An Adaptive, Open-Label, Randomized Phase 2 Study of Abemaciclib as a Monotherapy and in Combination With Other Agents Versus Choice of Standard of Care (Gemcitabine or Capecitabine) in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma
Phase: PHASE2
Conditions: Pancreatic Ductal Adenocarcinoma
Sponsor: Eli Lilly and Company

 
I3Y-MC-JPCJ(c) Clinical Protocol 
 
 
An Adaptive, Open-Label, Randomized Phase 2 Study of Abemaciclib as a Monotherapy and in 
Combination with Other Agents Versus Choice of Standard of Care (Gemcitabine or Capecitabine) in 
Patients with Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma 
 
NCT02981342 
 
Approval Date: 29-Jun-2017 
 
 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 1
LY2835219
Protocol I3Y-MC-JPCJ(c)
An Adaptive, Open-Label, Randomized Phase 2 Study of 
Abemaciclib as a Monotherapy and in Combination with 
Other Agents Versus Choice of Standard of Care 
(Gemcitabine or Capecitabine) in Patients with Previously 
Treated Metastatic Pancreatic Ductal Adenocarcinoma
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
Protocol Approved by Lilly:  22 July 2016
Amendment (a) Approved by Lilly on 20 September 2016.
Amendment (b) Electronically Signed and Approved by Lilly on 15-Apr-2017.
Amendment (c) Electronically Signed and Approved by Lilly on Date provided below.
Approval Date: 29-Jun-2017 GMT

I3Y-MC-JPCJ(c) Clinical Protocol
Page 2
LY2835219
Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................29
3.1.
Study Rationale............................................................................................................29
3.2.
Background..................................................................................................................29
3.2.1.
Pancreatic Ductal Adenocarcinoma......................................................................29
3.2.2.
Cyclin-Dependent Kinases 4 and 6 and Role in Pancreatic 
Ductal Adenocarcinoma.......................................................................................30
3.2.3.
Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of 
Rapamycin (mTOR) Pathway and Role in Pancreatic Ductal 
Adenocarcinoma ..................................................................................................31
3.2.4.
Transforming Growth Factor-Beta and Role in Pancreatic 
Ductal Adenocarcinoma.......................................................................................32
3.3.
Benefit/Risk Assessment..............................................................................................33
4.
Objectives and Endpoints..................................................................................................34
5.
Study Design.....................................................................................................................36
5.1.
Overall Design .............................................................................................................36
5.2.
Number of Patients.......................................................................................................37
5.3.
End of Study Definition ...............................................................................................38
5.4.
Scientific Rationale for Study Design...........................................................................38
5.4.1.
Rationale for Amendment (a)...............................................................................38
5.4.2.
Rationale for Amendment (b)...............................................................................39
5.4.3.
Rationale for Amendment (c)...............................................................................39
5.5.
Justification for Doses of Investigational Treatments....................................................39
6.
Study Population...............................................................................................................41
6.1.
Inclusion Criteria..........................................................................................................41
6.2.
Exclusion Criteria ........................................................................................................43
6.3.
Lifestyle Restrictions....................................................................................................44
6.4.
Screen Failures.............................................................................................................44
7.
Treatments........................................................................................................................45
7.1.
Treatments Administered .............................................................................................45
7.1.1.
Packaging and Labelling ......................................................................................45
7.2.
Method of Treatment Assignment ................................................................................46
7.2.1.
Selection and Timing of Doses.............................................................................47
7.3.
Blinding .......................................................................................................................48

I3Y-MC-JPCJ(c) Clinical Protocol
Page 3
LY2835219
7.4.
Dosage Modification....................................................................................................48
7.4.1.
Dosage Modifications for Investigational Agents .................................................48
7.4.2.
Dosage Modifications for Gemcitabine ................................................................51
7.4.3.
Dosage Modifications for Capecitabine................................................................52
7.5.
Preparation/Handling/Storage/Accountability...............................................................53
7.6.
Treatment Compliance .................................................................................................53
7.7.
Concomitant Therapy...................................................................................................54
7.7.1.
Surgery for Cancer...............................................................................................54
7.7.2.
Management of Diarrhea......................................................................................54
7.7.3.
Management of Hyperglycemia............................................................................55
7.7.4.
Supportive Management for Stomatitis/Mucositis ................................................55
7.7.5.
Concurrent Use of Inducers and Inhibitors of CYP3A4, 
Substrates of CYPS with Narrow Therapeutic Range, or 
Drugs Causing QTc Prolongation.........................................................................56
7.8.
Treatment after the Safety Lead-in, the End of Stage 1, and Study 
Completion ..................................................................................................................57
7.8.1.
End of Safety Lead-in ..........................................................................................57
7.8.2.
End of Stage 1......................................................................................................57
7.8.3.
Study Completion ................................................................................................57
7.8.4.
Continued Access.................................................................................................57
8.
Discontinuation Criteria ....................................................................................................59
8.1.
Discontinuation from Study Treatment.........................................................................59
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................59
8.2.
Discontinuation from the Study....................................................................................59
8.3.
Lost to Follow-Up........................................................................................................60
9.
Study Assessments and Procedures ...................................................................................61
9.1.
Efficacy Assessments...................................................................................................61
9.1.1.
Appropriateness of Assessments ..........................................................................62
9.2.
Adverse Events ............................................................................................................62
9.2.1.
Serious Adverse Events........................................................................................63
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................63
9.2.3.
Summary of Adverse Event/Serious Adverse Event 
Reporting Guidelines ...........................................................................................64
9.2.4.
Complaint Handling.............................................................................................64
9.3.
Treatment of Overdose.................................................................................................65
9.4.
Safety...........................................................................................................................65
9.4.1.
Cardiac Monitoring..............................................................................................65
9.4.2.
Guidance for Monitoring of Renal Function in Patients on 
Abemaciclib.........................................................................................................66

I3Y-MC-JPCJ(c) Clinical Protocol
Page 4
LY2835219
9.4.3.
Other Safety Measures .........................................................................................66
9.4.4.
Safety Monitoring ................................................................................................67
9.5.
Pharmacokinetics .........................................................................................................67
9.6.
Pharmacodynamics ......................................................................................................67
9.7.
Pharmacogenomics ......................................................................................................68
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................68
9.8.
Biomarkers...................................................................................................................68
9.8.1.
Blood Samples for Nonpharmacogenetic Biomarker 
Research ..............................................................................................................69
9.8.2.
Tissue Samples for Nonpharmacogenetic Biomarker 
Research ..............................................................................................................69
9.9.
Health Outcomes..........................................................................................................70
9.9.1.
Pain Intensity .......................................................................................................70
9.9.2.
Health-Related Quality of Life .............................................................................71
9.9.3.
Resource Utilization.............................................................................................71
10.
Statistical Considerations ..................................................................................................72
10.1. Sample Size Determination ..........................................................................................72
10.2. Populations for Analyses..............................................................................................72
10.3. Statistical Analyses ......................................................................................................73
10.3.1.
Efficacy Analyses ................................................................................................73
10.3.2.
Safety Analyses....................................................................................................74
10.3.3.
Other Analyses.....................................................................................................75
10.3.3.1.
Patient Disposition..........................................................................................75
10.3.3.2.
Patient Characteristics ....................................................................................75
10.3.3.3.
Concomitant Therapy .....................................................................................75
10.3.3.4.
Poststudy-Treatment-Discontinuation Therapy ...............................................75
10.3.3.5.
Treatment Compliance....................................................................................75
10.3.3.6.
Pharmacokinetic/Pharmacodynamic Analyses ................................................76
10.3.3.7.
Biomarker Analyses .......................................................................................76
10.3.3.8.
Health Outcome/Quality of Life Analyses ......................................................76
10.3.3.9.
Healthcare Resource Utilization......................................................................77
10.3.4.
Subgroup Analyses ..............................................................................................77
10.3.5.
Stage 1 Analyses..................................................................................................77
11.
References ........................................................................................................................78

I3Y-MC-JPCJ(c) Clinical Protocol
Page 5
LY2835219
List of Tables
Table
Page
Table JPCJ.2.1.
Baseline Schedule of Activities ..............................................................14
Table JPCJ.2.2.
On-Study-Treatment Schedule of Activities—Abemaciclib 
Monotherapy (Arm A)............................................................................16
Table JPCJ.2.3.
On-Study-Treatment Schedule of Activities—Abemaciclib Plus 
LY3023414 (Arm B) ..............................................................................18
Table JPCJ.2.4.
On-Study-Treatment Schedule of Activities—Abemaciclib Plus 
Galunisertib (Safety Lead-In) .................................................................20
Table JPCJ.2.5.
On-Study-Treatment Schedule of Activities—Standard of Care 
Capecitabine (Arm D) ............................................................................23
Table JPCJ.2.6.
On-Study-Treatment Schedule of Activities—Standard of Care 
Gemcitabine (Arm D).............................................................................25
Table JPCJ.2.7.
Post-Treatment Follow-Up Schedule of Activities ..................................27
Table JPCJ.2.8.
Continued Access Schedule of Activities................................................28
Table JPCJ.4.1.
Stage 1 Objectives and Endpoints...........................................................34
Table JPCJ.4.2.
Objectives and Endpoints Stage 2...........................................................35
Table JPCJ.7.1.
Treatment Regimens...............................................................................45
Table JPCJ.7.2.
Common Treatment-Related Adverse Events for Investigational 
Agents....................................................................................................49
Table JPCJ.7.3.
Dose Reductions for Investigational Agents............................................50
Table JPCJ.7.4.
Gemcitabine Dose Modifications for Hematological Toxicity.................51
Table JPCJ.7.5.
Capecitabine Dose Modifications ...........................................................53
Table JPCJ.9.1.
Assessment Guide for Adverse Events and Serious Adverse Events .......64
Table JPCJ.10.1.
Probability of Stopping at Stage 1...........................................................72

I3Y-MC-JPCJ(c) Clinical Protocol
Page 6
LY2835219
List of Figures
Figure
Page
Figure JPCJ.5.1.
Illustration of study design......................................................................37
Figure JPCJ.7.1.
Continued access diagram.......................................................................58

I3Y-MC-JPCJ(c) Clinical Protocol
Page 7
LY2835219
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................84
Appendix 2.
Study Governance, Regulatory, and Ethical Considerations....................88
Appendix 3.
Clinical Laboratory Tests........................................................................91
Appendix 4.
Sampling Schedule for Pharmacokinetics and Biomarkers......................92
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............96
Appendix 6.
Echocardiographic Guidelines ................................................................97
Appendix 7.
Inducers and Inhibitors of CYP3A or Substrates of CYPS with 
Narrow Therapeutic Range...................................................................100
Appendix 8.
Drugs Associated with QT Interval Prolongation..................................101
Appendix 9.
Creatinine Clearance Formula...............................................................102
Appendix 10.
Dose Modification Recommendations for Study Treatment-Related 
Toxicities .............................................................................................103
Appendix 11.
Protocol Amendment I3Y-MC-JPCJ(c) Summary 
An Adaptive, Open-Label, Randomized Phase 2 Study of 
Abemaciclib as a Monotherapy and in Combination with Other 
Agents Versus Choice of Standard of Care (Gemcitabine or 
Capecitabine) in Patients with Previously Treated Metastatic 
Pancreatic Ductal Adenocarcinoma ......................................................107

I3Y-MC-JPCJ(c) Clinical Protocol
Page 8
LY2835219
1.
Synopsis
Protocol Title:
An adaptive, open-label, randomized Phase 2 study of abemaciclib as a monotherapy and in combination with other 
agents versus choice of standard of care (gemcitabine or capecitabine) in patients with previously treated metastatic 
pancreatic ductal adenocarcinoma
Rationale:
Cyclin-dependent kinase (CDK)4 and CDK6 pathway alterations, along with Kirsten rat sarcoma (KRAS)
mutations, are key molecular signatures that occur in approximately 90% of pancreatic ductal adenocarcinoma 
(PDAC).  Abemaciclib, a CDK4 and CDK6 inhibitor, has shown activity in KRAS mutant pancreatic cancer cell 
lines and has acceptable safety and tolerability in clinical studies. Given the relevance of the CDK4 and CDK6 
pathway in PDAC, the activity of abemaciclib in KRAS mutant pancreatic cancer cell lines, acceptable safety and 
tolerability of abemaciclib in clinical studies, and the unmet medical need, this study aims to explore the safety and 
efficacy of abemaciclib in patients with PDAC.
This study also aims to explore the safety and efficacy of abemaciclib in combination with LY3023414, an orally 
available, potent selective inhibitor of the class I phosphatidylinositol 3-kinase (PI3K) isoforms, mammalian target 
of rapamycin (mTOR), and DNA-dependent protein kinase, in patients with PDAC.  Upstream mitogenic growth 
factors, including PI3K, induce the expression of Cyclin D1, which further activates the Cyclin D1-CDK4 and 
CDK6 complex. Frequent activating aberrations of PI3K/mTOR signaling have been reported in several cancers.  A 
potent impact of CDK4 and C.
DK6 inhibition in PDAC models has been observed; however, in the majority of models analyzed, acquired/intrinsic 
resistance has resulted through bypassing of this inhibition.  PI3K/mTOR inhibitors demonstrated cooperative 
effects in combination with a CDK4 and CDK6 inhibitor in a pancreatic cancer tumor model. Synergistic activity of 
CDK4 and CDK6 and PI3K/mTOR blockade has been observed in other tumor models, and clinical trials are 
ongoing exploring this strategy.
Galunisertib (LY2157299) is a small molecule designed to selectively inhibit the serine/threonine kinase of the 
transforming growth factor beta (TGF-β) receptor type I (TGF-RI).  In PDAC, an increase in expression of 
epithelial-mesenchymal transition triggering factors, including TGF-, has been observed and may contribute to the 
high metastatic potential. In pancreatic cancer cells, a CDK4 and CDK6 inhibitor exerted growth-inhibitory effects,
although a TGF-RI inhibitor alone was unable to suppress colony growth in 3-D culture.  However, when the 
TGF-RI inhibitor was combined with a CDK4 and CDK6 inhibitor, optimal growth inhibition was achieved.  
These preclinical data provide a basis for exploring the combination of abemaciclib and galunisertib in the current 
study, although with amendment (c) the assessment of this combination is being discontinued.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 9
LY2835219
Objectives and Endpoints:
STAGE 1
Objectives
Endpoints
Primary

To evaluate disease control rate of the abemaciclib 
treatment arms versus the standard-of-care arm
(gemcitabine or capecitabine)

Disease control rate is the percentage of patients 
with a best overall response of stable disease, 
complete response, or partial response according to 
RECIST 1.1.
Secondary

To evaluate objective response rate of the 
abemaciclib treatment arms versus the 
standard-of-care arm

Objective response rate is the percentage of patients 
with a best overall response of complete response or 
partial response according to RECIST 1.1.

Evaluate safety and tolerability of the abemaciclib 
treatment arms
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs and SAEs

Clinical laboratory tests and vital signs

PK of abemaciclib and its metabolites as well as 
LY3023414

Exposure of abemaciclib and LY3023414
Abbreviations:  PK = pharmacokinetics; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1; 
TEAE = treatment-emergent adverse event; SAE = serious adverse event.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 10
LY2835219
STAGE 2
Objectives
Endpoints
Primary

To evaluate progression-free survival of the 
abemaciclib treatment arms versus the 
standard-of-care arm (gemcitabine or capecitabine)

Progression-free survival is measured from the date 
of randomization to the date of objective 
progression or the date of death due to any cause,
whichever is earlier.
Secondary

To evaluate disease control rate of the abemaciclib 
treatment arms versus the standard-of-care arm

Disease control rate is the percentage of patients 
with a best overall response of stable disease, 
complete response, or partial response according to 
RECIST 1.1.

To evaluate clinical benefit rate of the abemaciclib 
treatment arms versus the standard-of-care arm

Clinical benefit rate is the percentage of patients 
with a best overall response of complete response, 
or partial response, or stable disease for ≥6 months 
according to RECIST 1.1.

To evaluate objective response rate of the 
abemaciclib treatment arms versus the 
standard-of-care arm

Objective response rate is the percentage of patients 
with a best overall response of complete response or 
partial response according to RECIST 1.1.

To evaluate duration of response of the abemaciclib 
treatment arms versus the standard-of-care arm

Duration of response is measured from the date of 
first evidence of complete response or partial 
response to the date of objective progression or the 
date of death due to any cause, whichever is earlier.

To evaluate overall survival of the abemaciclib 
treatment arms versus the standard-of-care arm

Overall survival is measured from the date of 
randomization to the date of death from any cause.

Evaluate the kinetics of carbohydrate antigen (CA) 
19-9

Change from baseline in CA 19-9

Evaluate safety and tolerability
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs and SAEs

Clinical laboratory tests and vital signs

To evaluate pain and symptom burden of the 
abemaciclib treatment arms by best response group 
(partial response, stable disease, progressive 
disease) versus the standard-of-care arm

modified Brief Pain Inventory short form (mBPI-sf) 
and the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-
Core 30 (EORTC QLQ-C30)

PK of abemaciclib and its metabolites as well as 
LY3023414

Exposure of abemaciclib and LY3023414

Exposure-response for abemaciclib and LY3023414

Drug exposure and efficacy outcomes such as 
objective response rate or progression-free survival
and safety outcomes such as neutropenia and 
diarrhea
Abbreviations:  CA = carbohydrate antigen; PK = pharmacokinetics; RECIST 1.1 = Response Criteria in Solid 
Tumors Version 1.1; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 11
LY2835219
Overall Design:
Study I3Y-MC-JPCJ is a multicenter, randomized, open-label, Phase 2 trial in patients with metastatic pancreatic 
ductal adenocarcinoma who have been previously treated with at least one, but no more than 2, prior therapies for 
metastatic disease.  At least one of the prior therapies must have been either gemcitabine-based or fluoropyrimidine-
based therapy.  The safety and efficacy of each investigational arm will be assessed versus the standard-of-care arm 
by implementing a 2-stage design.  For Stage 1, the primary analyses of safety and efficacy will be evaluated for 
each of 2 investigational arms versus a standard-of-care arm approximately 16 weeks after the last planned Stage 1 
patient enters treatment.  The 2 investigational arms include abemaciclib monotherapy (Arm A) and abemaciclib 
plus LY3023414 (PI3K/mTOR dual inhibitor; Arm B).  The comparator arm will be choice of standard-of-care 
(gemcitabine or capecitabine; Arm D).  Following the completion of the Stage 1 assessment, any treatment arm(s) 
with a disease control rate (DCR) difference ≥ 0 as compared to the standard-of-care (Arm D) will be selected to 
advance to Stage 2.  Enrollment in the nonadvancing arm(s) will be discontinued.  For the treatment arms that 
advance to Stage 2, additional patients will be randomized equally among the treatment arms (Stage 2) for further 
evaluation of safety and efficacy.
Number of Patients:
Safety Lead-in:
According to the initial protocol, prior to initiating Stage 1 of the study, a safety lead-in period for abemaciclib plus 
galunisertib was to be conducted with up to 12 patients.  At the time of amendment (c), Lilly determined no 
additional patients would be enrolled to the safety lead-in and that Arm C (abemaciclib plus galunisertib) would be 
removed from the study.
Stage 1:
For Stage 1, a total of approximately 75 patients (25 patients per arm) will be randomized in a 1:1:1 ratio to 
3 treatment arms.  Randomization will be stratified by number of prior systemic therapies (1 versus 2).
Stage 2:
For the treatment arms that meet the decision criteria to advance to Stage 2 (DCR difference ≥ 0 in abemaciclib 
containing arms vs. the standard-of-care arm), 50 additional patients will be randomized to each experimental arm,
as well as to the standard-of-care arm.  The arms that advance to Stage 2 will enroll a total of approximately 
75 patients per arm (including 25 patients from Stage 1).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 12
LY2835219
Treatment Arms and Duration:
Dose and Schedule
Arm
A
Abemaciclib (CDK4 and CDK6 inhibitor) 200 mg BID with or without food continuous dosing for 28-day 
cycles
Ba
Abemaciclib 150 mg BID with or without food continuous dosing for 28-day cycles
LY3023414 (PI3K/mTOR dual inhibitor) 150 mg BID with or without food continuous dosing for 28-day 
cycles
D
Standard-of-Care Choice of:
     Gemcitabine 1000 mg/m2 over 30 minutes 
     intravenously on the following days of a 28-day cycle.
          •   Cycle 1:  Days 1, 8, 15, and 22
          •   Cycle 2 and beyond:  Days 1, 8, and 15
                               OR
     Capecitabine 1250 mg/m2 administered orally BID within 30
     minutes after a meal (morning and evening; equivalent to 2500
     mg/m2 total daily dose) for 2 weeks followed by a 1-week rest 
     period given as 21-day cycles
Abbreviations:  BID = twice daily; CDK = cyclin-dependent kinase; PI3K = phosphatidylinositol 3-kinase
a
Oral combination agents are to be taken at approximately the same time.  There is no specific order of 
administration.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 13
LY2835219
2.
Schedule of Activities

I3Y-MC-JPCJ(c) Clinical Protocol
Page 14
LY2835219
Table JPCJ.2.1.
Baseline Schedule of Activities
Day Relative to C1D1
28
14
7
Procedure
Instructions
Informed consent
X
ICF must be signed before any 
protocol-specific procedures are performed.
Inclusion/exclusion criteria
X
Physical examination
X
Vital signs
X
Including height and weight temperature, blood 
pressure, pulse rate, and respiration rate
ECOG performance status
X
Medical history
X
Including assessment of preexisting conditions 
and historical illnesses
Substance usage
X
Including tobacco and alcohol use
Prior anticancer therapies and current 
medications
X
AE collection
X
CTCAE Version 4.0.  To be reported only after 
study eligibility is confirmed.
Radiologic imaging 
(Tumor Assessment)
X
RECIST 1.1.  Imaging studies (CT or MRI scan 
of the chest, abdomen, and pelvis) are
performed locally (Day -28 to Day -1) at
baseline.  It is recommended that CT imaging
of the abdomen and pelvis be performed with 
IV contrast, whenever possible. If this is not
feasible/advisable secondary to hypersensitivity 
or other conditions, then gadolinium-enhanced
MRI is preferred. For patients with known
serious allergic reactions to CT contrast 
material, a CT of the chest without contrast and 
contrast-enhanced MRI of the abdomen/pelvis
are encouraged.
Hematology
X
Performed by central laboratory.  Local labs 
may be used for eligibility and treatment 
decisions, but a duplicate sample must be 
submitted to the central laboratory.
Clinical chemistry
X
Performed by central laboratory.  NOTE:  
Fasting labs must be drawn for all patients at 
screening in order to appropriately assess 
glucose.  Local labs may be used for eligibility 
and treatment decisions, but a duplicate sample 
must be submitted to the central laboratory.
Coagulation
X
PTT or INR performed locally only for those 
patients receiving oral coumarin-derivative 
anticoagulants
Cystatin C
X
Performed by central laboratory to assess renal 
function
CA 19-9
X
Performed by central laboratory
HbA1c
X
Performed by central laboratory

I3Y-MC-JPCJ(c) Clinical Protocol
Page 15
LY2835219
Day Relative to C1D1
28
14
7
Procedure
Instructions
Serum pregnancy test
X
Performed by local laboratory.  Applies only to 
women of childbearing potential.  Must have a
negative serum pregnancy test within 7 days of 
the first dose of study drug (that is, Day -7 to
Day -1).
ECG
X
To be performed and read locally.
Administer mBPI-sf and EORTC 
QLQ-C30 questionnaires
X
Patient should complete mBPI-sf and EORTC 
prior to extensive interaction with site staff.
Sample Collection
See Appendix 4.
Tissue samples
X
Confirm archival tumor tissue available.  For 
patients without available FFPE tumor tissue at 
baseline, a core needle biopsy (minimum 3 
cores) obtained prior to study treatment 
initiation is highly encouraged, but not 
required.
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CA = carbohydrate antigen; CT = computed 
tomography; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 
= European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; 
FFPE = formalin-fixed, paraffin-embedded; HbA1c = hemoglobin A1c; ICF = informed consent form; 
INR = international normalized ratio; IV = intravenous; mBPI-sf = modified Brief Pain Inventory short form; 
MRI = magnetic resonance imaging; PTT = partial prothrombin time; RECIST 1.1 = Response Criteria in Solid 
Tumors Version 1.1 (Eisenhauer et al. 2009).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 16
LY2835219
Table JPCJ.2.2.
On-Study-Treatment Schedule of Activities—Abemaciclib Monotherapy (Arm A)
Note:  Screening procedures performed within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
Day within Cycle
28-Day Cycle
28-Day Cycles
28-Day Cycles
Cycle 1
Cycle 2
Cycle 3 - n
1
14
1
14
1
Procedure
Instructions
Physical examination
X
X
X 
X
X
Vital signs
X
X
X
X
X
Includes weight, temperature, blood pressure, pulse rate, and respiration rate
Concomitant medication
X
X
X
X
X
AE collection
X
X
X
X
X
CTCAE Version 4.0
ECOG performance status
X
X
X
X
X
Radiologic imaging
(Tumor Assessment)
X
(every 8 weeks)

Performed locally according to RECIST 1.1, by the same method used at baseline, 
every 8 weeks (±3 days) following randomization until radiographic disease 
progression, death, or study completion, whichever occurs first.

Performed as scheduled, even if study treatment is delayed or omitted.

If patient has known metastases to chest, chest CT is also to be conducted on the same 
schedule.  If no known chest metastases at screening, then chest CT should be repeated 
every 24 weeks (±3 days). It is recommended that CT imaging of the abdomen and 
pelvis be performed with IV contrast, whenever possible.

If IV contrast is not feasible/advisable secondary to hypersensitivity or other conditions, 
then gadolinium-enhanced MRI is preferred.
Hematology
X
X
X
X
X
Performed by central laboratory 3 days prior to each visit (more frequent assessments may 
be performed if clinically indicated).  Local labs may be used for eligibility and treatment 
decisions, but a duplicate sample must be submitted to the central laboratory.
Clinical chemistry
X
X
X
X
X
Performed by central laboratory 3 days prior to each visit (more frequent assessments may 
be performed if clinically indicated).  Local labs may be used for eligibility and treatment 
decisions, but a duplicate sample must be submitted to the central laboratory.
Coagulation
X
X
X
3 days prior to Day 1 of each cycle, PTT or INR performed locally only for those patients 
receiving oral coumarin-derivative anticoagulants.
CA 19-9
X
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 17
LY2835219
Day within Cycle
28-Day Cycle
28-Day Cycles
28-Day Cycles
Cycle 1
Cycle 2
Cycle 3 - n
1
14
1
14
1
Procedure
Instructions
Additional tissue sample, 
if applicable
X
X
If a participant in this study elects to have a surgical procedure at any time during the study
that involves removal of tumor, then FFPE tumor from that procedure may also be 
requested.  Patients undergoing surgery during the study should have study treatment 
suspended for 7 days prior to surgery, as well as 7 days post-operatively.
Urine pregnancy test
X
X
Applies only to women of childbearing potential.
Where required by local law or regulation, perform once every 28 days (±7 days) prior to 
dispensing study treatment.
Administer mBPI-sf and 
EORTC QLQ-C30 
questionnaires
X
X
X
Administer mBPI-sf and EORTC QLQ-C30 prior to administration of study treatment and 
prior to significant interaction with site staff.
ECG
X
(approximately 
Cycle 7)
To be performed and read locally following 6 months (±15 days) of therapy.  Additional 
ECG assessments should be performed as clinically indicated.
Study Drug
   Dispense abemaciclib
X
X
X
Abemaciclib is taken orally BID, approximately every 12 hours, on Days 1 through 28 of 
each cycle without regard to food.
Sample collection
For all sample collection, see Appendix 4.
Pharmacokinetics
Pharmacogenetics
Biomarkers
Abbreviations:  AE = adverse event; BID = twice daily; CA = carbohydrate antigen; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events (NCI 2009); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 = European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; FFPE = formalin-fixed, paraffin-embedded; INR = international 
normalized ratio; IV = intravenous; mBPI-sf = modified Brief Pain Inventory short form; MRI = magnetic resonance imaging; PTT = partial prothrombin 
time; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 18
LY2835219
Table JPCJ.2.3.
On-Study-Treatment Schedule of Activities—Abemaciclib Plus LY3023414 (Arm B)
Note:  Screening procedures performed within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
28-Day Cycle
28-Day Cycles
28-Day Cycles
Cycle 1
Cycle 2 
Cycle 3- n
Day within Cycle
1
14
1
14
1
Procedure
Instructions
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
Includes weight, temperature, blood pressure, pulse rate, and respiration rate.
Concomitant medication
X
X
X
X
X
AE collection
X
X
X
X
X
CTCAE Version 4.0.
ECOG performance status
X
X
X
X
X
Radiologic imaging 
(Tumor Assessment)
X
(every 8 weeks)

Performed locally according to RECIST 1.1, by the same method used at baseline, 
every 8 weeks (±3 days) following randomization until radiographic disease 
progression, death, or study completion, whichever occurs first.

Performed as scheduled, even if study treatment is delayed or omitted.

If patient has known metastases to chest, chest CT is also to be conducted on the same 
schedule.  If no known chest metastases at screening, then chest CT should be repeated 
every 24 weeks (±3 days). It is recommended that CT imaging of the abdomen and 
pelvis be performed with IV contrast, whenever possible.

If IV contrast is not feasible/advisable secondary to hypersensitivity or other conditions, 
then gadolinium-enhanced MRI is preferred.
Hematology
X
X
X
X
X
Performed by central laboratory 3 days prior to each visit (more frequent assessments may 
be performed if clinically indicated).  Local labs may be used for eligibility and treatment 
decisions, but a duplicate sample must be submitted to the central laboratory.
Clinical chemistry
X
X
X
X
X
Performed by central laboratory.  NOTE:  Fasting labs must be drawn for patients in Arm B 
in order to appropriately assess glucose.  Samples may be obtained 3 days prior to each 
visit (more frequent assessments may be performed if clinically indicated).  Local labs may 
be used for eligibility and treatment decisions, but a duplicate sample must be submitted to 
the central laboratory.
Coagulation
X
X
X
3 days prior to Day 1 of each cycle, PTT or INR performed locally only for those patients 
receiving oral coumarin-derivative anticoagulants.
CA 19-9
X
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle.
HbA1c
X
To be performed 3 days prior to Cycle 3 Day 1 and every other cycle thereafter (C3D1, 
C5D1, C7D1, etc).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 19
LY2835219
28-Day Cycle
28-Day Cycles
28-Day Cycles
Cycle 1
Cycle 2 
Cycle 3- n
Day within Cycle
1
14
1
14
1
Procedure
Instructions
Additional tissue sample, 
if applicable
X
X
If a participant in this study elects to have a surgical procedure at any time during the study 
that involves removal of tumor, then FFPE tumor from that procedure may also be requested.  
Patients undergoing surgery during the study should have study treatment suspended for 7 
days prior to surgery, as well as 7 days post-operatively.
Urine pregnancy test
X
X
Applies only to women of childbearing potential.
Where required by local law or regulation, performed once every 28 days (±7 days) prior to 
dispensing study treatment.
Administer mBPI-sf and 
EORTC QLQ-C30 
questionnaires
X
X
X
BPI-sf and EORTC QLQ-C30 should be administered prior to administration of study 
treatment and prior to significant interaction with site staff.
ECG
X
(approximately 
Cycle 7)
To be performed and read locally following 6 months (±15 days) of therapy.  Additional 
ECG assessments should be performed as clinically indicated.
Study drug
     Dispense abemaciclib
X
X
X
Abemaciclib is taken orally BID, approximately every 12 hours, on Days 1 through 28 of 
each cycle without regard to food.  
     Dispense LY3023414
X
X
X
LY3023414 is taken orally BID, approximately every 12 hours on Days 1 through 28 of each 
cycle without regard to food.  
Sample collection
Pharmacokinetics
For all sample collection, see Appendix 4.
Pharmacogenetics
Biomarkers
Abbreviations:  AE = adverse event; BID = twice daily; C = Cycle; CA = carbohydrate antigen; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events (NCI 2009); D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 = European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; FFPE = formalin-fixed, paraffin-embedded; HbA1c = hemoglobin A1c; 
INR = international normalized ratio; IV = intravenous; mBPI-sf = modified Brief Pain Inventory short form; MRI = magnetic resonance imaging; PTT = partial prothrombin 
time; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 20
LY2835219
Table JPCJ.2.4.
On-Study-Treatment Schedule of Activities—Abemaciclib Plus Galunisertib (Safety Lead-In)
Notes:  Screening procedures performed within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
28-Day Cycle
28-Day Cycles
28-Day Cycles
Cycle 1
Cycle 2
Cycle 3 - n
Day within Cycle
1
14
1
14
1
Procedure
Instructions
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
Includes weight, temperature, blood pressure, pulse rate, and respiration rate.
Concomitant medication
X
X
X
X
X
AE collection
X
X
X
X
X
CTCAE Version 4.0.
ECOG performance status
X
X
X
X
X
Radiologic imaging 
(Tumor Assessment)
X
(every 8 weeks)

Performed locally according to RECIST 1.1, by the same method used at baseline, 
every 8 weeks (±3 days) following randomization until radiographic disease 
progression, death, or study completion, whichever occurs first.

Performed as scheduled, even if study treatment is delayed or omitted.

If patient has known metastases to chest, chest CT is also to be conducted on the same 
schedule.  If no known chest metastases at screening, then chest CT should be 
repeated every 24 weeks (±3 days). It is recommended that CT imaging of the 
abdomen and pelvis be performed with IV contrast, whenever possible.

If IV contrast is not feasible/advisable secondary to hypersensitivity or other 
conditions, then gadolinium-enhanced MRI is preferred.
Hematology
X
X
X
X
X
Performed by central laboratory 3 days prior to each visit (more frequent assessments may 
be performed if clinically indicated).  Local labs may be used for eligibility and treatment 
decisions, but a duplicate sample must be submitted to the central laboratory.
Clinical chemistry
X
X
X
X
X
Performed by central laboratory 3 days prior to each visit (more frequent assessments may 
be performed if clinically indicated).  Local labs may be used for eligibility and treatment 
decisions, but a duplicate sample must be submitted to the central laboratory.
Coagulation
X
X
X
3 days prior to Day 1 of each cycle, PTT or INR performed locally for only those patients 
receiving oral coumarin-derivative anticoagulants.
CA 19-9
X
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle.
Additional Tissue Sample, 
if applicable
X
X
If a participant in this study elects to have a surgical procedure at any time during the study
that involves removal of tumor, then FFPE tumor from that procedure may also be 
requested.  Patients undergoing surgery during the study should have study treatment 
suspended for 7 days prior to surgery, as well as 7 days post-operatively.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 21
LY2835219
28-Day Cycle
28-Day Cycles
28-Day Cycles
Cycle 1
Cycle 2
Cycle 3 - n
Day within Cycle
1
14
1
14
1
Procedure
Instructions
Urine pregnancy test
X
X
Applies only to women of childbearing potential.
Where required by local law or regulation, performed once every 28 days (±7 days) prior to 
dispensing study treatment.
Administer mBPI-sf, 
EORTC QLQ-C30 
questionnaires
X
X
X
mBPI-sf and EORTC QLQ-C30 should be administered prior to administration of study 
treatment and prior to significant interaction with site staff.
Cardiac Assessments
ECG
X
(approximately 
Cycle 7)
To be performed and read locally following 6 months (±15 days) of therapy.  Additional 
ECG assessments should be performed as clinically indicated.
Echocardiogram
X
≤7 days prior to Cycle 3 Day 1 and subsequently every 6 months (±15 days). To be 
performed and read locally. Additional echocardiogram assessments should be performed 
as clinically indicated (see Appendix 6).
Chest CT-scan with 
contrast or MRI (safety)
X
(approximately 
Cycle 7)
To be performed and read locally after 6 months (±15 days) of therapy and as clinically 
indicated for cardiac monitoring.  NOTE:  At the same time point post baseline, if a MRI or 
CT scan with contrast has been done for tumor assessment, this same scan may be used for 
safety assessment, provided the scan has properly assessed the great vessels and the heart.
Study Drug
    Dispense abemaciclib
X
X
X
Abemaciclib is taken orally BID, approximately every 12 hours, on Days 1 through 28 of 
each cycle without regard to food.
    Dispense galunisertib
X
X
X
Galunisertib is taken orally BID, approximately every 12 hours, on Days 1 through 14 of 
each cycle without regard to food.  Galunisertib is not taken on Days 15 through 28 of each 
cycle.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 22
LY2835219
28-Day Cycle
28-Day Cycles
28-Day Cycles
Cycle 1
Cycle 2
Cycle 3 - n
Day within Cycle
1
14
1
14
1
Sample Collection
Pharmacokinetics
For all sample collection, see Appendix 4.
Pharmacogenetics
Biomarkers
Abbreviations:  AE = adverse event; BID = twice daily; CA = carbohydrate antigen; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events 
(NCI 2009); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 = European Organization for Research and 
Treatment of Cancer Quality of Life.
Questionnaire-Core 30; FFPE = formalin-fixed, paraffin-embedded; INR = international normalized ratio; IV = intravenous; mBPI-sf = modified Brief Pain Inventory short form; 
MRI = magnetic resonance imaging; PTT = partial prothrombin time; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 23
LY2835219
Table JPCJ.2.5.
On-Study-Treatment Schedule of Activities—Standard of Care Capecitabine (Arm D)
Note:  Screening procedures performed within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
Day within Cycle
21-Day Cycles
21-Day Cycles
Cycle 1
Cycle 2- n
1
1
Procedure
Instructions
Physical examination
X
X
Vital signs
X
X
Includes weight, temperature, blood pressure, pulse rate, and respiration rate.
Concomitant medication
X
X
AE collection
X
X
CTCAE Version 4.0.
ECOG performance status
X
X
Radiologic imaging
(Tumor Assessment)
X
(every 8 weeks)

Performed locally according to RECIST 1.1, by the same method used at 
baseline, every 8 weeks (±3 days) following randomization until radiographic 
disease progression, death, or study completion, whichever occurs first.

Performed as scheduled, even if study treatment is delayed or omitted.

If patient has known metastases to chest, chest CT is also to be conducted on 
the same schedule.  If no known chest metastases at screening, then chest CT 
should be repeated every 24 weeks (±3 days). It is recommended that CT 
imaging of the abdomen and pelvis be performed with IV contrast, whenever 
possible.

If IV contrast is not feasible/advisable secondary to hypersensitivity or other 
conditions, then gadolinium-enhanced MRI is preferred.
Hematology
X
X
Performed by central laboratory 3 days prior Day 1 of each cycle (more frequent 
assessments may be performed if clinically indicated).  Local labs may be used for 
eligibility and treatment decisions, but a duplicate sample must be submitted to the 
central laboratory.
Clinical chemistry
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle (more 
frequent assessments may be performed if clinically indicated).  Local labs may be 
used for eligibility and treatment decisions, but a duplicate sample must be 
submitted to the central laboratory.
Coagulation
X
X
3 days prior to Day 1 of each cycle, PTT or INR performed locally for only those 
patients receiving oral coumarin-derivative anticoagulants.
CA 19-9
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 24
LY2835219
Day within Cycle
21-Day Cycles
21-Day Cycles
Cycle 1
Cycle 2- n
1
1
Procedure
Instructions
Additional tissue sample, if 
applicable
X
If a participant in this study elects to have a surgical procedure at any time during 
the study that involves removal of tumor, then FFPE tumor from that procedure 
may also be requested.  Patients undergoing surgery during the study should have 
study treatment suspended for 7 days prior to surgery, as well as 7 days 
post-operatively.
Urine pregnancy test
X
Applies only to women of childbearing potential
Where required by local law or regulation, performed once every 21 days (±7 days) 
prior to dispensing study treatment.
Administer mBPI-sf and EORTC 
QLQ-C30 questionnaires
X
X
mBPI-sf and EORTC QLQ-C30 should be administered prior to administration of 
study treatment and prior to significant interaction with site staff.
ECG
X
(approximately 
Cycle 9)
To be performed and read locally following 6 months (±15 days) of therapy.  
Additional ECG assessments should be performed as clinically indicated.
Study drug
    Dispense capecitabine
X
X
Capecitabine is taken orally BID, approximately every 12 hours, on Days 1 through 
14 of each cycle. Patients should take capecitabine with water within 30 minutes 
after a meal.  Capecitabine is not taken on Days 15 through 21 of each cycle.
Sample collection
For all sample collection, see Appendix 4.
Pharmacokinetics
Pharmacogenetics
Biomarkers
Abbreviations:  AE = adverse event; BID = twice daily; CA = carbohydrate antigen; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events (NCI 2009); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 = European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; FFPE = formalin-fixed, paraffin-embedded; INR = international 
normalized ratio; IV = intravenous; mBPI-sf = modified Brief Pain Inventory short form; MRI = magnetic resonance imaging; PTT = partial prothrombin 
time; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 25
LY2835219
Table JPCJ.2.6.
On-Study-Treatment Schedule of Activities—Standard of Care Gemcitabine (Arm D)
Note:  Screening procedures performed within 72 hours prior to Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
Day within Cycle
28-Day
Cycle
28-Day 
Cycles
Cycle 1
Cycle 2-n
1
8
15
22
1
8
15
Procedure
Instructions
Physical examination
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Includes weight, temperature, blood pressure, pulse rate, and respiration rate.
NOTE:  Weight is required only on Day 1 of each cycle.
Concomitant medication
X
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
X
CTCAE Version 4.0.
ECOG performance status
X
X
Radiologic imaging 
(Tumor Assessment)
X

Perform according to RECIST 1.1, by the same method used at baseline, 
performed locally, every 8 weeks (±3 days; approximately Cycle 3, Day 1 and 
every other cycle thereafter) until radiographic disease progression, death, or study 
completion, whichever occurs first.

Performed as scheduled, even if study treatment is delayed or omitted.

If patient has known metastases to chest, chest CT is also to be conducted on the 
same schedule.  If no known chest metastases at screening, then chest CT should 
be repeated every 24 weeks (±3 days). It is recommended that CT imaging of the 
abdomen and pelvis be performed with IV contrast, whenever possible.

If IV contrast is not feasible/advisable secondary to hypersensitivity or other 
conditions, then gadolinium-enhanced MRI is preferred.
Hematology
X
X
X
X
X
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle. Local labs may 
be used for eligibility and treatment decisions prior to Day 1 of each cycle, but a 
duplicate sample must be submitted to the central laboratory.  Local labs to be done per 
institutional guidelines prior to infusions on subsequent days of each cycle (central labs 
not required for each subsequent infusion within a cycle).
Clinical chemistry
X
X
X
X
X
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle. Local labs may 
be used for eligibility and treatment decisions prior to Day 1 of each cycle, but a 
duplicate sample must be submitted to the central laboratory.  Local labs to be done per 
institutional guidelines prior to infusions on subsequent days of each cycle (central labs 
not required for each subsequent infusion within a cycle).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 26
LY2835219
Day within Cycle
28-Day
Cycle
28-Day 
Cycles
Cycle 1
Cycle 2-n
1
8
15
22
1
8
15
Procedure
Instructions
CA 19-9
X
X
Performed by central laboratory 3 days prior to Day 1 of each cycle
Additional tissue sample, if 
applicable
X
If a participant in this study elects to have a surgical procedure at any time during the 
study that involves removal of tumor, then FFPE tumor from that procedure may also 
be requested.  Patients undergoing surgery during the study should have study 
treatment suspended for 7 days prior to surgery, as well as 7 days post-operatively.
Urine pregnancy test
X
Applies only to women of childbearing potential
Where required by local law or regulation, performed once every 28 days (±7 days) 
prior to dispensing study treatment.
Administer mBPI-sf and EORTC 
QLQ-C30 questionnaires
X
X
mBPI-sf and EORTC QLQ-C30 should be administered prior to administration of 
study treatment and prior to significant interaction with site staff.
ECG
X
To be performed and read locally following 6 months (±15 days) of therapy 
(approximately Cycle 7).  Additional ECG assessments should be performed as 
clinically indicated.
Study drug
    Administer gemcitabine
X
X
X
X
X
X
X
Gemcitabine will be administered intravenously over approximately 30 minutes (and at 
a maximum of approximately 60 minutes).  As a general rule of gemcitabine treatment, 
it should be administered every 7 (±3) days.
Sample collection
For all sample collection, see Appendix 4.
Pharmacokinetics
Pharmacogenetics
Biomarkers
Abbreviations:  AE = adverse event; BID twice daily; CA = carbohydrate antigen; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events (NCI 2009); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EORTC QLQ-C30 = European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; FFPE = formalin-fixed, paraffin-embedded; INR = international 
normalized ratio; IV = intravenous; mBPI-sf = modified Brief Pain Inventory short form; MRI = magnetic resonance imaging; PTT = partial prothrombin 
time; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 27
LY2835219
Table JPCJ.2.7.
Post-Treatment Follow-Up Schedule of Activities
Visit
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
801
802-8XX
Procedure
Instructions
Physical examination
X
Vital signs
X
Includes weight, temperature, blood 
pressure, pulse rate, and respiration rate.
Concomitant medication
X
AE collection
X
X
CTCAE Version 4.0. During the 
Long-Term Follow-up, only AEs that 
are related to study treatment or protocol 
procedures will be collected.  The 
frequency of evaluation is based upon 
the judgment of the investigator.
ECOG performance status
X
Radiologic imaging
X
X
For patients that discontinued study 
treatment prior to disease progression, 
perform every 8 weeks (± 3 days)
according to RECIST 1.1, by the same 
method used at baseline and throughout 
the study, until:

the patient has objective disease 
progression, or

the study’s primary analysis of PFS.
After the patient has objective disease 
progression, radiologic tests are no 
longer required, and the patient will have 
follow up approximately every 60 days
(7 days) until death or study 
completion.
Collection of survival information
X
X
Following Short-term follow-up, 
perform every 60 days (7 days) until 
death or study completion.  If an in-
person visit is not possible, confirm 
survival by contacting the patient 
directly via phone.
Collection of 
post-study-treatment anticancer 
therapy information
X
X
Following Short-term follow-up, 
perform every 60 days (7 days) until 
death or study completion.
Hematology
X
Performed by central laboratory.
Clinical chemistry
X
Performed by central laboratory.
Coagulation
X
PTT or INR to be performed locally for 
only those patients receiving 
capecitabine during the study treatment 
period.
CA 19-9
X
Performed by central laboratory.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 28
LY2835219
Visit
Short-Term 
Follow-Upa
Long-Term 
Follow-Upb
801
802-8XX
Administer mBPI-sf and EORTC 
QLQ-C30 questionnaires
X
ECG
X
Sample collection
Pharmacogenetics
For all sample collection, see 
Appendix 4.
Biomarkers
Abbreviations:  AE = adverse event; CA = carbohydrate antigen; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events (NCI 2009); ECOG = Eastern Cooperative Oncology Group (Oken et 
al. 1982); EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30; INR = international normalized ratio; mBPI-sf = modified Brief Pain Inventory short 
form; PFS = progression-free survival MRI = magnetic resonance imaging; PTT = partial prothrombin time; 
RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).
a
Short-term follow-up procedures are to be performed approximately 30 days (±7 days) after the patient and the 
investigator agree that the patient will no longer continue study treatment. No follow-up procedures will be 
performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and 
consent.
b Long-term follow-up begins the day after short-term follow-up is completed and continues until the patient’s 
death or study completion.  During long-term follow-up, patients will have a follow-up visit every 60 days 
(±7 days).
Table JPCJ.2.8.
Continued Access Schedule of Activities
Study 
Treatment
Follow-Upa
Visit
501-5XX
901
Procedureb
Instructions
AE collection
X
X
CTCAE Version 4.0
Administer/dispense study 
drug
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events.
a
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient will no 
longer continue treatment in the continued access period and lasts approximately 30 days (±7 days). No 
follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.
b
Imaging assessments will be done at the investigator’s discretion based on the standard of care.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 29
LY2835219
3.
Introduction
3.1.
Study Rationale
The most common genetic mutations in pancreatic ductal adenocarcinoma (PDAC) include 
KRAS and CDK2NA, each of which occurs in approximately 90% of cases (Jones et al. 2008; 
Biankin et al. 2012; Chiorean and Coveler 2015).  Mutation of KRAS leads to uncontrolled 
activation of multiple downstream intracellular signaling pathways, contributing to tumor cell 
proliferation.  However, in clinical trials, KRAS inhibitors have been largely unsuccessful, thus 
an emphasis has been placed on downstream pathways (Iriana et al. 2016).
Abemaciclib, a cyclin-dependent kinase (CDK) 4 and CDK6 inhibitor, has shown single-agent 
antiproliferative activity in KRAS mutant pancreatic cancer cell lines (Eli Lilly and Company 
[Lilly] data on file) and has an acceptable safety and tolerability profile in clinical studies.  In 
addition, in preclinical models of pancreatic cancer a synergistic effect of CDK4 and CDK6 
inhibitors in combination with phosphatidylinositol 3-kinase (PI3K)/mammalian target of 
rapamycin (mTOR) or transforming growth factor beta receptor type I (TGF-RI) inhibitors has 
been demonstrated (Liu and Korc 2012; Franco et al. 2014).  Given the unmet medical need for 
second- and third-line treatment options, this study aims to explore the safety and efficacy of 
abemaciclib monotherapy, as well as abemaciclib in combination with other agents (including a 
PI3K/mTOR dual inhibitor), versus choice of standard of care (gemcitabine or capecitabine) in 
patients with previously treated metastatic PDAC.
3.2.
Background
3.2.1. Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma is considered one of the most lethal solid tumors, likely to 
become the second-leading cause of cancer deaths in the United States by 2020.  Although the 
survival for most cancers has shown a steady increase, the estimated 5-year survival rate for 
metastatic PDAC is only 2.4% (Weinberg et al. 2015).  Worldwide, the incidence of pancreatic 
cancer ranges from 1 to 10 cases per 100,000, with adenocarcinoma accounting for 85% of these 
cases (Ryan et al. 2014).  The poor prognosis is attributable to a lack of clinical symptoms and a 
delay in diagnosis until the cancer has reached an advanced stage.  In addition, PDAC is 
unusually resistant to both cytotoxic and molecularly targeted anticancer agents (Ryan et al 
2014; Schober et al. 2015).
Currently, preferred first-line therapy options for patients with metastatic PDAC include the 
combination of 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), 
gemcitabine plus nab-paclitaxel, or single-agent gemcitabine.  In select patients with good 
performance status, second-line therapy for patients previously treated with gemcitabine-based 
therapy includes fluoropyrimidine-based therapy and clinical trial participation; for those patients 
previously treated with fluoropyrimidine-based therapy, the recommended second-line options
are gemcitabine-based therapy, the combination of 5-FU, leucovorin, and liposomal irinotecan (if 
no prior irinotecan), or clinical trial participation (National Comprehensive Cancer Network 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 30
LY2835219
[NCCN] Guidelines Version 1.2017).  Additional second-line options include gemcitabine or 
fluorouracil monotherapies if patients have either an Eastern Cooperative Oncology Group 
(ECOG) performance status (PS) of 2 or a comorbidity profile that precludes more aggressive 
regimens (Sohal et al. 2016). In the third-line setting, no standard of care exists; 
recommendations are to provide palliative and best supportive care or enroll patients in a clinical 
trial.
Recently, a Phase 3 study in patients previously treated with gemcitabine-based therapy has 
shown that nanoliposomal irinotecan (Onivyde™[Merrimack Pharmaceuticals, Cambridge, MA, 
USA]) in combination with 5-FU and leucovorin compared to 5-FU and leucovorin alone
resulted in improvement in progression-free survival (PFS) of 3.1 months versus 1.5 months and
in overall survival (OS) of 6.1 months compared to 4.2 months (Wang-Gillam et al. 2016). In a 
retrospective review of patients treated in the second-line setting with gemcitabine monotherapy, 
PFS was 2.0 months and OS was 5.7 months (da Rocha Lino et al. 2015).  A Phase 2 study of 
second-line ruxolitinib and capecitabine versus capecitabine alone in patients previously treated 
with a gemcitabine-based therapy resulted in a PFS rate of 13% at 3 months and median OS of 
4.3 months for patients receiving capecitabine monotherapy (Hurwitz et al. 2015).
Despite advances in both first- and second-line therapies for PDAC, OS remains poor, and 
treatment of PDAC remains an unmet medical need.  Current second- and third-line treatments
for metastatic disease have limited efficacy and novel therapies are urgently needed.  Given these 
data, the current study will use gemcitabine alone or capecitabine alone as the standard-of-care 
treatment for the control arm.
3.2.2. Cyclin-Dependent Kinases 4 and 6 and Role in Pancreatic 
Ductal Adenocarcinoma
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
proper regulation of cell proliferation (Sherr 1996; Ortega et al. 2002).  Cyclin-dependent 
kinases 4 and 6 (CDK4 and CDK6) participate in a complex with the D-type cyclins to initiate 
progression through the G1 restriction point.  The CDK4 and CDK6 – Cyclin D1 complex 
regulates the G1 restriction point through phosphorylation and inactivation of the retinoblastoma 
(Rb) tumor suppressor protein, thereby promoting S phase entry.  Alterations in this pathway 
occur frequently in human cancers, including PDAC, and involve 1) loss of functional CDK 
inhibitors, such as p16INK4A, through deletion or epigenetic silencing, 2) activating mutations 
and/or overexpression of CDK4 and CDK6 or the D-type cyclins, and 3) loss of functional Rb 
through mutation or deletion.  Except for tumors with functional loss of Rb, which functions 
downstream of the CDK4 and CDK6 – Cyclin D1 complex, most 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 is to prevent cell cycle progression 
through the G1 restriction point, thus arresting tumor growth.
A key regulator of cell cycle progression in the CDK4 and CDK6/Cyclin D/Rb pathway is the 
CDK inhibitor, p16INK4A.  The catalytic activity leading to reduced phosphorylation of Rb, and 
thus G1 cell cycle arrest, is inhibited when p16INK4A binds to CDK4 and 6. In more than 90% of 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 31
LY2835219
PDACs, p16INK4A is inactivated due to a genetic alteration in CDKN2A, which leads to excessive 
activation of Cyclin D-CDK4 and 6 signaling (Biankin et al. 2002; Jones et al 2008; Ryan et al 
2014; Goel and Sun 2015).  In addition, overexpression of Cyclin D1, due to amplification of 
CCND1, occurs in approximately 68% of pancreatic cancers and is associated with a poor 
prognosis (Biankin et al. 2002).  Several preclinical reports have indicated that cell lines with 
loss or mutations of CDKN2A or loss of p16 protein expression are particularly sensitive to 
CDK4 and CDK6 inhibitors (Wiedemeyer et al. 2010; Konecny et al. 2011).
Abemaciclib (LY2835219) is a selective and potent small molecule inhibitor of CDK4 and 
CDK6. Abemaciclib prevents Rb phosphorylation, blocking progression from G1 into S phase 
of the cell cycle, leading to suppression of tumor growth in preclinical models following 
short-duration target inhibition.  Abemaciclib has broad antitumor activity in preclinical 
pharmacology models, acceptable physical and pharmacokinetic (PK) properties, and an 
acceptable toxicity profile in nonclinical species.  In vitro, abemaciclib has demonstrated
antiproliferative activity in some KRAS mutant pancreatic cancer cell lines (Lilly data on file).  
In addition, single-agent abemaciclib has demonstrated an acceptable toxicity profile and 
evidence of clinical activity in breast and non-small cell lung cancers (Dickler et al. 2016; 
Patnaik et al. 2016).
Given the relevance of the CDK4 and CDK6 pathway in PDAC, the activity of abemaciclib in 
KRAS mutant cancer cell lines, the acceptable toxicity profile of abemaciclib in clinical studies, 
and the unmet medical need, this study aims to explore the safety and efficacy of abemaciclib in 
patients with PDAC.
3.2.3. Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of 
Rapamycin (mTOR) Pathway and Role in Pancreatic Ductal 
Adenocarcinoma
The expression of Cyclin D1 is induced by mitogenic growth factors, acting through various 
upstream signaling pathways. These signaling pathways, including mitogen-activated protein 
kinase and PI3K, converge downstream at the Cyclin D1-CDK4 and CDK6 complex, leading to 
its activation. Frequent activating aberrations of PI3K/mTOR signaling have been reported for 
several cancers (Opitz et al. 2008; Courtney et al. 2010; Miller et al. 2011; Varghese et al. 2011). 
PI3K and mTOR signaling is stimulated by various growth factors and their receptors (including 
insulin) and regulates cell metabolism, growth, survival, proliferation, and motility. A potent 
impact of CDK4 and CDK6 inhibition in PDAC models has been observed; however, in the 
majority of models analyzed, acquired/intrinsic resistance has resulted in bypassing of this 
inhibition.  As it is widely recognized that combination targeted therapies may be required for 
successful treatment of pancreatic cancer, a series of targeted agents were screened in 
conjunction with a CDK4 and CDK6 inhibitor in cell viability assays.  Based upon this 
screening, PI3K/mTOR inhibitors demonstrated cooperative effects in combination with a CDK4 
and CDK6 inhibitor in a pancreatic cancer tumor model (Franco et al. 2014).  Synergistic activity 
of CDK4 and CDK6 and PI3K/mTOR blockade has been observed in other preclinical tumor 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 32
LY2835219
models (Gopalan et al. 2013; Ku et al. 2016), and clinical trials are ongoing exploring this 
strategy.
This study also aims to explore the safety and efficacy of LY3023414, an orally available, potent 
and selective inhibitor of the class I PI3K isoforms, mTOR, and deoxyribonucleic acid (DNA)-
dependent protein kinase (DNA-PK), in combination with abemaciclib in patients with PDAC.  
LY3023414 has demonstrated an acceptable toxicity profile, and though limited efficacy data are 
available to date, preliminary evidence of single-agent activity was observed in the Phase 1 
Study I6A-MC-CBBA (CBBA) in patients with solid tumors (Lilly data on file)
3.2.4. Transforming Growth Factor-Beta and Role in Pancreatic 
Ductal Adenocarcinoma
Transforming growth factor-beta (TGF-) has been shown to be a tumor promoter in advanced, 
metastatic cancer (de Caestecker et al. 2000; Massagué et al. 2000; Wakefield and Roberts 2002; 
Derynck and Zhang 2003).  In pancreatic cancer, TGF-has been involved in tumor progression 
(Miyazono 2000), by activating matrix metalloproteinase-2 and the urokinase plasminogen 
pathway (Ellenrieder et al 2001).  The TGF-pathway is one of 12 core signaling pathways in 
pancreatic cancer, and mutations in the TGF-receptors or the downstream transcription factors 
(SMAD) occur in 90% to 100% of tumors (Jones et al. 2008).  In preclinical models of 
pancreatic cancer, TGF-signaling induces Rb phosphorylation, and hence inactivation, leading 
to cellular proliferation (Biankin et al. 2002; Ouyang et al. 2014). Several mechanisms have 
been proposed to explain the tumor-promoting activity of TGF-β, such as increased tumor 
neovascularization, immunosuppression leading to the escape of tumor immune surveillance, and 
increased migration and invasion resulting in metastasis (Akhurst and Derynck 2001; Derynck et 
al. 2001; Siegel and Massagué 2003).
Hence, recent studies have recognized that TGF-plays 
an important role in the progression of pancreatic cancer (Truty and Urrutia 2007).  These 
combined effects on the tumor microenvironment by TGF-β promote tumor progression and 
therefore, a TGFβ-RI kinase inhibitor is expected to cause arrest of tumor growth and metastasis 
in patients with PDAC.
Galunisertib (LY2157299) is a small molecule designed to selectively inhibit the 
serine/threonine kinase of TGF-RI.  Thus, the antitumor effect of galunisertib is expected to 
result in an increased tumor immune surveillance, reduced metastatic spread, and decreased 
tumor-associated neoangiogenesis.  In a recent first-in-human dose study, Study H9H-MC-
JBAH, single-agent administration of galunisertib was associated with partial tumor responses in 
patients with relapsed glioblastoma multiforme.  In addition, galunisertib has shown a favorable 
toxicity profile and preliminary activity in pancreatic cancer in the clinic.  In a randomized, 
double-blind, Phase 2 study (Study H9H-MC-JBAJ) in patients with PDAC comparing
gemcitabine plus galunisertib versus gemcitabine plus placebo, higher PFS and OS were 
observed in the gemcitabine plus galunisertib arm (3.7 vs 2.8 months and 9.1 vs 7.6 months, 
respectively).  The subgroup of patients with baseline TGF1 levels ≤4224 pg/mL had a median 
OS of 10.9 versus 7.2 months (hazard ratio [HR] = 0.68), respectively, and decreases in TGF-1 
occurred with treatment, correlating with improved OS (Melisi et al. 2016).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 33
LY2835219
In PDAC, an overexpression of epithelial-mesenchymal transition triggering factors, including 
TGF-, has been observed and may contribute to the high metastatic potential.  In pancreatic 
cancer cells, a CDK4 and CDK6 inhibitor was found to exert growth-inhibitory effects, although 
a TGF-RI inhibitor alone was unable to suppress colony growth in 3-dimensional culture.  
However, when the TGF-βRI inhibitor was combined with a CDK4 and CDK6 inhibitor, optimal 
growth inhibition was achieved (Liu and Korc 2012).  These preclinical data provide a basis for 
exploring the combination of abemaciclib and galunisertib in the current study, although, with 
amendment (c) the assessment of this combination is being discontinued (see Section 5.4.3).
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, galunisertib, and LY3023414
are to be found in their respective Investigator’s Brochure (IB).
More detailed information about the known and expected benefits and risks of capecitabine and 
gemcitabine may be found in their respective product labels.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 34
LY2835219
4.
Objectives and Endpoints
Table JPCJ.4.1 shows the objectives and endpoints of Stage 1.
Table JPCJ.4.2 shows the objectives and endpoints of Stage 2.
Table JPCJ.4.1.
Stage 1 Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate disease control rate of the abemaciclib 
treatment arms versus the standard-of-care arm 
(gemcitabine or capecitabine)

Disease control rate is the percentage of patients 
with a best overall response of stable disease, 
complete response, or partial response according to 
RECIST 1.1.
Secondary

To evaluate objective response rate of the 
abemaciclib treatment arms versus the 
standard-of-care arm

Objective response rate is the percentage of patients 
with a best overall response of complete response or 
partial response according to RECIST 1.1.

Evaluate safety and tolerability of the abemaciclib 
treatment arms
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs and SAEs

Clinical laboratory tests and vital signs

PK of abemaciclib and its metabolites as well as 
LY3023414

Exposure of abemaciclib and LY3023414
Tertiary

Assess the relationship between biomarkers and 
clinical outcome

Biomarker research may be assessed from tumor, 
whole blood, and plasma samples, unless precluded 
by local regulations.
Abbreviations:  PK = pharmacokinetics; RECIST = Response Criteria in Solid Tumors Version 1.1; SAE = serious 
adverse event; TEAE = treatment-emergent adverse event.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 35
LY2835219
Table JPCJ.4.2.
Objectives and Endpoints Stage 2
Objectives
Endpoints
Primary

To evaluate progression-free survival of the 
abemaciclib treatment arms versus the 
standard-of-care arm (gemcitabine or capecitabine)

Progression-free survival is measured from the date 
of randomization to the date of objective 
progression or the date of death due to any cause, 
whichever is earlier.
Secondary

To evaluate disease control rate of the abemaciclib 
treatment arms versus the standard-of-care arm

Disease control rate is the percentage of patients 
with a best overall response of stable disease, 
complete response, or partial response according to 
RECIST 1.1.
To evaluate clinical benefit rate of the abemaciclib 
treatment arms versus the standard-of-care arm
Clinical benefit rate is the percentage of patients 
with a best overall response of complete response, 
or partial response, or  stable disease for ≥6 months
according to RECIST 1.1.

To evaluate objective response rate of the 
abemaciclib treatment arms versus the 
standard-of-care arm

Objective response rate is the percentage of patients 
with a best overall response of complete response or 
partial response according to RECIST 1.1

To evaluate duration of response of the abemaciclib 
treatment arms versus the standard-of-care arm

Duration of response is measured from the date of 
first evidence of complete response or partial 
response to the date of objective progression or the 
date of death due to any cause, whichever is earlier.

To evaluate overall survival of the abemaciclib 
treatment arms versus the standard-of-care arm

Overall survival is measured from the date of 
randomization to the date of death from any cause.

Evaluate the kinetics of carbohydrate antigen (CA)
19-9

Change from baseline in CA 19-9

Evaluate safety and tolerability
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs and SAEs

Clinical laboratory tests and vital signs

To evaluate pain and symptom burden of the 
abemaciclib treatment arms by best response group 
(partial response, stable disease, or progressive 
disease) versus the standard-of-care arm

modified Brief Pain Inventory short form (mBPI-sf) 
and the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-
Core 30 (EORTC QLQ-C30)

PK of abemaciclib and its metabolites as well as 
LY3023414

Exposure of abemaciclib and LY3023414

Exposure-response for abemaciclib and LY3023414

Drug exposure and efficacy outcomes such as 
objective response rate or progression-free survival 
and safety outcomes such as neutropenia and 
diarrhea
Tertiary

Assess the relationship between biomarkers and 
clinical outcome

Biomarker research may be assessed from tumor, 
whole blood, and plasma samples, unless precluded 
by local regulations.
Abbreviations:  CA = carbohydrate antigen; PK = pharmacokinetics; RECIST = Response Criteria in Solid Tumors 
Version 1.1; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 36
LY2835219
5.
Study Design
5.1.
Overall Design
Study I3Y-MC-JPCJ (JPCJ) is a multicenter, randomized, open-label, Phase 2 study in patients 
with metastatic PDAC who have been previously treated with at least one, but no more than 2 
prior therapies.  At least one of the prior therapies must have been either gemcitabine-based or 
fluoropyrimidine-based therapy.  This study will evaluate the safety and efficacy of abemaciclib 
as a monotherapy or in combination with other agents versus choice of standard of care 
(gemcitabine or capecitabine) by implementing a 2-stage design.
No safety data had been generated for the combination of abemaciclib and galunisertib.  
Therefore, a Safety Lead-in Period was included in the original protocol (see Section 7.2).
The combination of abemaciclib and LY3023414 was assessed in a Phase 1b study (I3Y-MC-
JPBJ) in patients with non-small cell lung cancer. Of 5 patients treated with abemaciclib 150 mg 
twice daily (BID) plus LY3023414 200 mg BID, 2 patients experienced dose-limiting toxicities 
(DLTs).  However, of 3 patients treated with 150 mg abemaciclib BID plus LY3023414 150 mg 
BID,  none experienced a DLT. Therefore, the maximum tolerated dose (MTD) of LY3023414
in combination with abemaciclib was determined to be 150 mg BID.
With amendment (c), Stage 1 of the study will randomize patients 1:1:1 into each of the 
following arms (25 patients per arm):

Arm A: Abemaciclib (LY2835219),

Arm B: Abemaciclib plus LY3023414 (PI3K/mTOR Dual Inhibitor), or

Arm D: Choice of Standard of Care (gemcitabine or capecitabine).
For Stage 1, the analyses of safety and efficacy will be evaluated approximately 16 weeks after 
the last planned Stage 1 patient enters treatment.  All data accumulated during this period 
(beyond 16 weeks for some patients, if available), will be included in the analysis.  Initial 
evaluations will compare investigational arms (Arms A and B) with the standard-of-care arm 
(Arm D), and will include assessment of disease control rate (DCR; complete response 
[CR]+partial response [PR]+stable disease [SD]).  Following the completion of the 
Stage 1assessment, any treatment arm(s) with a DCR difference ≥ 0 as compared to the standard-
of-care arm (Arm D) will be selected to advance to Stage 2. Enrollment in the nonadvancing 
arm(s) will be discontinued.  While the analysis for Stage 1 is ongoing, enrollment for all arms 
may continue until the assessment is complete.  Any patients enrolled during the time that Stage 
1 analysis is ongoing will be included in planned enrollment for Stage 2.
For the treatment arms that advance to Stage 2, an additional 50 patients will be randomized 
equally to each arm for further evaluation of safety and efficacy.  The primary analysis of 
Stage 2 will be conducted when at least 120 total PFS events have occurred for the combination 
of each individual abemaciclib-containing arm and the standard-of-care arm, or all planned 
patients have been enrolled in Stage 2, whichever comes later.  Data from both Stages 1 and 2 
will be pooled for this analysis.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 37
LY2835219
Figure JPCJ.5.1 illustrates the study design.
Abbreviations:  ECOG = Eastern Cooperative Oncology Group; DCRdiff = disease 
control rate difference; N = number of patients; R = randomize; RECIST 
v1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; PS = performance 
status.
a    At the time of amendment (c), Lilly determined no additional patients would be enrolled to the safety    
lead-in.
Figure JPCJ.5.1.
Illustration of study design.
5.2.
Number of Patients
Prior to initiating Stage 1 of the study, a safety lead-in period with abemaciclib plus galunisertib
was to be conducted with up to 12 patients (see Section 7.2); however, as discussed in more 
detail in Section 5.4.3, Lilly has decided not to continue the assessment of abemaciclib in 
combination with galunisertib.
For Stage 1, a total of approximately 75 patients (25 patients per arm) will be randomized in a 
1:1:1 ratio to 3 treatment arms.  Randomization will be stratified by number of prior systemic 
therapies (1 versus 2).  For Stage 2, the treatment arms that meet the decision criteria to advance 
to Stage 2 (DCR difference ≥0 in abemaciclib containing arms vs. the standard-of-care arm),
50 additional patients will be randomized to each experimental arm, as well as to the 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 38
LY2835219
standard-of-care arm.  The arms that advance to Stage 2 will enroll a total of 75 patients per arm 
(including 25 patients from Stage 1).
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.
5.4.
Scientific Rationale for Study Design
Study JPCJ is a Phase 2 adaptive design study that will be conducted in 2 stages.  Stage 1 will
permit decision-making in order to determine if either abemaciclib monotherapy or abemaciclib 
in combination with other agents provides a level of disease control that is at least comparable to 
the standard of care.  Any arms demonstrating evidence of disease control comparable to or 
better than the standard of care would merit exploration in a larger population in order to assess 
PFS, and thus these arms would advance to Stage 2 in the current study.
Although treatment guidelines recommend the use of combination therapies in the second-line 
setting for metastatic PDAC, there is no consensus on the standard of care in patients who have 
failed first-line therapy.  Further, no standard of care exists in the third-line setting.  Based upon 
historical data, the recommended second-line combination therapies do not provide significant 
survival benefit over gemcitabine or capecitabine monotherapies.  The median OS for patients in 
a German single-center cohort receiving second-line treatments including XELOX, FOLFOX, 
gemcitabine (± erlotinib), or FOLFIRI was 5.4 months (Maier-Stocker et al. 2014), which is 
comparable to the OS observed in prior studies (Section 3.2.1) with gemcitabine (5.7 months) 
and capecitabine (4.3 months).  Another single-institution retrospective study demonstrated a 
median OS of approximately 5 months in patients treated with gemcitabine/Nab-paclitaxel in the 
second-line setting (Bertocchi et al. 2015).  Given the lack of consensus on standard of care in 
the disease setting being studied, and the similarity in OS between combination therapies and 
monotherapies, gemcitabine and capecitabine monotherapies were chosen for the standard-of-
care arm.
5.4.1. Rationale for Amendment (a)
The rationale for amendment (a) was based primarily on feedback received from the US Food 
and Drug Administration.  Changes for amendment (a) included the following:

Incorporated a Day 14 visit during Cycles 1 and 2 for all investigational arms

Removed pharmacokinetic, pharmacogenetic, and biomarker sample collection from 
tables in Section 2, reader directed to Appendix 4 for sample timing, Appendix 4 updated

Added tertiary objective for Stage 1 for biomarkers

Included statement regarding status of Study JPBJ safety assessment of abemaciclib in 
combination with LY302414

Incorporated language to clarify disease control rate analysis

Added information for the galunisertib dose justification

Updated inclusion criterion [7] to require specific creatinine clearance (CrCl) in addition 
to serum creatinine, added Appendix 9 for calculation and updated Appendix 3 for 
clarification

I3Y-MC-JPCJ(c) Clinical Protocol
Page 39
LY2835219

Modified exclusion criterion [18] to exclude only “symptomatic” CNS metastasis

Clarified rescreening language

Clarified text regarding definition of “not tolerated” for safety lead-in and revised DLT 
definitions

Clarified text on dosage modifications and included Appendix 10 to provide guidance for 
specific toxicities for each arm

Information added for first periodic safety review.
5.4.2. Rationale for Amendment (b)
The rationale for amendment (b) was based on the results of Study JPBJ, a food effect study for 
LY3023414 (I6A-EW-CBBB [Study CBBB]), and to clarify additional sections of the protocol.  
Major changes for amendment (b) included the following:

Reduced the starting dose of LY3023414 to be administered in combination with 
abemaciclib to reflect the MTD (150 mg BID) as determined in Study JPBJ

Removed the restriction for taking LY3023414 at least 1 hour before or after a meal.  
Study CBBB determined that LY3023414 can be administered irrespective of food 
intake, as the difference in exposure observed with and without food was not considered 
to be clinically relevant given the inter-subject variability.  Further, toxicity was 
determined to not be a concern based on dietary state.

Added flexibility to the timing of the C3D1 echocardiogram for patients receiving 
galunisertib in order to accommodate this procedure which may be performed by a 
facility at a location other than the investigative site

Updated most common treatment-related AEs for abemaciclib and LY3023414 in 
Table JPCJ.7.2 to align with 2016 IB updates.
5.4.3. Rationale for Amendment (c)
Study JPCJ was amended to discontinue enrollment to the safety lead-in for abemaciclib plus 
galunisertib and remove Arm C (abemaciclib in combination with galunisertib) as well as all 
galunisertib-related baseline procedures and eligibility requirements.
The combination testing strategy for study JPCJ was reassessed considering other priorities with 
Lilly molecules in clinical development, and it was decided not to continue the investigation of 
abemaciclib in combination with galunisertib in this study. This decision was not triggered by 
safety concerns with the combination.
5.5.
Justification for Doses of Investigational Treatments
The dose of abemaciclib monotherapy (200 mg BID) used in this study is the MTD identified in
the Phase 1 Study I3Y-MC-JPBA (JPBA) for patients with advanced cancer (either solid tumor 
or lymphoma). Generally, in Phase 1b combination studies, the dose of abemaciclib selected to 
be administered with other anticancer therapies is 150 mg BID due to overlapping toxicities and 
DLTs occurring at higher doses. In Study JPBA, abemaciclib inhibited CDK4 and CDK6 as 
indicated by inhibition of pRb and topoII alpha, which results in cell cycle inhibition upstream of 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 40
LY2835219
the G1 restriction point at concentrations achieved by doses of 50 mg to 200 mg BID. This 
inhibition was associated with clinical benefit.
The dose of LY3023414 (150 mg BID) used in this study was the MTD identified in
combination with abemaciclib 150 mg BID in the Phase 1b Study JPBJ.
The dose of galunisertib (150 mg BID) used in the safety lead-in period has demonstrated a 
favorable risk/benefit profile across multiple studies, when administered as a single agent or in 
combination with various chemotherapies.  The galunisertib dose was identified based on results 
from preclinical pharmacodynamic biomarkers and non-clinical toxicology models, which 
allowed for a prospective definition of a therapeutic window. Simulations suggested that target-
related inhibition of p-SMAD (a downstream target of TGF-β activation) by more than 50% for 
at least 8 hours, should provide sufficient activity, while minimizing the potential for 
cardiovascular toxicity.  Plasma exposures observed in clinical trials following administration of 
150 mg BID are within this predicted therapeutic window (Gueorguieva et al. 2014).  
Furthermore, clinical trials utilizing 150 mg BID have demonstrated activity in hepatocellular 
and pancreatic cancer patients (Faivre et al. 2014; Melisi et al. 2016), without significant 
toxicity.
The current study will assess the safety and pharmacokinetics (PK) of abemaciclib 150 mg BID 
plus galunisertib 150 mg BID for the 7 patients enrolled in a safety lead-in period at the time of 
amendment (c), but will not assess this combination in the randomized period of the study.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 41
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]
have cytologically or histologically confirmed diagnosis of ductal 
adenocarcinoma of the pancreas.
[2]
have metastatic disease with documented disease progression following 
previous treatment with at least 1, but no more than 2 prior therapies for 
metastatic disease, with at least 1 of the prior therapies having been either 
gemcitabine-based or fluoropyrimidine-based therapy.  Neoadjuvant and/or 
adjuvant therapies for localized resectable or unresectable PDAC each count 
as a line of therapy if multiagent chemotherapy regimens were administered 
(and neoadjuvant regimen was different than adjuvant regimen) and if the 
patient progressed with metastatic disease during treatment or within 6 months 
of completion of (neo)adjuvant therapy.
Note:  Treatment with targeted therapies or immunotherapies for metastatic 
disease are counted toward the number of prior systemic therapies.
[3]
have the presence of measurable disease as defined by Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Eisenhauer et al. 2009).
[4]
have a performance status (PS) of 0 to 1 on the ECOG scale (Oken et al. 
1982).
[5]
is a patient for whom treatment with monotherapy chemotherapy such as 
gemcitabine or capecitabine is a reasonable choice.
[6]
have discontinued all previous treatments for cancer (including cytotoxic 
chemotherapy, molecularly targeted therapy, radiotherapy, immunotherapy, 
and investigational therapy) for at least 14 days prior to receiving the initial 
dose of study treatment, and recovered from the acute effects of therapy 
(treatment-related toxicity resolved to baseline) except for residual alopecia or 
peripheral neuropathy.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 42
LY2835219
[7]
have adequate organ function, as defined below:
System
Laboratory Value
Hematologic
ANC
1.5 × 109/L
Growth factors should not be administered to enable a 
patient to satisfy study inclusion criteria.
Platelets
100 × 109/ L
Hemoglobin
≥8 g/dL
Transfusions to increase the patient’s hemoglobin level to 
5 mmol are permitted; however, study treatment must not 
begin until the day after the transfusion.
Hepatic
Total bilirubin
1.5 × ULN
ALT and AST
2.5 × ULN OR
5 × ULN if the liver has tumor involvement
Patients may have endoscopic or radiologic stenting to treat 
biliary obstructions.  If so, then, bilirubin must return to 
≤1.5 times ULN and AST and ALT to ≤5 times ULN prior 
to enrollment.
Increased bilirubin up to 2.5 times ULN is acceptable if this 
elevation is not associated with other signs of liver toxicity 
or can be explained by mechanical obstruction.  The 
investigator needs to obtain the approval from the Lilly 
clinical research physician prior to including such a patient.
Renal
Serum creatinine 
1.5 × ULN or calculated CrCl ≥50 mL/min by Cockcroft-
Gault formula (Appendix 9).
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; ANC = absolute 
neutrophil count; CrCl = Creatinine Clearance; ULN = upper limit of normal.
[8]
are at least 18 years old at the time of screening or of an age acceptable 
according to local regulations, whichever is older.
[9]
men must be sterile or agree to use an effective method of contraception or a 
highly effective method of contraception during the study and for at least 
6 months following the last dose of study drug.
Refer to Appendix 1 for definitions of effective method of contraception and 
highly effective method of contraception.
[10] women of child-bearing potential must:
a.
have a negative serum pregnancy test within 7 days prior to study 
treatment initiation, and
b. agree to use a highly effective method of contraception during the study 
and for at least 6 months following the last dose of study drug.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 43
LY2835219
Refer to Appendix 1 for the definition of highly effective method of 
contraception.
[11] have given written informed consent prior to any study-specific procedures.
[12] are able to swallow capsules and tablets.
[13] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] have a serious concomitant systemic disorder or preexisting condition (for 
example, active infection including human immunodeficiency virus, history of 
major surgical resection involving the stomach or small bowel, or preexisting 
Crohn’s disease or ulcerative colitis) that, in the opinion of the investigator, 
would compromise the patient’s safety or ability to adhere to the protocol.
[15] have a personal history of any of the following conditions:  syncope of either 
unexplained or cardiovascular etiology, ventricular arrhythmia (including, but 
not limited to, ventricular tachycardia and ventricular fibrillation), or sudden 
cardiac arrest.
Exception:  Patients with controlled atrial fibrillation for ≥30 days prior to 
study treatment initiation are eligible.
[16] Deleted Criterion
[17] have insulin-dependent diabetes mellitus.  Patients with type 2 diabetes 
mellitus are eligible if adequate control of blood glucose level is obtained by 
oral anti-diabetics as documented by hemoglobin A1c (HbA1c) <7%.
[18] have symptomatic central nervous system metastasis.  Screening of 
asymptomatic patients is not required for enrollment.
[19] have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy 
for a minimum of 2 years.
[20] have had major surgery within 7 days prior to initiation of study drug to allow for 
postoperative healing of the surgical wound and site(s).
[21] are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study.  If a patient is currently enrolled in a clinical trial 
involving nonapproved use of a device, then agreement with the investigator 
and Lilly clinical research physician (CRP) is required to establish eligibility.
[22] have received treatment with a drug that has not received regulatory approval 
for any indication within 14 days prior to receiving the initial dose of study 
treatment.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 44
LY2835219
[23] have previously received treatment with any CDK4 and 6 inhibitor or PI3K 
and/or mTOR inhibitor or have a known hypersensitivity to any component of 
the investigational products in this study.
[24] have a known hypersensitivity to investigator’s choice of standard of care 
(gemcitabine or capecitabine) in anticipation that the patient may be 
randomized to Arm D.
[25] are pregnant or breastfeeding
6.3.
Lifestyle Restrictions
Patients should avoid consuming grapefruit juice.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened no more than once (after signing a new informed consent form [ICF] and being 
assigned a new patient number), and only after discussion with and permission from the Lilly 
CRP or designee.
Repeating of laboratory tests during the screening period does not constitute re-screening.  
Screening laboratory tests may not be repeated more than twice in order to meet eligibility 
during the screening period.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 45
LY2835219
7.
Treatments
7.1.
Treatments Administered
Table JPCJ.7.1 shows the treatment regimens.  Study treatment is defined as any of the 
individual study drugs (inclusive of standard of care) and/or the combination study drug.
Table JPCJ.7.1.
Treatment Regimens
Dose and Schedule
Arm
A
Abemaciclib (CDK4 and CDK6 inhibitor) 200 mg BID with or without food continuous dosing for 
28-day cycles
Ba
Abemaciclib 150 mg BID with or without food continuous dosing for 28-day cycles
LY3023414 (PI3K/mTOR dual inhibitor) 150 mg BID with or without food continuous dosing for 
28-day cycles
D
Standard-of-Care Choice of:
     Gemcitabine 1000 mg/m2 over 30 minutes 
     intravenously on the following days of a 28-day cycle.
          •   Cycle 1:  Days 1, 8, 15, and 22
          •   Cycle 2 – n:  Days 1, 8, and 15
                                OR
     Capecitabine 1250 mg/m2 administered orally BID within 30 
     minutes after a meal (morning and evening; equivalent to 2500 
     mg/m2 total daily dose) for 2 weeks followed by a 1-week rest 
     period given as 21-day cycles.
Abbreviations:  BID = twice daily; CDK = cyclin-dependent kinase
a
Oral combination agents are to be taken at approximately the same time.  There is no specific order of 
administration.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the study treatments to the patient, study site 
personnel, and/or the patient’s legal representative

verifying that instructions are followed properly

maintaining accurate records of study drug dispensing and collection

at the end of the study, returning all unused study treatment to Lilly, or its 
designee, unless Lilly and sites have agreed all unused study treatment is to be 
destroyed by the site, as allowed by local law
7.1.1. Packaging and Labelling
All study treatments will be provided by Lilly.  Clinical trial materials will be labeled according 
to the country’s regulatory requirements.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 46
LY2835219
7.2.
Method of Treatment Assignment
Safety Lead-in
Based on the original protocol, prior to the randomized portion of the study (Stage 1 and Stage 2) 
up to 12 patients who satisfied all inclusion criteria and none of the exclusion criteria were to be 
enrolled to a safety lead-in period.  Initially, 6 patients were to be enrolled to receive abemaciclib 
plus galunisertib.  If the combination of abemaciclib 150 mg BID and galunisertib 150 mg BID
was not tolerated (that is, more than one patient experienced a DLT within the first 28-day 
cycle), then the dose of abemaciclib was to be reduced to 100 mg BID and an additional 6 
patients enrolled at this dose.  If the combination was not tolerated (that is, more than one patient 
experienced a DLT within the first 28-day cycle) at the reduced dose of abemaciclib, then 
patients were not to be enrolled to the abemaciclib plus galunisertib arm (Arm C).
For the safety lead-in, any patient who was discontinued from the study before receiving at least 
75% of the planned doses of abemaciclib and galunisertib in Cycle 1 was deemed nonevaluable 
for assessment of that dose level and was replaced, unless that patient experienced a DLT before 
withdrawal. Nonevaluable patients were to be replaced to ensure that no fewer than 6 patients 
received at least 75% of the planned doses of abemaciclib and galunisertib in Cycle 1, unless 
enrollment to that cohort was stopped because more than one patient at that dose level 
experienced a DLT.
At the time of amendment (c), Lilly determined no additional patients would be enrolled to the 
safety lead-in and that Arm C would be removed from the study.  A total of 7 patients had been 
enrolled in the safety lead-in and 2 were still on treatment.  Ongoing patients enrolled to the 
safety lead-in may continue on study treatment if, at the discretion of the treating investigator, 
the patients are benefiting from therapy and not considered at risk from a safety standpoint.
Toxicities were graded according to Common Terminology Criteria for Adverse Events Version 
4.0 (CTCAE v4.0).  If multiple toxicities were observed, the presence of DLTs was to be based 
on the most severe toxicity experienced.  During the Safety Lead-in Period only, DLTs were
defined as any of the following events that occurred during the first cycle of administration of the 
combination of abemaciclib and galunisertib and were considered by the investigator to be 
attributable to either study treatment alone or the combination of the two:

Grade 3 or 4 nonhematologic toxicity (except for nausea, vomiting, diarrhea, or 
electrolyte disturbance)

Grade 3 or 4 nausea or electrolyte disturbance that persisted more than 48 hours despite 
maximal supportive intervention

Grade 3 vomiting or diarrhea that persisted more than 48 hours despite maximal 
supportive intervention

Grade 4 vomiting or diarrhea of any duration

Grade 4 hematologic toxicity that persisted more than 5 days

Grade 3 thrombocytopenia with bleeding

Grade 4 thrombocytopenia of any duration

Grade 3 or 4 neutropenia with fever

I3Y-MC-JPCJ(c) Clinical Protocol
Page 47
LY2835219
As further enrollment to the Safety Lead-in will not occur and Arm C is removed with 
amendment (c), the randomized portion of the study will begin.  Randomization will be stratified 
by number of prior systemic therapies (1 versus 2).
The period between randomization to study treatment and the first dose (Cycle 1, Day 1) should 
not exceed 7 days.
Stage 1
Patients will be randomized 1:1:1 among the investigational arms and the standard-of-care arm, 
to provide a total of 25 patients per arm.  Patients assigned to the standard-of-care arm (Arm D) 
will be administered either gemcitabine or capecitabine, at the discretion of the investigator.  In 
determining which standard-of-care therapy to administer, the investigator should take into 
consideration NCCN Guidelines, which indicate that patients previously treated with 
gemcitabine-based therapy should receive capecitabine and patients previously treated with 
fluoropyrimidine-based therapy should receive gemcitabine.
Stage 2
An additional 50 patients will be randomized to each investigational arm that passes Stage 1 as 
well as in the standard-of-care arm.
The interactive web-response system (IWRS) will be used to assign unique patient identification 
numbers and study treatment to each patient in the Safety Lead-In, Stages 1, and Stage 2.
7.2.1. Selection and Timing of Doses
A cycle is defined as an interval of 28 days for all study treatments except capecitabine (21-day 
cycle).  During all cycles, oral study treatments should be taken with a glass of water at 
approximately the same time each day.  Patients should not chew or crush these study treatments.  
If the patient misses or vomits a dose of oral study treatment, the patient should skip the dose and 
take the next dose as scheduled.  For patients assigned to the safety lead-in or Arm B, 
combination agents are to be taken at approximately the same time, in no specific order of 
administration.
A delay of a cycle due to holiday, weekend, bad weather, or other unforeseen circumstances will 
be permitted for a maximum of 7 days and not counted as a protocol deviation.  A cycle delay 
due to toxicity is permitted up to 14 days (see Section 7.4). In the event only 1 of 2 study 
treatments for patients in the safety lead-in or Arm B is suspended or if each study treatment is 
reintroduced in a sequential manner, Day 1 of the next cycle is considered the date that the first 
of the individual study treatments is dispensed and administered to the patient.
The actual doses of gemcitabine and capecitabine to be administered will be determined by 
calculating the patient’s body surface area at the beginning of each cycle.  If the patient’s weight 
does not fluctuate by more than 10% from the weight used to calculate the prior dose, the dose 
will not need to be recalculated.  A 5% variance in the calculated total dose will be allowed for 
ease of dose administration.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 48
LY2835219
A patient may continue to receive study treatment until he or she meets 1 or more of the 
specified reasons for discontinuation (as described in Section 8).
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
7.4.1. Dosage Modifications for Investigational Agents
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 4.0 will be used to assess AEs.  Treatment may be 
suspended for a maximum of 14 days to allow a patient sufficient time for recovery from study 
treatment-related toxicity.  If a patient does not recover from the toxicity within 14 days from the 
time of last treatment, the patient should be considered for permanent discontinuation from study 
treatment.  In exceptional circumstances, a delay >14 days is permitted upon agreement between 
the investigator and the Lilly CRP.  Patients in the safety lead-in receiving galunisertib must 
receive a minimum of 10 days of dosing in a 28-day cycle.
This section is intended to be a guideline for the investigator and cannot fully replace the 
investigator’s best judgment. The investigator should assess the contribution of each individual 
investigational agent to the AE and differentiate from disease-related signs and symptoms before 
deciding on a dose suspension or reduction.  In assessing to which study treatment to assign a 
toxicity for the purposes of dose adjustments, the investigator may consult Table JPCJ.7.2, which 
includes the most common treatment-related AEs reported in the IB for each investigational 
agent.  This listing of common treatment-related AEs is not exhaustive; investigators should 
consider all preclinical and clinical data provided in the respective IB (or product label in the 
case of Arm D) for each agent when determining whether to adjust a patient’s study treatment.  
Additional dose modification guidance for patients experiencing events that are considered by 
the investigator to be related to at least 1 investigational agent can be found in Appendix 10.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 49
LY2835219
Table JPCJ.7.2.
Common Treatment-Related Adverse Events for Investigational 
Agents
Investigational Agents
Most Common Treatment-Related Adverse Events
Abemaciclib
diarrhea (63.0%), nausea (45.1%), fatigue (40.5%), vomiting (24.9%), 
white blood cell count decreased (24.9%), platelet count decreased 
(23.1%), neutrophil count decreased (22.5%), anemia (19.7%), 
anorexia (17.3%), creatinine increased (11.0%), and weight loss 
(10.4%)
LY3023414
nausea (36.1%), fatigue (34.0%), vomiting (29.7%), decreased appetite 
(23.4%), diarrhea (20.2%), rash (13.8%), and oral mucositis (11.7%)
Galunisertib
nausea (10.6%), fatigue (7.8%), diarrhea (7.2%), vomiting (7.2%), and 
pruritus (5.5%)
Dose reductions for investigational agents should be as shown in Table JPCJ.7.3.  Study 
treatment must be reduced sequentially by one dose level unless an exception is granted in 
consultation with the Lilly CRP.  Mid-cycle dose reductions for abemaciclib may be 
implemented by informing patients to reduce the number of 50-mg capsules taken for each dose 
(with dose reductions appropriately documented in the electronic case report form [eCRF]); 
however, mid-cycle dose reductions of LY3023414 and galunisertib will require patients to 
return to the clinic and the site to call the IWRS Help Desk to dispense new study treatment.  If 1 
study treatment (Safety Lead-in or Arm B) has been 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.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 50
LY2835219
Table JPCJ.7.3.
Dose Reductions for Investigational Agents
Dose Reduction
First
Second
Third
Fourth
Abemaciclib
(monotherapy)
200 mg BID
150 mg BID
100 mg BID 
50 mg BID
discontinue
Abemaciclib 
(combination)
150 mg BID
100 mg BID
50 mg BID
discontinue
LY3023414
150 mg BID
100 mg BID
discontinue
Galunisertib
150 mg BID
80 mg BID
discontinue
Abbreviation:  BID = twice daily.
For patients requiring a dose reduction of investigational agents, any re-escalation to a prior dose 
level is permitted only after consultation with the Lilly CRP.
Hematologic Toxicities
If a patient experiences Grade 4 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of the study treatment must be reduced by 
1 dose level as outlined in Table JPCJ.7.3.
If a patient experiences Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of study treatment may be reduced by 1 dose 
level as outlined in Table JPCJ.7.3 at the discretion of the investigator. If the patient experiences 
a recurrent episode of Grade 3 hematologic toxicity, then dosing must be suspended (until the 
toxicity resolves to at least Grade 2) and the dose of study treatment must be reduced by 1 dose 
level.
If a patient requires administration of blood cell growth factors, the dose of study treatment must 
be suspended for at least 48 hours after the last dose of blood cell growth factors was 
administered and until toxicity resolves to at least Grade 2 then reduced by 1 dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.
Hematologic toxicities must resolve to either baseline or at least Grade 2 prior to reinitiation of 
investigational agents.
Nonhematologic Toxicities
If a patient experiences Grade ≥3 nonhematologic toxicity, then dosing must be suspended (until 
the toxicity resolves to either baseline or at least Grade 1) and the dose of study treatment must 
be reduced by 1 dose level as outlined in Table JPCJ.7.3.  Exceptions are as follows for Grade ≥3 
nonhematologic toxicities possibly related to LY3023414:

Grade 3 fasting hyperglycemia that resolves to ≤Grade 2 within 7 days

Grade 3 mucositis that resolves to Grade ≤2 within 7 days

Grade 3 fatigue that resolves to Grade ≤2 within 5 day

toxicities that can be controlled with adequate treatment, such as nausea, vomiting, skin 
rash, diarrhea, or asymptomatic electrolyte disturbances

I3Y-MC-JPCJ(c) Clinical Protocol
Page 51
LY2835219
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
see below) that does not resolve with maximal supportive measures within 7 days to either 
baseline or at least Grade 1, then dosing may be suspended (until the toxicity resolves to either 
baseline or at least Grade 1) and the dose of study treatment may be reduced by 1 dose level as 
outlined in Table JPCJ.7.3 at the discretion of the investigator.
If a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve with 
maximal supportive measures (see Section 7.7.2) within 24 hours to at least Grade 1, then study 
treatment should be suspended (until the toxicity resolves to at least Grade 1) and the dose of 
study treatment may be reduced by 1 dose level as outlined in Table JPCJ.7.3 at the discretion of 
the investigator. If the same dose level was resumed and diarrhea recurs despite maximal 
supportive measures, the dose of study treatment must be reduced by 1 dose level as outlined in 
Table JPCJ.7.3.
Before the start of each cycle, nonhematologic toxicity (except alopecia and fatigue) must 
resolve to either baseline or at least Grade 1.  Patients receiving galunisertib must receive a 
minimum of 10 days of dosing in a 28-day cycle.  If a patient does not recover from the toxicity 
within 14 days from the time of last treatment, the patient should be considered for permanent 
discontinuation from study treatment.  In exceptional circumstances, a delay >14 days is 
permitted upon agreement between the investigator and the Lilly CRP.
7.4.2. Dosage Modifications for Gemcitabine
The safety profile of gemcitabine as a single agent is well characterized in studies of a variety of 
malignancies (Gemzar® gemcitabine HCl [for injection] prescribing instructions page [WWW]), 
in which patients received gemcitabine 800 mg/m2 to 1250 mg/m2. For these patients, the
hematologic toxicity was mild with only 1% to 4% of patients having Grade 3/4 
thrombocytopenia, 1% to 7% having Grade 3/4 anemia, and 6% to 19% of patients having 
Grade 3/4 neutropenia. The most common (≥5%) Grade 3 /4 nonhematologic toxicities of this 
regimen were nausea/vomiting, increased ALT, increased alkaline phosphatase, and increased
AST. All of these toxicities are monitorable, manageable, and reversible. Therefore, Lilly
recommends to reduce gemcitabine only to manage hematologic toxicities of neutropenia and 
thrombocytopenia or if nonhematologic toxicity arises.
The gemcitabine dose can be adjusted following Table JPCJ.7.4 in the event of a hematologic 
toxicity, as this presents the in-label recommendations for dose reductions for gemcitabine when 
used as monotherapy.
Table JPCJ.7.4.
Gemcitabine Dose Modifications for Hematological Toxicity
ANC Preinfusion
(×109/L)
Platelet Preinfusion
(×109/L)
% Full Dose
≥1.0
and
≥100
100
≥0.5 to <1.0
or
≥50 to <100
75
<0.5
or
<50
Hold
Abbreviation:  ANC = absolute neutrophil count.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 52
LY2835219
A new cycle of gemcitabine will not be given unless the ANC is ≥1.0×109/L and platelets are
≥100×109/L. All nonhematologic toxicities (excluding alopecia) should also return to CTCAE 
Grade ≤1 or baseline prior to reinitiating treatment. Treatment may be delayed up to 4 weeks 
after completion of the 28-day cycle to allow sufficient time for recovery.
For nonhematologic toxicities, gemcitabine should be permanently discontinued in the event any 
of the following occur:  unexplained dyspnea or other evidence of severe pulmonary toxicity, 
severe hepatic toxicity, hemolytic-uremic syndrome, capillary leak syndrome, or posterior 
reversible encephalopathy syndrome.  Gemcitabine should be suspended or the dose reduced by 
50% for other severe (Grade 3 or 4) nonhematologic toxicity until resolved. No dose 
modifications are recommended for alopecia, nausea, or vomiting.
For patients who have a gemcitabine dose reduction within a cycle, subsequent dose escalation to
the original dose will be allowed, providing that the patient tolerates the cycle given at the
reduced dose level.
If a patient requires a second reduction within a cycle and after a dose re-escalation, the dose
should not be re-escalated to the higher level a second time. The patient should continue to
receive the reduced dose for the remainder of the study. If a patient requires a second reduction
after a cycle is completed, the dose should not be re-escalated to the higher level a second time
unless, in the opinion of the investigator, this is likely not to result in additional toxicity.
Patients requiring more than 2 consecutive dose reductions (within a cycle or after a cycle is
completed) for gemcitabine-related hematologic and/or nonhematologic toxicity, will be 
discontinued from the study unless there is clinical benefit for the patient. 
7.4.3. Dosage Modifications for Capecitabine
The safety profile of capecitabine as monotherapy has been characterized for patients with 
colorectal and breast cancers.  In the studies of patients with colorectal and breast cancers 
(Xeloda® capecitabine [tablets for oral use] prescribing instructions page [WWW]), patients 
received monotherapy with capecitabine 1250 mg/m2 BID.  For these patients, the incidence of 
Grade 3/4 hematologic abnormalities (neutropenia, thrombocytopenia, or decreases in 
hemoglobin) was low. Common nonhematologic Grade 3/4 toxicities include diarrhea, 
abdominal pain, hand-and-foot syndrome, and hyperbilirubinemia. Of note, elderly patients
(≥65 years) may experience a higher incidence of Grade 3/4 toxicities and therefore therapy may 
be initiated at a lower dose per the discretion of the investigator and institutional guidelines.
The capecitabine dose can be adjusted following Table JPCJ.7.5, as this presents the in-label 
recommendations for dose reductions for capecitabine when used as monotherapy.  Once the 
dose has been reduced, it should not be subsequently increased. Doses omitted for toxicity 
should not be replaced. Capecitabine will not be given unless the ANC is ≥1.5×109/L and 
platelets are ≥100×109/L. If Grade 3/4 neutropenia or thrombocytopenia occurs, stop therapy 
until condition resolves.  If hand-and-foot syndrome occurs, stop treatment until event resolves 
or decreases in intensity.  For management of diarrhea, see Section 7.7.2.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 53
LY2835219
Table JPCJ.7.5.
Capecitabine Dose Modifications
CTCAE Grade
During a Course of Therapy
Dose Adjustment for Next 
Treatment (% of starting dose)
Grade 1
Maintain dose level
Maintain dose level
Grade 2
     1st appearance
Interrupt until resolved to Grade 0 to 1
100
     2nd appearance
75
     3rd appearance
50
     4th appearance
Discontinue treatment permanently
-
Grade 3
     1st appearance
Interrupt until resolved to Grade 0 to 1
75
     2nd appearance
50
     3rd appearance
Discontinue treatment permanently
-
Grade 4
Discontinue permanently or if physician 
deems it to be in the patient’s best interest 
to continue, interrupt until resolved to 
Grade 0 to 1
50
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009).
7.5.
Preparation/Handling/Storage/Accountability
All study treatments will be provided by Lilly.  Clinical trial materials will be labeled according 
to the country’s regulatory requirements.
Abemaciclib will be supplied by Lilly as capsules for oral administration.  Abemaciclib capsules 
should be stored according to the temperature range listed on the product label, and should not be 
opened, crushed, or chewed.  Patients should store the abemaciclib capsules in the original 
package provided and be instructed to keep all medication out of reach of children.
LY3023414 will be supplied by Lilly as tablets for oral administration. LY3023414 should be 
stored according to the temperature range listed on the product label, and should not be crushed 
or dissolved.
Galunisertib will be supplied by Lilly as tablets in blister packs.  Galunisertib should be stored 
according to the temperature range listed on the product label, and the tablet should remain in the 
blister pack until just prior to administration.
All commercial products will be supplied and labeled according to country regulation 
requirements. Products should be stored according to the label instructions.
7.6.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by counting returned tablets/capsules.  Deviations from the prescribed dosage regimen 
should be recorded in the case report form (CRF).
A patient will be considered significantly noncompliant if he or she misses more than 25% of the 
planned doses for study treatment in a cycle.  A patient will also be considered significantly 
noncompliant if he or she is judged by the investigator to have intentionally or repeatedly taken 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 54
LY2835219
more than the prescribed amount of medication.  As outlined in Section 7.4, dose suspensions 
due to treatment-related toxicities may occur and will not result in a patient being considered as 
noncompliant.
7.7.
Concomitant Therapy
Patients should receive full supportive care therapies concomitantly during the study, including 
antiemetic treatment as per institutional guidelines.
The use of granulocyte-colony stimulating factor is permitted during investigational therapy at 
the discretion of the investigator as prescribed per American Society for Clinical Oncology
guidelines (Smith et al. 2015).  Growth factors should not be administered to enable a patient to 
satisfy study inclusion criteria. Dosing of study drug must be suspended if the administration of 
growth factors is required and must not be recommenced within 48 hours of the last dose of 
growth factors having been administered.  Following the administration of growth factors, the 
dose of study drug must be reduced by 1 dose level, if a dose reduction for the specific event 
necessitating the use of the growth factors has not already occurred.
Use of erythropoietin is allowed (Rizzo et al. 2008).
For patients assigned to abemaciclib treatment arms (safety lead-in as well as Arms A and B) or 
those assigned to Arm D who are receiving capecitabine, prothrombin time or international 
normalized ratio must be routinely monitored if patients are receiving concomitant oral 
coumarin-derivative anticoagulants.
For patients in Arm B requiring initiation of or changes to oral antidiabetic medications for blood 
glucose control, the first choice recommendation is sitagliptin because of low potential for drug 
interactions mediated via cytochrome P450 (CYP) 3A and renal transporters.  Additional options 
may include repaglinide or low-dose sulfonylureas (with due precautions, including standard 
education of patients regarding the signs of hypoglycemia).
No other chemotherapy, immunotherapy, radiation therapy, hormonal cancer therapy, or 
experimental medications will be permitted while the patients are participating in this study.  
Any disease progression requiring anticancer therapy will be cause for early discontinuation 
from the study.
7.7.1. Surgery for Cancer
A patient may receive surgery (for example, metastasectomy) during the study treatment period 
if clinically indicated.  Patients undergoing surgery should have study treatment suspended for at 
least 7 days prior to surgery, as well as 7 days postoperatively to allow for wound-healing.  If a 
patient undergoes a surgical procedure that involves removal of tumor, then formalin-fixed 
paraffin-embedded (FFPE) tumor from that procedure may be requested.
7.7.2. Management of Diarrhea
Upon treatment initiation, patients assigned to abemaciclib treatment arms (Safety Lead-In as 
well as Arms A and B) or those assigned to Arm D who are receiving capecitabine should 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 55
LY2835219
receive instructions on the management of diarrhea.  In the event of diarrhea, supportive 
measures should be initiated as early as possible.  These include the following:

At the first sign of loose stools, the patient should initiate antidiarrheal therapy (for 
example, loperamide) and notify the investigator/site for further instructions and 
appropriate follow-up.

Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to at least Grade 1,
study treatment should be suspended until diarrhea is resolved to at least Grade 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 intravenous [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.
7.7.3. Management of Hyperglycemia
Hyperglycemia has been observed in patients treated with LY3023414.  Patients who develop 
hyperglycemia during the study should be treated according to the American Diabetes 
Association and European Association for the Study of Diabetes consensus guidelines.  It is 
recommended to start treatment with an oral antidiabetic medication, preferably sitagliptin. 
Additional options may include repaglinide or low-dose sulfonylureas (with due precautions, 
including standard education of patients regarding the signs of hypoglycemia) (see Section 7.7).
7.7.4. Supportive Management for Stomatitis/Mucositis
Stomatitis, including oral mucositis, has been observed in patients treated with LY3023414. 
Prophylactic treatment and early recognition of this AE is highly important.  Early and active 
management includes the promotion of good oral hygiene.  Topical treatments with 
corticosteroids and mouthwashes similar to those used for management of 
chemotherapy-induced stomatitis are recommended.  However, mouthwashes containing alcohol, 
peroxide, iodine, and thyme derivatives should be avoided as they may exacerbate the condition. 
Antifungal agents should not be used unless fungal infection has been diagnosed.  Patients also 
should be advised to avoid acidic, spicy, and hard or crunchy foods, and to consume foods that 
are tepid rather than hot in temperature to prevent the potential for mechanical injury.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 56
LY2835219
7.7.5. Concurrent Use of Inducers and Inhibitors of CYP3A4,
Substrates of CYPS with Narrow Therapeutic Range, or Drugs 
Causing QTc Prolongation
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-time curve) 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).  Based on these findings, grapefruit juice as well as 
inducers (for example, phenytoin or carbamazepine) and inhibitors of CYP3A4 should be
substituted or avoided if possible (Appendix 7).
In addition, in vitro studies in primary cultures of human hepatocytes indicate that abemaciclib
and its active metabolites LSN2839567 and LSN3106726, down regulate messenger ribonucleic 
acid (mRNA) of CYPs including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A 
at clinically relevant concentrations.  The mechanism of down regulation and its clinical
relevance are presently not understood. Caution should be exercised when coadministering 
substrate drugs of CYPs with narrow therapeutic margin (Appendix 7).
Abemaciclib and its major metabolites inhibit the efflux transporters P-glycoprotein and breast 
cancer resistant protein and renal transporters organic cation transporter 2, multidrug and toxin 
extrusion protein 1 (MATE1) and MATE2-K at clinically relevant concentrations.  Therefore, 
substrates of these transporters such as metformin and those with a narrow therapeutic index 
such as digoxin and dofetilide should be substituted or avoided if possible.
For LY3023414, preclinical data suggested potential inhibition of CYP3A4-mediated 
metabolism and potential corrected QT (QTc) interval prolongation likely secondary due to the 
sustained hyperglycemia induced by LY3023414 at plasma concentrations exceeding the ones 
observed in patients (for details, see the IB for LY3023414).  Clinically, no obvious trend for 
QTc prolongation has been observed in patients receiving LY3023414.  The clinical data from 
Study CBBA indicate LY3023414 is a weak inhibitor of CYP3A4, as concomitant 
administration of LY3023414 and midazolam leads to an increased exposure of midazolam (fold 
increase:  mean 1.46).  LY3023414 may lead to an increase in exposure to abemaciclib and other 
CYP3A4 substrates.  Therefore, caution should be exercised when coadministering substrate 
drugs that are substrates of CYP3A4 with narrow therapeutic margin (Appendix 7) or drugs 
causing QTc interval prolongations (Appendix 8).  As stated above, grapefruit juice as well as 
inducers and inhibitors of CYP3A4 should be substituted or avoided if possible (Appendix 7).
Galunisertib is cleared predominantly by oxidative metabolism, with identified (inactive) 
metabolites accounting for 76% of the recovered dose, compared to only 13% of the dose being 
excreted as intact parent drug in the urine and feces combined (Study H9H-MC-JBAM). An 
in vitro substrate depletion approach using recombinant human CYP enzymes showed that 99% 
of the in vitro hepatic CYP-mediated clearance of galunisertib was linked to CYP3A, with 
CYP2C19 accounting for the remaining 1%.  As such, potent CYP3A inhibitors may have the 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 57
LY2835219
potential to increase exposures of galunisertib.  There are no specific drug-drug interactive 
studies conducted to date.
7.8.
Treatment after the Safety Lead-in, the End of Stage 1, and Study
Completion
7.8.1. End of Safety Lead-in
Following the completion of the Safety Lead-in assessment, patients who are still on study 
treatment may continue to receive study treatment until discontinuation criteria have been met.  
Investigators will continue to follow the Schedule of Activities (Section 2) for all patients until 
notified by Lilly that study completion has occurred.
7.8.2. End of Stage 1
Following the completion of the Stage 1 assessment, some treatment arms may not advance to 
Stage 2.  Patients who are still on study treatment at the time of treatment arm discontinuation
may continue to receive study treatment until discontinuation criteria have been met.  
Investigators will continue to follow the Schedule of Activities (Section 2) for all patients until 
notified by Lilly that study completion has occurred.
7.8.3. Study Completion
Study completion will occur following the primary analysis of PFS after Stage 2, as determined 
by Lilly (that is, 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.  End of Study is defined in Section 5.3.
7.8.4. Continued Access
Patients (Safety Lead-in, Stage 1, and Stage 2) who are still on study treatment at the time of 
study completion may continue to receive study treatment until discontinuation criteria have 
been met (Figure JPCJ.7.1).
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.
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 the day after the patient and the 
investigator agree to discontinue study treatment and lasts approximately 30 (±7) days.  
Follow-up procedures will be performed as shown in the Continued Access Schedule of 
Activities (Table JPCJ.2.8).
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.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 58
LY2835219
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
Figure JPCJ.7.1.
Continued access diagram.
Study Treatment Period
a Lilly will notify sites when the 
continued access period begins and ends. 
b Final analysis of progression-free survival.  
Lilly will notify sites when study completion occurs.
c End of study occurs at the last visit or 
last scheduled procedure for the last patient.
Study Completionb
Study treatment
Continued access 
follow-up
(approximately 30 days)
Continued Access Perioda
End of Studyc
Study treatment
Continued access 
follow-up
(approximately 30 days)
Study treatment
Continued access 
follow-up
(approximately 30 days)
Stage 1
Stage 2
Safety
Lead-in
Patient meets
discontinuation 
criteria

I3Y-MC-JPCJ(c) Clinical Protocol
Page 59
LY2835219
8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
For patients assigned to the Safety Lead-in or Arm B, if 1 study drug is discontinued due to 
toxicity, patients may continue to receive the other study drug until a discontinuation criterion 
has been met.
Patients will be discontinued from all study treatment in the following circumstances:

the patient is enrolled in any other clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

the patient becomes pregnant during the study.  See Section 9.2 regarding regulatory 
reporting requirements on fetal outcome and breast-feeding.

the patient is significantly noncompliant with study procedures and/or treatment

disease progression

unacceptable toxicity

the patient has undergone the maximum allowable dose reductions 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 (for example, parents, legal guardian, or caregiver) requests that 
the patient be discontinued from study treatment
Patients who are discontinued from 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
If Lilly or the investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CRP to allow the 
inadvertently enrolled patient to continue in the study with or without study treatment.
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

I3Y-MC-JPCJ(c) Clinical Protocol
Page 60
LY2835219

the patient requests to be discontinued from the study

the patient’s designee (for example, parents, legal guardian, or caregiver) requests that 
the patient be discontinued from the study
Patients who discontinue from the study early will continue to be followed according to the 
Post-Treatment Schedule of Activities (Section 2).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  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.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 61
LY2835219
9.
Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study.
Appendix 3 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
Tumor assessments will be performed according to RECIST v.1.1 (Eisenhauer et al. 2009) for 
each patient at screening (within 28 days of randomization) and subsequently approximately 
every 8 weeks (±3 days).  Upon initiation of Stage 2, Lilly or its designee will collect and store 
all tumor assessment images; retrospective collection of Stage 1 images will occur only for those 
arms that advance to Stage 2.  An independent review of imaging scans may be performed by an 
independent panel of radiologists.
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, MRI is also acceptable 
in certain situations, such as when body scans are indicated or if there is a concern about 
radiation exposure associated with CT.  Intravenous contrast is required unless medically 
contraindicated.
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with IV contrast). A PET scan alone or as part of a PET-CT may be performed 
for additional analyses but cannot be used to assess response according to RECIST v.1.1 
(Eisenhauer et al. 2009).
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Radiological scan of the thorax, abdomen, and pelvis is required at screening; 
subsequently, scans of the thorax for tumor assessments (CT of the chest for safety is required 
per the Schedule of Activities for patients in the safety lead-in; see Section 9.4.1) are required 
only for those patients with evidence of disease on the baseline scan or if clinically indicated 
(that is, progressive disease is suspected).
Partial response or CR will not require confirmation to be considered a response.  In the case of 
SD, postbaseline tumor assessments must have met the SD criteria at least once after 
randomization at a minimum interval of 6 weeks to assign a best response of SD.
See Section 10.3.1 for definitions of the efficacy endpoints.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 62
LY2835219
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 trials.
9.2.
Adverse Events
A clinical study AE is any untoward medical event associated with the use of a drug in humans, 
whether or not it is considered related to that drug. The investigator will use CTCAE v4.0 
(National Cancer Institute [NCI] 2009) to assign AE terms and severity grades.  Any minor 
version of CTCAE v4.0 (for example, Version 4.0X) may be used for this study.  Minor CTCAE 
v4.0 updates from the NCI will not necessitate a protocol amendment.
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 electronic data entry 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 electronic data entry 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 electronic data entry.
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 electronic data entry, clarifying, if possible, the 
circumstances leading to the dose modification or discontinuation of treatment.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 63
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

considered significant by the investigator for any other reason:  important medical events 
that may not result in death, be life-threatening, or require hospitalization may be 
considered serious, based upon appropriate medical judgment
Although all AEs after signing the ICF are recorded in the electronic data entry, SAE reporting 
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.
9.2.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 64
LY2835219
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and associated 
detailed guidances.
9.2.3. Summary of Adverse Event/Serious Adverse Event Reporting 
Guidelines
The AE and SAE reporting guidelines are summarized in Table JPCJ.9.1.
Table JPCJ.9.1.
Assessment Guide for Adverse Events and Serious Adverse 
Events
Timing
Types of AEs/SAEs Reported
Baseline
Starts at the signing of informed consent and ends at 
randomization/assignment to study treatment
Preexisting conditions
All AEs
SAEs  related to protocol procedure
On study treatment
Starts at first dose of study treatment and ends the day 
after the patient and the investigator agree that the 
patient will no longer continue study treatment
All AEs regardless of relatedness
All SAEs regardless of relatedness (except SAEs due 
to progressive disease unless the investigator also 
deems there to be a possible contribution related to 
study treatment or protocol procedures)
Short-term follow-up
Starts the day after the patient and the investigator 
agree that the patient will no longer continue study 
treatment and lasts approximately 30 days (±7 days)
All AEs related to study treatment
All SAEs regardless of relatedness (except SAEs due 
to progressive disease unless the investigator also 
deems there to be a possible relation with study 
treatment or protocol procedure)
Long-term follow-up, if necessary
Ongoing or new AEs/SAEs possibly related to study 
treatment or protocol procedures
Continued access treatment period
All AEs/SAEs (same as for patients on study 
treatment)
Continued access follow-up
Starts the day after the patient and the investigator 
agree that the patient will no longer continue study 
treatment in the continued access period and lasts 
approximately 30 days (±7 days).
All AEs/SAEs as above for initial follow-up visit 
and then as needed for subsequent continued 
follow-up visits
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
9.2.4. 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, 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.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 65
LY2835219
9.3.
Treatment of Overdose
Refer to the respective IBs for abemaciclib, LY3023414, and galunisertib and the product labels 
for gemcitabine and capecitabine.
9.4.
Safety
9.4.1. Cardiac Monitoring
In addition to electrophysiological assessments of the heart for all patients in this study, the most 
important evaluations are dictated by the galunisertib preclinical findings. Hence, cardiotoxicity 
monitoring must be performed for patients participating in the Safety Lead-in of this study, based 
on echocardiographs with Doppler and Chest CT/MRI (see Schedule of Activities [Section 2] 
and Appendix 6). The chest CT/MRI of the ascending aorta and aortic arch should be performed 
according to institutional guidelines. The same imaging techniques used at baseline should be 
used for each patient throughout the evaluation period.
Electrocardiograms (all patients)
For each patient, a 12-lead digital ECG will be collected according to the Schedule of Activities
(see Section 2).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection. ECGs may be obtained at 
additional times, if clinically indicated.
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible and ideally while the patient is still 
present for immediate patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/QTc interval from baseline, or 
other clinically significant quantitative or qualitative change from baseline, is present, the 
investigator will assess the patient for symptoms (for example, palpitations, near syncope, or 
syncope) and to determine if the patient can continue in the study. The investigator or qualified 
designee is responsible for determining if any change in patient management is needed and must 
document his/her review of the ECG printed at the time of evaluation.
Chest CT Scan with Contrast or MRI (Safety Lead-in Patients Only)
A chest CT scan with contrast or MRI was required at screening for all patients in the Safety 
Lead-in and subsequently according to the Schedule of Activities (see Section 2) for these 
patients.  The purpose of this safety assessment is to detect aneurysm formation of the ascending 
aorta and aortic arch.  If a CT scan with contrast or MRI has been done as part of the patient’s 
tumor assessment, this scan may be used for safety screening if the scan has properly assessed 
the great vessels and the heart. The same method of assessment used at screening should be used 
for each patient throughout the evaluation period.
Echocardiogram with Doppler (Safety Lead-in Patients Only)
Echocardiography with Doppler (ECHO/Doppler) was locally assessed at screening for all 
patients in the Safety Lead-in and subsequently according to the Schedule of Activities (see 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 66
LY2835219
Section 2) for these patients, and safety decisions made by physicians or a team of people who 
are qualified by experience or training. Individuals so qualified must be identified at each Safety 
Lead-in site. The same person should be responsible for reading the ECHO on any individual 
study patient.
For patients who develop clinically significant changes, ECHO should continue to be performed 
at 2-month intervals until clinically stable for 6 months, then every 6 months thereafter.  If the 
patient has clinically significant cardiac findings at the 30-day follow-up visit, ECHO will be 
repeated every 2 months for 6 months.  If there are no clinically significant cardiac findings at 
the 30-day follow-up visit, a repeat ECHO will be performed within 6 months of the last ECHO.  
If there were no clinically significant cardiac findings at the last cardiac assessment conducted 
within the last 30 days and the patient has started another treatment, the 30-day follow-up visit 
ECHO will not be performed.
9.4.2. Guidance for Monitoring of Renal Function in Patients on 
Abemaciclib
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C calculated glomerular filtration rate (see 
Section 3.2.4 of the abemaciclib IB for additional background).  Increases in serum creatinine 
occurred within the first 2 weeks of treatment, remained stable through the treatment period, and 
were reversible upon treatment discontinuation.  If deterioration of renal function is suspected, 
serum creatinine should not be the only measure used to assess a patient’s renal function.  Based 
on this information, it is suggested that for those patients with an increased serum creatinine test 
result while receiving abemaciclib, a serum cystatin-C test can be performed to confirm renal 
function.  Cystatin-C blood concentration depends almost entirely on the glomerular filtration 
rate and is not affected by diet, nutrition, inflammation, or malignant disease.  Dose alterations 
(omission, reduction, or discontinuation) should not solely be based on interpretation of serum 
creatinine values because these may not reflect renal function.
9.4.3. Other Safety Measures
For each patient, vital signs, laboratory tests, or other tests should be collected as shown in the 
Schedule of Activities (Section 2).
Blood samples will be collected to determine whether patients meet inclusion/exclusion criteria 
and to monitor patient health. Enrollment and treatment decisions may be based upon results of 
tests performed locally. If local laboratory tests are used for this purpose, then a duplicate 
specimen must be submitted to the central laboratory.  Local laboratory tests performed for 
eligibility purposes must include analytes with associated eligibility criteria (absolute neutrophil 
count, platelet count, hemoglobin, total bilirubin, alanine aminotransferase, aspartate 
aminotransferase, serum creatinine, and HbA1c), as well as fasting glucose, at a minimum.  
Subsequent to enrollment, local laboratory tests may include the institution’s standard chemistry 
and hematology panels, but must be performed under fasting conditions to assess glucose for all 
patients participating in Arm B; Arm B must also include HbA1c.  Discrepancies between local 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 67
LY2835219
and central laboratory results that may have an impact on eligibility or treatment decisions will 
not be considered protocol deviations.
Any clinically significant findings from ECGs, ECHOs, safety CT scans, labs, vital sign 
measurements, and other study procedures that result in a diagnosis should be reported via 
electronic data entry as an AE.
9.4.4. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.  The first periodic safety review of the randomized portion of the study (Stage 1) will 
occur after 10 patients have been randomized to each treatment arm and completed 1 cycle (28 
days) or have discontinued treatment.
If a patient experiences elevated alanine aminotransferase (ALT) 5× upper limit of normal 
(ULN) and elevated total bilirubin 2× ULN in the absence of liver metastases, clinical and 
laboratory monitoring should be initiated by the investigator. For patients entering the study 
with ALT or aspartate aminotransferase (AST) >3× ULN in the presence of liver metastases, 
monitoring should be triggered if ALT or AST is elevated to >2× baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities. To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP regarding collection of specific recommended 
clinical information and follow-up laboratory tests.  See Appendix 5.
9.5.
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected as shown in Appendix 4. During the Safety 
Lead-in, patients receiving the combination of abemaciclib and galunisertib will undergo intense 
PK sampling.  For all patients participating in the study, the PK sample collection should occur 
on the day that clinical laboratory samples are collected for the purposes of eligibility or health 
monitoring, corresponding to the originally planned next visit/cycle.
Blood samples will be used to determine the concentrations of abemaciclib and its metabolites, 
LY3023414, and galunisertib.  A patient diary will be used as source to collect the date and time 
of study treatment doses for the 3 days preceding collection of PK samples.
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon by the investigator and Lilly.
Bioanalytical samples collected to measure abemaciclib plus its metabolites, LY3023414, and 
galunisertib concentrations will be retained for a maximum of 1 year following the last patient 
visit for the study.
9.6.
Pharmacodynamics
Sample collection for pharmacodynamic parameters is covered in Section 9.8.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 68
LY2835219
9.7.
Pharmacogenomics
9.7.1. Whole Blood Samples 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 PDAC.  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 for a 
maximum of 15 years after the last patient visit for the study, or for a shorter period if local 
regulations and/or ethical review boards (ERBs)/institutional review boards (IRBs) impose 
shorter time limits, at a facility selected by Lilly or its designee.  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 in the development of abemaciclib or 
LY3023414 or after these study treatments become commercially available.
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, candidate gene studies, and 
epigenetic analyses.  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, pharmacodynamics, 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 DNA, RNA, 
proteins, lipids, and other cellular elements.
As part of Lilly’s ongoing efforts to understand the relationship between cancer, genetics, and 
response to therapy, this study will analyze biomarkers relevant to abemaciclib, galunisertib, 
LY3023414, gemcitabine, capecitabine, immune function, cell cycle, and/or PDAC, and/or for 
related research methods or validation of 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 trial. 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 9.8.1 and 9.8.2.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 69
LY2835219
9.8.1. Blood Samples for Nonpharmacogenetic Biomarker Research
Plasma samples for nonpharmacogenetic biomarker research will be collected as specified in
Appendix 4, where local regulations allow.
Samples will be examined for biomarkers related to variable responses in those treated with 
abemaciclib, galunisertib, LY3023414, gemcitabine, or capecitabine, including the mechanisms 
of action involving immune function, cell cycle regulation, and/or PDAC, and/or for related 
research methods or validation of diagnostic tools or assays.
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 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, at a facility 
selected by Lilly or its designee.  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 in the development of abemaciclib, galunisertib, or LY3023414 or after these
study treatments become commercially available.
9.8.2.
Tissue Samples for Nonpharmacogenetic Biomarker Research
Tumor tissue samples will be examined for biomarkers related to abemaciclib, galunisertib, 
LY3023414, gemcitabine, capecitabine, immune function, cell cycle, and/or PDAC, and/or for 
related research methods or validation of diagnostic tools or assays.
Collection of the following tumor tissue sample is required for all patients in order to participate 
in this study:  FFPE tumor tissue obtained from the primary tumor or metastatic site as a block or 
unstained slides.  However, if this sample is not available for a patient or provision of the sample 
is restricted by local regulations, a protocol deviation will not be incurred and the patient is 
eligible for the study.  Due diligence should be used to make sure that tumor sample (not a 
normal adjacent or a tumor margin sample) is provided.  Pathology report accompanying 
archival tissue may also be requested. The 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.  Archival blocks will be sectioned and 
returned to the study site. Slides and tissue samples collected on-study will not be returned.  For 
patients without available FFPE tumor tissue at baseline, a core needle biopsy (minimum 3 
cores) obtained prior to study treatment initiation is highly encouraged, but not required.
Patients may be asked to undergo collection of an additional core needle biopsy specimen and 
blood sample after treatment with abemaciclib, LY3023414, gemcitabine, or capecitabine has 
been initiated or after disease progression.  If requested, this biopsy specimen and blood sample 
will be used to further investigate molecular features that may explain treatment response and 
resistance mechanisms.
Samples will be retained 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, at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 70
LY2835219
to questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in the development of abemaciclib, galunisertib, or LY3023414 or after these 
study drugs become commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  However, existing technologies, including mutation profiling, copy number 
variability, gene expression, multiplex assays, and/or immunohistochemistry, may be performed 
on these tissue samples to assess potential associations with these biomarkers and clinical 
outcomes.
9.9.
Health Outcomes
The primary health outcomes research goal is to determine if abemaciclib therapy is able to 
palliate pain, as measured by the modified Brief Pain Inventory-short form (mBPI-sf)
(Cleeland and Ryan 1994). Additionally, the European Organisation for Research and Treatment 
of Cancer (EORTC) QLQ-C30 (Aaronson et al. 1993) will assess the broader impact of
abemaciclib therapy on symptoms, functioning and quality of life.
Patient-reported questionnaires should be completed by patients when a linguistically validated 
language translation is available in which the patient is fluent or literate.
At each time point identified in the Study Schedule (Section 2), a paper copy of the mBPI-sf and 
EORTC QLQ-C30 questionnaires should be administered to the patient prior to extensive 
interaction with site staff and study drug administration.
9.9.1. Pain Intensity
The mBPI-sf (Cleeland and Ryan 1994) is an 11-item instrument used as a multiple-item 
measure of cancer pain intensity.  In addition to pain intensity (4 items), the mBPI-sf is designed 
for patients to record the presence of pain in general, pain relief, and pain interference with 
function (general activity, mood, ability to walk, ability to perform normal work, relations with 
others, sleep, and enjoyment of life).
Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales
anchored at 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can
imagine or completely interferes).  The mBPI-sf recall period is 24 hours, and typical completion
time for this instrument is less than 5 minutes. Focused analysis will be on “worst pain”.
Use of pain medication will be assessed in conjunction with the mBPI-sf assessment. Data on
each individual prescription and over-the-counter analgesic medication will be recorded on the
Concomitant Medications eCRF. The use of pain medications should be reviewed with the
patient at each subsequent visit.  Any changes to analgesic use (new or stopped analgesics) will
be recorded on the eCRF. Pain medication will be classified into medication categories, using
the World Health Organization analgesic ladder. A medication category will be assigned based
on the maximum analgesic therapy administered for that cycle on a routine basis.
The BPI population will include all patients who completed at least 1 baseline followed by at
least 1 BPI “worst pain” postbaseline assessment.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 71
LY2835219
9.9.2. Health-Related Quality of Life
Broadly used in cancer trials, validated, and available in over 80 different languages, the EORTC
QLQ-C30 (Aaronson et al. 1993) is a reliable and validated tool. The EORTC QLQ-C30 
self-reported general cancer instrument (Aaronson et al. 1993) consists of 30 items covered by
1 of 3 dimensions:

global health status/quality of life (2 items)

functional scales (15 total items addressing either physical, role, emotional, cognitive,
or social functioning)

symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, 
dyspnea, insomnia, appetite loss, constipation, diarrhea, or financial impact)
The EORTC QLQ-C30 is administered per the Study Schedule (Section 2).  The recall period is 
the past week, completion time is typically 5 to 7 minutes, and the questionnaire will be scored 
as described by the EORTC scoring manual (Fayers et al. 2001). The EORTC population will 
include all patients who completed at least 1 baseline followed by at least 1 EORTC postbaseline 
assessment.
9.9.3. Resource Utilization
Investigators will be asked to report the use of concomitant medications (in particular,
analgesics, growth factors, or antidiarrheals), blood product transfusions, and hospitalization 
days.  This information should be collected at baseline, during the study, and at the 30-day
follow-up visit.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 72
LY2835219
10. Statistical Considerations
10.1. Sample Size Determination
According to the original study protocol, prior to randomization for Stage 1, approximately 6 to 
12 patients were to be enrolled in the safety lead-in part of the study.  However, with amendment 
(c), no additional patients will be enrolled to the safety lead-in and Arm C (abemaciclib plus 
galunisertib) will be removed.
During Stage 1, 25 patients will be treated per arm to provide a preliminary assessment of tumor 
response and assessment of safety.  The null hypothesis is based on the assumption that the DCR 
is no greater than 50%; Table JPCJ.10.1 shows the probability of stopping at the end of Stage 1 
(ranges from 11% to 72%) for DCR differences ranging from -10% (experimental arm DCR 
worse than standard of care) to 15% (experimental arm DCR better than standard of care).
At the end of Stage 1, an additional 50 patients will be enrolled in each of the advancing 
treatment arms from Stage 1, giving a total of approximately 75 patients in each treatment arm 
(combined Stage 1 and 2).  This will allow the detection of PFS HR of 0.65 (median PFS of 
2.3 months in abemaciclib containing arms vs. 1.5 months in the standard-of-care arm) with a 
two-tailed log-rank test at 0.10 significance level and a power of 76%.  Analysis for Stage 2 will 
be performed when approximately 120 total events have occurred for the combination of each 
individual abemaciclib-containing arm and the standard-of-care arm, or all planned patients have 
been enrolled in Stage 2, whichever comes later.
Table JPCJ.10.1.
Probability of Stopping at Stage 1
Null DCR
Alternative DCR
DCR Difference
Sample Size
Probability of abemaciclib 
containing treatment arm to 
stop at Stage 1 (that is, not 
advancing to Stage 2)
0.5
0.40
-0.10
25
0.72
0.5
0.50
0
25
0.44
0.5
0.65
0.15
25
0.11
Abbreviation:  DCR = disease control rate.
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, and health 
economics analyses.
Safety population:  will include all randomized patients who received any quantity of study 
treatment, regardless of their eligibility for the study.  The safety evaluation will be performed 
based on the first dose of study treatment a patient actually received, regardless of the arm to 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 73
LY2835219
which he or she 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 study treatment and have baseline and at least 1 postbaseline evaluable PK sample.
Biomarker population:  will include the subset of patients 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 otherwise stated, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and all confidence intervals (CIs) 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 described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report.  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
10.3.1. Efficacy Analyses
Stage 1 analysis will be performed approximately 16 weeks after the last planned Stage 1 patient 
enters treatment.  All tumor assessment data accumulated during this period (beyond 16 weeks 
for some patients, if available), will be included in the assessment of DCR.  This analysis will 
compare DCR in the investigational arms (Arms A and B) to the standard-of-care arm (Arm D).  
Following the completion of the Stage 1 assessment, any treatment arm(s) with a DCR difference 
≥0 as compared to the standard of care (Arm D) will be selected to advance to Stage 2.  
Enrollment may continue while Stage 1 analysis is ongoing.  Any patients enrolled during the 
Stage 1 analysis will not be included in Stage 1 analysis but will be included in the analysis at 
the end of Stage 2.
The primary analysis of Stage 2 will be conducted when at least 120 total PFS events have 
occurred for the combination of each individual abemaciclib-containing arm and the 
standard-of-care arm, or all planned patients have been enrolled in Stage 2, whichever comes 
later.  Data from both Stages 1 and 2 will be pooled for this analysis.
The stratification factors are captured in the IWRS and on eCRFs. Unless otherwise stated, all 
stratification analyses will be based on the stratification factors per CRF.
Key efficacy parameters are defined as follows:
ORR:  The denominator of objective response rate (ORR) includes each randomized patient.  
The numerator includes those patients counted in the denominator with a best overall tumor 
response of PR or CR.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 74
LY2835219
DCR:  Using the same denominator as for ORR, the numerator of the DCR includes those 
patients counted in the denominator with a best tumor response of SD, PR, or CR.
DOR:  The duration of response (DOR) is defined only for responders (patients with a CR or 
PR). It is measured from the date of first evidence of a CR or PR to the date of objective 
progression or the date of death due to any cause, whichever is earlier.  If a responder is not 
known to have died or have objective progression as of the data inclusion cutoff date, DOR will 
be censored at the date of the last complete objective progression-free disease assessment.
PFS:  The PFS time is measured from the date of randomization to the date of objective 
progression or the date of death due to any cause, whichever is earlier.  The censoring is taken in 
the following order:

if a patient does not have a complete baseline disease assessment, then the PFS time 
will be censored at the randomization date, regardless of whether or not objectively 
determined disease progression or death has been observed for the patient; otherwise,

if a patient is not known to have died or have objective progression as of the data 
inclusion cutoff date for the analysis, the PFS time will be censored at the last 
complete objective progression-free disease assessment date.
Additional sensitivity analysis using alternate censoring rules may be conducted.  Additional 
details regarding these censoring rules will be defined in the SAP.
OS:  OS duration is measured from the date of randomization to the date of death from any 
cause.  For each patient who is not known to have died as of the data-inclusion cutoff date, OS 
will be censored at the last known alive date.
ORR, DCR, DOR, and PFS will be assessed based on RECIST 1.1.
For time-to-event parameters, such as PFS, OS, and DOR, the Kaplan-Meier method will be used 
to estimate parameters (for example, medians, quartiles, 3 months, and 6 month event rates)
(Kaplan and Meier 1958).  Comparison between abemaciclib-containing treatment arms and the 
standard-of-care arm will be done using the log-rank test stratified by randomization strata.  An 
unstratified log-rank test will also be performed.  The stratified and unstratified Cox proportional 
hazard model (Cox 1972) will be used to estimate the HR and corresponding 95% CI.
The ORR and DCR of each treatment arm will be calculated as defined by RECIST 1.1. All
rates will be compared between abemaciclib-containing treatment arms and the standard-of-care 
arm based on a normal approximation for the difference between the rates.
Full details around analyses will be included in the SAP.
All rates will be compared between treatment arms based on a normal approximation for the
difference between the rates.
10.3.2. Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 75
LY2835219
Adverse events will be reported using a unified CTCAE/Medical Dictionary for Regulatory 
Activities (MedDRA™) reporting process:

The CTCAE v4.0 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and System Organ Class (SOC) of the corresponding MedDRA 
Lower Level Term (LLT), unless the reported CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’, the MedDRA LLT, PT, and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Safety analyses will include summaries of the following:

treatment-emergent AEs, including severity and possible relationship to study drug

treatment-emergent SAEs, including possible relationship to study drug

treatment-emergent AEs leading to dose adjustments

discontinuations from study treatment due to treatment-emergent AEs or death

treatment-emergent abnormal changes in laboratory 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 summary of the 
number and percentage of patients entered into the study, enrolled 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.
10.3.3.2. Patient Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population considered for regulatory approval.
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics.
10.3.3.3. Concomitant Therapy
A summary of prior and concomitant medications by treatment arm will be reported.
10.3.3.4. Poststudy-Treatment-Discontinuation Therapy
The numbers and percentages of patients receiving poststudy-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.
10.3.3.5. Treatment Compliance
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated patients by treatment arm.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 76
LY2835219
Study treatment compliance will be assessed as the proportion of treatment that is actually taken, 
relative to what is expected, after accounting for protocol-defined dose adjustments.
10.3.3.6. Pharmacokinetic/Pharmacodynamic Analyses
PK analyses will be conducted on all patients who have received at least 1 dose of investigational 
agent and have evaluable PK samples and sufficient dosing information.
Mean population PK parameters for abemaciclib in plasma (for example, clearance, exposure, 
volume of distribution) and inter-individual PK variability will be computed using nonlinear 
mixed effect modelling (NONMEM).
Likewise, and if warranted by the data, mean population PK parameters for LY3023414 and 
galunisertib in plasma and interindividual variability estimates will also be computed using 
nonlinear mixed-effect modelling implemented in NONMEM.
The observed concentrations of abemaciclib and metabolites, LY3023414, and galunisertib, may 
be summarized by time and dose.
Pharmacodynamic samples will be collected as specified in the Study Schedule and PK and 
Pharmacodynamics (PD) Sampling Schedule (Appendix 4).  Refer to these attachments 
(including footnotes) for important information about these samples and their collection.
Furthermore, PD data (such as neutrophil, lymphocyte, or platelet counts in blood) collected in 
this study may also be analyzed by means of NONMEM and connected to the population PK 
model in a PK/PD model.
Pharmacodynamic data from all patients undergoing PD assessments will be analyzed.  The PD 
data will be combined and exploratory analyses will be conducted to determine if a relationship 
exists between plasma concentration and PD effect(s) in humans.  Interpatient variability in 
human PD response may also be assessed.
10.3.3.7. Biomarker Analyses
Correlative analyses will be performed to investigate associations between biomarkers and 
clinical endpoints as deemed appropriate.
10.3.3.8. Health Outcome/Quality of Life Analyses
For each instrument, the compliance rate (overall, and by baseline [Screening, Cycle 1 Day 1], 
on-therapy [Cycle 2 Day 1 and later], and follow-up) by treatment arm will be calculated as the 
number of completed assessments divided by the number of expected assessments (that is, 
patients still on study).  Compliance rates, reasons for noncompliance, and data collected for 
each instrument will be summarized by treatment arm.
A multivariate mixed repeated model will be applied to compare the trend over time for a 
prespecified total score/domain score/item of interest between treatment arms and by response 
group (PR, SD, or progressive disease); the model will include time, treatment, and interaction of 
time and treatment, and may be adjusted for other covariates.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 77
LY2835219
Time to deterioration in a total score/domain score/item will be summarized descriptively using 
the Kaplan-Meier method (Kaplan and Meier 1958), and a comparison between treatment arms 
will be made using the Cox proportional hazards models (Cox 1972).
10.3.3.9. Healthcare Resource Utilization
Hospitalizations, transfusions, and concomitant medication categories (for example, analgesics, 
growth factors, and antidiarrheals) during study treatment will be summarized descriptively by 
treatment arm.
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. Stage 1 Analyses
The Stage 1 analysis of efficacy will be conducted under the guidance of an Assessment 
Committee (AC) after the last planned Stage 1 patient has enrolled and completed at least 
16 weeks of treatment or have discontinued (whichever comes earlier). All data accumulated 
during this period (beyond 16 weeks for some patients, if available), will be included in the 
analysis.  The purpose of this analysis is to evaluate safety and efficacy (DCR) to select which 
arms will continue to Stage 2. The AC will include an external physician as well as the study 
statistician, Global Patient Safety physician, and Medical Director.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 78
LY2835219
11. References
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JC, Kaasa S, Klee MC, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw KC, Sullivan M, Takeda F. The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst. 1993;85(5):365-376.
Akhurst RJ, Derynck R. TGF-beta signaling in cancer--a double-edged sword. Trends Cell Biol. 
2001;11(11):S44-S51.
Arizona Cert Center for Education and Research on Therapeutics page. Available at:
https://crediblemeds.org/. Accessed 30 June 2016
Bertocchi P, Abeni C, Meriggi F, Rota L, Rizzi A, Di Biasi B, Aroldi F, Ogliosi C, Savelli G, 
Rosso E, Zaniboni A. Gemcitabine plus nab-paclitaxel as second-line and beyond treatment 
for metastatic pancreatic cancer: a single institution retrospective analysis. Rev Recent Clin 
Trials. 2015;10(2):142-145.
Biankin AV, Biankin SA, Kench JG, Morey AL, Lee CS, Head DR, Eckstein RP, Hugh TB, 
Henshall SM, Sutherland RL. Aberrant p16(INK4A) and DPC4/Smad4 expression in 
intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal 
adenocarcinoma. Gut. 2002;50(6):861–868.
Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, 
Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, 
Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, 
Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, 
Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, 
Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, 
Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, 
Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N; Australian Pancreatic Cancer Genome 
Initiative, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, 
Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, 
Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche 
RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, 
Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, 
Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann 
KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, 
Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, 
Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA Grimmond SM. 
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 
2012;491(7424):399-405.
Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging 
targeted therapies. Drug Des Dev Ther. 2015;9:3529-3545.
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 
Singapore. 1994;23(2):129-138.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 79
LY2835219
Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. 
J Clin Oncol. 2010;28(6):1075-1083.
Cox DR. Regression models and life-tables. J R Stat Soc Ser B. 1972;74(2):187-220.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
da Rocha Lino A, Abrahão CM, Brandão RM, Gomes JR, Ferrian AM, Machado MC, 
Buzaid AC, Maluf FC, Peixoto RD. Role of gemcitabine as second-line therapy after 
progression on FOLFIRINOX in advanced pancreatic cancer: a retrospective analysis. 
J Gastrointest Oncol. 2015;6(5):511-515.
de Caestecker MP, Piek E, Roberts AB. Role of transforming growth factor-beta signaling in 
cancer. J Natl Cancer Inst. 2000;92(17):1388-1402.
Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer 
progression. Nat Genet. 2001;29(2):117-129.
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family 
signalling. Nature. 2003;425(6958):577-584.
Dickler MN, Tolaney SM, Rugo HS, Cortes J, Diéras V, Patt DA, Wilkiers H, Frenzel M, 
Koustenis A, Baselga J. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 
and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after 
chemotherapy for advanced disease. J Clin Oncol. 2016;34(suppl 15):510.
Ellenrieder V, Hendler SF, Ruhland C, Boeck W, Adler G, Gress TM. TGF-beta-induced 
invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the 
urokinase plasminogen activator system. Int J Cancer. 2001;93(2):204-211.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
Faivre SJ, Santoro A, Kelley RK, Merle P, Gane E, Douillard JY, Waldschmidt D, Mulcahy MF, 
Costentin C, Minguez B, Papappicco P, Gueorguieva I, Cleverly A, Deaiah D, Lahn MM, 
Ameryckx S, Benhadji KA, Raymond E, Giannelli G. A phase 2 study of a novel transforming 
growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in 
patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2014;32(suppl 
3):LBA173.
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A; EORTC Quality of 
Life Group. The EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels (Belgium): European 
Organisation for Research and Treatment of Cancer; 2001.
Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination 
with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 
2014;5(15):6512-6525.
Gemzar® gemcitabine HCl (for injection) prescribing instructions page. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s077lbl.pdf. Accessed 
July 19, 2016.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 80
LY2835219
Goel G, Sun W. Novel approaches in the management of pancreatic ductal adenocarcinoma: 
potential promises for the future. J Hematol Oncol. 2015;8:44.
Gopalan PK, Gordillo-Villegas A, Zajac-Kaye M, et al. Cancer Res. 2013;73(suppl 8):693.
Gueorguieva I, Cleverly AL, Stauber A, Sada Pillay N, Rodon JA, Miles CP, Yingling JM 
Lahn MM. Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 
monohydrate based on a pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol. 
2014;77(5):796-807.
Hurwitz HI, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade SM 3rd, Nemunaitis JJ, Stella PJ, 
Pipas JM, Wainberg ZA, Manges R, Garrett WM, Hunter DS, Clark J, Leopold L, Sandor V, 
Levy RS. Randomized, double-blind, Phase II study of ruxolitinib or placebo in combination 
with capecitabine in patients with metastatic pancreatic cancer for whom therapy with 
gemcitabine has failed. J Clin Oncol. 2015;33(34):4039-4047.
Iriana S, Ahmed S, Gong J, Annamalai AA, Tuli R, Hendifar AE. Targeting mTOR in pancreatic 
ductal adenocarcinoma. Front Oncol. 2016;6:99.
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, 
Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES Kamiyama M, Walter K, 
Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, 
Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, 
Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE Kinzler KW. Core 
signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 
2008;321(5897):1801-1806.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc. 
1958;53:457-481.
Khouri SJ, Maly GT, Suh DD, Walsh TE. A practical approach to the echocardiographic 
evaluation of diastolic function. J Am Soc Echocardiogr. 2004;17(3):290-297.
Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, Yang G, Chalukya M,
Wang HJ, Anderson L, Kalli KR, Finn RS, Ginther C, Jones S, Velculescu VE, Riehle D,
Cliby WA, Randolph S, Koehler M, Hartmann LC, Slamon DJ. Expression of p16 and 
retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res.
2011;17(6):1591-1602.
Ku BM, Yi SY, Koh J, Bae YH, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. The CDK4/6 
inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and 
neck squamous cell carcinoma. Oncotarget. 2016;7(12):14803-14813.
Liu F, Korc M. Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances 
invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012;11(10):2138-2148.
Maier-Stocker C, Bitzer M, Malek NP, Plentz RR. Analysis of second-line chemotherapies for 
ductal pancreatic adenocarcinoma in a German single-center cohort. Scand J Gastroenterol. 
2014;49(12):1480-1485.
Massagué J, Blain SW, Lo RS. TGF-beta signaling in growth control, cancer, and heritable 
disorders. Cell. 2000;103(2):295-309.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 81
LY2835219
Melisi D, Garcia-Carbonero, Macarulla T, Pezet D, Deplanque G, Fuchs M, Trojan J, Oettle H, 
Kozloff M, Cleverly A, Gueorguieva I, Desaiah D, Lahn MMF, Blunt A, Benhadji KA, 
Tabernero J. A phase II, double-blind study of galunisertib+gemcitabine vs 
gemcitabine+placebo in patients with unresectable pancreatic cancer. J Clin Oncol.
2016;34(suppl 15):4019.
Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in 
breast cancer. J Clin Oncol. 2011;29(33):4452-4461.
Miyazono K. TGF-beta/SMAD signaling and its involvement in tumor progression. Biol Pharm 
Bull. 2000;23(10):1125-1130.
[NCCN] National Comprehensive Cancer Network Treatment Guidelines Version 1.2017. 
Available at: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed 
06 March 2017.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. 2009. Published date: 
29 May 2009.
Oh JK, Seward JB, Tajik AJ. The echo manual. 3rd ed. Philadelphia (PA): Lippincott, Williams 
Wilkins; 2006.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-655.
Opitz I, Soltermann A, Abaecherli M, Hinterberger M, Probst-Hensch N, Stahel R, Moch H, 
Weder W. PTEN expression is a strong predictor of survival in mesothelioma patients. Eur J 
Cardiothorac Surg. 2008;33(3):502-506.
Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. 
Biochim Biophys Acta. 2002;1602(1):73-87.
Ouyang H, Gore J, Deitz S, Korc M. MicroRNA-10b enhances pancreatic cancer cell invasion by 
suppressing TIP30 expression and promoting EGF and TGF-β actions. Oncogene.
2014;33(38):4664-4674.
Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, 
Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, 
Nguyen TS, Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, 
Flaherty KT, Wen PY, Shapiro GI. Efficacy and safety of abemaciclib, an inhibitor of CDK4 
and CDK6, for patients with breast cancer, non–small cell lung cancer, and other solid tumors. 
Cancer Discov. 2016;6(7):740-753.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
Society of Clinical Oncology; American Society of Hematology. Use of epoetin and 
darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American 
Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-149. 
Erratum in: J Clin Oncol. 2008;26(7):1192.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 82
LY2835219
Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med.
2014;371(11):1039-1049.
Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672-1677.
Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, 
Reicheck N, Sahn D, Schnittger I, Silverman NH, Tajik AJ. Recommendations for quantitation 
of the left ventricle by two-dimensional echocardiography: American Society of 
Echocardiography Committee on Standards, Subcommittee on Quantitation of 
Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2(5):358-367.
Schober M, Javed MA, Beyer G, Le N, Vinci A, Sund M, Neesse A, Krug S. New advances in 
the treatment of metastatic pancreatic cancer. Digestion. 2015;92(3):175–184.
Siegel PM, Massagué J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer.
Nat Rev Cancer. 2003;3(11):807-821.
Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. 
Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the 
Framingham Heart Study). Am J Cardiol. 1999;83(6):897-902.
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, Armitag 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.
Sohal DP, Mangu PB, Khorana AA, Shah MA, Philip PA, O’Reilly EM, Uronis HE, 
Ramanathan RK, Crane CH, Engebretson A, Ruggiero JT, Copur MS, Lau M, Urba S, 
Laheru D. Metastatic pancreatic cancer: American Society of Clinical Oncology clinical 
practice guideline. 2016;34(23):2784-2796.
Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology.
2007;7(5-6):423-435.
Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a 
morphophysiologic expression of left ventricular diastolic dysfunction and relation to 
cardiovascular risk burden. Am J Cardiol. 2002;90(12):1284-1289.
Varghese S, Chen Z, Bartlett DL, Pingpank JF, Libutti SK, Steinberg SM, Wunderlich J, 
Alexander HR Jr. Activation of the phosphoinositide-3-kinase and mammalian target of 
rapamycin signaling pathways are associated with shortened survival in patients with 
malignant peritoneal mesothelioma. Cancer. 2011;117(2):361-371.
Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. 
Curr Opin Genet Dev. 2002;12(1):22-29.
Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, 
Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, 
Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study 
Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic 
cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, 
open-label, Phase 3 trial. Lancet. 2016;387(10018):545–557.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 83
LY2835219
Weinberg BA, Yabar CS, Brody JR, Pishvaian MJ. Current standards and novel treatment 
options for metastatic pancreatic adenocarcinoma. Oncology (Williston Park). 
2015;29(11):809-820.
Wiedemeyer WR, Dunn IF, Quayle SN, Zhang J, Chheda MG, Dunn GP, Zhuang L,
Rosenbluh J, Chen S, Xiao Y, Shapiro GI, Hahn WC, Chin L. Pattern of retinoblastoma 
pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci 
USA. 2010;107(25):11501-11506.
Xeloda® capecitabine (tablets for oral use) prescribing instructions page. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20896lbl.pdf. Accessed July 19,
2016.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, 
Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, 
Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of 
the severity of native valvular regurgitation with two-dimensional and Doppler 
echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 84
LY2835219
Appendix 1.
Abbreviations and Definitions
Term
Definition
5-FU
5-fluorouracil
AC
assessment committee
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.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BID
twice daily
CA
carbohydrate antigen
CDK
cyclin-dependent kinase
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
collection database
a computer database where clinical trial data are entered and validated.
CR
complete response
CRF/eCRF
case report form / electronic case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer.
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DLT
dose-limiting toxicities
DNA
deoxyribonucleic acid

I3Y-MC-JPCJ(c) Clinical Protocol
Page 85
LY2835219
DNA-PK
DNA-dependent protein kinase
DOR
duration of response
ECG
electrocardiogram
ECHO
echocardiography
ECOG
Eastern Cooperative Oncology Group
effective method of 
contraception
effective method of contraception means male condom with spermicide, female condom 
with spermicide, diaphragm with spermicide, cervical sponge, or cervical cap with
spermicide.
Also see the definition of highly effective method of contraception.
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
enroll
act of assigning a patient to a treatment.  Patients who are enrolled in the trial are those 
who have been assigned to a treatment.
enter
patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB/IRB
ethical review board / institutional review board
FFPE
formalin-fixed, paraffin-embedded
FOLFIRINOX
5-fluorouracil, leucovorin, irinotecan, and oxaliplatin
GCP
good clinical practice
HbA1c
hemoglobin A1c
highly effective 
method of 
contraception
combined oral contraceptive pill and mini-pill, NuvaRing®, implantable contraceptives, 
injectable contraceptives (such as Depo-Provera®), intrauterine device (such as 
Mirena® and ParaGard®), contraceptive patch for women <90 Kg (<198 pounds), 
bilateral tubal occlusion, total abstinence, or vasectomy.
Also see the definition of effective method of contraception.
HR
hazard ratio
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
INR
international normalized ratio
interim analysis
analysis of clinical trial data conducted before the final reporting database is 
created/locked.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 86
LY2835219
investigational 
product
pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
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 
planned 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 irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive web-response system
IV
intravenous
KRAS
Kirsten rat sarcoma
LLT
lower level term
LVEF
left ventricular ejection fraction
MATE
multidrug and toxin extrusion protein
mBPI-sf
modified Brief Pain Inventory short form
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
mTOR
mammalian target of rapamycin
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NONMEM
nonlinear mixed effect modelling
OS
overall survival
PD
pharmacodynamics
PDAC
pancreatic ductal adenocarcinoma
PET
positron emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase

I3Y-MC-JPCJ(c) Clinical Protocol
Page 87
LY2835219
PK
pharmacokinetics
PR
partial response
PT
preferred term
PTT
partial prothrombin time
QTc
corrected QT interval
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
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.
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
statistical analysis plan
screen
act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event:  an untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TGF-β
transforming growth factor beta
TGF-RI
TGF-β receptor type I
ULN
upper limit of normal

I3Y-MC-JPCJ(c) Clinical Protocol
Page 88
LY2835219
Appendix 2.
Study Governance, Regulatory, and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any study procedures and prior to the administration of study treatment.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
Ethical Review
Documentation of ERB/IRB 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 ICH guideline on GCP.
The study site’s ERBs/IRBs should be provided with the following:

the current IBs, Package Inserts, and/or Summaries of Product Characteristics and 
updates during the course of the study

the ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance 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

applicable laws and regulations.
Some obligations of Lilly may be assigned to a third-party organization.
Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 89
LY2835219
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. 
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

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
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 Lilly, 
applicable regulatory agencies, and applicable ERBs/IRBs with direct access to original source 
documents.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into Lilly-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 

I3Y-MC-JPCJ(c) Clinical Protocol
Page 90
LY2835219
database system.  All validated data will subsequently be transferred to the Lilly data warehouse, 
using standard Lilly file transfer processes.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome (PRO) measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the 
ERB/IRB 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 or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 91
LY2835219
Appendix 3.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya:
Hemoglobin
Sodium
Hematocrit
Magnesium 
Erythrocyte count (RBC)
Phosphorus 
Mean cell volume (MCV)
Potassium
Mean cell hemoglobin concentration (MCHC)
Chloride
Leukocytes (WBC)
Calcium
Neutrophils (segmented and bands)
Albumin
Lymphocytes
Total protein
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Creatinine Clearancef
Platelets
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Total bilirubin and direct bilirubin
Renal Functiona,d:
Glucose (fasting)c
Cystatin C
Lactate dehydrogenase 
Uric Acid 
Coagulationb,e:
Partial thromboplastin time (PTT) or 
HbA1ca,c
International normalized ratio (INR)
Serum pregnancy test (women of childbearing 
potential only)b
Tumor Markera:
CA19-9
Urine pregnancy test (women of childbearing potential 
only and only where required by local law or 
regulations)b
Abbreviations:  HbA1c = glycated hemoglobin; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated (central) laboratory.
b
Assayed by investigator-designated (local) laboratory.
c
Performed at screening for all patients, and subsequently only for patients receiving LY3023414 (PI3K/mTOR 
inhibitor; Arm B).
d
Performed at screening for all patients, and subsequently as clinically indicated to assess renal function.
e
Performed locally at screening for all patients receiving oral coumarin-derivative anticoagulants and 
subsequently except those patients participating in Arm D and receiving gemcitabine.
f Calculated by Lilly-designated (central) laboratory using Cockcroft-Gault formula only at the screening visit for 
eligibility purposes.  If using local laboratories for eligibility purposes, please see Appendix 9 for calculation.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 92
LY2835219
Appendix 4.
Sampling Schedule for Pharmacokinetics and 
Biomarkers
It is essential that the exact date and time of dose administration for the 3 days prior to PK 
sampling is recorded in the patient diary and transcribed into the eCRF.  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 time is 
normal and expected.  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.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 93
LY2835219
Sampling Schedule for Pharmacokinetics—Abemaciclib Monotherapy (Arm A)
PK Sample 
Number
Cycle(C) and 
Day(D)
PK Sampling Timea
1
C1D1
2 h after abemaciclib dosed in 
clinic
2
C2D1b
Predose (0 h)
3
C3D1b
Predose (0 h)
4
C4D1b
Predose (0 h)
Abbreviations:  h = hours; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites.
b
Samples should be drawn prior to any study treatment on these days.  In the event of a delay to a cycle due to 
toxicity, these predose samples should be drawn on the day when the cycle would have normally begun, to be 
close in time to the labs upon which the decision whether or not to begin a cycle is made.
Sampling Schedule for Pharmacokinetics—Abemaciclib + LY3023414 (Arm B)
PK Sample 
Number
Cycle and 
Day
PK Sampling Timea
1
C1D1
2 h after combination
2
C2D1
b
Predose (0 h)
3
C3D1b
Predose (0 h)
4
C4D1b
Predose (0 h)
Abbreviations:  C = cycle; D = day; h = hour; PK = pharmacokinetics.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites concentrations.  Separate samples of approximately 2 mL of whole blood will be drawn for 
measurement of LY3023414 concentrations.  Abemaciclib and LY3023414 will be administered together, 
approximately at the same time.
b
Samples should be drawn prior to any study treatment on these days.  In the event of a delay to a cycle due to 
toxicity, these pre-dose samples should be drawn on the day when the cycle would have normally begun, to be 
close in time to the labs upon which the decision whether or not to begin a cycle is made.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 94
LY2835219
Intense Sampling Schedule for Pharmacokinetics of Abemaciclib + Galunisertib 
(Safety Lead-in)
PK Sample 
Number
Cycle and 
Day
Dosing of Study Drugs
PK Sampling Time for 
Abemaciclib and Galunisertib
1
C1D1
Abemaciclib
Galunisertib
Predose (0 h)b
2
C1D1
30 min after combination (0.5 h)
3
C1D1
1 hour after combination (1 h)
4
C1D1
2 hours after combination (2 h)
5
C1D1
4 hours after combination (4 h)
6
C1D1
6 hours after combination (6 h)
7
C1D1
8 hours after combination (8 h)
(±1.5 hour to accommodate clinic 
hours)
8
C1D14
Abemaciclib
Galunisertib
Predose (0 h)b
9
C1D14
30 min after combination (0.5 h)
10
C1D14
1 hour after combination (1 h)
11
C1D14
2 hours after combination (2 h)
12
C1D14
4 hours after combination (4 h)
13
C1D14
6 hours after combination (6 h)
14
C1D14
8 hours after combination (8 h) (± 
1.5 hour to accommodate clinic 
hours)
15
C2D1
Abemaciclib
Galunisertib
Predose (0 h)c
16
C3D1
Abemaciclib
Galunisertib
Predose (0 h)c
17
C4D1
Abemaciclib
Galunisertib
Predose (0 h)c
Abbreviations:  C = cycle; D = day; h = hour; min = minute; PK = pharmacokinetic(s).
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites concentrations.  Separate samples of approximately 2 mL of whole blood will be drawn for 
measurement of galunisertib concentrations.  Abemaciclib and galunisertib will be administered together, 
approximately at the same time.
b
If a patient will have galunisertib dosing suspended prior to D14, that the patient should be brought in for PK on 
the morning of the last day of dosing, if possible.
c
Samples should be drawn prior to any study treatment on these days.  In the event of a delay to a cycle due to 
toxicity, these predose samples should be drawn on the day when the cycle would have normally begun, to be 
close in time to the labs upon which the decision whether or not to begin a cycle is made.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 95
LY2835219
Biomarker Sampling Schedule for All Patients
Sample 
Number
Cycle 
and Day
Plasma 
Sampling 
Time
Whole Blood 
Sample (Pharmaco-
genetics)
1
C1D1
Predose
X
1b
C1D14
Predosea
2
C2D1
Predose
3
C3D1
Predose
4-n
C4-n D1
X
30DFU
X
Abbreviations:  30DFU = 30 day follow-up; C = cycle; D = day.
a
For safety lead-in and Arms A, B, and C only.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 96
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 Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time (PT)
Leukocytes (WBC)
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Recommended Autoimmune Serology:
Aspartate aminotransferase (AST)
Anti-nuclear antibodya
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibodya
Creatine phosphokinase (CPK) 
Anti actin antibodya
Abbreviations:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated (central) laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 97
LY2835219
Appendix 6.
Echocardiographic Guidelines
Echocardiography
In this study, ECHO images were to be acquired with the purpose of ascertaining that patients 
enrolled in the Safety Lead-in have (and maintain during the study) baseline normal cardiac 
structure and function, normal pulmonary artery pressure, and absence of significant valvular 
disease (defined herein as no valvular regurgitation except for mild tricuspid, mild mitral, or mild
aortic regurgitation, and no more than mild mitral or aortic valvular stenosis).  Repeated ECHOs 
in each patient will be performed to establish the cardiac safety of galunisertib by comparison 
with the initial studies.  Determination of normalcy status requires objective evaluation of 
cardiac chamber size and function and attention to the use of appropriate techniques in the 
performance of the ECHO examinations, in particular the use of standardized settings during the 
acquisitions of color flow Doppler imaging.  Therefore, because quantitative ECHO is the goal, 
stringent criteria for image quality and reproducibility are essential.
In addition to qualitative assessment of valvular regurgitation when or if detected (trace, mild, 
moderate, or severe according to Singh et al. [1999] and Zoghbi et al. [2003; see below]) and 
qualitative/quantitative assessment of valvular stenosis when or if detected (mild, moderate, or 
severe, using mean and peak pressure gradient in mm Hg and orifice area in cm2 as applicable), 
other ECHO parameters to be serially quantified are:  LV cavity size (diameters, volumes), LV 
ejection fraction, LV mass and mass index, diastolic function based on mitral flow velocity, 
mitral deceleration time, pulmonary venous flow pattern, tissue Doppler, extrapolation of LV 
end-diastolic pressure by E/Em, left atrial volume index, and extrapolation of pulmonary artery 
systolic pressure when obtainable.
An ECHO with no clinically significant abnormalities is one defined specifically as:  the LV 
(Schiller et al. 1989) internal dimension in diastole should be 2.8 cm/m2, the left atrial (Tsang 
et al. 2002) end-systolic volume should be 36 mL/M2, the left ventricular ejection fraction (Oh 
et al. 2006) should be 50% without regional wall motion abnormalities, 2-dimensional 
ECHO-derived LV mass index (Schiller et al. 1989) should be 115 g/M2 for males and 99 
g/M2 for females, the pulmonary artery pressure should be normal (tricuspid regurgitation jet 
velocity 2.5 m/s and/or pulmonary valve flow acceleration time 120 ms), the LV diastolic 
function (Khouri et al. 2004) should be normal (screening:  mitral deceleration time 150 ms and 
250 ms, mitral E/A ratio 0.75 and 1.5, mitral E velocity divided by Doppler mitral annular 
velocity [E/Em] <15), and there should be no evidence for pericardial or congenital or heart 
disease.  In addition, there should be no evidence for more than mild mitral or aortic stenosis 
(mitral valve area should be >2.0 cm2 and aortic valve area should be >1.5 cm2) and no evidence
of more than mild mitral or aortic regurgitation (Singh et al. 1999; Zoghbi et al. 2003).  Patients 
enrolled in the study may have evidence for tricuspid (trace or mild), pulmonary, mitral (trace or 
mild), or aortic (trace or mild) regurgitation by Doppler techniques (Singh et al. 1999; Zoghbi et 
al. 2003).

I3Y-MC-JPCJ(c) Clinical Protocol
Page 98
LY2835219
References
Khouri SJ, Maly GT, Suh DD, Walsh TE. A practical approach to the echocardiographic 
evaluation of diastolic function. J Am Soc Echocardiogr. 2004;17(3):290-297.
Oh JK, Seward JB, Tajik AJ. The echo manual. 3rd ed. Philadelphia: Lippincott, Williams 
Wilkins; 2006.
Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, 
Reicheck N, Sahn D, Schnittger I, Silverman NH, Tajik AJ. Recommendations for quantitation 
of the left ventricle by two-dimensional echocardiography: American Society of 
Echocardiography Committee on Standards, Subcommittee on Quantitation of 
Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2(5):358-367.
Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. 
Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the 
Framingham Heart Study). Am J Cardiol. 1999;83(6):897-902.
Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as 
morphophysiologic expression of left ventricular diastolic dysfunction and relation to 
cardiovascular risk burden. Am J Cardiol. 2002;90(12):1284-1289.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Craft CD, Levine RA, 
Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, 
Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of 
the severity of native valvular regurgitation with two-dimensional and Doppler 
echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 99
LY2835219
Appendix:  Qualitative and Quantitative Parameters for Grading Valvular (Mitral 
and Aortic) Regurgitation Severity
Please refer to references below for information on qualitative and quantitative parameters for 
grading valvular (mitral and aortic) regurgitation severity.
Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. 
Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the 
Framingham Heart Study). Am J Cardiol. 1999;83(6):897-902.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Craft CD, Levine RA, 
Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, 
Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of 
the severity of native valvular regurgitation with two-dimensional and Doppler 
echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 100
LY2835219
Appendix 7.
Inducers and Inhibitors of CYP3A or 
Substrates of CYPS 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.
Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St. John’s wort
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if clinically 
indicated.
Inhibitors of CYP3A
All HIV protease inhibitors
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenadine

I3Y-MC-JPCJ(c) Clinical Protocol
Page 101
LY2835219
Appendix 8.
Drugs Associated with QT Interval 
Prolongation
Drugs with a Risk of Torsades de Pointes
amiodarone
clarithromycin
halofantrine
pentamidine
terfenadine
arsenic trioxide
disopyramide
haloperidol
pimozide
thioridazine
astemizole
dofetilide 
ibutilide
probucol
vandetanib
bepridil
domperidone
levomethadyl
procainamide
chlorpromazine
droperidol
mesoridazine
quinidine
cisapride
citalopram
erythromycin
flecainide
methadone
moxifloxacin
sotalol
sparfloxacin
Drugs with a Possible Risk of Torsades de Pointes
alfuzosin
felbamate
lithium
ranolazine
voriconazole
amantadine
fingolimod
moexipril/HCTZ
risperidone
ziprasidone
atazanavir
foscarnet
nicardipine
roxithromycin
azithromycin
chloral hydrate
clozapine
dolasetron
dronedarone
eribulin
escitalopram
fosphenytoin
gatifloxacin
gemifloxacin
granisetron
indapamide
isradipine
lapatinib
nilotinib
octreotide
ofloxacin
ondansetron
oxytocin
paliperidone
perflutren lipid microspheres
sertindole
sunitinib
tacrolimus
tamoxifen
telithromycin
tizanidine
vardenafil
famotidine
levofloxacin
quetiapine
venlafaxine
Drugs with a Conditional Risk of Torsades de Pointes
amitriptyline
doxepin
itraconazole
ritonavir
trimipramine
ciprofloxacin
fluconazole
ketoconazole
sertraline
clomipramine
fluoxetine
nortriptyline
solifenacin
desipramine
galantamine
paroxetine
trazodone
diphenhydramine
imipramine
protriptyline
trimethoprim-Sulfa
Source:  Arizona Cert Center for Education and Research on Therapeutics page [WWW].

I3Y-MC-JPCJ(c) Clinical Protocol
Page 102
LY2835219
Appendix 9.
Creatinine Clearance Formula
Note: This formula is to be used for calculating CrCl from local laboratory results only.
For serum creatinine 
concentration in mg/dL:
CrCl=
(140−agea) (wt) 0.85 (if female) or 1.0 (if male)
(mL/min)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl=
(140−agea) (wt) 0.85 (if female) or 1.0 (if male)
(mL/min)
0.81 serum creatinine 
(mol/L)
a
Age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault 1976.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 103
LY2835219
Appendix 10. Dose Modification Recommendations for 
Study Treatment-Related Toxicities
Study JPCJ Dose Adjustment Guidance for Study Treatment-Related Toxicities – Arm A
Toxicity Type
Toxicity Severity
Suspend Abemaciclib
Dose-Reduce Abemaciclib
Hematologic
(Neutropenia, 
thrombocytopenia, or 
anemia)
Grade 4
Yes
Yes
Hematologic
(Neutropenia, 
thrombocytopenia, or 
anemia)
Grade 3
Yes
Investigator discretion
Hematologic
Recurrent Grade 3
Yes
Yes
Hematologic: 
Patient requires 
blood cell growth 
factors
Regardless of severity
(Growth factors used 
according to ASCO 
Guidelines)
Yes (for at least 48 hours 
after last dose of blood cell 
growth factors)
Yes
Nonhematologic
(except diarrhea)
Persistent or recurrent 
Grade 2 not resolving with 
maximal supportive measures 
within 7 days
Investigator discretion
Investigator discretion
Nonhematologic
Grade 3 or 4
Yes
Yesa
Diarrhea
Requires hospitalization or 
Grade 3 or 4
Yes
Yes
Diarrhea
Persistent or recurrent 
Grade 2 not resolving with 
maximal supportive measures 
within 24 hours
Recommended
Investigator discretion
Diarrhea
Recurrence despite maximal 
supportive measures after 
resuming same dose 
following initial Grade 2 
diarrhea
Yes
Yes
Abbreviations:  ASCO = American Society of Clinical Oncology.
a
Except toxicities that can be controlled with adequate treatment such as asymptomatic electrolyte disturbances, 
hyperlipidemia, skin rash, nausea, or vomiting.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 104
LY2835219
Study JPCJ Dose Adjustment Guidance for Study Treatment-Related Toxicities – Arm B
Toxicity Type
Toxicity Severity
Suspend 
Abemaciclib
Dose-Reduce 
Abemaciclib
Suspend 
LY3023414
Dose-Reduce LY3023414
Hematologic
(Neutropenia)
Grade 4
Yes
Yes
Yes
Yes, if not resolved to ≤Grade 2 
within 7 days;
if re-occurring dose reduce
Hematologic
(Thrombocytopenia or anemia)
Grade 4
Yes
Yes
Yes
Yes
Hematologic
(Neutropenia, 
thrombocytopenia, or anemia)
Grade 3
Yes
Investigator 
discretion
Yes
Investigator discretion
Hematologic
Recurrent Grade 3
Yes
Yes
See adjustment for 
neutropenia, 
thrombocytopenia, 
and anemia
See adjustment for neutropenia,  
thrombocytopenia, and anemia
Hematologic: Patient requires 
blood cell growth factors
Regardless of severity 
(Growth factors used 
according to ASCO 
Guidelines)
Yes (for at least 
48 hours after last 
dose of blood cell 
growth factors)
Yes
Yes (for at least 
48 hours after last 
dose of blood cell 
growth factors)
Investigator discretion
Diarrhea
Requires hospitalization or 
Grade 3 or 4
Yes
Yes
Recommended
Investigator discretion
Diarrhea
Persistent or recurrent Grade 2 
not resolving with maximal 
supportive measures within 
24 hours
Recommended
Investigator 
discretion
Recommended
Investigator discretion
Diarrhea
Recurrence despite maximal 
supportive measures after 
resuming same dose following 
initial Grade 2 diarrhea
Yes
Yes
Investigator 
discretion
Investigator discretion
Stomatitis
Grade 4
Yes
Yes
Yes
Yes
Stomatitis
Grade 3 
Yes
Yes
Yes
Yes, if not resolved despite 
supportive measures to 
≤Grade 2 within 7 days;
if re-occurring dose reduce
Stomatitis
Persistent or recurrent Grade 2 
not resolving with maximal 
supportive measures 
Investigator 
discretion
Investigator 
discretion
Investigator 
discretion
Investigator discretion

I3Y-MC-JPCJ(c) Clinical Protocol
Page 105
LY2835219
Toxicity Type
Toxicity Severity
Suspend 
Abemaciclib
Dose-Reduce 
Abemaciclib
Suspend 
LY3023414
Dose-Reduce LY3023414
Hyperglycemia
Grade 4
Investigator 
discretion
Investigator 
discretion
Yes
Yes if not resolved despite 
corrective treatment to 
≤Grade 2 within 24 hours;
if re-occurring dose reduce
Hyperglycemia
Grade 3 
Investigator 
discretion
Investigator 
discretion
No –
Initiate/intensify 
corrective 
treatment
Yes, if not resolved despite 
corrective treatment to 
≤Grade 2 within 7 days;
if re-occurring dose reduce
Hyperglycemia
Grade 2 
No –
Initiate/intensify 
corrective 
treatment
No
No –
Initiate/intensify 
corrective 
treatment
No
Other nonhematologic 
Grade 3 or 4
Yes
Yes a
Yes
Yes a
Abbreviations:  ASCO = American Society of Clinical Oncology.
a
Except toxicities that can be controlled with adequate treatment such as asymptomatic electrolyte disturbances, hyperlipidemia, skin rash, nausea, or vomiting.

I3Y-MC-JPCJ(c) Clinical Protocol
Page 106
LY2835219
Study JPCJ Dose Adjustment Guidance for Study Treatment-Related Toxicities – Safety Lead-in
Toxicity Type
Toxicity Severity
Suspend 
Abemaciclib
Dose-Reduce 
Abemaciclib
Suspend 
Galunisertib
Dose-Reduce 
Galunisertib
Cardiotoxicity 
(Moderate or severe heart valve toxicity, 
severe valvular regurgitation [as determined 
by ECHO], congestive heart failure, or 
aneurysm)
Grade 3 or 4
No
No
Yes –
permanently
Not applicable
Hematologic
(Neutropenia, thrombocytopenia, or anemia)
Grade 4
Yes
Yes
Yes
Yes
Hematologic
(Neutropenia, thrombocytopenia, or anemia)
Grade 3
Yes
Investigator 
discretion
Yes
Investigator 
discretion
Hematologic
Recurrent Grade 3
Yes
Yes
Yes
Investigator 
discretion
Hematologic: Patient requires blood cell 
growth factors
Regardless of severity (Growth 
factors used according to 
ASCO Guidelines)
Yes (for at least 
48 hours after 
last dose of 
blood cell 
growth factors)
Yes
Yes (for at least 
48 hours after 
last dose of 
blood cell 
growth factors)
Investigator 
discretion
Diarrhea
Requires hospitalization or 
Grade 3 or 4
Yes
Yes
Recommended
Investigator 
discretion
Diarrhea
Persistent or recurrent Grade 2 
not resolving with maximal 
supportive measures within 
24 hours
Recommended
Investigator 
discretion
Recommended
Investigator 
discretion
Diarrhea
Recurrence despite maximal 
supportive measures after 
resuming same dose following 
initial Grade 2 diarrhea
Yes
Yes
Investigator 
discretion
Investigator 
discretion
Pruritus
Grade 3 or 4
Investigator 
discretion
Investigator 
discretion
Yes
Yes
Pruritus
Persistent or recurrent Grade 2 
not resolving with maximal 
supportive measures 
Investigator 
discretion
Investigator 
discretion
Yes
Investigator 
discretion
Other nonhematologic
Grade 3 or 4
Yes
Yes a
Yes
Yes a
Abbreviations:  ASCO = American Society of Clinical Oncology; ECHO = echocardiogram.
a
Except toxicities that can be controlled with adequate treatment such as asymptomatic electrolyte disturbances, nausea, or vomiting.

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 107
LY2835219
Appendix 11. Protocol Amendment I3Y-MC-JPCJ(c) 
Summary 
An Adaptive, Open-Label, Randomized Phase 2 Study of 
Abemaciclib as a Monotherapy and in Combination with 
Other Agents Versus Choice of Standard of Care 
(Gemcitabine or Capecitabine) in Patients with Previously 
Treated Metastatic Pancreatic Ductal Adenocarcinoma
Overview
Protocol I3Y-MC-JPCJ (A Phase 1 First-in-Human Dose Study of LY3023414 in Patients with 
Advanced Cancer) has been amended.  The new protocol is indicated by Amendment (c) and will 
be used to conduct the study in place of any preceding version of the protocol.
The major overall changes and rationale for the changes made to this protocol are as follows:

Title page and document header were updated to reflect the approval date of the previous 
amendment and/or the current amendment status (c).

The study design section was updated to reflect the removal of the abemaciclib plus 
galunisertib arm (Arm C) from Stages 1 and 2 and indicates that no additional patients 
would be enrolled to the safety lead-in based on Sponsor’s decision.

Appropriate modifications and adjustments were made in exclusion criteria and
treatments to align with the modified study design.

Other minor corrections and editorial changes were made throughout the protocol to 
improve clarity and to secure alignment with the intended study design. These changes 
are not documented below.

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 108
LY2835219
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
1.
Synopsis
Galunisertib (LY2157299) is a small molecule designed to selectively inhibit the serine/threonine kinase of the 
transforming growth factor beta (TGF-β) receptor type I (TGF-RI).  In PDAC, an increase in expression of 
epithelial-mesenchymal transition triggering factors, including TGF-, has been observed and may contribute to the 
high metastatic potential.  In pancreatic cancer cells, a CDK4 and CDK6 inhibitor exerted growth-inhibitory effects, 
although a TGF-RI inhibitor alone was unable to suppress colony growth in 3-D culture.  However, when the 
TGF-RI inhibitor was combined with a CDK4 and CDK6 inhibitor, optimal growth inhibition was achieved.  
These preclinical data provide a basis for exploring the combination of abemaciclib and galunisertib in the current 
study, although with amendment (c) the assessment of this combination is being discontinued.
STAGE 1
Objectives
Endpoints
Primary

To evaluate disease control rate of the abemaciclib 
treatment arms versus the standard-of-care arm 
(gemcitabine or capecitabine)

Disease control rate is the percentage of patients 
with a best overall response of stable disease, 
complete response, or partial response according to 
RECIST 1.1.
Secondary

To evaluate objective response rate of the 
abemaciclib treatment arms versus the 
standard-of-care arm

Objective response rate is the percentage of patients 
with a best overall response of complete response or 
partial response according to RECIST 1.1.

Evaluate safety and tolerability of the abemaciclib 
treatment arms
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs and SAEs

Clinical laboratory tests and vital signs

PK of abemaciclib and its metabolites, as well as
LY3023414

Exposure of abemaciclib, and LY3023414, and 
galunisertib
STAGE 2

To evaluate pain and symptom burden of the 
abemaciclib treatment arms by best response group 
(partial response, stable disease, progressive 
disease) versus the standard-of-care arm

modified Brief Pain Inventory short form (mBPI-sf) 
and the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-
Core 30 (EORTC QLQ-C30)

PK of abemaciclib and its metabolites, as well as
LY3023414 and galunisertib

Exposure of abemaciclib, and LY3023414 and 
galunisertib

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 109
LY2835219

Exposure-response for abemaciclib and
LY3023414and galunisertib

Drug exposure and efficacy outcomes such as 
objective response rate or progression-free survival 
and safety outcomes such as neutropenia and 
diarrhea
Overall Design:
Study I3Y-MC-JPCJ is a multicenter, randomized, open-label, Phase 2 trial in patients with metastatic pancreatic 
ductal adenocarcinoma who have been previously treated with at least one, but no more than 2, prior therapies for 
metastatic disease.  At least one of the prior therapies must have been either gemcitabine-based or fluoropyrimidine-
based therapy.  The safety and efficacy of each investigational arm will be assessed versus the standard-of-care arm 
by implementing a 2-stage design.  For Stage 1, the primary analyses of safety and efficacy will be evaluated for 
each of 3 2 investigational arms versus a standard-of-care arm approximately 16 weeks after the last planned Stage 1 
patient enters treatment.  The 3 2 investigational arms include abemaciclib monotherapy (Arm A) and, abemaciclib 
plus LY3023414 (PI3K/mTOR dual inhibitor; Arm B), and abemaciclib plus galunisertib (Arm C).
Number of Patients:
Safety Lead-in:
According to the initial protocol, pPrior to initiating Stage 1 of the study, a safety lead-in period for abemaciclib plus 
galunisertib willwas to be conducted with up to 12 patients.  At the time of amendment (c), Lilly determined no 
additional patients would be enrolled to the safety lead-in and that Arm C (abemaciclib plus galunisertib) would be 
removed from the study.Initially, 6 patients will be enrolled to a safety lead-in period for abemaciclib plus 
galunisertib.  Pending an assessment of safety after 1 cycle (28 days) of treatment, 6 additional patients may be 
enrolled to the safety lead-in.
Stage 1:
For Stage 1, a total of approximately 100 75 patients (25 patients per arm) will be randomized in a 1:1:1:1 ratio to 
4 3 treatment arms.  Randomization will be stratified by number of prior systemic therapies (1 versus 2).

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 110
LY2835219
Treatment Arms and Duration:
Dose and Schedule
Arm
A
Abemaciclib (CDK4 and CDK6 inhibitor) 200 mg BID with or without food continuous dosing for 28-day 
cycles
Ba
Abemaciclib 150 mg BID with or without food continuous dosing for 28-day cycles
LY3023414 (PI3K/mTOR dual inhibitor) 150 mg BID with or without food continuous dosing for 28-day 
cycles
Ca
Abemaciclib 150 mg BIDb with or without food continuous dosing for 28-day cycles
Galunisertib (TGF-RI inhibitor) 150 mg BID with or without food dosed for 14 days followed by 14 days 
rest for 28-day cycles
D
Standard-of-Care Choice of:
     Gemcitabine 1000 mg/m2 over 30 minutes 
     intravenously on the following days of a 28-day cycle.
          •   Cycle 1:  Days 1, 8, 15, and 22
          •   Cycle 2 and beyond:  Days 1, 8, and 15
                                 OR
     Capecitabine 1250 mg/m2 administered orally BID within 30
     minutes after a meal (morning and evening; equivalent to 2500
     mg/m2 total daily dose) for 2 weeks followed by a 1-week rest 
     period given as 21-day cycles
Abbreviations:  BID = twice daily; CDK = cyclin-dependent kinase; PI3K = phosphatidylinositol 3-kinase;
TGFβ-RI = transforming growth factor beta receptor type I.
a
Oral combination agents are to be taken at approximately the same time.  There is no specific order of 
administration.
b
The dose of abemaciclib in combination with galunisertib may be reduced to 100 mg BID based on safety 
data from the Safety Lead-In Period

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 111
LY2835219
Table JPCJ.2.1.
Baseline Schedule of Activities
Day Relative to C1D1
28
14
7
Procedure
Instructions
Serum pregnancy test
X
Performed by local laboratory.  Applies only to 
women of childbearing potential.  Must have a
negative serum pregnancy test within 7 days of 
the first dose of study drug (that is, Day -7 to
Day -1).
ECG
X
To be performed and read locally
Administer mBPI-sf and EORTC 
QLQ-C30 questionnaires
X
Patient should complete mBPI-sf and EORTC 
prior to extensive interaction with site staff.
Cardiac Assessments
ECG
X
To be performed and read locally
Echocardiogram
X
To be performed and read locally (see 
Appendix 6)
Chest CT scan with contrast or MRI 
(safety)
X
Performed locally for cardiac monitoring
NOTE:  At screening, if the MRI or CT scan 
with contrast done for tumor assessment has 
properly assessed the great vessels and the 
heart, this same scan may be used for safety 
screening.
Sample Collection
See Appendix 4.
Tissue samples
X
Confirm archival tumor tissue available.  For 
patients without available FFPE tumor tissue at 
baseline, a core needle biopsy (minimum 3 
cores) obtained prior to study treatment 
initiation is highly encouraged, but not 
required.
3.1.
Study Rationale
Given the unmet medical need for second- and third-line treatment options, this study aims to 
explore the safety and efficacy of abemaciclib monotherapy, as well as abemaciclib in 
combination with other agents (including a PI3K/mTOR dual inhibitor and a TGF-RI inhibitor), 
versus choice of standard of care (gemcitabine or capecitabine) in patients with previously 
treated metastatic PDAC
3.2.4.Transforming Growth Factor-Beta and Role in Pancreatic Ductal 
Adenocarcinoma
In PDAC, an overexpression of epithelial-mesenchymal transition triggering factors, including 
TGF-, has been observed and may contribute to the high metastatic potential.  In pancreatic 
cancer cells, a CDK4 and CDK6 inhibitor was found to exert growth-inhibitory effects, although 
a TGF-RI inhibitor alone was unable to suppress colony growth in 3-dimensional culture.  
However, when the TGF-βRI inhibitor was combined with a CDK4 and CDK6 inhibitor, optimal 
growth inhibition was achieved (Liu and Korc 2012).  These preclinical data provide a basis for 

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 112
LY2835219
exploring the combination of abemaciclib and galunisertib in the current study, although, with 
amendment (c) the assessment of this combination is being discontinued (see Section 5.4.3).
4.
Objectives and Endpoints
Table JPCJ. 4.1.
Stage 1 Objectives and Endpoints
Secondary

To evaluate objective response rate of the 
abemaciclib treatment arms versus the 
standard-of-care arm

Objective response rate is the percentage of patients 
with a best overall response of complete response or 
partial response according to RECIST 1.1.

Evaluate safety and tolerability of the abemaciclib 
treatment arms
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs and SAEs

Clinical laboratory tests and vital signs

PK of abemaciclib and its metabolites, as well as
LY3023414, and galunisertib

Exposure of abemaciclib and LY3023414 
Tertiary

Assess the relationship between biomarkers and 
clinical outcome

Biomarker research may be assessed from tumor, 
whole blood, and plasma samples, unless precluded 
by local regulations.
Table JPCJ. 4.2.
Objectives and Endpoints Stage 2
Objectives
Endpoints
Secondary

To evaluate disease control rate of the abemaciclib 
treatment arms versus the standard-of-care arm

Disease control rate is the percentage of patients 
with a best overall response of stable disease, 
complete response, or partial response according to 
RECIST 1.1.
To evaluate clinical benefit rate of the abemaciclib 
treatment arms versus the standard-of-care arm
Clinical benefit rate is the percentage of patients with a 
best overall response of complete response, or partial 
response, or  stable disease for ≥6 months according to 
RECIST 1.1.

To evaluate objective response rate of the 
abemaciclib treatment arms versus the 
standard-of-care arm

Objective response rate is the percentage of patients 
with a best overall response of complete response or 
partial response according to RECIST 1.1

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 113
LY2835219

To evaluate duration of response of the abemaciclib 
treatment arms versus the standard-of-care arm

Duration of response is measured from the date of 
first evidence of complete response or partial 
response to the date of objective progression or the 
date of death due to any cause, whichever is earlier. 

To evaluate overall survival of the abemaciclib 
treatment arms versus the standard-of-care arm

Overall survival is measured from the date of 
randomization to the date of death from any cause.

Evaluate the kinetics of carbohydrate antigen (CA) 
19-9

Change from baseline in CA 19-9

Evaluate safety and tolerability
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs and SAEs

Clinical laboratory tests and vital signs

To evaluate pain and symptom burden of the 
abemaciclib treatment arms by best response group 
(partial response, stable disease, or progressive 
disease) versus the standard-of-care arm

modified Brief Pain Inventory short form (mBPI-sf) 
and the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-
Core 30 (EORTC QLQ-C30)

PK of abemaciclib and its metabolites, as well as 
LY3023414, and galunisertib

Exposure of abemaciclib and LY3023414, and 
galunisertib

Exposure-response for abemaciclib and
LY3023414, and galunisertib

Drug exposure and efficacy outcomes such as 
objective response rate or progression-free survival 
and safety outcomes such as neutropenia and 
diarrhea
5.1.
Overall Design
Study I3Y-MC-JPCJ (JPCJ) is a multicenter, randomized, open-label, Phase 2 study in patients 
with metastatic PDAC who have been previously treated with at least one, but no more than 2 
prior therapies.  At least one of the prior therapies must have been either gemcitabine-based or 
fluoropyrimidine-based therapy.  This study will evaluate the safety and efficacy of abemaciclib 
as a monotherapy or in combination with other agents versus choice of standard of care 
(gemcitabine or capecitabine) by implementing a 2-stage design.
Currently, nNo safety data have had been generated for the combination of abemaciclib and 
galunisertib.  Therefore, a Safety Lead-in Period was included in the original protocolprior to the 
randomization of patients to each of 4 study arms, a safety lead-in period will be conducted with 
up to 12 patients (see Section7.2).
Following the safety lead-inWith amendment (c), Stage 1 of the study will randomize patients 
1:1:1:1 into each of the following arms (25 patients per arm):

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 114
LY2835219

Arm A:  Abemaciclib (LY2835219),

Arm B:  Abemaciclib plus LY3023414 (PI3K/mTOR Dual Inhibitor), or

Arm C:  Abemaciclib plus galunisertib (LY2157299, TGF-RI Inhibitor), or

Arm D:  Choice of Standard of Care (gemcitabine or capecitabine).
For Stage 1, the analyses of safety and efficacy will be evaluated approximately 16 weeks after 
the last planned Stage 1 patient enters treatment.  All data accumulated during this period 
(beyond 16 weeks for some patients, if available), will be included in the analysis.  Initial 
evaluations will compare investigational arms (Arms A and, B, and C) with the standard-of-care 
arm (Arm D), and will include assessment of disease control rate (DCR;
Old Figure deleted

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 115
LY2835219
New Figure Inserted
Abbreviations:  ECOG = Eastern Cooperative Oncology Group; DCRdiff = disease 
control rate difference; N = number of patients; R = randomize; RECIST 
v1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; PS = performance 
status.
a    At the time of amendment (c), Lilly determined no additional patients would be 
enrolled to the safety    lead-in.
Figure JPCJ.5.1.
Illustration of study design
5.2.
Number of Patients
Prior to initiating Stage 1 of the study, a safety lead-in period with abemaciclib plus galunisertib
wasill to be conducted with up to 12 patients. Initially, 6 patients will be enrolled to receive 
abemaciclib plus galunisertib.  Pending an assessment of safety after 1 cycle (28 days) of 
treatment, 6 additional patients may be enrolled to the safety lead-in at a reduced dose of 
abemaciclib (see Section7.2), however, as discussed in more detail in Section 5.4.3, Lilly has 
decided not to continue the assessment of abemaciclib in combination with galunisertib.
For Stage 1, a total of approximately 100 75 patients (25 patients per arm) will be randomized in 
a 1:1:1:1 ratio to 4 3 treatment arms. 

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 116
LY2835219
5.4.
Scientific Rationale for Study Design
Study JPCJ is a Phase 2 adaptive design study that will be conducted in 2 stages.  Stage 1 
(following completion of the safety lead-in period) will permit decision-making in order to 
determine if either abemaciclib monotherapy or abemaciclib in combination with other agents 
provides a level of disease control that is at least comparable to the standard of care.  
5.4.3.Rationale for Amendment (c)
Study JPCJ was amended to discontinue enrollment to the safety lead-in for abemaciclib plus 
galunisertib and remove Arm C (abemaciclib in combination with galunisertib), as well as all 
galunisertib-related baseline procedures and eligibility requirements.
The combination testing strategy for study JPCJ was reassessed considering other priorities with 
Lilly molecules in clinical development, and it was decided not to continue the investigation of 
abemaciclib in combination with galunisertib in this study. This decision was not triggered by 
safety concerns with the combination.
5.6.5.5.
Justification for Doses of Investigational Treatments
The dose of LY3023414 (150 mg BID) used in this study was the MTD identified in 
combination with abemaciclib 150 mg BID in the Phase 1b Study JPBJ.
The dose of galunisertib (150 mg BID) used in this studye safety lead-in period has demonstrated 
a favorable risk/benefit profile across multiple studies, when administered as a single agent or in 
combination with various chemotherapies.  
The current study will assess the safety and pharmacokinetics (PK) of abemaciclib 150 mg BID 
plus galunisertib 150 mg BID in for the 7 patients enrolled in a safety lead-in period at the time 
of amendment (c), but will not assess this combination in the randomized period of the study
prior to initiation of Stage 1.
6.2.
Exclusion Criteria
[15] have a personal history of any of the following conditions:  syncope of either 
unexplained or cardiovascular etiology, ventricular arrhythmia (including but 
not limited to ventricular tachycardia and ventricular fibrillation), or sudden 
cardiac arrest.
Exception:  Patients with controlled atrial fibrillation for ≥30 days prior to 
study treatment initiation are eligible.severe cardiac disease:

Myocardial infarction within 6 months prior to study screening, unstable angina 
pectoris, New York Heart Association Class III/IV congestive heart failure, or 
uncontrolled hypertension.

Documented major electrocardiogram (ECG) abnormalities, at the investigator’s 
discretion (for example, symptomatic or sustained atrial or ventricular 
arrhythmias, second- or third-degree atrioventricular block, bundle branch blocks, 

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 117
LY2835219
ventricular hypertrophy, or recent myocardial infarction), not responding to 
medical treatments or not clinically stable for at least 6 months prior to study 
screening.

Major cardiac abnormalities documented by echocardiography (ECHO) with 
Doppler that are not clinically stable for at least 6 months prior to study 
screening (for example, severe heart valve function defect and/or left 
ventricular ejection fraction [LVEF] <50%, evaluation based on the 
institutional lower limit of normal).  For additional details, refer to 
Echocardiography Protocol (Appendix 6).
[16] Predisposing conditions that are consistent with development of aneurysms of 
the ascending aorta or aortic stress (for example, family history of aneurysms, 
Marfan Syndrome, bicuspid aortic valve, or evidence of damage to the large 
vessels of the heart documented by Computed Tomography [CT] scan or 
magnetic resonance imaging [MRI] with contrast).Deleted Criterion
[23] have previously received treatment with any CDK4 and 6 inhibitor, TGF-
inhibitor, or PI3K and/or mTOR inhibitor or have a known hypersensitivity to 
any component of the investigational products in this study.

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 118
LY2835219
Table JPCJ. 7.1. Treatment Regimens
Dose and Schedule
Arm
A
Abemaciclib (CDK4 and CDK6 inhibitor) 200 mg BID with or without food continuous dosing for 
28-day cycles
Ba
Abemaciclib 150 mg BID with or without food continuous dosing for 28-day cycles
LY3023414 (PI3K/mTOR dual inhibitor) 150 mg BID with or without food continuous dosing for 
28-day cycles
Ca
Abemaciclib 150 mg BIDb with or without food continuous dosing for 28-day cycles
Galunisertib (TGF-RI inhibitor) 150 mg BID with or without food dosed for 14 days followed by 
14 days rest for 28-day cycles
D
Standard-of-Care Choice of:
     Gemcitabine 1000 mg/m2 over 30 minutes 
     intravenously on the following days of a 28-day cycle.
          •   Cycle 1:  Days 1, 8, 15, and 22
          •   Cycle 2 – n:  Days 1, 8, and 15
                                OR
     Capecitabine 1250 mg/m2 administered orally BID within 30 
     minutes after a meal (morning and evening; equivalent to 2500 
     mg/m2 total daily dose) for 2 weeks followed by a 1-week rest 
     period given as 21-day cycles.
Abbreviations:  BID = twice daily; CDK = cyclin-dependent kinase; TGF-RI = transforming growth factor beta 
receptor type I.
a
Oral combination agents are to be taken at approximately the same time.  There is no specific order of 
administration.
b
The dose of abemaciclib in combination with galunisertib may be reduced to 100 mg BID based on safety data 
from the Safety Lead-In Period.
7.2.
Method of Treatment Assignment
Safety Lead-in
For the safety lead-in, any patient who was discontinued from the study before receiving at least 
75% of the planned doses of abemaciclib and galunisertib in Cycle 1 was deemed nonevaluable 
for assessment of that dose level and was replaced, unless that patient experienceds a DLT before 
withdrawal.
Based on the original protocol, pPrior to the randomized portion of the study (Stage 1 and Stage 
2), up to 12 patients who satisfiedy all inclusion criteria and none of the exclusion criteria will 
bewere to be enrolled to a safety lead-in period.  Initially, 6 patients willwere to be enrolled to 
receive abemaciclib plus galunisertib.  If the combination of abemaciclib 150 mg BID and 
galunisertib 150 mg BID is was not tolerated (that is, more than one patient experiences 
experienced a DLT within the first 28-day cycle), then the dose of abemaciclib will was to be 

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 119
LY2835219
reduced to 100 mg BID and an additional 6 patients enrolled at this dose.  If the combination is 
was not tolerated (that is, more than one patient experienceds a DLT within the first 28-day 
cycle) at the reduced dose of abemaciclib, then patients will were not to be enrolled to the 
abemaciclib plus galunisertib arm (Arm C).
For the safety lead-in, any patient who is was discontinued from the study before receiving at 
least 75% of the planned doses of abemaciclib and galunisertib in Cycle 1 wasill be deemed 
nonevaluable for assessment of that dose level and may bewas replaced unless that patient 
experienceds a DLT before withdrawal.  Nonevaluable patients may bewere to be replaced to 
ensure that no fewer than 6 patients received at least 75% of the planned doses of abemaciclib 
and galunisertib in Cycle 1 at each dose level, unless enrollment to that cohort hwas stopped 
because more than one patient at that dose level has experienced a DLT.  
At the time of amendment (c), Lilly determined no additional patients would be enrolled to the 
safety lead-in and that Arm C would be removed from the study.  A total of 7 patients had been 
enrolled in the safety lead-in and 2 were still on treatment.  Ongoing patients enrolled to the 
safety lead-in may continue on study treatment if, at the discretion of the treating investigator, 
the patients are benefiting from therapy and not considered at risk from a safety standpoint.
While it is not expected, it is possible that galunisertib will enhance the toxicity of abemaciclib 
or vice versa.  Toxicities werewill be graded according to Common Terminology Criteria for 
Adverse Events Version 4.0 (CTCAE v4.0).  If multiple toxicities wereare observed, the 
presence of DLTs was toshould be based on the most severe toxicity experienced.  During the 
Safety Lead-in Period only, DLTs werewill be defined as any of the following events that 
occurred during the first cycle of administration of the combination of abemaciclib and 
galunisertib and awere considered by the investigator to be attributable to either study treatment 
alone or the combination of the two:

Grade 3 or 4 nausea or electrolyte disturbance that persistsed more than 48 hours despite 
maximal supportive intervention

Grade 3 vomiting or diarrhea that persistsed more than 48 hours despite maximal 
supportive intervention

Grade 4 vomiting or diarrhea of any duration

Grade 4 hematologic toxicity that persisteds more than 5 days

Grade 3 thrombocytopenia with bleeding

Grade 4 thrombocytopenia of any duration

Grade 3 or 4 neutropenia with fever
After completion of As further enrollment to the Safety Lead-in will not occur and Arm C is 
removed with amendment (c), the randomized portion of the study will begin.  Randomization 
will be stratified by number of prior systemic therapies (1 versus 2).
Stage 1

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 120
LY2835219
Patients will be randomized 1:1:1:1 among the investigational arms and the standard-of-care 
arm, to provide a total of 25 patients per arm.  Patients assigned to the standard-of-care arm 
(Arm D) will be administered either gemcitabine or capecitabine, at the discretion of the 
investigator. In determining which standard-of-care therapy to administer, the investigator 
should take into consideration NCCN Guidelines, which indicate that patients previously treated 
with gemcitabine-based therapy should receive capecitabine and patients previously treated with 
fluoropyrimidine-based therapy should receive gemcitabine.
7.2.1.Selection and Timing of Doses
Patients should not chew or crush these study treatments.  If the patient misses or vomits a dose 
of oral study treatment, the patient should skip the dose and take the next dose as scheduled.  For 
patients assigned to the safety lead-in or Arm B or C, combination agents are to be taken at 
approximately the same time, in no specific order of administration.
A delay of a cycle due to holiday, weekend, bad weather, or other unforeseen circumstances will 
be permitted for a maximum of 7 days and not counted as a protocol deviation.  A cycle delay 
due to toxicity is permitted up to 14 days (see Section 7.4.4).  In the event only 1 of 2 study 
treatments for patients in the safety lead-in or Arms B or C is suspended or if each study 
treatment is reintroduced in a sequential manner, Day 1 of the next cycle is considered the date 
that the first of the individual study treatments is dispensed and administered to the patient.
7.4.1.Dosage Modifications for Investigational Agents
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 4.0 will be used to assess AEs.  Treatment may be 
suspended for a maximum of 14 days to allow a patient sufficient time for recovery from study 
treatment-related toxicity.  If a patient does not recover from the toxicity within 14 days from the 
time of last treatment, the patient should be considered for permanent discontinuation from study 
treatment.  In exceptional circumstances, a delay >14 days is permitted upon agreement between 
the investigator and the Lilly CRP.  Patients in the safety lead-in receiving galunisertib must 
receive a minimum of 10 days of dosing in a 28-day cycle.
Dose reductions for investigational agents should be as shown inTable JPCJ.7.3.  Study 
treatment must be reduced sequentially by one dose level unless an exception is granted in 
consultation with the Lilly CRP.  Mid-cycle dose reductions for abemaciclib may be 
implemented by informing patients to reduce the number of 50-mg capsules taken for each dose 
(with dose reductions appropriately documented in the electronic case report form [eCRF]); 
however, mid-cycle dose reductions of LY3023414 and galunisertib will require patients to 
return to the clinic and the site to call the IWRS Help Desk to dispense new study treatment.  If 1 
study treatment (Safety Lead-in or Arm B or C) has been maximally dose-reduced due to toxicity 
and the toxicity has not resolved, patients may continue to receive the other study treatment at 

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 121
LY2835219
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.
7.4.2.Dosage Modifications for Gemcitabine
A new cycle of gGemcitabine will not be given unless the ANC is ≥1.0×109/L and platelets are 
≥100×109/L.  All nonhematologic toxicities (excluding alopecia) should also return to CTCAE 
Grade ≤1 or baseline prior to reinitiating treatment.  Treatment may be delayed up to 4 weeks 
after completion of the 28-day cycle to allow sufficient time for recovery.
7.7.
Concomitant Therapy
For patients assigned to abemaciclib treatment arms (safety lead-in as well as Arms A and, B, 
and C) or those assigned to Arm D who are receiving capecitabine, prothrombin time or 
international normalized ratio must be routinely monitored if patients are receiving concomitant 
oral coumarin-derivative anticoagulants
7.7.2.Management of Diarrhea
Upon treatment initiation, patients assigned to abemaciclib treatment arms (Safety Lead-In, as 
well as Arms A,and B, and C) or those assigned to Arm D who are receiving capecitabine should 
receive instructions on the management of diarrhea.  In the event of diarrhea, supportive 
measures should be initiated as early as possible.  These include the following:
8.1.
Discontinuation from Study Treatment
For patients assigned to the Safety Lead-in or Arm B or Arm C, if 1 study drug is discontinued 
due to toxicity, patients may continue to receive the other study drug until a discontinuation 
criterion has been met.
Patients will be discontinued from all study treatment in the following circumstances:
8.2.
Discontinuation from the Study
Patients who discontinue from the study early will continue to be followed according to the Post-
Treatment have end-of-study procedures performed as shown in the Schedule of Activities
(Section 2).
9.1.
Efficacy Assessments
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Radiological scan of the thorax, abdomen, and pelvis is required at screening; 
subsequently, scans of the thorax for tumor assessments (CT of the chest for safety is required 
per the Schedule of Activities for patients in the safety lead-in Arm C; see Section 9.4.1) are 
required only for those patients with evidence of disease on the baseline scan or if clinically 
indicated (that is, progressive disease is suspected).

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 122
LY2835219
9.4.1.Cardiac Monitoring
Hence, cardiotoxicity monitoring must be performed for patients participating in the Safety 
Lead-in or Arm C of this study, based on echocardiographs with Doppler and Chest CT/MRI 
(see Schedule of Activities [Section 2] andAppendix 6).
Chest CT Scan with Contrast or MRI (Safety Lead-in and Arm C Patients Only)
A chest CT scan with contrast or MRI is was required at screening for all patients in the Safety 
Lead-in, and subsequently according to the Schedule of Activities (see Section 2) for these 
patients participating in the Safety Lead-in or Arm C.  The purpose of this safety assessment is to 
detect aneurysm formation of the ascending aorta and aortic arch.  If a CT scan with contrast or 
MRI has been done as part of the patient’s tumor assessment, this scan may be used for safety 
screening if the scan has properly assessed the great vessels and the heart.  The same method of 
assessment used at screening should be used for each patient throughout the evaluation period.
Echocardiogram with Doppler (Safety Lead-in and Arm C Patients Only)
Echocardiography with Doppler (ECHO/Doppler) will was be locally assessed at screening for 
all patients in the Safety Lead-in, and subsequently according to the Schedule of Activities (see 
Section 2) for these patients participating in the Safety Lead-in or Arm C, and safety decisions 
made by physicians or a team of people who are qualified by experience or training.  Individuals 
so qualified must be identified at each Saferty Lead-in site.  The same person should be 
responsible for reading the ECHO on any individual study patient.  Echocardiograms will be as 
performed as indicated in the Schedule of Activities (see Section 2) and according to Appendix 6 
for all patients at screening, and subsequently for all patients participating in the Safety Lead-in 
or Arm C.  The ECHO will be read locally
9.5.
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected as shown in Appendix 4.  During the Safety 
Lead-in as well as Stage 1, patients receiving the combination of abemaciclib and galunisertib 
will undergo intense PK sampling until notified by Lilly that this intense sampling is no longer 
required.  Subsequently, a sparse sampling schedule will be implemented.  For all patients 
participating in any of the stages/arms the study, the PK sample collection should occur on the 
day that clinical laboratory samples are collected for the purposes of eligibility or health 
monitoring, corresponding to the originally planned next visit/cycle
9.7.1.Whole Blood Samples for Pharmacogenetic Research
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 for a 
maximum of 15 years after the last patient visit for the study, or for a shorter period if local 
regulations and/or ethical review boards (ERBs)/institutional review boards (IRBs) impose 
shorter time limits, at a facility selected by Lilly or its designee.  This retention period enables 
use of new technologies, response to questions from regulatory agencies, and investigation of 

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 123
LY2835219
variable response that may not be observed until later in the development of abemaciclib, 
galunisertib, or LY3023414 or after these study treatments become commercially available
9.8.2. Tissue Samples for Nonpharmacogenetic Biomarker Research
Patients may be asked to undergo collection of an additional core needle biopsy specimen and 
blood sample after treatment with abemaciclib, galunisertib, LY3023414, gemcitabine, or 
capecitabine has been initiated or after disease progression.  If requested, this biopsy specimen 
and blood sample will be used to further investigate molecular features that may explain 
treatment response and resistance mechanisms.
9.9.
Health Outcomes
The primary health outcomes research goal is to determine if abemaciclib combination therapy is 
able to palliate pain, as measured by the modified Brief Pain Inventory-short form (mBPI-sf)
(Cleeland and Ryan 1994).  Additionally, the European Organisation for Research and Treatment 
of Cancer (EORTC) QLQ-C30 (Aaronson et al. 1993) will assess the broader impact of
abemaciclib combination therapy on symptoms, functioning and quality of life.
10.1. Sample Size Determination
According to the original study protocol, pPrior to randomization for Stage 1, approximately 6 to 
12 patients will were to be enrolled in the safety lead-in part of the study.  However, with 
amendment (c), no additional patients will be enrolled to the safety lead-in and Arm C 
(abemaciclib plus galunisertib) will be removed.
10.3.1.
Efficacy Analyses
Stage 1 analysis will be performed approximately 16 weeks after the last planned Stage 1 patient 
enters treatment.  All tumor assessment data accumulated during this period (beyond 16 weeks 
for some patients, if available), will be included in the assessment of DCR.  This analysis will 
compare DCR in the investigational arms (Arms A, and B, and C) to the standard-of-care arm 
(Arm D).  
10.3.5.
Stage 1 Analyses
The Stage 1 analysis of efficacy will be conducted under the guidance of an internal Assessment 
Committee (AC) after the last planned Stage 1 patient has enrolled and completed at least 
16 weeks of treatment or have discontinued (whichever comes earlier).  All data accumulated 
during this period (beyond 16 weeks for some patients, if available), will be included in the 
analysis.  The purpose of this analysis is to evaluate safety and efficacy (DCR) to select which 
arms will continue to Stage 2.  The AC will include an external physician as well as the study 
statistician, Global Patient Safety physician, and Medical Director.
Appendix 4.
Sampling Schedule for Pharmacokinetics and 
Biomarkers

I3Y-MC-JPCJ(c) Clinical Protocol
  Page 124
LY2835219
Intense Sampling Schedule for Pharmacokinetics of Abemaciclib + Galunisertib 
(Safety Lead-in and Arm C) 
Intense PK sampling will be performed until notified by Lilly that this intense sampling is no 
longer required.  Subsequently, the sparse sampling schedule will be implemented
Sparse Sampling Schedule for Pharmacokinetics—Abemaciclib + Galunisertib 
(Safety Lead-in and Arm C)
Sparse PK sampling will be performed ONLY after notification by Lilly that intense sampling is 
no longer required.
PK Sample 
Number
Cycle and 
Day
PK Sampling Timea
1
C1D1
2 h after combination
2
C1D14b
Predose (0 h)
3
C2D1
c
Predose (0 h)
4
C3D1c
Predose (0 h)
5
C4D1c
Predose (0 h)
Abbreviations:  C = cycle; D = day; h = hour; PK = pharmacokinetic(s).
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites concentrations.  Separate samples of approximately 2 mL of whole blood will be drawn for 
measurement of galunisertib concentrations.  Abemaciclib and galunisertib will be administered together.
b
If a patient will have galunisertib dosing suspended prior to D14, that the patient should be brought in for PK on 
the morning of the last day of dosing, if possible.
c
Samples should be drawn prior to any study treatment on these days.  In the event of a delay to a cycle due to 
toxicity, these predose samples should be drawn on the day when the cycle would have normally begun, to be 
close in time to the labs upon which the decision whether or not to begin a cycle is made.
Appendix 6.
Echocardiographic Guidelines
Echocardiography
In this study, ECHO images will were be acquired with the purpose of ascertaining that patients 
enrolled in the Safety Lead-in in the study have (and maintain during the study) baseline normal 
cardiac structure and function, normal pulmonary artery pressure, and absence of significant 
valvular disease (defined herein as no valvular regurgitation except for mild tricuspid, mild 
mitral, or mild aortic regurgitation, and no more than mild mitral or aortic valvular stenosis).

Leo Document ID = 70ff869a-01f4-4e80-9672-ce2aefd1fca4
Approver: 
Approval Date & Time: 29-Jun-2017 11:17:23 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 29-Jun-2017 15:45:39 GMT
Signature meaning: Approved
PPD
PPD