If a participant with baseline 
results of ...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥5x ULN or 
ALT or AST ≥3x ULN concurrent with TBL ≥2x 
ULN 
ALT or AST ≥1.5x ULN 
ALT or AST ≥3x baseline or 
ALT or AST ≥2x baseline concurrent with TBL ≥2x 
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 (Appendix 5) 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), and 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, and 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 (Appendix 5). Based on the circumstances and the 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 64 
LY2835219 
investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography, endoscopic retrograde cholangiopancreatography, cardiac 
echocardiogram, and/or a liver biopsy.  
For patients who experienced hepatotoxicity and resumed treatment, AST, ALT, and bilirubin 
should be monitored every week for the first month, every 2 weeks for the following 2 months, 
and monthly thereafter. 
9.4.2.2. 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 enrolled with baseline ALT or AST <1.5 ULN 
 Elevation of serum ALT or AST to ≥5x ULN on 2 or more consecutive blood tests 
 The combination of elevated ALT or AST ≥3x ULN and elevated TBL ≥2x ULN 
In participants enrolled with baseline ALT or AST ≥1.5x ULN 
 Elevated ALT or AST ≥3x baseline on 2 or more consecutive tests 
 The combination of elevated ALT or AST ≥2x baseline and elevated TBL ≥2x ULN 
In all study participants  
 Discontinuation from study treatment due to a hepatic event or abnormality of liver tests 
 Occurrence of a hepatic event considered to be a SAE 
9.4.2.3. Guidance for Monitoring Renal Function  
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine 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 adjustments (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 nonhematological 
toxicities (Table JPCM.7) if considered related to blinded study drug. 
9.4.2.4. Guidance for Venous Thromboembolic Events  
In breast cancer, venous thromboembolic event (VTE) has been identified as an adverse drug 
reaction for abemaciclib in combination with ET. In the randomized Phase 3 studies in breast 
cancer participants who received abemaciclib in combination with ET, a greater number of 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 65 
LY2835219 
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 nonsmall cell lung cancer, no increased rates of VTEs were observed as 
compared to the incidence of VTEs for these particular patient populations who were treated 
with other anticancer agents. At this time, the mechanism underlying the association between 
abemaciclib and the occurrence of VTEs is not known.  
Monitor participants for signs and symptoms of deep vein thrombosis and pulmonary embolism 
and treat as medically appropriate.  
Dose modifications and management of abemaciclib/placebo should follow the protocol 
guidance for nonhematological toxicities in Section 7.4.1.1, Table JPCM.7.  
9.4.2.5. 
Guidance for Interstitial Lung Disease/Pneumonitis  
Interstitial lung disease/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 7.4.1.1, Table JPCM.7 for guidance on dose adjustments of abemaciclib/placebo 
for participants with ILD/pneumonitis (see Appendix 9 for ILD/pneumonitis CTCAE grades). 
Discontinue abemaciclib in cases of severe (Grade 3 or Grade 4) ILD/pneumonitis.  
9.4.2.6. 
Guidance for Hypertension, Hypokalemia, Fluid Retention, and 
Cardiovascular Adverse Reactions Due to Mineralocorticoid Excess  
Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence 
of increased mineralocorticoid levels resulting from CYP17 inhibition. 
Monitor patients for hypertension, hypokalemia, and symptoms of fluid retention at least once a 
month. Patients with low potassium while on study or a history of hypokalemia from a 
pre-existing or concurrent medical condition should be considered for more frequent laboratory 
electrolyte evaluation per investigator’s discretion. Control hypertension and correct 
hypokalemia before and during treatment.  
Closely monitor patients whose underlying medical conditions might be compromised by 
increases in blood pressure, hypokalemia, or fluid retention such as those with heart failure, 
recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. QT prolongation 
and Torsades de Pointes have been observed in patients who develop hypokalemia while taking 
abiraterone. The safety of abiraterone acetate in patients with left ventricular ejection fraction 
<50% has not been established.  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 66 
LY2835219 
Refer to abiraterone acetate prescribing information. 
9.4.2.7. 
Guidance for Adrenocortical Insufficiency  
Adrenocortical insufficiency was reported in patients receiving abiraterone acetate in 
combination with prednisone, following interruption of daily steroids and/or with concurrent 
infection or stress.  
Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients 
are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. 
Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions 
associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If 
clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical 
insufficiency. Increased dosage of corticosteroids may be indicated before, during and after 
stressful situations. 
Refer to abiraterone acetate prescribing information. 
9.4.2.8. 
Guidance for Hypoglycemia  
Severe hypoglycemia has been reported when abiraterone acetate was administered to patients 
with preexisting diabetes receiving medications containing thiazolidinediones (including 
pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and after 
discontinuation of treatment with abiraterone acetate. Assess if antidiabetic drug dosage needs to 
be adjusted to minimize the risk of hypoglycemia. 
Refer to abiraterone acetate prescribing information. 
9.5. Pharmacokinetics  
Blood samples for PK analysis will be collected as shown in Appendix 4. 
Plasma 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 LSN3106726, 
LSN2839567, abiraterone, and prednisone will be determined using validated liquid 
chromatography with tandem mass spectrometry (LC-MS/MS) methods. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study. During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses (such as 
quantification of circulating metabolites and/or protein binding work). 
A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon by the investigator and Lilly. 
Drug concentration information that could unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
9.6. Pharmacodynamics  
See Sections 9.5 and 9.8. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 67 
LY2835219 
9.7. Pharmacogenomics  
9.7.1. Whole Blood Sample for Pharmacogenetic Research  
A whole blood sample will be collected for pharmacogenetic analysis as specified in 
Appendix 4, where local regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable response to study treatment and 
to investigate genetic variants thought to play a role in mCRPC. Assessment of variable response 
may include evaluation of AEs or differences in efficacy. 
All samples will be coded with the patient number. These samples and any data generated can be 
linked back to the patient only by the study site personnel. 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 use of new technologies, response to questions from regulatory 
agencies, and investigation of variable response that may not be observed until later. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing technologies include whole genome and exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies. 
Regardless of the technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8. Biomarkers  
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements. 
This study will analyze biomarkers relevant to abemaciclib or abiraterone acetate, mechanism of 
action of abemaciclib or abiraterone acetate, the variable response to study drug(s), immune 
function, and pathways associated with cancer. These samples may also be used to develop 
related research methods or to validate diagnostic tools or assays. 
Samples for biomarker research will be collected as specified in Appendix 4, where local 
regulations allow. 
It is possible that biomarker data for patients in the study have already been generated from 
samples that were collected and analyzed prior to enrolling in this study. This may include data 
generated from genetic analyses. If available, these data may be requested from medical records 
for use in the research described in Sections 9.7.1, 9.8.1, and 9.8.2. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 68 
LY2835219 
9.8.1. Tissue Samples for Biomarker Research  
Tissue samples for biomarker research will be collected for the purposes described in 
Section 9.8. The following samples for biomarker research will be collected according to the 
sampling schedule in Appendix 4, where local regulations allow. 
Collection of the following tumor tissue sample(s) is required for Part 1 and Part 2 and optional 
for Part 3: 
 Tumor biopsy of at least 1 metastatic site, which should be collected following 
determination of eligibility and before initiating study treatment. 
 Biopsy of newly emerged radiographic metastases is desired and preferable to the biopsy 
of previously existing lesions whenever possible. 
 Soft-tissue as well as bony metastatic lesions will be considered acceptable. Soft-tissue 
biopsy is preferred to bone biopsy whenever possible. 
 Adequate archival metastatic tissue can be used in lieu of a new biopsy if the biopsy was 
done within 12 weeks prior to randomization AND no treatment was initiated from 
biopsy to study entry. 
Collection of the following tumor tissue sample(s) is optional for all patients participating in this 
study:  
 Biopsy of metastatic lesion at the time of disease progression (the progressing metastatic 
lesion preferred). If a patient discontinues study for a reason other than radiographic 
progression, the second optional biopsy should be considered only if the patient has 
completed at least 6 cycles of study treatment. 
At the time of tissue collection, every effort should be made to ensure that adequate tumor 
sample (not a normal adjacent tissue sample or a tumor margin sample) is provided.  
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. 
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. 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 69 
9.8.2. Other Samples for Biomarker Research 
The following samples for biomarker research will be collected according to the sampling 
schedule in Appendix 4, where local regulations allow: 
• 
whole blood for circulating tumor cell collection 
• 
Plasma. 
A maximum of 4 samples may be drawn, collected, or removed at additional study time points, if 
wairnnted and agreed upon by the investigator and Lilly. 
All samples will be coded with the patient number. These samples and any data generated can be 
linked back to the patient only by the study site personnel. 
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 sho1ier period if local regulations and/or 
ERBs/lRBs impose sho1ter time limits. This retention pe1iod enables use of new technologies, 
response to questions from regulato1y 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 perf01med on these tissue samples to assess potential associations between these biomarkers 
and clinical outcomes. 
9.9. Health Economics 
9.9.1. 
Patient-Reported Outcomes 
Patient-repo1ted outcome (PRO) measures will be administered manually, by paper and pencil 
methods, to assess prostate cancer related pain and health-related quality of life (HRQoL). The 
following 3 PRO questionnaires will be included in this study: the Worst Pain Nume1ic Rating 
Scale (NRS), 
Questionnaires should be administered in the language the pa1ticipant 
is fluent or literate; according to the Schedule of Activities (Section 2), first the Worst Pain NRS, 
second 
Endpoints and analyses using the below PRO measures will be described in the SAP. 
Worst Pain NRS 
The single-item Worst Pain NRS derived from the validated 15-item Brief Pain lnvento1y Sho1i 
Fo1m (BPI-SF) (Cleeland and Ryan 1994) and is scored according to the BPI-SF User Guide 
(Cleeland 2009). This Worst Pain NRS item measures worst pain over the last 24 homs on a Oto 
10-point NRS, where 0 is 'no pain' and 10 is 'pain as bad as you can imagine'. 
-
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 70 
9.9.2. Health Care Resource Utilization 
fuvestigators will be asked to report the use of all concomitant medications (in pa1ticular, 
analgesics, bisphosphonates, and RANK-L targeted agents), blood product transfusions, 
radiation therapy, surge1y , and hospitalization days. 
Data on analgesic medication use will be recorded on the Concomitant Medication eCRF. The 
use of pain medications from the previous visit should be reviewed with the patient at each 
subsequent visit. fufo1mation on new or stopped analgesics should be recorded. This info1m ation 
should be collected during the study and at the 30-day follow-up visit. Analgesic use will be 
classified into categories according to the World Health Organization - Analgesic Ladder (WHO-
AL; Chung 2014; WHO 2018). The steps of the ladder are: 1) no analgesia, 2) nonopioids (e.g., 
salicylates and other nonsteroidal anti-inflammatory mugs [NSAIDs]), 3) weak opioids (e.g., 
codeine), and 4) strong opioids (e.g., morphine, oxycodone, hydromorphone, or methadone). 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
10. Statistical Considerations 
10.1. Sample Size Determination 
Page 71 
Patients emolled in Part 1, Pait 2, and Part 3 (if applicable) will be combined to form the 
experimental group (approximately I patients from Parts 1 and 2 in abemaciclib plus 
abiraterone acetate and prednisone, with an additional I patients from Part 3 if opened) and 
control group (approximately I patients from Pa1ts 1 and 2 in placebo plus abiraterone acetate 
and prednisone, with an additional I patients from Part 3 if opened). 
Radiographic progression-free survival is the primary endpoint for the study. The overall Type I 
errnr is controlled at a one-sided alpha level of 0.025 for the study. Group-sequential design and 
an extension of Chen's 2-in-l adaptive design (Chen 2018) will be used to accommodate the 
event-driven plan for the futility, interims, and final rPFS analyses (see Section 10.3.1.1 for 
details). If Part 3 is opened, the final rPFS analysis will be performed after approximately 
PFS events have occurred (i.e., an approximately -
censoring rate). If Part 3 is not 
opened, the final rPFS analysis will be performed after approximately 
rPFS events have 
occmTed (i.e., an approximately 
censoring rate). 
mther details on the marginal and conditional operating characteristics of this design can 
be found in the SAP, both for the assumed hazard ratio of 
and other possible effect sizes. 
10.2. Populations for Analyses 
The following populations will be defined for this study: 
Intention-to-treat (ITT) population: will include all randomized patients. The ITT analysis of 
efficacy data will consider allocation of patients to treatment groups as randomized and not by 
actual treatment received. This population will be used for all baseline, efficacy ( except for soft 
tissue tumor response related endpoints such as best overall response), and health economics 
analyses. 
Measurable disease population: will include all randomized patients who have measurable 
disease in soft tissue at baseline according to modified RECIST v 1.1. This population will be 
used for efficacy analyses based on soft tissue tumor response related endpoints such as best 
overall response. 
Safety population: will include all randomized patients who received at least one dose of any 
study drug, regardless of their eligibility for the study. The safety evaluation will be performed 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 72 
based on the first dose of study treatment a patient actually received, regardless of the aim to 
which he was randomized. The safety population will be used for all dosing/exposure, safety, 
and resource utilization analyses. 
Pharmacokinetic population: will include all randomized patients who received at least 1 dose 
of any study drng and have evaluable PK samples and sufficient dosing info1mation. 
Biomarker population: will include the subset of patients from the ITT population from whom 
a valid assay result has been obtained. 
10.3. Statistical Analyses 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Unless othe1wise stated, all tests of treatment effects will be conducted at a I-sided alpha level of 
.025, and all Cls will be given at a 2-sided 95% level. 
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 desclibed in the protocol, and the justification for making the change, will be described 
in the SAP and the clinical study repo1t. Additional explorato1y analyses of the data will be 
conducted as deemed approp1iate. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. 
10.3. 1. Efficacy Analyses 
10.3.1.1. Radiographic Progression Free Survival 
The prima1y endpoint of this study is rPFS. The rPFS time is measured from the date of 
randomization to the earliest date of investigator-determined radiographic disease progression 
(by objective radiographic disease assessment per RECIST vl. l 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 randomization if no post-initiation 
(i.e., post-baseline) radiographic assessment is available. The detailed censoring rnles are 
described in the SAP. 
There is 1 planned futility analysis, up to 2 planned adaptive interim analyses, and 1 final 
analysis for rPFS in this study. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 73 
The study will only be positive based on the final analysis of rPFS, the prima1y endpoint. If 
positive, testing of secondaiy endpoints will proceed as described in the SAP. 
The futility and adaptive interim rPFS analyses will be perf01med by the DMC. The 
requirements for unblinding the sponsor at the interim analysis are found in Section 10.3.5. 
The primary analysis of rPFS to test the superiority of experimental group to control group in 
improving rPFS time will be perf01med on the ITT population at an experiment-wise one-sided 
alpha level of 0.025 and will use the log-rank test strntified by the randomization factors of: 
• 
Radiographic progression at study entry (yes/no) 
• 
Measurable disease (yes/no) 
• 
Prior docetaxel for mHSPC (yes/no). 
These stratification factors were chosen because they represent important prognostic factors 
and/or an imbalance may bias the results. The coITesponding hazard ratio (HR) between 
tr·eatment groups will be estimated using a stratified Cox regression model (Cox 1972), stratified 
by the randomization str·ata. In addition, the Kaplan-Meier method (Kaplan and Meier 1958) will 
be used to estimate the rPFS curves as well as rPFS rates at 3, 6, 9, and 12 months for each 
tr·eatment group. 
If Pait 3 is opened for enrollment, then at the time of the prin1aiy analysis ofrPFS, rPFS by 
BICR will also be assessed using the same methods. Fmther details on the comparison of rPFS 
by investigator-dete1mined radiographic progression and rPFS by BICR can be found in the SAP. 
10.3.1.2. Overall Survival 
Overall survival is defined as the time from randomization until 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 is an imp01tant secondaiy endpoint for 
this study. Fmther details concerning OS analyses can be found in the SAP. 
10.3.1.3. Time to Prostate-Specific Antigen Progression 
Time to PSA progression is a seconda1y endpoint of this study. The PSA progression is defined 
as a 2'.:25% increase and an absolute increase of2'.: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 dete1mining PSA progression. Time to PSA progression is measured from the date of 
randomization 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 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 74 
LY2835219 
randomization if no post-initiation (i.e., post-baseline) PSA assessment is available. The detailed 
censoring rules are described in the SAP. 
The time to PSA progression analysis to test the superiority of the experimental group to the 
control group in improving time to PSA progression will be performed on the ITT population 
and will use the log-rank test stratified by the randomization factors. 
The corresponding hazard ratio between treatment groups will be estimated using a stratified 
Cox regression model (Cox 1972), stratified by the randomization strata. In addition, the Kaplan-
Meier method (Kaplan and Meier 1958) will be used to estimate the time to PSA progression 
survival curves as well as rates at 3, 6, 9, and 12 months for each treatment group. These rates 
will be compared based on a normal approximation for the difference between the rates. 
10.3.1.4. Objective Response Rate and Duration of Response  
Other secondary efficacy endpoints related to soft tissue tumor response will be defined as 
shown in Table JPCM.10. 
Table JPCM.10. 
Soft Tissue Tumor Response Related Endpoints  
Endpoint 
Definition 
ORR 
The proportion of patients with a soft tissue BOR of CR or PR according to RECIST v1.1, per 
investigator assessment 
DoR 
The time from the date of first evidence of a 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 
Abbreviations: BOR = best overall response; CR = complete response; DoR = duration of response; 
ORR = objective response rate; PCWG3 = Prostate Cancer Working Group 3; PR = partial response; RECIST v 
1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1. 
 
The ORR of each treatment group will be calculated using the measurable disease population. 
All rates will be compared between the experimental and control groups based on a normal 
approximation for the difference between the rates. 
The DoR time is defined only for responders (patients with a best overall response of CR or PR) 
in the measurable disease population. A Kaplan-Meier analysis of DoR will be performed to 
estimate the DoR curve for each treatment group. Further details can be found in the SAP. 
10.3.1.5. Time to Symptomatic Progression  
Time to symptomatic progression is defined as the time from randomization to any of the 
following (whichever occurs earlier): 
 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. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 75 
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. Details 
concerning time to symptomatic progression analyses can be found in the SAP. 
10.3.1.6. Other Exploratory Endpoints 
10.3.2. 
Safety Analyses 
All patients who receive at least 1 dose of any study dmg will be evaluated for safety and 
toxicity. 
The Medical Dictionary for Regulato1y Activities (MedDRA) Version 21.0 (or higher) will be 
used to map repo1ted AEs to MedDRA te1ms. The MedDRA Lower Level Te1m 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 Prefe1Ted Te1m (PT) 
within SOC. Prefe1Ted terms identified by Medical as clinically identical or synonymous will be 
grouped together under a single consolidated PT. For example, 'Neutropenia' and 'Neutrophil 
count decreased' will be repmted as 'Neutropenia.' All listings and summaries will use the PT 
resulting from this process. The National Cancer Institute (NCI) CTCAE v 5.0 will serve as the 
reference document for grading the severity of all AEs and other symptoms. 
Safety analyses will include summaries of the following: 
• 
TEAEs, including severity and possible relationship to any study dmg and/or study 
treatment 
• 
treatment-emergent SAEs, including possible relationship to study dmg and/or study 
treatment 
• 
AEs leading to dose adjustments of each study treatment 
• 
discontinuations from study treatment due to AEs or death 
• 
treatment-emergent abnormal changes in laboratmy values 
• 
treatment-emergent abnormal changes in vital signs. 
10.3.3. 
Other Analyses 
10.3.3.1. Patient Disposition 
A detailed description of patient disposition will be provided, including a summaiy of the 
number and percentage of patients entered into the study, emolled in the study, and treated, as 
well as number and percentage of patients completing the study, as defined in the SAP, or 
discontinuing ( overall and by reason for discontinuation). A summary of all important protocol 
deviations will be provided. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 76 
LY2835219 
10.3.3.2. Patient Characteristics  
Patient characteristics at baseline will be summarized by treatment group: 
 Patient demographics 
 Baseline disease characteristics 
 Pre-existing conditions 
 Historical illnesses 
 Prior anticancer therapy. 
Other patient characteristics will be summarized as deemed appropriate. 
10.3.3.3. Treatment Compliance  
Treatment compliance will be summarized for all treated patients by treatment group. 
Compliance information for blinded study drug will be collected through tablets/capsules counts 
at each cycle/visit. The estimate of percent compliance will be given by: 
Percent Compliance =
Actual cumulative dose taken
Expected cumulative dose to be taken  x 100 
The actual cumulative dose taken will be determined based on counting the number of 
tablets/capsules units returned at each visit and subtracting that number from the number of 
tablets/capsules 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. 
Compliance information for abiraterone acetate and prednisone will be collected through patient 
dosing diaries and/or patient recall on the number of doses actually taken in the previous cycle. 
Otherwise, the estimate of percent compliance will be done using the same formula/calculation 
for blinded study drug percent compliance. 
10.3.3.4. Extent of Exposure  
The number of cycles received, dose omissions, dose reductions, and dose intensity will be 
summarized for all treated patients by treatment group. 
10.3.3.5. Concomitant Therapy  
A summary of prior and concomitant medications by treatment group will be reported. 
10.3.3.6. Post-Study-Treatment-Discontinuation Therapy  
The numbers and percentages of patients 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. 
10.3.3.7. Pharmacokinetic/Pharmacodynamic Analyses  
Pharmacokinetic analyses will be conducted on all patients who have received at least 1 dose of 
any study drug and have evaluable PK samples and sufficient dosing information. Measures will 
be taken to support the timely availability of the results of PK analyses. These measures will 
include periodic transfers for review of data relevant to PK analyses including dosing and 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 77 
LY2835219 
bioanalytical results. No efficacy data will be included in the early-snapshot PK datasets. Finally, 
this early PK analysis will be conducted by a separate team of PK analysts, independent of the 
core study team. 
The observed concentrations of abemaciclib will be summarized by time and dose. The observed 
concentrations of prednisone and abiraterone will be summarized by time. 
Mean population PK parameters for abemaciclib (and metabolites, if warranted) in plasma (e.g., 
clearance, exposure, volume of distribution) and inter-individual PK variability may be analyzed 
using a population PK approach with nonlinear mixed-effect modeling (NONMEM) software. 
The effect of the combination treatment prednisone and abiraterone acetate on abemaciclib may 
also be evaluated using a population PK approach. 
Pharmacodynamic samples will be collected as specified in the Study Schedule and PK and PD 
Sampling Schedule (Appendix 4). Refer to these attachments (including footnotes) for important 
information about these samples and their collection. 
Furthermore, if warranted, PD data (such as neutrophil counts in blood or PSA) collected in this 
study may also be analyzed by means of NONMEM and connected to the population PK model 
in a PK/PD model. 
10.3.3.8. Biomarker Analyses  
Sections 9.8.1 and 9.8.2 describe 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 by treatment arm and overall, 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. 
10.3.3.9. Health Outcome/Quality-of-Life Analyses  
All health outcome, quality of life, and heath utilization analyses will be described in the SAP. 
10.3.4. 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. 
10.3.5. Interim Analyses  
There are planned interim analyses for safety, 1 planned interim analysis for futility, and up to 
2 planned adaptive interim analyses. The first safety interim analysis described below will be 
reviewed by an AC made up of Lilly members not involved in the day to day study conduct to 
identify the RP2D using only safety and PK data. All other interim analyses will be reviewed by 
an independent DMC made up of external members, none of whom are involved as study 
investigators. Unblinding details are specified in the unblinding plan section of the SAP or in a 
separate unblinding plan document. Further details may also be found in the DMC Charter. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 78 
10.3.5.1. Safety Interim Analyses 
The first safety interim analysis is planned at 
The AC members will review safety and 
available PK data at the interim analysis to deteimine the dose of abemaciclib (RP2D) in 
combination with abiraterone acetate plus prednisone for Pait 2. fu the case of unacceptable 
and/or unmanageable toxicity of the combination, the AC may recommend teimination of the 
study upon completion of Pait 1. This analysis will only use PK and safety data, and will be the 
only unblinded analysis the AC will review. After dose selection, only the DMC will be 
authorized to review unblinded data. 
Additionally, the DMC will review safety as described in the DMC chaiter, no less than 
approximately every 6 months. At each applicable interim analysis, the DMC may recommend 
the trial continue without modifications, continue with specific modifications, or be stopped for 
safety concerns. There will be no prespecified mies for stopping the trial due to safety concerns. 
The DMC members will review unblinded safety data at each applicable interim analysis. If a 
significant safety signal is identified, the DMC may recommend a protocol amendment, 
teimination of emollment, and/or teim ination of study treatment. The recommendations of the 
DMC will be communicated to the Lilly Senior Management Designee and, if necessaiy, an 
futernal Review Committee. 
fu the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the treatment group level, members of the DMC can conduct additional analyses of the safety 
data. Additionally, unblinding of a limited number of Lilly representatives external to the study 
team may be required for evaluation of selected SAEs for determination of regulatmy reporting. 
10.3.5.2. Futility/Adaptive Interim Analyses 
The interim analysis for futility is planned after approximately I rPFS events have been 
obseived. Futility for the interim analysis will be deteimined in teims of rPFS. The DMC should 
recommend stopping the trial for futility if the obseived hazard ratio is •
. The DMC will 
consider all evidence, including safety and other efficacy parameters, in malcing this decision. 
The planned adaptive interim analyses are based on rPFS, and will occur at approximately 
and, if necessa1y, atl rPFS events. The adaptive interim analyses will be conducted to 
deteimine whether Pait 3 of the study should be opened for emollment. The expansion decision 
criteria will be based on the conditional probability that the final rPFS analysis, given Pait 3 will 
be opened for emollment, will be positive. Fmther details on the decision rule, the model used 
for the decision criteria, and simulation results illustrating their operating characteristics can be 
found in the SAP. Should Pali 3 be opened for emollment after the first adaptive interim analysis 
at I rPFS events, a second adaptive interim analysis will not be perfoimed. 
The sponsor has no intent to stop the study based on the adaptive interim analyses and all 
patients will continue follow-up for all study objectives until study close. fu addition, patients 
will remain blinded for the duration of the study unless the criteria in Section 7.3 are met. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 79 
LY2835219 
Only the DMC is authorized to evaluate unblinded adaptive interim and futility analyses. Study 
sites will receive information about interim results only if they need to know for the safety of 
their patients. 
 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 80 
11. References 
Chung KC, Barlev A, Braun AH, Qian Y, Zagari M. Assessing analgesic use in patients with 
advanced cancer: development of a new scale-the analgesic quantification algorithm. Pain 
Med. 2014;15(2):225-232. 
Cleeland CS. The Brief Pain Inventmy user guide. 2009;1-63. 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Invento1y. Ann Acad Med 
Singap. 1994;23(2):129-138. 
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;7 4(2): 187-220. 
Crawford J, Armitage J, Balducci L, Bennett C, Blayney DW, Cataland SR, Dale DC, Demetri 
GD, Erba HP, Foran J, Freifeld AG, Goemann M, Heaney ML, Htoy S, Hudock S, Kloth DD, 
Kuter DJ, Lyman GH, Michaud LB, Miyata SC, Tallman MS, Vadhan-Raj S, Westervelt P, 
Wong MK; National Comprehensive Cancer Network. Myeloid growth factors. J Natl Compr 
Cancer Netw. 2009;7(1):64-83. 
de Bono JS, Logothetis CJ, Molina A, Fizazi K, No1th S, Chu L, Chi KN, Jones RJ, Goodman 
OB Jr, Saad F, Staffmth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, 
Patterson H, Hainswmth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz 
M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; 
COU-AA-301 Investigators. Abiraterone and increased smv ival in metastatic prostate cancer. 
N Engl J Med. 2011;364(21):1995-2005. 
Dickier MN, Tolaney SM, Rugo HS, C01t es J, Dieras V, Patt D, Wildiers H, Rudis CA, 
O'Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, 
A Phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients 
with refractmy HR +/HER2- metastatic breast cancer. Clin Cancer Res. 2017 ;23(17):5218-
5224. 
Eisenhauer EA, Therasse P, Bogae1ts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247. 
Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Ozgiiroglu M, Ye 
D, Feyerabend S, Protheroe A, De Pone P, Kheoh T, Park YC, Todd MB, Chi KN; 
LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive 
prostate cancer. N Engl J Med. 2017;377(4):352-360. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 81 
Goetz MP, Ma1tin M, Di Leo A, Im SA, Awada A, F01Tester T, Frenzel M, Cox J, Baniga S, Toi 
M, Iwata H, Johnston S. MONARCH 3: abemaciclib as initial therapy for patients with HR+, 
HER2- advanced breast cancer - results from the preplanned final PFS analysis [abstract]. 
AACR Annual Meeting 2018. 14-18 April 2018; Chicago IL. Philadelphia (PA) AACR; 2018. 
Abstract m CT040. 
James ND, Sydes MR, Clarke NW, Mason MD, Deamaley DP, Spears MR, Ritchie AW, Parker 
CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, 
Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, 
Chowdhmy S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hethelington J, Hughes R, 
Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh 0, Peedell C, Protheroe A, 
Robinson AJ, Srihari N, Srinivasan R, Staffmth J, Sundar S, Tolan S, Tsang D, Wagstaff J, 
Pa1mar MK; STAMPEDE investigators. Addition of docetaxel, zoledronic acid, or both to 
first-line long-te1m hormone therapy in prostate cancer (STAMPEDE): smvival results from 
an adaptive, multia1m, multistage, platform randomised controlled trial. Lancet 
2016;387:1163-1177. 
James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Deamaley DP, Ritchie AWS, 
Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhmy S, Cross WR, 
Gillessen S, Parker CC, Russell JM, Be1thold DR, Brawley C, Adah F, Aung S, Birtle AJ, 
Bowen J, Brock S, Chakrabmti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, 
Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh 0 , 
Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar 
MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously 
treated with hormone therapy. N Engl J Med. 2017;377:338-351. 
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481. 
Lonergan, PE, Tindall, DJ. Androgen receptor signaling in prostate cancer development and 
progression. J Carcinog. 2011;10:20. 
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Te1minology 
Criteria for Adverse Events, Version 5.0, DCTD, NCI, NIH, DHHS. 2017. Publish date: 27 
November 2017. 
Noonan KL, Nmth S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of 
abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing 
after enzalutamide. Ann On col. 2013 ;24(7): 1802-1807. 
Oken MM, Creech RH, Tormey DC, Ho1ton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655. 
Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. 
Biochim Biophys Acta. 2002;1602(1):73-87. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 82 
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, 
Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR; Ameiican Society of 
Clinical Oncology; American Society of Hematology. American Society of Clinical 
Oncology/American Society of Hematology clinical practice guideline update on the use of 
epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996-5010. 
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, 
Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel 
H, Mukhe1jee SD, Suttmann H, Genitsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, 
Pantuck A, Winquist E, Rigano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, 
RathkopfDE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without 
previous chemotherapy. N Engl J Med. 2013;368(2):138-148. 
Sartor 0 , de Bono JS. Metastatic prostate cancer. N Engl J Med. 2018;378(17):1653-1654. 
Scher HI, Monis MJ, Basch E, Heller G. End points and outcomes in castration-resistant prostate 
cancer: from clinical trials to clinical practice. J Clin Oncol. 2011;29(27):3695-3704. 
Scher HI, Monis MJ, Stadler WM, Rigano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, 
Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath El, Hussain M, 
Kelly WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, 
Sa1tor 0 , Small EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, Nelson PS, Schwa1tz 
LH, Halabi S, Kantoff PW, Almstrong AJ; Prostate Cancer Clinical Trials Working Group 3. 
Trial design and objectives for castration-resistant prostate cancer: updated recommendations 
from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12): 1402-
1418. 
Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T, Jentzmik F, 
Stoeckle M, Schrader M, Henmann E, Cronauer MV. Enzalutamide in castration-resistant 
prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65:30-36. 
[SEER] SEER Cancer Stat Facts: Prostate Cancer. National Cancer Institute. Bethesda, MD 
2017. Available at: https://seer.cancer.gov/statfacts/html/prost.html. Accessed 18 June 2018. 
Shen CJ. Cancer Cell Cycles. Science. 1996;274:1672-1677. 
Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva 0 , Okera M, Masuda N, 
Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Bauiga S, Smith IC, Bourayou N, 
Llombart-Cussac A. MONARCH 2: abemaciclib in combination with fulvestrant in women 
with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine 
therapy. J Clin Oncol. 2017;35(25):2875-2884. 
LY2835219 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 83 
Slud E, Wei LJ. The01y and Method: Two-Sample Repeated Significance Tests Based on the 
Modified Wilcoxon Statistic. J Amer Stat Assoc. 1982;77(380):862-868. 
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, A.lmitage JO; 
American Society of Clinical Oncology. Recommendations for the Use of WBC growth 
factors: American Society of Clinical Oncology clinical practice guideline update. J Clin 
Oncol. 2015;33(28):3199-3212. 
Smith MR, Saad F, Rathkopf DE, Mulders PF A, de Bono JS, Small EJ, Shore ND, Fizazi K, 
Kheoh T, Li J, De Pone P, Todd MB, Yu MK, Ryan CJ. Clinical outcomes from androgen 
signaling-directed therapy after treatment with abiraterone acetate and prednisone in patients 
with metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-302. Eur 
Urol. 2017;72(1):10-13. 
Sweeney CJ, Chen YH, Carducci M, Liu G, Janard DF, Eisenberger M, Wong YN, Hahn N, 
Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, 
DiPaola RS. Chemoho1monal therapy in metastatic ho1m one-sensitive prostate cancer. N Engl 
J Med. 2015;373(8):737-746. 
[WHO] World Health Organization. WHO guidelines for the pharmacological and 
radiotherapeutic management of cancer pain in adults and adolescents. Geneva: World Health 
Organization; 2018. 
LY2835219 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 84 
LY2835219 
Appendix 1. Abbreviations and Definitions  
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADT 
androgen-deprivation therapy 
AE 
Adverse event: any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the concentration-versus-time curve 
BICR 
blinded, independent, central review 
blinding/masking 
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment. Unless otherwise specified, blinding will remain in effect until final 
database lock. 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not. 
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received. 
BP 
blood pressure 
BPI-SF 
Brief Pain Inventory Short Form 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
Approved on 30 Apr 2024 GMT

13Y-MC-JPCM(f) Clinical Protocol 
Page 85 
CMV 
CNS 
collection database 
CR 
CRF 
CRP/CRS 
CT 
CTCAE 
CYP 
DCSI 
DBL 
DNA 
ECG 
ECOG 
eCRF 
effective method of 
contraception 
end of study 
enroll 
enter -
ERB 
ESA 
LY2835219 
cytomegalovims 
central nervous system 
a computer database where clinical study data are entered and validated. 
complete response 
case repo11 fonn 
Clinical Research Physician/Clinical Research Scientist: hldividual responsible for the 
medical conduct of the study. 
computed tomography 
Conunon Temtinology Ctiteria for Adverse Events 
cytochrome P450 
Developmental Core Safety Infonnation 
direct bilimbin 
deoxyii bonucleic acid 
electrocardiogram 
Eastern Cooperative Oncology Group 
electronic case repm1 fmm 
For all col111tries except Japan, effective method of contraception means male condom 
with spennicide, female condom with spemlicide, diaphragm with spennicide, cervical 
sponge, or ce1vical cap with spennicide. 
For Japan, effective method of contraception means bilateral tubal ligation, male 
condom with spennicide, intrauterine device that has been in place for at least 3 months 
before the first dose of study treatment, or an oral contraceptive pill taken for at least 3 
months before the first dose of study treatment. 
date of the last visit or last scheduled procedme shown in the Schedule of Activities 
(Section 2) for the last patient. 
The act of assigning a patient to a treatment. Patients who are emolled in the study are 
those who have been assigned to a treatment. 
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ethical review board 
e1ythropoiesis-stimulating agent 
Approved on 30 Apr 2024 GMT 

13Y-MC-JPCM(f) Clinical Protocol 
Page 86 
ET 
EU -
FDA 
GCP 
G-CSF 
GDPR 
GFR 
GGT 
HER2-
HR+ 
HR 
HRQoL 
1B 
ICF 
ICH 
interim analysis 
investigational 
product 
IRB 
ITT 
IV 
IWRS 
LY2835219 
endocrine therapy 
Emopean Union 
Food and Drug Administration 
good clinical practice 
granulocyte colony-stimulating factor 
EU General Data Protection Regulation 
glomerular filtration rate 
gamma-glutamyl t:ransferase 
human epidennal growth factor receptor 2-negative 
honnone receptor-positive 
hazard ratio 
health-related quality oflife 
Investigator's Brochme 
inf01med consent f01m 
International Council for Hannonisation (fonnerly the International Conference on 
Ha1monisation) 
an analysis of clinical study data conducted before the final repo1ting database is 
created/locked. 
A phaimaceutical fo1m of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products ah-eady on the market when used or 
assembled (fo1mulated or packaged) in a way different from the authorized fo1m, 
marketed products used for an unauthorized indication, or marketed products used to 
gain fmther info1mation about the authorized fo1m. 
institutional review board 
intention-to-treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
plaimed treatment regimen) rather than the actual treatment given. It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group iITespective of their compliance to the 
plaI1lled comse of treatment. 
intravenous 
interactive Web-response system 
Approved on 30 Apr 2024 GMT 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 87 
LY2835219 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LHRH 
luteinizing hormone-releasing hormone 
MATE 
multidrug and toxin-extrusion protein 
MBC 
metastatic breast cancer 
mCRPC 
metastatic castration-resistant prostate cancer 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involves a failure to uphold one or 
more of the five “rights” of medication use: the right participant, the right drug, the 
right dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• 
dose omission associated with an AE or a product complaint 
• 
dispensing or use of expired medication 
• 
use of medication past the recommended in-use date 
• 
dispensing or use of an improperly stored medication 
• 
use of an adulterated dosage form or administration technique inconsistent 
with the medication's labeling (for example, Summary of Product 
Characteristics, IB, local label, protocol), or 
• 
shared use of cartridges, prefilled pens, or both. 
MedDRA 
Medical Dictionary for Regulatory Activities 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
mTOR 
mammalian target of rapamycin 
MUGA 
multigated acquisition scan 
NCI 
National Cancer Institute 
NONMEM 
nonlinear mixed-effect modeling 
NRS 
Numerical Rating scale 
NSAI 
nonsteroidal aromatase inhibitor 
NSAID 
nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 88 
LY2835219 
OCT2 
organic cation transporter 2 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PCa 
prostate cancer 
PCS 
prostate cancer subscale 
PCWG2 
Prostate Cancer Working Group 2 
PCWG3 
Prostate Cancer Working Group 3 
PD 
pharmacodynamic(s) 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
performance status 
PT 
MedDRA Preferred Term 
randomize 
the process of assigning patients to an experimental group on a random basis. 
Rb 
retinoblastoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
reporting database 
A point-in-time copy of the collection database. The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data. 
rescreen 
to screen a patient who was previously declared a screen failure for the same study 
RNA 
ribonucleic acid 
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. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 89 
LY2835219 
screen failure 
patient who does not meet one or more criteria required for participation in a study 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SOC 
MedDRA System Organ Class 
SSE 
symptomatic skeletal event 
study completion 
occurs following the final analysis of overall survival, as determined by Lilly. 
SUSARs 
suspected unexpected serious adverse reactions 
Refers to an adverse event that occurs in a clinical trial participant, which is assessed by 
the sponsor and or study investigator as being unexpected, serious, and as having a 
reasonable possibility of a causal relationship with the study intervention. 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event: an untoward medical occurrence that emerges during 
a defined treatment period, having been absent at baseline, or worsens relative to the 
baseline state, and does not necessarily have to have a causal relationship with this 
treatment. 
ULN 
upper limit of normal 
VTE 
venous thromboembolic event 
WHO 
World Health Organization 
WHO-AL 
World Health Organization - Analgesic Ladder 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 90 
LY2835219 
Appendix 2. Clinical Laboratory Tests  
 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 91 
LY2835219 
Clinical Laboratory Tests 
 
Hematology: laboratorya 
Local 
Central 
Leukocytes (WBC) 
 
X 
Neutrophilsb 
 
X 
Lymphocytes 
 
X 
Monocytes 
 
X 
Eosinophils 
 
X 
Basophils 
 
X 
Erythrocytes (RBC) 
 
X 
Hemoglobin (HGB) 
 
X 
Hematocrit (HCT) 
 
X 
Mean corpuscular volume (MCV) 
 
X 
Mean corpuscular hemoglobin concentration (MCHC) 
 
X 
Platelets (PLT) 
 
X 
 
 
 
Coagulation: laboratory 
Local 
Central 
Activated partial thromboplastin time (aPTT) or partial 
thromboplastin time (PTT) 
X 
 
International normalized ratio (INR) or Prothrombin time (PT) 
X 
 
 
 
 
Clinical Chemistry: laboratorya 
Local 
Central 
Serum Concentrations of: 
 
 
Alanine aminotransferase (ALT) 
 
X 
Albumin 
 
X 
Alkaline phosphatase 
 
X 
Aspartate aminotransferase (AST) 
 
X 
Bilirubin, direct 
 
X 
Bilirubin, total 
 
X 
Blood urea nitrogen (BUN) or blood urea 
 
X 
Calcium 
 
X 
Cholesterol 
 
X 
Creatine kinase (CK) 
 
X 
Cystatin C 
 
X 
Creatinine 
 
X 
Glucose, nonfasting 
 
X 
High-density lipoproteins (HDL) 
 
X 
Lactate dehydrogenase (LDH) 
 
X 
Low-density lipoproteins (LDL) 
 
X 
Magnesium 
 
X 
Phosphate 
 
X 
Potassium 
 
X 
Protein 
 
X 
Sodium 
 
X 
Triglycerides 
 
X 
Urate 
 
X 
 
 
 
Urinalysis: laboratory 
Local 
Central 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 92 
LY2835219 
Blood 
X 
 
Glucose 
X 
 
Ketones 
X 
 
pH 
X 
 
Protein 
X 
 
Specific gravity 
X 
 
Urine leukocyte esterase 
X 
 
 
 
 
Other Tests: laboratorya 
Local 
Central 
PSA 
 
X 
Testosterone 
 
X 
Abbreviations: CRF = case report form; PSA = prostate-specific antigen; RBC = red blood cells; WBC = white 
blood cells. 
a Enrollment and treatment decisions may be based on local laboratory results. A duplicate sample must still be 
sent to the central laboratory. Differences between these samples will not constitute a protocol deviation. 
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. 
 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 93 
LY2835219 
Appendix 3. Study Governance, Regulatory, and 
Ethical Considerations  
Informed Consent 
The investigator is responsible for: 
 ensuring that the patient/patient’s legal representative understands the nature of 
the study, the potential risks and benefits of participating in the study, and that the 
patient’s participation is voluntary 
 ensuring that informed consent is given by each patient/patient’s legal 
representative. This includes obtaining the appropriate signatures and dates on the 
informed consent form (ICF) prior to the performance of any study procedures 
and prior to the administration of study treatment. 
 providing a copy of the signed ICF(s) to the patient/patient’s legal representative 
and retaining a copy of the signed ICF in the site file 
 answering any questions the patient/patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that 
may be relevant to the patient’s/patient’s legal representative’s willingness to 
continue the patient’s participation in the study. 
Ethical Review 
Documentation of ERBs/IRBs approval of the protocol and the ICF must be provided to Lilly 
before the study may begin at the investigative site(s). Lilly or its representatives must approve 
the ICF, including any changes made by the ERBs/IRBs, before it is used at the investigative 
site(s). All ICFs must be compliant with the International Council for Harmonisation (ICH) 
guideline on good clinical practice (GCP). 
The study site’s ERBs/IRBs should be provided with the following: 
 the protocol, protocol amendments, and relevant protocol addenda and the current 
Investigator’s Brochure (IB) or package labeling, Patient Information Leaflet, 
Package Insert, or Summary of Product Characteristics and updates during the 
course of the study 
 ICF 
 other relevant documents (for example, curricula vitae advertisements). 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and with: 
 consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
 applicable ICH GCP Guidelines 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 94 
LY2835219 
 applicable laws and regulations. 
Some obligations of Lilly may be assigned to a third-party organization. 
Investigator Information 
Physicians with a specialty in oncology or urology will participate as investigators in this clinical 
study. 
Investigator Reporting Requirements 
The investigator will be responsible for reporting to the sponsor or designee significant issues 
related to participant safety, participant rights, or data integrity. 
Protocol Signatures 
Lilly’s responsible medical officer will approve the protocol, confirming that, to the best of his 
or her knowledge, the protocol accurately describes the planned design and conduct of the study. 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative. 
Final Report Signature 
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
If the lead investigator is unable to serve as the clinical study report coordinating investigator, 
another investigator will be chosen by Lilly to fulfill this role. 
The Lilly responsible medical officer and statistician will approve the final clinical study report 
for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following: 
 provide instructional material to the study sites, as appropriate 
 provide sponsor start-up training to instruct the investigators and study 
coordinators. This training will give instruction on the protocol, the completion of 
the CRFs, and study procedures 
 make periodic visits to the study site 
 be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
 review and verify data reported to detect potential errors. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 95 
LY2835219 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
The investigator will keep records of all original source data. This might include laboratory tests, 
medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data-capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered a source and for the confirmation that data reported 
are accurate and complete by signing the CRF. 
Additionally, clinical outcome assessment (COA) data (questionnaires, scales, self-reported diary 
data, etc.) will be collected by the subject, via a paper source document and will be transcribed 
by the investigator site personnel into the EDC system. 
Data collected via the sponsor-provided data capture system(s) will be stored at third-party 
organizations (at third parties). The investigator will have continuous access to the data during 
the study and until decommissioning of the data capture system(s). Prior to decommissioning, 
the investigator will receive an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor to protect the participant’s 
personal data. Any participant information, such as 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 the participant’s 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 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 96 
LY2835219 
described in the informed consent. This is done by the site personnel through the informed 
consent process. 
The participant must be informed through the informed consent by the site personnel that their 
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 information security, data integrity, and data 
protection. These processes address management of data transfer, and prevention and 
management of unauthorized access, disclosure, dissemination, alteration, or loss of information 
or personal data. These processes include appropriate contingency plan(s) for appropriate and 
timely response in the event of a data security breach. 
The transfer of personal data is subject to appropriate safeguards through contractual agreements 
and processes. The sponsor’s processes are compliant with local privacy laws and relevant 
legislations, including the General Data Protection Regulation. 
Study and Site Closure 
Discontinuation of Study Sites 
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP. 
Discontinuation of the Study 
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 
Communication of Suspended or Terminated Dosing 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by phone and/or email) 
as soon as possible. It will be a requirement that investigators respond upon receipt to confirm 
that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 97 
LY2835219 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 98 
LY2835219 
Appendix 4. Sampling Schedule for 
Pharmacokinetics/Pharmacodynamics  
Dosing dates and times are required to be collected on the appropriate form 1 day prior to the PK 
samples. The exact date and time of collection of each venous blood sample must also be 
recorded on the laboratory requisition. 
Due to practical and logistical concerns, some deviation from the specified sampling is possible. 
Sites should keep in mind that drawing the sample and recording the actual time on the 
appropriate form are of principal importance. Differences from the time specified in the protocol 
are not considered protocol deviations as long as samples are collected and accurate dates and 
times are recorded in a timely manner on the appropriate forms. The schedule for PK sampling is 
summarized in the table below. The date and exact time of collection for each venous blood 
sample should be documented on the laboratory requisition. The intention of this sampling 
schedule beyond the first dose is to coincide with standard laboratories, for example, those that 
are used to determine how to begin the next cycle of dosing (e.g., hepatic monitoring, 
hematology, and clinical chemistry that can be done ≤3 days before the first day of a cycle). 
Hence, these samples should be taken close in time to those other laboratories. This should avoid 
difficulties or questions associated with how to handle sampling if the decision is made to hold 
or delay the dose. 
Pharmacokinetic Sampling Schedule 
Cycle(C) and 
Day(D) 
PK Sample Number 
Sampling Time PK from Blooda 
C1D1 
1 
Pre dose 
C1D1 
2 
Any time 30 minutes or more after blinded study treatment dose 
C1D15 
3 
Any time after blinded study treatment dose 
C2D1 
4 
Any time after blinded study treatment dose 
C2D15 
5 
Any time after blinded study treatment dose 
C3D1 
6 
Any time after blinded study treatment dose 
Abbreviation: PK = pharmacokinetic. 
a Samples of approximately 4 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites LSN3106726, LSN2839567, abiraterone and prednisone. 
Note: The time of abiraterone acetate, prednisone, and blinded study drug dose taken before the sample must be 
recorded on the day the PK sample is drawn. 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 99 
LY2835219 
Biomarker Sampling Schedule 
Cycle(C) and 
Day(D) 
Tumor Tissue 
Plasma Biomarker 
Blood 
PGx Whole 
blood 
Baseline  
(Day -28 to Day -1) 
Xa (mandatory for 
Part 1 and Part 2, 
optional for Part 3) 
 
 
 
 
C1D1 
 
Predose 
Predose 
Predosec 
C2D1 
 
X 
X 
 
C3D1 
 
X 
X 
 
Short-term 
follow-up 
(Visit 801) 
Xb (optional) 
X 
 
 
Abbreviation: PGx = pharmacogenetics. 
a To meet study eligibility criteria for Part 1 and Part 2, patients must have metastatic disease amenable to biopsy 
of at least 1 metastatic site for biomarker analysis. Soft-tissue as well as bony metastatic lesions will be 
considered acceptable. Soft-tissue biopsy is preferred to bone biopsy whenever possible. Adequate archival 
metastatic tissue can be used in lieu of a new biopsy if the biopsy was done within 12 weeks prior to 
randomization and no treatment was initiated from biopsy to study entry. 
b Optional biopsy of metastatic lesion at the time of disease progression (the progressing metastatic lesion 
preferred) or if the patient discontinues study treatment for reasons other than progressive disease and have been 
on study treatment for ≥6 cycles. 
c Collect once. Sample can be collected at a subsequent timepoint if not collected on Cycle 1 Day 1. 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 100 
LY2835219 
Appendix 5. Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality  
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly clinical research physician. 
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 9.4.2 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 IgA (Quantitative) 
Hepatitis A Virus (HAV) Testing: 
Immunoglobulin IgG (Quantitative) 
  HAV Total Antibody 
Immunoglobulin 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 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 101 
LY2835219 
  Hepatitis B core IgM antibody  
Anti-nuclear antibody (ANA) 
  Hepatitis B core IgG antibody  
Anti-smooth muscle antibody (ASMA) a 
  HBV DNA d 
Anti-actin antibody b 
Hepatis C Virus (HCV) Testing: 
Epstein-Barr Virus (EBV) Testing: 
  HCV antibody 
  EBV antibody 
  HCV RNA d 
  EBV DNA d 
Hepatitis D Virus (HDV) Testing: 
Cytomegalovirus (CMV) Testing: 
  HDV antibody 
  CMV antibody 
Hepatitis E Virus (HEV) Testing: 
  CMV DNA d 
  HEV IgG antibody 
Herpes Simplex Virus (HSV) Testing: 
  HEV IgM antibody 
  HSV (Type 1 and 2) antibody  
  HEV RNA d 
  HSV (Type 1 and 2) DNA d 
Microbiology c 
Liver Kidney Microsomal Type 1 (LKM-1) 
Antibody 
Culture: 
 
  Blood 
 
  Urine 
 
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. 
d Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 102 
LY2835219 
Appendix 6. Protocol JPCM ECOG Performance Status  
ECOG Performance Status 
Activity Status 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
 
2 
Ambulatory and capable of all selfcare but unable to 
carry out any work activities. Up and about more than 
50% of waking hours 
 
3 
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours 
 
4 
Completely disabled. Cannot carry on any selfcare. 
Totally confined to bed or chair 
 
5 
Dead. 
 
Source: Oken et al. 1982 
 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 103 
LY2835219 
Appendix 7. Protocol JPCM RECIST Criteria 1.1  
Response and progression will be evaluated in this study using the international criteria proposed 
by the new Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009). 
Measurability of Tumor at Baseline 
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable. 
Measurable disease is defined by the presence of at least 1 measurable lesion. If a metastatic 
lymph node is more amenable to biopsy than the primary breast lesion, the lymph node can be 
used for study biopsies. 
Measurable 
Tumor lesions: Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of: 
 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 
 10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers) 
 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm). 
Nonmeasurable  
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Special Considerations for Lesion Measurability 
Bone lesions:  
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability. 
 Blastic bone lesions are non-measurable. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 104 
LY2835219 
Cystic lesions:  
 Simple cysts should not be considered as malignant lesions (neither measurable 
nor nonmeasurable)  
 Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions if they meet the definition of measurability. If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions. 
Lesions with Prior Local Treatment: 
 Tumor lesions situated at a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion.  
Baseline Documentation of Target and Non-Target Lesion 
Target Lesions  
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. Non-nodal Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements. 
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of 15 mm by 
CT scan. All measurements are to be recorded in the eCRF in millimeters (or decimal fractions 
of centimeters [cm]). 
Nontarget Lesions 
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline. Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’ In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
eCRF (for example, multiple liver metastases recorded as 1 liver lesion). 
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions. 
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed. 
Specifications by Methods of Measurement 
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed. All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 105 
LY2835219 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.  
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient. If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and follow-
up should be guided by the tumor type under investigation and the anatomic location of the 
disease.  
Clinical Lesions: Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules). For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of the lesion 
is recommended. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may be reviewed at the end of the 
study. 
Chest X-ray: Chest CT is preferred over chest X-ray when progression is an important endpoint. 
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung. 
CT and MRI: CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm. When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (for example, for body scans). If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances.  
Ultrasound: Ultrasound should not be used to measure lesion size. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor Markers: Tumor markers alone cannot be used to assess tumor response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR). Specific guidelines for both prostate-specific antigen (PSA) response 
(in recurrent prostate cancer) and CA-125 response (in recurrent ovarian cancer) have been 
published. Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and CR in rare cases, if required by protocol (for example, residual lesions in 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 106 
LY2835219 
tumor types such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (for example, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease.  
Pet Scan (FDG-PET, PET CT): PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality. If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan. 
Bone Scan: If lesions measured by bone scan are reported at baseline, it is necessary to repeat the 
bone scan when trying to identify a CR or PR in target disease or when progression in bone is 
suspected. 
Response Criteria 
Evaluation of Target Lesions 
Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must 
have normalized. 
Partial Response: At least a 30% decrease in the sum of diameter of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease: At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (including the baseline sum if that is the smallest). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. The appearance of 1 or more new lesions is also considered progression. 
For equivocal findings of progression (for example, very small and uncertain new lesions, cystic 
changes, or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Not Evaluable: When an incomplete radiologic assessment of target lesions is performed or there 
is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response. 
Evaluation of Nontarget Lesions 
Complete Response: Disappearance of all nontarget lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological or normal in size (<10 mm short axis). 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 107 
LY2835219 
Non-CR/non-PD: Persistence of 1 or more nontarget lesions and/or maintenance of tumor marker 
level above the normal limits. 
Progressive Disease: Unequivocal progression of existing nontarget lesions. The appearance of 1 
or more new lesions is also considered progression. 
Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation. The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions. The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial. 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. Table APP.7.1 provides a summary of the overall response status calculation at 
each time point for patients who have measurable disease at baseline. 
Table APP.7.1. 
Time Point Response: Patients with Target (Nontarget) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; 
NE = inevaluable. 
 
Table APP.7.2 is to be used when patients have nonmeasurable disease only. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 108 
LY2835219 
Table APP.7.2. 
Time Point Response: Patients with Nontarget Disease Only 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = nonevaluable; PD = progressive disease. 
a non-CR/non-PD is preferred over stable disease for nontarget disease. 
 
Frequency of Tumor Re-Evaluation 
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment. In the context of Phase 2 
studies in which the beneficial effect therapy is not known, follow-up every 6 to 8 weeks is 
reasonable. Normally, all target and nontarget sites are evaluated at each assessment using the 
same method. However, bone scans may need to be repeated only when CR is identified in target 
disease or when progression in bone is suspected. 
Confirmatory Measurement/Duration of Response 
Confirmation: 
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. The confirmation of response is particularly important in 
nonrandomized trials in which response (CR/PR) is the primary end point. In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met. To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan. To confirm a PR or SD, a 
full assessment of target lesions that were present at baseline must occur; assessment of 
nontargets is not required. 
However, in randomized trials (Phase 2 or 3) or studies in which SD or progression is the 
primary endpoint, confirmation of response is not required. However, elimination of the 
requirement may increase the importance of central review to protect against bias, in particular 
of studies that are not blinded. 
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from first dose. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study). 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 109 
LY2835219 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD). 
Independent Review of Response and Progression 
When objective response (CR+PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study. If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 110 
LY2835219 
Appendix 8. Protocol JPCM Strong and Moderate 
Inducers of CYP3A4, Strong Inhibitors of CYP3A4, 
Substrates of CYP2D6 with Narrow Therapeutic 
Range, and Transporter Substrates with Narrow 
Therapeutic Range  
The information in this attachment is provided for guidance to investigators and 
does not preclude the use of these medications if clinically indicated. Please refer to 
Section 7.7 Concomitant Therapy. 
This list is not intended to be exhaustive. With available information continually 
evolving, the status of every relevant drug cannot be guaranteed. Please consult with 
the medical monitor in case of any doubt about a potential drug-drug interaction. 
Strong Inducers of CYP3A4 
Aminoglutethimide 
Apalutamide 
Carbamazepine (daily dose exceeding 600 mg) 
Enzalutamide 
Fosphenytoin (see also phenytoin) 
Ivosidenib 
Lumacaftor 
Mitotane 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampicin (rifampin) 
Rifapentine 
St. John’s wort 
 
Moderate Inducers of CYP3A4 
Bosentan 
Carbamazepine (daily dose 600 mg or lower) 
Cenobamate 
Dabrafenib 
Danshen (Salvia miltiorrhiza) 
Efavirenz 
Elagolix 
Encorafenib 
Etravirine 
Genistein 
Lopinavir (alone) 
Lorlatinib 
Modafinil 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 111 
LY2835219 
Nafcillin (intravenous) 
Pentobarbital 
Primidone 
Sotorasib 
Thioridazine 
Tocilizumab (atlizumab) 
 
Strong inhibitors of CYP3A4 
Atazanavir and cobicistat 
Boceprevir 
Ceritinib 
Clarithromycin 
Cobicistat (see atazanavir and cobicistat) 
Conivaptan 
Danoprevir and ritonavir 
Elvitegravir and ritonavir 
Fosamprenavir and ritonavir 
Grapefruit juice 
Idelalisib 
Indinavir and ritonavir  
Itraconazole 
Josamycin 
Ketoconazole 
 
CYP2D6 Substrates with Narrow Therapeutic Range 
 
Astemizole 
Flecainide 
Mexiletine 
Pimozide 
Propafenone 
Thioridazine 
 
Transporter Substrates with Narrow Therapeutic Range 
Dabigatran 
Digoxin 
Dofetilide 
Metformin 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 112 
LY2835219 
Appendix 9. Protocol JPCM 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 to 
6 stools per day over 
baseline; moderate 
increase in ostomy 
output compared to 
baseline; limiting 
instrumental ADL 
Increase of ≥7 stools per 
day over baseline; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self-care 
ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Definition: a disorder characterized by an increase in frequency and/or loose watery bowel movements. 
Respiratory, Thoracic, and Mediastinal Disorders 
Pneumonitis 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL 
Severe symptoms; limiting 
self-care ADL; oxygen 
indicated 
Life-threatening 
respiratory compromise; 
urgent intervention 
indicated (e.g., 
tracheotomy or 
intubation) 
Death 
Definition: a disorder characterized by inflammation focally or diffusely affecting the lung parenchyma. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 113 
LY2835219 
Investigations 
Alanine 
aminotransferase 
(ALT) increased  
>ULN through 3.0 x 
ULN if baseline was 
normal; 1.5 through 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 through 5.0 x 
ULN if baseline was 
normal; >3.0 through 
5.0 x baseline if 
baseline was abnormal 
>5.0 through 20.0 x ULN if 
baseline was normal; >5.0 
through 20.0 x baseline if 
baseline was abnormal 
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal 
Death 
Definition: a finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood 
specimen. 
Aspartate 
aminotransferase 
(AST) increased 
>ULN through 3.0 x 
ULN if baseline was 
normal; 1.5 through 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 through 5.0 x 
ULN if baseline was 
normal; >3.0 through 
5.0 x baseline if 
baseline was abnormal 
>5.0 through 20.0 x ULN if 
baseline was normal; >5.0 
through 20.0 x baseline if 
baseline was abnormal 
>20.0 x ULN if baseline 
was normal; >20.0 x 
baseline if baseline was 
abnormal 
Death 
Definition: a finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood 
specimen. 
Abbreviation: ADL = activities of daily living; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; ULN = upper 
limit of normal. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 114 
LY2835219 
Appendix 10. Provisions for Changes in Study Conduct 
During Exceptional Circumstances  
Implementation of this Appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in consultation with the 
investigator. 
Exceptional Circumstances 
Exceptional circumstance are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing Changes under Exceptional Circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
Additional notification to these groups will not typically be required unless they have specific 
conditions in which notification is required. To protect the safety of study participants, urgent 
changes may be implemented before approval but need to be reported as soon as possible. All 
approvals must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for Making a Change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making such changes are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study, and maintaining the integrity of the 
study.  
Informed Consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined below in Section 1, Remote visits, 
 alternate delivery of study treatment and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in Study Conduct During Exceptional Circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 115 
LY2835219 
The following changes in study conduct (e.g., telemedicine versus on-site) will not be considered 
protocol deviations. 
1. Remote visits 
In exceptional circumstances, study visits may be done remotely using telemedicine. In 
source documents and the eCRF, the study site must capture the visit method, with a specific 
explanation for any data missing and document as protocol violations, when applicable.  
Telemedicine: 
Telemedicine visits using interactive technology-assistance (that is, at a minimum video 
and/or audio technology) may be performed by an investigator in lieu of on-site visits to 
complete required study assessments as outlined in Section 2.  
Study procedures that may be performed by an investigator using telemedicine include the 
following: 
 Informed consent 
 Inclusion/exclusion assessments; medical history 
 Telehealth physical examination (if allowed by local regulation) 
 AE assessments; review and update on concomitant medications 
 ECOG performance status 
 Evaluation of symptomatic progression  
 PRO assessments; review of patient diary; drug compliance evaluations for all study 
treatment 
 Survival status; post-discontinuation anticancer therapies.  
Other alternative locations:  
In exceptional circumstances, imaging procedures required during screening, on-study 
treatment, or follow-up may be performed at an alternate location than the study site or 
designated facility. Imaging includes: CT or MRI scan (of chest, abdomen, and pelvis), 
radionuclide bone scan, MRI/CT (MRI preferred) of the brain (if clinically indicated), and 
ECHO/multigated acquisition scan (MUGA) scans. See Section 2 for details. 
The protocol requirements regarding the reporting of AEs, SAEs, and product complaints 
remain unchanged. Furthermore, every effort should be made to enable participants to return 
to on-site visits as soon as reasonably possible, while ensuring the safety of both the 
participant and the site staff. 
2. Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 116 
LY2835219 
3. Study treatment and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study treatment or study tools (e.g., 
participant diaries) during regularly scheduled on-site visits, the site should work with the 
sponsor to determine appropriate actions. These actions may include:  
 asking the participant’s caregiver or designee to go to the site and receive study 
treatment or study tools on a participant’s behalf, or  
 arranging delivery of study treatment and/or study supplies. 
These requirements must be met and documented in the participant’s medical records before 
action is taken: 
 Alternate delivery of study treatment should be performed in a manner that does not 
compromise treatment blinding and ensures product integrity. The existing protocol 
requirements for product accountability remain unchanged, including verification of 
participant’s receipt of study treatment. 
 When delivering study treatment to a location other than the study site (for example, 
participant’s home), the investigator or designated site staff should follow local 
regulation and ensure oversight of the shipping process to ensure accountability and 
product quality (that is, storage conditions maintained and intact packaging upon 
receipt). 
 Instructions should be provided to the participant or caregiver on the final disposition 
of any unused study treatment, empty product bottles, or completed patient diaries. 
4. Screening period guidance  
To ensure safety of study participants, laboratory values and other eligibility assessments 
completed during screening are required as outlined in the protocol.  
In exceptional circumstances, Cycle 1 Day 1 visit must occur within 35 days from date of 
signed informed consent and will not constitute as a protocol violation. Any screening 
procedures that fall outside of the required windows per the Schedule of Activities 
(Section 2) must be repeated. See Protocol JPCM Section 6.4 for additional details on screen 
failures. 
Participants who are unable to complete screening within the 35-day window and are not able 
to repeat screening procedures will be documented in eCRF as a screen failure due to 
exceptional circumstances. 
5. Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, 
participants should complete the usual Schedule of Activities outlined in Section 2. To 
maximize the possibility that these visits can be conducted as on-site visits, the windows for 
visits may be adjusted, upon further guidance from the sponsor. This minimizes missing data 
and preserves the intended conduct of the study. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 117 
LY2835219 
This table describes the allowed adjustments to visit windows. 
Visit Number Tolerance 
Day 1 of all 
cycles  
The relative day within dosing cycle and visit window may 
be adjusted to ±5 days. 
All other 
treatment 
visits  
Follow Protocol JPCM; Schedule of Activities Section 2.  
 
For participants whose visits have extended windows, additional study treatment may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
Changes to study conduct will be documented: 
 Sites will document all remote visits in the study files and eCRF (where applicable) 
including telemedicine, local imaging and procedures, study treatment, or screening 
period guidance. Documentation should include details of which participants, visits 
type, and study procedures were affected by exceptional circumstances. 
 Dispensing/shipment records of study treatment and relevant communications, 
including delegation, should be filed with site study records. 
Source documents generated during a telemedicine visit should be part of the investigator’s 
source documentation.
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 118 
LY2835219 
Appendix 11. Protocol Amendment History  
Amendment Summary of Changes Table for the current amendment is located before the Table 
of Contents (TOC). 
Amendment [e]: (08-Sep-2023)  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment e: 
The protocol was amended to correct the EudraCT Number. 
Section # and Name 
Description of Change 
Brief Rationale 
Cover Page 
Revised incorrect EudraCT 
Number: 2014-001502-18 to the 
correct EudraCT Number: 2016-
004276-21 
Correction 
1. Synopsis 
3.1.4. Rationale for Amendment 
(d) 
Added rationale for Amendment 
(d)  
Addition 
11. Appendix 11: Protocol 
Amendment History 
Added amendment (d) summary 
of changes table 
To update the amendment history 
 
Amendment [d]: (30-Aug-2023)  
This amendment is considered to be nonsubstantial.  
Overall Rationale for the Amendment: 
The protocol was amended to comply with the new European Union Clinical Trial Regulation 
(EU-CTR). The table listing strong and moderate inducers and strong inhibitors of CYP3A4 in 
Appendix 8 was updated. 
Changes and rationale are summarized in the table below; minor typographical or formatting 
edits are not presented in the table. 
Section # and Name 
Description of Change 
Brief Rationale 
1. Synopsis 
Added subsections 
 Regulatory Agency 
Identifier Numbers (Eudra 
CT and EU CT numbers)” 
 Study Population 
 Ethical Considerations of 
Benefit/Risk 
 Data Monitoring 
Committee 
Compliance with EU-CTR 
7.1. Treatments Administered 
Added table describing 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 119 
LY2835219 
Section # and Name 
Description of Change 
Brief Rationale 
authorization as defined by 
EU-CTR for abemaciclib, 
abiraterone acetate, and 
prednisone, and the definition 
for study treatment 
7.1.1. Packaging and Labeling 
Updated language on 
packaging and labeling 
9.2. Adverse Events 
Updated events meeting the 
AE definition 
9.2.1. Serious Adverse Events 
Updated regulatory reporting 
of SAEs 
10.3. Statistical Analyses 
Added a statement on 
handling of missing, unused, 
and spurious data 
Appendix 1. Abbreviations 
and Definitions 
Added new abbreviations to 
the list 
Appendix 3. Study 
Governance, Regulatory, and 
Ethical Considerations 
Added required language on 
investigator reporting 
requirements 
Added required language on 
data protection 
Added required language for 
communication of suspended 
or terminated dosing and time 
frame for posting of summary 
of results as specified by 
local law or regulation 
Appendix 8. Protocol JPCM 
Strong and Moderate Inducers 
of CYP3A4, Strong Inhibitors 
of CYP3A4, Substrates of 
CYP2D6 with Narrow 
Therapeutic Range, and 
Transporter Substrates with 
Narrow Therapeutic Range 
Updated table listing strong 
and moderate inducers and 
strong inhibitors of CYP3A4 
Update 
Added back the list of 
transporter substrates with 
narrow therapeutic range 
which was inadvertently 
omitted in Amendment c 
Correction 
Amendment [c]: (11-Mar-2021)  
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: 
See Section 3.1.3. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 120 
LY2835219 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Section 5.1. 
Overall Design, 
Section 5.2. Number of 
Patients, Section 7.2. 
Method of Treatment 
Assignment 
Addition of Part 3 of the study: 
Part 3 will open if the prespecified expansion 
criteria in an adaptive interim analysis are met and 
will randomize approximately 170 additional 
patients to Arm A or Arm B, for a total of 
350 patients to be enrolled. 
Adaptive Design 
Synopsis, Section 4. 
Objectives and 
Endpoints, Section 5.4.4. 
PSA Progression as an 
Efficacy Endpoint, 
Section 9.1.2. 
Definitions of Efficacy 
Measures, 
Section 10.3.1.3. Time 
to Prostate-Specific 
Antigen Progression 
Time to prostate-specific antigen (PSA) 
progression was changed from a coprimary 
objective to a secondary objective. Accordingly, 
PSA Progression as an Efficacy Endpoint is 
removed from Section 5.4.4 and the planned 
primary analysis for time to PSA progression was 
removed from Section 10.3.1.3. 
 
 
 
Adaptive Design 
Synopsis, Section 4. 
Objectives and 
Endpoints, Section 5.4.3. 
Radiographic PFS as an 
Efficacy Endpoint  
Added “rPFS by blinded, independent, central 
review (BICR)” as a secondary objective if Part 3 
is opened for enrollment. 
Addition 
Synopsis, Section 4. 
Objectives and 
Endpoints 
Patient-reported pain was changed from an 
exploratory to a secondary objective, and “time to 
worst pain progression” was added as a secondary 
endpoint.  
Addition 
Synopsis, Section 7.3.1. 
Unblinding at Interim 
Analyses, 10.3.5 Interim 
Analyses 
Duplication of preexisting language from 
Section 5.1. Overall Design and Section 10.3.5. 
Interim Analyses, to reinforce that the assessment 
committee (AC) is composed of Lilly members not 
involved in the day-to-day study conduct 
Clarification 
Synopsis, Section 5.1. 
Overall Design, 
Section 7.3.1. 
Unblinding at Interim 
Analyses 
Clarification regarding the independent data 
monitoring committee (DMC) conducting interim 
analyses 
Clarification 
Section 2. Schedule of 
Activities 
 
Deletion of Urinalysis during the ‘on 
treatment’ period 
 
Reinforcing that ‘on treatment’ tumor 
imaging should be performed at specified 
 
Deletion 
 
 
Clarification  
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Section # and Name 
Description of Change 
intervals independent of treatment delays 
• 
Section 3 .1.3. Rationale 
Addition of rationale for Amendment C 
for Amendment C 
Section 4. Objectives 
and Endpoints, 
Section 9 .9 .1 .1. 
Definitions of Patient-
Rep01ted Outcome 
Endpoints 
Section 5.1. Overall 
Design 
Section 5.1. Overall 
Design, Section 7 .1. 
Treatments 
Administered 
Section 5.1. Overall 
Design 
Section 6.1. Inclusion 
Criteiion 7; 
Section 9 .8.1. Tissue 
Samples for Biomarker 
Research 
Section 6.1. Inclusion 
Criteiion 5 
Section 6.2. Exclusion 
LY2835219 
Addition of timelines and details for planned 
analyses 
Added that the AC has determined the 
recommended Phase 2 dose (RP2D) of 
abemaciclib to be 
Updated Figure JPCM.1. study design. 
Stipulated that baseline tumor tissue collection is 
optional for Pait 3. 
Claiified that Prostate Cancer Working Group 3 
(PCWG3) c1iteiia for bone progression at tJ.ial 
entJ.y refers to the appearance of'.:::2 new bone 
lesions 
Exclusion Criterion 15: 3 months or 5 half-lives 
washout for rior investi ational roduct chan ed 
Approved on 30 Apr 2024 GMT 
Page 121 
Brief Rationale 
• 
Addition related 
to exploratoiy 
objective for 
Pait 3, 
Clarification of 
instrnctions 
Addition 
Addition/Clarification 
Addition 
Addition 
Adaptive Design 
Addition 
Cla1ification 
Claiification 

I3Y-MC-JPCM(f) Clinical Protocol 
Page 122 
LY2835219 
Section # and Name 
Description of Change 
Brief Rationale 
Criteria  
“whichever is longer” to “whichever is shorter” 
Section 6.4. Screen 
Failures 
Interval between rescreenings changed from “at 
least 4 weeks” to “at least 2 weeks” 
Update 
Section 7.2.1. Selection 
and Timing of Doses 
Added language regarding additional study 
treatment to be dispensed for planned cycle delays 
after discussion with Lilly Clinical Research 
Physician/Clinical Research Scientist (CRP/CRS). 
Addition 
Section 7.3. Blinding, 
Section 7.3.2. 
Emergency Unblinding 
Moved text from Section 7.3.2 Emergency 
Unblinding to Section 7.3 Blinding and updated 
language to reinforce that unblinding of the 
investigator and the patient at the time of 
documented objective disease progression is 
permitted to ensure optimal patient management 
and/or facilitate selection of subsequent treatment. 
Addressing regulatory 
feedback 
Section 7.4.1.2 
Abemaciclib/Placebo 
and Abiraterone acetate 
and Dose Adjustments 
and Delays - Increased 
ALT/AST 
Added Table JPCM.8. and corresponding text for 
abemaciclib/placebo and abiraterone acetate and 
dose adjustments and delays for increased alanine 
aminotransferase (ALT)/aspartate 
aminotransferase (AST).  
To condense text and to 
update dose adjustments 
for ALT/AST increase 
from language 
previously in 
Section 7.7.2.3  
Section 7.7. 
Concomitant Therapy 
Updated language for CYP3A modulators and 
transporter substrates.  
Update to align with 
current guidance 
Section 7.4.1.2. 
Abemaciclib/Placebo 
and Abiraterone acetate 
Dose Adjustments and 
Delays for Increased 
ALT/AST, Section 7.7.2 
Supportive Care, 
Section 9.4.2 Safety 
Monitoring 
Moved Guidance for Monitoring Renal Function 
from Section 7.7.2.2 to Section 9.4.2.3 under 
Safety Monitoring. 
 
Updated and moved Guidance for Abnormal Liver 
Function Test from Section 7.7.2.3 to: 
- Section 7.4.1.2. Abemaciclib/Placebo and 
Abiraterone acetate Dose Adjustments and Delays 
for Increased ALT/AST and to  
- Section 9.4.2.1 Hepatic Safety Monitoring under 
Safety Monitoring 
 
Added Section 9.4.2.4 Guidance for Venous 
Thromboembolic Events under Safety Monitoring 
 
Moved Guidance for Interstitial Lung Disease 
(ILD)/Pneumonitis from Section 7.7.2.4 to 
Section 9.4.2.5 under Safety Monitoring 
 
Updated and moved Guidance for Hypertension, 
These changes were 
made to group all 
guidances previously 
under Section 7.7.2 
Supportive Care to 
Section 9.4.2 Safety 
Monitoring.  
 
Updates were made to 
align with Abemaciclib 
Investigator’s Brochure 
(IB) and/or Abiraterone 
prescribing information 
updates. 
 
 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 123 
LY2835219 
Section # and Name 
Description of Change 
Brief Rationale 
Hypokalemia, and Fluid Retention Due to 
Mineralocorticoid Excess from Section 7.7.2.7 to 
Section 9.4.2.6 under Safety Monitoring 
 
Added Section 9.4.2.7 Guidance for 
Adrenocortical Insufficiency under Safety 
Monitoring 
 
Added Section 9.4.2.8 Guidance for 
Hypoglycemia under Safety Monitoring 
Section 9.1.2. 
Definitions of Efficacy 
Measures, 
Section 10.3.1.1. 
Radiographic 
Progression Free 
Survival 
Added language regarding Radiographic 
progression-free survival (rPFS) by BICR; moved 
language regarding worst pain NRS to 
Section 9.9.1. 
Update  
Section 9.8.1. Tissue 
Samples for Biomarker 
Research 
Deleted the requirement for discussion with the 
Lilly CRP/CRS for use of archival metastatic 
tissue. 
Deletion 
Section 9.9.1 Patient-
reported Outcomes, 
Section 9.9.1.1. 
Definitions of Patient-
Reported Outcome 
Endpoints 
Added section and corresponding subsection.  
Addition 
Section 9.9.2. Health 
Care Resource 
Utilization 
Added section.  
Addition 
Section 10. Statistical 
Considerations 
Revised planned statistical analyses to account for 
changes to primary endpoint, interim analyses, and 
the addition of Part 3. 
Adaptive Design 
Section 10.3.1.2. Overall 
Survival 
Moved subsection from Section 10.3.1.4 to 
Section 10.3.1.2.  
Editorial 
Section 10.3.3.9. Health 
Outcome/Quality-of-
Life Analyses 
Revised section.  
Revision 
Section 10.3.5.2. 
Futility/Adaptive 
Revised section title and text to describe adaptive 
interim analyses and criteria for opening 
Adaptive Design 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 124 
LY2835219 
Section # and Name 
Description of Change 
Brief Rationale 
Interim Analyses 
enrollment to Part 3. 
Appendix 4  
Updated table and footnote to align with changes 
throughout the protocol.  
Added Footnote c to clarify that pharmacogenetics 
(PGx) whole blood sample can be collected at 
subsequent timepoints if not collected at Cycle 1 
Day 1.  
Update/Clarification 
Appendix 8  
Deleted medications to align with current CYP3A 
guidance 
Deletion  
Appendix 9  
Added ALT and AST to the Common 
Terminology Criteria for Adverse Events 
(CTCAE 5.0) grading table and updated Appendix 
title and summary text. 
Addition  
Appendix 10 
Added provision for changes in study conduct 
during exceptional circumstances. 
Addition 
Throughout 
Minor editorial and formatting changes made for 
clarity; changed Phase 2 to Phase 2/3; changed 
“solid oral dosage units” to “tablets/capsules” 
Other 
 
Amendment [b]: (28-Feb-2020)  
The overall changes and rationale for the changes made to this protocol are as follows: 
 
An update to the title including the name of the study, CYCLONE 2. 
 
A clarification was made in the synopsis outlining the time of treatment initiation from 
randomization. 
 
The protocol was updated to bring references to abemaciclib into alignment with the 
sponsor’s standard language. 
 
A data monitoring committee was added to perform unblinded safety and futility/efficacy 
analyses. 
 
A clarification was added to the SoA defining baseline procedure timing as days prior to 
randomization consistent with the synopsis. 
 
A clarification was added to the SoA confirming procedures will be performed according to 
calendar days, regardless of treatment delays.  
 
A clarification was added to the instructions of ECOG PS, hematology, chemistry, and 
urinalysis further clarifying procedures assessed at baseline do not need repeated at C1D1 if 
assessed ≤3 days prior to treatment initiation.  
 
Section 3.1.1 and Section 3.1.2 was added to provide the rationale for Amendment a and 
Amendment b respectively.  
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 125 
LY2835219 
 
A clarification was made to Section 5.4.2 to prior treatments and text was updated with 
recent approvals. 
 
A clarification was made to Exclusion Criteria 14 to update text with recent approvals.  
 
A clarification was made to Section 6.3 and Section 7 further clarifying patients should 
refrain from grapefruit, pomegranate, and their juice while on study. 
 
A clarification was made to Section 7.2.1 confirming a delay or earlier start due to holiday, 
weekend, bad weather, or unforeseen circumstances will be permitted up to 7 days.  
 
An update was made to the dose modification guidance and the safety language for 
ILD/pneumonitis. These updates are in alignment with changes made in the development 
core safety information of the Investigator’s Brochure. In addition, the hepatic safety 
monitoring guidance was updated. 
 
Changes to Section 7.7.2.3, the Special Hepatic Safety Data Collection, and Appendix 5 were 
done to ensure a comprehensive evaluation of patients with treatment emergent abnormal 
liver tests and to align with current guidance from the Lilly Liver and Gastrointestinal (GI) 
Safety Advisory Committee. 
 
A clarification was made to PSA and testosterone labs in Appendix 2 ensuring consistency 
with other labs. 
 
The pneumonitis CTCAE definition was added for investigator convenience.  
 
Other minor editorial changes were made to add clarity. 
Amendment [a]: (31-Oct-2018) 
The overall changes and rationale for the changes made to this protocol are as follows: 
 
An update the synopsis to reflect changes made throughout the protocol.  
 
Clarifications were made to the schedule of activities including the timing of chemistry labs 
and confirming hypokalemia correction prior to ECG collection. 
 
A deletion of ECOG performance score on Day 15 of Cycle 1 and 2. 
 
An addition of symptomatic progression assessment to the Schedule of Activities. 
 
An update of the CTCAE version throughout the protocol. 
 
An update throughout the protocol allowing the use of prednisolone where prednisone is not 
commercially available. 
 
A clarification to the timing of when short-term follow-up begins. 
 
An update to the background on abemaciclib with new approvals globally. 
 
An addition of the endpoint symptomatic skeletal event to the time to symptomatic 
progression objective. 
Approved on 30 Apr 2024 GMT

I3Y-MC-JPCM(f) Clinical Protocol 
Page 126 
LY2835219 
 
A clarification in Section 5.1 to further clarify where blinded study treatment has been dose 
reduced below the selected RP2D. 
 
A clarification in Section 5.1 to further clarify why stratification factors were chosen.  
 
A change to inclusion criteria 2 to exclude patients with large cell neuroendocrine carcinoma 
and carcinoid tumors. 
 
A clarification to exclusion criteria 17 to allow for investigator judgment instead of Lilly 
CRP. 
 
A clarification to exclusion criteria 23 to further clarify infections. 
 
An update to exclusion criteria 27 as well as throughout the protocol updating excluded 
concomitant medications.  
 
A change to Section 7.4.1.1 with updated toxicity dose adjustments and delays to blinded 
study treatment. 
 
A change to Section 7.7 adding dabigatran to the list of medications to be avoided or 
substituted if possible. 
 
A clarification was made to Section 7.7.2.2 for guidance for monitoring renal function. 
 
An update was made to Section 7.7.2.6 guidelines for hypertension, hypokalemia, and fluid 
retention due to mineralocorticoid excess. 
 
An update to Section 8.1.1 to further clarify and reinforce that the protocol is not intended to 
permit the enrollment of patients who do not meet eligibility criteria. 
 
A clarification to Table JPCM.7. was made to the confirmatory scan for progressed patients 
at week 17 or greater.  
 
A clarification to Section 9.1.2 defining secondary objectives, DoR and ORR. 
 
A clarification to Section 9.4.2 was made to clarify hepatic monitoring depend upon the 
severity and persistence of observed laboratory test abnormalities. 
 
A change to Section 9.4.2.1. was made to update requirements for special hepatic safety data 
collection. 
 
A clarification to Section 9.8.1 to further clarify the collection of required tumor tissue 
samples.  
 
An addition to clinical chemistry clinical laboratory test in Appendix 2 adding Cystatin C, 
HDL, LDL, and triglycerides. 
 
Other minor editorial changes were made to add clarity. 
Approved on 30 Apr 2024 GMT

Signature Page for VY-CLIN-151605 vl.0 
1~ -~~02409,22,25 GMT+OOOO 
Signature Page for VY-CLIN-151605 vl.0 
Approved on 30 Apr 2024 GMT