Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo Plus Cisplatin and Gemcitabine as First-Line Treatment in Patients With Advanced or Metastatic Biliary Tract Cancer
Phase: PHASE2
Conditions: Biliary Tract Cancer, Metastatic Cancer, Advanced Cancer
Sponsor: Eli Lilly and Company

Protocol I3O-MC-JSBF(a) 
 
 
Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo plus 
Cisplatin and Gemcitabine as First-Line Treatment in Patients with Advanced or Metastatic 
Biliary Tract Cancer 
 
NCT02711553 
 
Approval Date: 30-Mar-2016 
 
 
 

I3O-MC-JSBF(a) Clinical Protocol
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Protocol I3O-MC-JSBF(a)
Randomized, Double-Blind, Phase 2 Study of Ramucirumab 
or Merestinib or Placebo plus Cisplatin and Gemcitabine as 
First-Line Treatment in Patients with Advanced or Metastatic 
Biliary Tract Cancer
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
merestinib (LY2801653) and ramucirumab (LY3009806), 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.
Merestinib (LY2801653) and Ramucirumab (LY3009806)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 09-Dec 2015.
Amendment (a) Electronically Signed and Approved by Lilly on
on approval date provided below.
Approval Date: 30-Mar-2016 GMT

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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................24
3.1.
Study Rationale............................................................................................................24
3.1.1.
Biliary Tract Cancers ...........................................................................................24
3.1.1.1.
Rationale for Exploration of Ramucirumab Combination 
Therapy in BTC..............................................................................................24
3.1.1.2.
Rationale for Exploration of Merestinib Combination 
Therapy in BTC..............................................................................................25
3.2.
Background..................................................................................................................27
3.2.1.
Ramucirumab.......................................................................................................27
3.2.2.
Merestinib............................................................................................................27
3.3.
Benefit/Risk Assessment..............................................................................................30
4.
Objectives and Endpoints..................................................................................................31
5.
Study Design.....................................................................................................................32
5.1.
Overall Design .............................................................................................................32
5.2.
Number of Patients.......................................................................................................33
5.3.
End of Study Definition ...............................................................................................33
5.4.
Scientific Rationale for Study Design...........................................................................33
5.5.
Justification for Dose ...................................................................................................34
5.5.1.
Cisplatin and Gemcitabine ...................................................................................34
5.5.2.
Merestinib............................................................................................................34
5.5.3.
Ramucirumab.......................................................................................................34
6.
Study Population...............................................................................................................37
6.1.
Inclusion Criteria..........................................................................................................37
6.2.
Exclusion Criteria ........................................................................................................39
6.3.
Lifestyle Restrictions....................................................................................................41
6.4.
Screen Failures.............................................................................................................41
7.
Treatments........................................................................................................................42
7.1.
Treatments Administered .............................................................................................42
7.1.1.
Packaging and Labelling ......................................................................................43
7.1.1.1.
Ramucirumab or Placebo (Intravenous) ..........................................................43
7.1.1.2.
Merestinib or Placebo (Oral)...........................................................................43
7.1.1.3.
Gemcitabine ...................................................................................................43
7.1.1.4.
Cisplatin.........................................................................................................44

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7.2.
Method of Treatment Assignment ................................................................................44
7.2.1.
Selection and Timing of Doses.............................................................................44
7.2.1.1.
Premedication.................................................................................................45
7.2.1.1.1.
Premedication Prior to Administration of 
Ramucirumab/Placebo (Intravenous) ........................................................45
7.2.1.1.2.
Premedication Prior to Administration of Cisplatin 
and Gemcitabine.......................................................................................45
7.2.1.2.
Administration of Ramucirumab/Placebo (Intravenous)..................................45
7.2.1.2.1.
Treatment Requirements for Ramucirumab/Placebo 
(Intravenous) ............................................................................................45
7.2.1.3.
Administration of Merestinib/Placebo (Oral) ..................................................46
7.2.1.4.
Administration of Cisplatin.............................................................................46
7.2.1.5.
Administration of Gemcitabine.......................................................................47
7.3.
Blinding .......................................................................................................................47
7.3.1.
Emergency Unblinding ........................................................................................47
7.3.2.
Inadvertent Unblinding ........................................................................................48
7.4.
Dosage Modification....................................................................................................48
7.4.1.
Ramucirumab/Placebo (IV) Dose Modifications ..................................................48
7.4.1.1.
Ramucirumab/Placebo Dose Modifications for AESIs....................................49
7.4.1.2.
Ramucirumab/Placebo Dose Modifications for Non-
AESIs.............................................................................................................52
7.4.2.
Gemcitabine and Cisplatin Dose Modifications ....................................................52
7.4.3.
Merestinib /Placebo (Oral) Dose Modifications....................................................53
7.5.
Preparation/Handling/Storage/Accountability...............................................................54
7.6.
Treatment Compliance .................................................................................................54
7.7.
Concomitant Therapy...................................................................................................54
7.7.1.
Supportive Care ...................................................................................................55
7.7.1.1.
Colony-Stimulating Factors............................................................................55
7.7.1.2.
Erythropoiesis-Stimulating Agents .................................................................55
7.7.1.3.
Antidiarrheal Agents.......................................................................................55
7.7.1.4.
Antiemetic Therapy........................................................................................56
7.7.1.5.
Analgesic Agents............................................................................................56
7.7.2.
Prohibited Medication..........................................................................................56
7.7.3.
Restricted Therapies.............................................................................................56
7.7.4.
Other Study Conditions:  Surgery (or Procedure) during 
Study Treatment Period........................................................................................57
7.7.5.
Merestinib / Placebo (Oral) – Drug-Drug Interactions ..........................................57
7.8.
Treatment after the End of the Study............................................................................57
7.8.1.
Continued Access.................................................................................................58

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8.
Discontinuation Criteria ....................................................................................................60
8.1.
Discontinuation from Study Treatment.........................................................................60
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................61
8.2.
Discontinuation from the Study....................................................................................62
8.3.
Lost to Follow-Up........................................................................................................62
9.
Study Assessments and Procedures ...................................................................................63
9.1.
Efficacy Assessments...................................................................................................63
9.1.1.
Efficacy Assessments at Baseline and During Study 
Treatment.............................................................................................................63
9.1.2.
Efficacy Assessments During Postdiscontinuation Follow-
Up........................................................................................................................64
9.1.3.
Health Outcome/Quality of Life Measures ...........................................................65
9.1.3.1.
Functional Assessment of Cancer Therapy Hepatobiliary 
(FACT-Hep) Questionnaire ............................................................................65
9.1.3.2.
EuroQol 5-Dimension 5-Level (EQ-5D-5L) 
Questionnaire .................................................................................................65
9.1.4.
Appropriateness of Assessments ..........................................................................65
9.2.
Adverse Events ............................................................................................................65
9.2.1.
Adverse Events of Special Interest for Ramucirumab...........................................66
9.2.1.1.
Infusion-Related Reactions.............................................................................66
9.2.1.1.1.
Guidelines for Reporting IRRs..................................................................67
9.2.1.2.
Hypertension ..................................................................................................67
9.2.1.3.
Proteinuria......................................................................................................67
9.2.1.4.
Thromboembolic Events.................................................................................67
9.2.1.4.1.
Arterial Thromboembolic Events..............................................................67
9.2.1.4.2.
Venous Thromboembolic Events ..............................................................67
9.2.1.5.
Bleeding/Hemorrhage.....................................................................................68
9.2.1.6.
Gastrointestinal Perforation ............................................................................68
9.2.1.7.
Reversible Posterior Leukoencephalopathy Syndrome....................................68
9.2.1.8.
Congestive Heart Failure ................................................................................69
9.2.1.9.
Fistula Formation ...........................................................................................69
9.2.1.10.
Surgery and Impaired Wound Healing............................................................69
9.2.1.11.
Liver Failure and Other Significant Liver Injury.............................................69
9.2.2.
Serious Adverse Events........................................................................................69
9.2.3.
Suspected Unexpected Serious Adverse Reactions ...............................................70
9.2.4.
Complaint Handling.............................................................................................71
9.3.
Treatment of Overdose.................................................................................................71
9.4.
Safety...........................................................................................................................71
9.4.1.
Other Safety Measures .........................................................................................71

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9.4.2.
Safety Monitoring ................................................................................................71
9.5.
Pharmacokinetics .........................................................................................................72
9.6.
Pharmacodynamics ......................................................................................................72
9.7.
Genetics .......................................................................................................................72
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................72
9.8.
Biomarkers...................................................................................................................73
9.8.1.
Samples for Nonpharmacogenetic Biomarker Research........................................73
9.8.2.
Tissue Samples for Research................................................................................74
9.8.3.
Immunogenicity Assessments ..............................................................................75
9.9.
Health Economics ........................................................................................................75
10.
Statistical Considerations ..................................................................................................76
10.1. Sample Size Determination ..........................................................................................76
10.2. Populations for Analyses..............................................................................................76
10.3. Statistical Analyses ......................................................................................................77
10.3.1.
Efficacy Analyses ................................................................................................77
10.3.2.
Health Outcome/Quality of Life Analyses............................................................79
10.3.2.1.
Functional Assessment of Cancer Therapy Hepatobiliary 
Questionnaire (FACT-Hep) ............................................................................79
10.3.2.2.
EuroQol 5-Dimension 5-Level (EQ-5D-5L)....................................................79
10.3.3.
Safety Analyses....................................................................................................80
10.3.4.
Other Analyses.....................................................................................................80
10.3.4.1.
Immunogenicity Analysis ...............................................................................80
10.3.4.2.
Patient Disposition..........................................................................................80
10.3.4.3.
Patient Characteristics ....................................................................................80
10.3.4.4.
Concomitant Therapy .....................................................................................80
10.3.4.5.
Postdiscontinuation Anticancer Therapy.........................................................81
10.3.4.6.
Treatment Compliance....................................................................................81
10.3.4.7.
Pharmacokinetics............................................................................................81
10.3.4.8.
Healthcare Resource Utilization......................................................................81
10.3.5.
Subgroup Analyses ..............................................................................................81
10.3.6.
Interim Analyses..................................................................................................81
11.
References ........................................................................................................................83

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List of Tables
Table
Page
Table JSBF.1.
Schedule of Screening Activities I3O-MC-JSBF.....................................13
Table JSBF.2.
Treatment Period, I3O-MC-JSBF ...........................................................16
Table JSBF.3.
Postdiscontinuation Follow-Up Schedule, I3O-MC-JSBF.......................20
Table JSBF.4.
Continued Access Schedule of Activities................................................23
Table JSBF.5.
In Vitro Inhibitory Activity of Merestinib against MET and Other 
Kinases...................................................................................................28
Table JSBF.6.
Merestinib In Vitro Inhibitory Activity Against MET-Activating 
Mutations in BaF3 Cells Cultured Without IL-3 .....................................29
Table JSBF.7.
Objectives and Endpoints .......................................................................31
Table JSBF.8.
Treatment Regimens/Dosing Schedule ...................................................42
Table JSBF.9.
Criteria to Be Met Prior to Each Ramucirumab Administration ..............46
Table JSBF.10.
Ramucirumab/Placebo Dose Reductionsa...............................................49
Table JSBF.11.
Dose-Modifications for Ramucirumab/Placebo Adverse Events of 
Special Interest.......................................................................................50
Table JSBF.12.
Gemcitabine and Cisplatin Dose Adjustment for Toxicity.......................53
Table JSBF.13.
PFS Event/Censoring Scheme ................................................................78

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List of Figures
Figure
Page
Figure JSBF.1.
Dendrogram of the in vitro cell-based activity of merestinib with 
IC50 less than 200 nM. ............................................................................29
Figure JSBF.2.
Illustration of study design......................................................................33
Figure JSBF.3.
Continued access diagram.......................................................................58

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................89
Appendix 2.
Study Governance, Regulatory, and Ethical Considerations....................93
Appendix 3.
Clinical Laboratory Tests........................................................................96
Appendix 4.
Sampling Schedule for Genetics/ 
Biomarkers/Immunogenicity/Pharmacokinetics/ 
Pharmacodynamics.................................................................................98
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ..........101
Appendix 6.
Creatinine Clearance Formula...............................................................102
Appendix 7.
ECOG Performance Status ...................................................................103
Appendix 9.
Permitted and Prohibited Concomitant Therapy (Arm A) .....................110
Appendix 10.
NCI-CTCAE v 4.0 Infusion-Related Reactions.....................................111
Appendix 11.
Hepatic Monitoring Algorithm for Patients in Oncology Clinical 
Trials....................................................................................................112
Appendix 12.
Protocol Amendment I3O-MC-JSBF(a) Summary:  Randomized, 
Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or 
Placebo plus Cisplatin and Gemcitabine as First-Line Treatment in 
Patients with Advanced or Metastatic Biliary Tract Cancer...................113
CCI

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1.
Synopsis
Protocol Title:
Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo plus Cisplatin and 
Gemcitabine as First-Line Treatment in Patients with Advanced or Metastatic Biliary Tract Cancer
Rationale:
This Phase 2, multicenter, double-blinded study is designed to evaluate the efficacy and safety of 2 new 
combinations for the treatment of first-line advanced or metastatic biliary tract cancer (BTC):
1.  Arm A:  ramucirumab (LY3009806, intravenous [IV]) in combination with cisplatin and gemcitabine (Arm A1) 
versus placebo (IV) plus cisplatin and gemcitabine (Arm A2)
2.  Arm B:  merestinib (LY2801653, oral) in combination with cisplatin and gemcitabine (Arm B1) versus placebo 
(oral) plus cisplatin and gemcitabine (Arm B2)

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Objectives and Endpoints:
Objectives
Endpoints
Primary
Evaluate the efficacy, in terms of PFS, in patients with 
advanced or metastatic BTC, for 

ramucirumab (8 mg/kg, IV) versus placebo, in 
combination with cisplatin (25 mg/m2, IV) and 
gemcitabine (1000 mg/m2, IV), on Days 1 and 8 of a 
21-day cycle.

merestinib (80 mg, oral each day) versus placebo, in 
combination with cisplatin (25 mg/m2, IV) and 
gemcitabine (1000 mg/m2 IV), on Days 1 and 8 of a 
21-day cycle.
PFS (objective progression or death), as determined by 
investigator assessment per RECIST 1.1
Secondary
Evaluate the efficacy, in combination with cisplatin and 
gemcitabine, in terms of OS, for ramucirumab versus 
placebo and merestinib versus placebo. 
OS
Evaluate the efficacy, in combination with cisplatin and 
gemcitabine, in terms of ORR and DCR for 
ramucirumab versus placebo and merestinib versus
placebo.
ORR and DCR

Safety profile of merestinib

Safety profile of ramucirumab
The safety endpoints evaluated will include but are not 
limited to the following:

TEAEs, AESIs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and physical 
examinations

PK of ramucirumab

PK of merestinib

Minimum ramucirumab concentration in serum 

Postdose merestinib concentration in plasma
Immunogenicity of ramucirumab
Blood samples for immunogenicity testing will be 
collected to determine antibody production against 
ramucirumab.
Evaluate PRO measures of disease-specific symptoms, 
in combination with cisplatin and gemcitabine, for 
ramucirumab versus placebo and merestinib versus 
placebo.
Functional Assessment of Cancer Therapy Hepatobiliary 
Questionnaire (FACT-Hep)
EuroQol 5-Dimension 5-Level (EQ-5D-5L) 
Abbreviations:  AESIs = adverse events of special interest; BTC = biliary tract cancer; DCR = disease control rate; 
IV = intravenous; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetics; PRO = patient-reported outcome; RECIST = Response Evaluation Criteria In Solid 
Tumors; SAEs = serious adverse events; TEAEs = treatment-emergent adverse events.
Overall Design:
Study I3O-MC-JSBF is a global, multicenter, randomized, double-blind, Phase 2 study in patients with advanced or 
metastatic BTC who have had no prior therapy for advanced or metastatic BTC.
Number of Patients:
The study will screen approximately 364 patients, and will randomize approximately 300 patients such that patients 
in each of the IV cohorts and the oral cohorts will be allocated to receive investigational treatment or control in a 2:1 
fashion.

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Treatment with all study drugs will be given in an outpatient setting.  Treatment will continue until there is evidence 
of disease progression or any other discontinuation criteria are met. Treatment with cisplatin and gemcitabine will 
be capped at a maximum of 8 cycles.  Treatment with the randomly assigned study therapy of ramucirumab, 
merestinib, or placebo will not be capped at a maximum number of cycles and should be continued until there is 
evidence of disease progression or any other discontinuation criteria are met.  During the planned treatment period, 
if one or more therapeutic agent is permanently discontinued for a reason other than progressive disease, then 
treatment with the other study agent(s) should continue and the patient should remain on study with full adherence 
to all protocol-related requirements.
Crossover between arms is not permitted.
Treatment Arms and Duration:
Dose and Schedule (q 21 Days)
Arm A
Ramucirumab/Placebo (IV) D1 and D8
Cisplatin (IV) D1 and D8
Gemcitabine (IV) D1 and D8
A1
8 mg/kg
25 mg/m2
1000 mg/m2
A2
equivalent volume
25 mg/m2
1000 mg/m2
Arm B
Merestinib/Placebo (oral with food)
Each Day
Cisplatin (IV) D1 and D8
Gemcitabine (IV) D1 and D8
B1
80 mg
25 mg/m2
1000 mg/m2
B2
Similar appearing placebo tablet(s)
25 mg/m2
1000 mg/m2
Abbreviations:  D = day; IV = intravenous; q = every.

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2.
Schedule of Activities

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Table JSBF.1.
Schedule of Screening Activities I3O-MC-JSBF
Baseline
Cycle
BL
Notes
Visit
0
Relative Day Prior to Cycle 1 Day 
1
28
14
7
Procedure 
Category
Prot. Ref.
Procedure
Study Entry/ 
Enrollment
6.1, 6.4, 
Appendix 2
Informed consent form signed
X
ICF must be signed prior to performance of any protocol-specific tests/procedures.  If the ICF is 
revised during the course of the study, re-consenting of patients may be required if deemed 
necessary by Lilly or the IRB/ERB.
6.1, 6.2, 7.2
Inclusion/exclusion evaluation 
X
Randomization by IWRS to be done once all the screening (baseline) assessments are completed.  
Patients will be randomized to treatment within 24 to 72 hours prior to Visit 1 (Day 1, Cycle 1).  
Every attempt should be made to randomize the patient as close as possible to Day 1 of Cycle 1 
and not more than 72 hours prior to Day 1.
Medical History
9.4
Medical History
X
Including preexisting conditions, historical illnesses, prior treatment and any alcohol/tobacco 
habits.
Physical Exam
Height
X
Height measurement to be performed at baseline only.
7.2.1
Weight
X
Include an estimation of the amount of weight loss that has occurred over the prior 1-month and 
6-month periods.  
9.4.1
Physical Exam/Vital Signs
X
Including temperature, blood pressure, pulse rate, respiration rate.  Physical exam to include a 
screening neuromuscular exam with focus on monitoring for tremors.
6.1, 
Appendix 7
ECOG PS
X
Patient-
Reported 
Outcomes
9.1.3.1
FACT-Hep questionnaire
X
The instruments should be completed before any extensive contact and consultation, which may 
bias patient responses.  It is recommended that the instruments be administered together, with the 
FACT-Hep completed first, followed by the EQ-5D-5L.
9.1.3.2
EQ-5D-5L questionnaire
X
Concomitant 
Medications
7.7
Concomitant Medications
X
Concomitant medications (including over the counter medications and supplements) will be 
recorded, including any taken within 30 days prior to randomization.

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Schedule of Screening Activities I3O-MC-JSBF
Baseline
Cycle
BL
Notes
Visit
0
Relative Day Prior to Cycle 1 Day 
1
28
14
7
Procedure 
Category
Prot. Ref.
Procedure
Adverse Events
9.2
AE collection and CTCAE v4.0 
grading (Preexisting conditions)
X
To be reported only after study eligibility is confirmed
Laboratory/
Diagnostic Tests
6.1,
Appendix 3
Hematology profile
X
6.1,
Appendix 3
Serum Chemistry profile
X
Two measurements are required that are separated by at least 5 days.  Serum chemistry to include 
TSH, free thyroxine (T4), and free triiodothyronine (T3).
6.1,
Appendix 3
Coagulation Profile
X
6.1,
Appendix 3
Urinalysis
X
Routine dipstick measurements, and if clinically indicated, microscopic analysis.  If urine 
dipstick or routine analysis indicates proteinuria ≥2+ at evaluations, a 24-hour urine collection 
(to assess protein) must be obtained.
6.1,
Appendix 3
Pregnancy Test
X
Required for women of child-bearing potential.  A serum β-HCG test (minimum sensitivity 
25 IU/L or equivalent units of β-hCG) must be done within 7 days prior to Day 1 of Cycle 1.  If 
required per local regulations and/or institutional guidelines, pregnancy testing can also be 
performed at other times during the study treatment period, the post discontinuation follow up 
period and the continued access period.
6.1, 
Appendix 6
Glomerular Filtration Rate
X
GFR of ≥ 50 ml/min/1.73 m2.  GFR should be calculated by the CKD-EPI equation, or GFR may 
also be measured using 24 hour urine collection or clearance of exogenous filtration markers 
(such as iothalamate or 51-CrEDTA or Tc99m-DTPA).
9.4.1
ECG
X

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Schedule of Screening Activities I3O-MC-JSBF
Baseline
Cycle
BL
Notes
Visit
0
Relative Day Prior to Cycle 1 Day 
1
28
14
7
Procedure 
Category
Prot. Ref.
Procedure
Efficacy 
Assessments
9.1.1, 
Appendix 8
Radiological Tumor Assessment 
(according to RECIST v1.1)
X
To be performed ≤28 days prior to Cycle 1 Day 1.  These scans can be assessed locally. 
Sample 
Collection
9.7.1, 
Appendix 4
DNA Genotyping Blood Sample 
(stored)
Refer to Appendix 
4, Table APP.4.1
Can be collected any time after eligibility has been confirmed throughout the trial.
9.8.1. 
Appendix 4
Whole blood, plasma, and serum 
samples for biomarkers
Refer to Appendix 
4, Table APP.4.1
Should only be taken after study eligibility is confirmed.
6.1, 9.8.2, 
Appendix 4
Tumor biopsy (new specimen or 
recent archived specimen, see 
Section 9.8.2)
X
Where possible review of medical records and routine labs should be performed to aid eligibility 
assessment before biopsy in order to minimize unnecessary procedures.
Abbreviations:  β-HCG = beta human chorionic gonadotropin; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; BL = baseline; 
CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance status; EQ-5D-5L = EuroQol 5-Dimension 5 Level; FACT-HEP = The Functional 
Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep) questionnaire consisting of the 27-item FACT-General (FACT-G) and the disease-specific 
18-item Hepatobiliary Subscale (HepCS-18); GFR = glomerular filtration rate; ICF = informed consent form; IRB/ERB = institutional review board/ethical
review board; IWRS = interactive web-response system; RECIST = Response Evaluation Criteria In Solid Tumors; TSH = thyroid-stimulating hormone; 
ULN = upper limit of normal; v = version.

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Table JSBF.2.
Treatment Period, I3O-MC-JSBF
After Cycle 1, a treatment delay at the start of a cycle (Day 1) of ±7 days, because of holidays, weekends, inclement weather, or other 
justifiable events, will be permitted and not counted as a protocol violation.  After the start of a cycle, treatment should continue on 
schedule if possible, but a variance of ± 3 days may be allowed to accommodate holidays, weekends, inclement weather, or other 
justifiable events.
Treatment Period
Study Period
Notes
Cycle (21-day cycle)
1-8
9+
Relative Day within 
Cycle)
1
2-7
8
9-21
1
2-7
8a
9-21
Procedure 
Category
Protocol 
Section
Procedure
Physical
Examination
9, 9.4.1
Physical Exam
X
X
Predose.  Physical exam to include visible or palpable tumor 
measurements and screening neuromuscular exam with focus 
on monitoring for tremors.
7.2.1
Weight, BSA
X
X
Predose. Weight and BSA are to be determined, as needed at 
each cycle until discontinuation of all IV study treatment(s).  If 
the patient’s weight does not fluctuate by more than ±10% 
from the weight used to calculate the prior dose, then the dose 
of IV study treatment will not need to be recalculated.
Appendix 7
ECOG PS
X
X
Predose. For ECOG PS, a time window of -3 days is 
permitted for the Cycle 1 Day 1 assessment.
9.4.1
Vital Signs
X
X
X
X
Predose.  Include temperature, blood pressure, pulse rate, 
respiration rate.  For the patient's first 2 doses of 
ramucirumab/placebo, measure all vital signs at the following 
time points:  (i) within 15 minutes prior to the infusion, (ii) 
after completion of the infusion, and (iii) at the end of the 
postinfusion observation period.  For all infusions of 
gemcitabine, cisplatin and all subsequent infusions of 
ramucirumab/placebo, measure blood pressure and pulse prior 
to the infusion and measure other vital signs as clinically 
indicated.

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Treatment Period, I3O-MC-JSBF
Treatment Period
Study Period
Notes
Cycle (21-day cycle)
1-8
9+
Relative Day within 
Cycle)
1
2-7
8
9-21
1
2-7
8a
9-21
Procedure 
Category
Protocol 
Section
Procedure
Patient-
Reported 
Outcomes
9.1.3.1
FACT-Hep 
questionnaire
X
X*
X
To be performed on Days 1 and 8 for Cycles 1 through 3 and 
on Day 1 for Cycle 4 onward.  May be completed up to 3 days 
prior to start of each cycle, prior to any infusion.  The 
instruments should be completed before any extensive contact 
and consultation, which may bias patient responses.  It is 
recommended that the instruments be administered together, 
with the FACT-Hep completed first, followed by the EQ-5D-
5L.  
9.1.3.2
EQ-5D-5L 
questionnaire
X
X*
X
Efficacy 
Assessment
9.1.1, 7.7.4, 
Appendix 8
Radiologic imaging 
(according to RECIST 
1.1) and tumor 
measurement
X*
*To be performed, by the same method used at baseline, every 
6 weeks (±7 days) after randomization (regardless of treatment 
delays) during the Study Treatment Period, until disease 
progression OR study completion or 14 months after 
randomization, whichever occurs first. Refer to footnote b for 
any patient whose disease has not progressed by 14 months 
after randomization.
A confirmatory radiological scan is required after documented 
progression has occurred in the previous 4 to 6 weeks.
Adverse 
Events
9.2
AE collection and 
CTCAE v4.0 grading
X
X
X
X
Throughout the cycle as needed.
Data on SAEs that occur before the end of trial will be stored in 
the collection database and the Lilly Safety System.
Concomitant 
Medications
7.7
Concomitant 
medication notation
X
X
Concomitant medications (including over the counter 
medications and supplements) will be recorded throughout the 
cycle as needed.

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Treatment Period, I3O-MC-JSBF
Treatment Period
Study Period
Notes
Cycle (21-day cycle)
1-8
9+
Relative Day within 
Cycle)
1
2-7
8
9-21
1
2-7
8a
9-21
Procedure 
Category
Protocol 
Section
Procedure
Laboratory/
Diagnostic 
Tests
Appendix 3
Hematology Profile 
X
X
X
Assessments performed within 3 days prior to each infusion 
may be used for treatment decisions, if the results are deemed 
still clinically valid by the treating investigator. 
Appendix 3
Full chemistry profile
X
X
X
Assessments performed within 3 days prior to Day 1 of the 
cycle may be used for treatment decisions, if the results are 
deemed still clinically valid by the treating investigator.  Day 8 
chemistry to be collected during Cycles 1 through 8.  
Thereafter, Day 8 collections will be optional as clinically 
indicated at the discretion of the treating investigator.
In Cycle 8, serum chemistry on any day in the cycle to include 
TSH, free thyroxine (T4), and free triiodothyronine (T3).
Appendix 3
Coagulation Profile
X
Baseline assessments may be used for treatment decisions for 
Cycle 1 D 1 if the baseline assessments were performed within 
7 days prior to Cycle 1 D1 and the results are deemed still 
clinically valid by the treating investigator.  Thereafter, 
perform within 3 days prior to D1 of every odd-numbered 
cycle.
Appendix 3
Urinalysis
X
X
For Arm A only: Perform dipstick or routine urinalysis within 
3 days prior to D1 of each cycle.  Baseline assessments may be 
used for treatment decisions for Cycle 1 D1 if the baseline 
assessments were performed within 7 days prior to Cycle 1 D1 
and the results are deemed still clinically valid by the treating 
investigator.  If baseline urine protein ≥2+ on dipstick or 
routine urinalysis, 24-hour urine protein results must be 
obtained prior to the first infusion.  See Table JSBF.11 for 
information about dose modifications required for proteinuria
Appendix 3
Pregnancy Test
X*
X*
* Required for women of child-bearing potential (WOCBP).  
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of β-hCG) to be performed in WOCBP every 
second cycle or per institutional guidelines, whichever is 
shorter.
Pregnancy test results will not be collected on the CRF.
Appendix 3
CA19-9, CEA, CA 125
X
X
Predose; Refer to Appendix 3.

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Treatment Period, I3O-MC-JSBF
Treatment Period
Study Period
Notes
Cycle (21-day cycle)
1-8
9+
Relative Day within 
Cycle)
1
2-7
8
9-21
1
2-7
8a
9-21
Procedure 
Category
Protocol 
Section
Procedure
Sample 
Collection
9.5, Appendix 4
PK
Refer to Appendix 4, Table APP.4.2 (Arm A), Table APP.4.3
(Arm B) and Table APP.4.4 (Arms A and B).
For Arm A:  If a patient experiences an IRR to 
ramucirumab/placebo, blood samples for both immunogenicity 
and PK analysis should be drawn, with no more than 15 
minutes’ time difference.  Samples will be taken at the 
following time points:  (1) as soon as possible after the onset of 
the IRR, (2) at the resolution of the IRR, and (3) 30 days after 
the IRR.
9.8.3, Appendix 
4, Table 
APP.4.2
Immunogenicity:  
Anti-ramucirumab 
antibodies
(For Arm A only) Refer to Appendix 4, Table APP.4.2
9.8.2, Appendix 
4
Tumor tissue
Refer to Appendix 4
At any time during the study, if tumor tissue becomes 
available, a sample should be provided.
9.8, Appendix 4
Whole blood, plasma, 
and serum samples for 
biomarkers
Refer to Appendix 4
During screening, on C1D1 (before dosing and at the end of 
study day), on C1D8, and then to coincide within 7 days of the  
Radiological Tumor Assessment at 6  and 12 weeks, and then 
every 12 weeks thereafter.
Premedicati
on
7.2.1.1.1
7.2.1.1.2
Premedication notation
X
X
X
X
Ramucirumab/Placebo:  Refer to Section 7.2.1.1.1.
Cisplatin and Gemcitabine:  Refer to Section 7.2.1.1.2. 
Study Drug
7.2.1.2
Ramucirumab/Placebo
X
X
X
X
For Arm A only.
7.2.1.3
Merestinib/Placebo
X
X
X
X
X
X
X
X
For Arm B only.
7.2.1.4
Cisplatin
X
X
For Arm A and B.
7.2.1.5
Gemcitabine
X
X
For Arm A and B.
Abbreviations:  β-hCG = beta human chorionic gonadotropin; AE = adverse event; ASCO = American Society of Clinical Oncology; BSA = body surface area; 
CRF = case report form; CRP = (Lilly) clinical research physician; CRS = (Lilly) clinical research scientist; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; D = Day; ECOG PS = Eastern Cooperative Oncology Group performance status; EQ-5D-5L = EuroQol 
5-Dimension 5 Level; FACT-HEP = The Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep) questionnaire consisting of the 27-item 
FACT-General (FACT-G) and the disease-specific 18-item Hepatobiliary Subscale (HepCS-18); IRR = infusion-related reaction; IV = intravenous; 
MRI = magnetic resonance imaging; PK = pharmacokinetic(s); RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; SAE = serious 
adverse event; TSH = thyroid-stimulating hormone; v = version; WOCBP = women of childbearing potential.
a
Patients who have completed treatment with cisplatin and gemcitabine and are no longer receiving IV treatment on Day 8 are not required to return to the
clinic on Day 8 of subsequent cycles
b Any patient whose disease has not progressed by 14 months after randomization (note that the patient may or may not still be on study treatment) will be 
evaluated for response every 12 weeks (±7 days) from 14 months after randomization, until disease progression OR study completion OR 3 years after 
randomization, whichever occurs first; then as per standard clinical practice after that.

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Table JSBF.3.
Postdiscontinuation Follow-Up Schedule, I3O-MC-JSBF
Postdiscontinuation Follow-up
Cycle
Short-term 
Follow-up
Long-term 
Follow-up
Notes
Visit
801
802-8XX
Duration
Refer to 
footnote for 
duration
Refer to 
footnote for 
duration
Procedure 
Category
Protocol 
Reference
Procedure
Physical 
Examination
7.2.1
Weight
X
9.4.1
Vital Signs
X
Include temperature, blood pressure, pulse rate, respiration rate.
6.1, Appendix 7
ECOG performance status
X
Patient-
Reported 
Outcomes
9.1.3.1
FACT-Hep questionnaire
X
The instruments should be completed before any extensive contact and consultation, 
which may bias patient responses.  It is recommended that the instruments be 
administered together, with the FACT-Hep completed first, followed by the 
EQ-5D-5L.
9.1.3.2
EQ-5D-5L questionnaire
X
Efficacy 
Assessment
9.1.2, 7.7.4, 
Appendix 8
Radiologic imaging (according 
to RECIST 1.1) and tumor 
measurement
X
X
Patients who discontinue study treatment for any reason other than disease 
progression will continue to undergo radiographic tumor assessments, by the same 
method used at baseline and throughout the study, every 6 weeks (±7 days) after 
randomization until disease progression OR study completion OR 14 months after 
randomization, whichever occurs first.  Refer to footnote a for any patient whose 
disease has not progressed by 14 months after randomization.
A confirmatory radiological scan is required after documented progression has 
occurred in the previous 4 to 6 weeks.  Thereafter, radiologic tests are no longer 
required and the patient will be followed for survival.
Survival 
information
9.1.2
Collection of survival 
information
X
X
Collection of survival data every 3 months (±7 days) until the patient’s death or study 
completion, whichever occurs first.  Whenever possible, survival follow-up is 
conducted in person. If an in-person visit is not possible, the site may confirm 
survival by contacting the patient directly via telephone.
Adverse 
Events
9.2
AE collection and CTCAE 
v4.0 grading
X
X
Data on SAEs that occur before the end of trial will be stored in the collection 
database and the Lilly Safety System.  During Postdiscontinuation Long-term Follow-
up, only SAEs that are related to protocol procedures or study treatment will be 
collected.
Concomitant 
Medications
7.7
Concomitant medication 
notation
X
Concomitant medications (including over the counter medications and supplements) 
will be recorded.

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Postdiscontinuation Follow-Up Schedule, I3O-MC-JSBF
Postdiscontinuation Follow-up
Cycle
Short-term 
Follow-up
Long-term 
Follow-up
Notes
Visit
801
802-8XX
Duration
Refer to 
footnote for 
duration
Refer to 
footnote for 
duration
Procedure 
Category
Protocol 
Reference
Procedure
Laboratory/
Diagnostic 
Tests
Appendix 3
Hematology
X
Appendix 3
Chemistry
X
Serum chemistry to include TSH, free thyroxine (T4), and free triiodothyronine (T3).
Appendix 3
Coagulation
X
Appendix 3
Urinalysis
X
Routine dipstick measurements, and if clinically indicated, microscopic analysis.  If 
urine dipstick or routine analysis indicates proteinuria ≥2+ at evaluations, a 24-hour 
urine collection (to assess protein) must be obtained.
Sample 
Collection 
9.5, Appendix 4
PK
Refer to Appendix 4, Table 
APP.4.2 (Arm A).
For Arm A:  If a patient experiences an IRR to ramucirumab, blood samples for both 
immunogenicity and PK analysis should be drawn, with no more than 15 minutes’ 
time difference.  Samples will be taken at the following time points:  (1) as soon as 
possible after the onset of the IRR, (2) at the resolution of the IRR, and (3) 30 days 
after the IRR.
9.8.3, Appendix 4, 
Table APP.4.2
Immunogenicity:  Anti-
ramucirumab antibodies
(For Arm A only) Refer to 
Appendix 4, Table APP.4.2.
9.8, Appendix 4
Whole blood, plasma, and 
serum samples for biomarkers
Refer to Appendix 4
Other
10.3.4.5
Collection of 
postdiscontinuation anticancer 
therapy
X
X

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Postdiscontinuation Follow-Up Schedule, I3O-MC-JSBF (concluded)
Abbreviations:  AE = adverse event; CRP = (Lilly) clinical research physician; CRS = (Lilly) clinical research scientist; CTCAE = Common Terminology 
Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = EuroQol 5-Dimension 5 Level; FACT-HEP = The Functional 
Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep) questionnaire consisting of the 27-item FACT-General (FACT-G) and the disease-specific 
18-item Hepatobiliary Subscale (HepCS-18); OS = overall survival; PK = pharmacokinetic(s); RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, 
version 1.1; SAEs = serious adverse events; TSH = thyroid-stimulating hormone.
Note:  No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.
Short-term Follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts approximately 
30 days.
Long-term Follow-up begins the day after Short-term Follow-up is completed and continues until the patient’s death or study completion.  Patients who 
discontinue study treatment for reasons other than disease progression will continue to undergo radiographic tumor assessments according to the timing stated 
in Section 9.1.2, by the same method used at baseline and throughout the study, until the patient has radiographic documentation of disease progression as 
defined by RECIST 1.1 or until study completion (that is, the final analysis of OS), whichever occurs first.  Patients will be followed for survival every 
3 months (±7 days) until the patient’s death or study completion, whichever occurs first.
a
Any patient whose disease has not progressed by 14 months after randomization (note that the patient may or may not still be on study treatment) will be 
evaluated for response every 12 weeks (±7 days) from 14 months after randomization, until disease progression OR study completion OR 3 years after 
randomization, whichever occurs first; then as per standard clinical practice after that.

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Table JSBF.4.
Continued Access Schedule of Activities
Continued Access Period
Notes
Treatment Period
Continued Access 
Follow-up
Cycle
X-Y
Follow-up
Visit
501-5XX
901
Relative day within 
a cycle
1
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Physical 
Examination
7.2.1
Weight
X
BSA to be calculated at each cycle until cisplatin and gemcitabine are
discontinued.
Adverse Events
9.2
AE collection and CTCAE grading
X
X
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System.
Sample 
Collection
9.5, 
Appendix 4
PK
Refer to Appendix 4, Table APP.4.2 (Arm A).
For Arm A:  If a patient experiences an IRR to ramucirumab, blood
samples for both immunogenicity and PK analysis should be drawn, 
with no more than 15 minutes’ time difference.  Samples will be taken 
at the following time points:  (1) as soon as possible after the onset of 
the IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
9.8.3, 
Appendix 4, 
Table 
APP.4.2
Immunogenicity:  Anti-ramucirumab 
antibodies
(For Arm A only) Refer to Appendix 4, Table 
APP.4.2.
Premedication
7.2.1.1.1
7.2.1.1.2
Premedication notation
X
Ramucirumab/Placebo:  Refer to Section 7.2.1.1.1.
Cisplatin and Gemcitabine:  Refer to Section 7.2.1.1.2.
Study Drug
7.2.1.2
Ramucirumab
X
After study completion, all patients who are on study treatment and 
who are eligible for continued access will be unblinded.  Patients 
receiving study treatment and experiencing ongoing clinical benefit and 
no undue risks may continue to receive study treatment in the 
Continued Access Period until one of the criteria for discontinuation is 
met (Section 8).  During the Continued Access Period, placebo will no 
longer be administered.
7.2.1.3
Merestinib
X
7.2.1.4
Gemcitabine
X
7.2.1.5
Cisplatin
X
Abbreviations:  AE = adverse event; BSA = body surface area; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction; 
IV = intravenous; PK = pharmacokinetics; SAE = serious adverse event.
Note:  No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.
Continued Access Period begins after study completion and ends at the end of trial.  During the Continued Access Period, patients on study treatment who 
continue to experience clinical benefit and no undue risks may continue to receive study treatment until one of the criteria for discontinuation is met.  The 
Continued Access Period includes Continued Access Follow-up.  During the Continued Access Period, required evaluations are shown in the table.  
Investigators will perform any other standard procedures and tests needed to treat and evaluate patients and to confirm patient eligibility to continue on 
treatment; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly will not routinely collect the results of these assessments.
Continued Access Follow-up begins the 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.
Note:  Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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3.
Introduction
3.1.
Study Rationale
This Phase 2, multicenter, double-blinded study is designed to evaluate the efficacy and safety of 
2 new combinations for the treatment of first-line advanced or metastatic biliary tract cancer 
(BTC):
1. Arm A: ramucirumab (LY3009806, intravenous [IV]) in combination with cisplatin and 
gemcitabine (Arm A1) versus placebo (IV) plus cisplatin and gemcitabine (Arm A2) 
2. Arm B: merestinib (LY2801653, oral) in combination with cisplatin and gemcitabine 
(Arm B1) versus placebo (oral) plus cisplatin and gemcitabine (Arm B2)
3.1.1. Biliary Tract Cancers
Biliary tract cancers (BTC) include a spectrum of invasive adenocarcinomas encompassing 
cancer of the gallbladder, intra- and extra-hepatic biliary ducts, and Ampulla of Vater (Hezel and 
Zhu 2008, Castro et al. 2013).  Globally, there are more than 178,000 new gall bladder cases, 
alone, diagnosed annually (Ferlay et al. 2013). The incidence and mortality of some forms of 
BTC are rising, especially in the United States and in some European countries (Chang et al. 
2009; Castro et al. 2013), and is the 7th leading cause of cancer mortality in Japan (Ferlay et al. 
2013). However, the majority of patients do not present at an early stage, and only about 10% of 
patients are surgical candidates (Hezel and Zhu 2008). 
In 2010, the Phase 3 randomized ABC-02 trial established gemcitabine plus cisplatin as the 
global standard of care in the first-line setting. This study demonstrated an advantage in overall 
survival (OS) and progression-free survival (PFS) in favor of the cisplatin / gemcitabine doublet 
versus gemcitabine (11.7 vs. 8.1 months; p<0.001 and 8.0 vs. 5.0 months; p<0.001, respectively)
(Valle et al. 2010).  While the results of the ABC-02 study established the combination of 
cisplatin and gemcitabine as a reference standard in this disease, improvements in treatment 
options are still required as demonstrated by the fact that half of patients still succumb to the 
disease at 1 year.
3.1.1.1.
Rationale for Exploration of Ramucirumab Combination Therapy in BTC
Vascular endothelial growth factor (VEGF), one of the main growth factors regulating 
angiogenesis, is overexpressed in 40% to 75% of BTC, especially at the invasive edge of the 
tumor (Giatromanolaki et al. 2003; Tang et al. 2006; Möbius et al. 2007; Yoshikawa et al 2008). 
VEGFR1 and VEGFR2 are also overexpressed in the adjacent endothelial cells (Benckert et al. 
2003).  Clinically, VEGF expression is also associated with the presence of metastases in 
intrahepatic cholangiocarcinoma (Yoshikawa et al. 2008); adverse prognosis in extrahepatic 
cholangiocarcinoma (Hida et al. 1999), and increased microvascular density (MVD) in both 
cholangiocarcinoma and gallbladder cancer (Giatromanolaki et al. 2003; Tang et al. 2006). High 
MVD is an independent adverse prognostic factor for disease-free survival after resection of 
extrahepatic cholangiocarcinoma and for OS in lymph node-negative intrahepatic 
cholangiocarcinoma and gallbladder cancer (Giatromanolaki et al. 2003; Shirabe et al. 2004; 
Möbius et al. 2007). 

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Targeted therapies have enhanced outcomes in combination with systemic chemotherapy in other 
malignancies (that is, colorectal, breast, and lung cancer) and are thought to be the future of 
systemic treatment for BTC, and studies with agents targeting angiogenesis have suggested 
targeting this pathway may provide benefit in treating BTC.  A Phase 2 trial of gemcitabine, 
oxaliplatin, and bevacizumab enrolled 35 patients with biliary cancers and resulted in a response 
rate of 40%, a PFS of 7.0 months and an OS of 12.7 months, which compared favorably with 
historic controls (Zhu et al. 2010). Lubner and colleagues reported a multicenter Phase 2 trial of 
bevacizumab and erlotinib in patients with unresectable biliary cancer. The confirmed partial 
response rate in this study was 12%, median OS was 9.9 months, and time to progression (TTP)
was 4.4 months, suggesting a regimen including an antiangiogenic agent has activity in this 
disease (Lubner et al 2010).  Modest anti-tumor efficacy against biliary cancers was also 
demonstrated with multitargeted anti-angiogenic tyrosine kinase inhibitors, including sorafenib 
and sunitinib (Bengala et al. 2010; Yi et al. 2012; Lee et al. 2013).
ABC-03, a double-blind placebo-controlled Phase 2 study of the pan-VEGF receptor tyrosine 
kinase inhibitor cediranib in combination with gemcitabine/cisplatin versus placebo with 
gemcitabine/cisplatin, demonstrated an improved radiological response rate (44% vs. 19%, 
p=0.0036), a 10% improvement in 6-month PFS survival (71% vs. 61%), and a 10% difference 
in 1-year survival (58 vs. 48%).  Toxicity of the cediranib/chemotherapy combination led to 
relatively early discontinuation of study drug (median 4.6 months), and an apparent early PFS 
benefit diminished soon after, suggesting that treatment with a well-tolerated anti-VEGFR 
therapy could result in greater benefit in combination with gemcitabine/cisplatin (Valle et al. 
2015). 
Ramucirumab, is a recombinant human monoclonal antibody (mAb) of the immunoglobulin G, 
subclass 1 (IgG1) that specifically binds to the extracellular domain of VEGF Receptor 2 with 
high affinity, thus blocking VEGF binding and inhibiting angiogenesis. Ramucirumab has 
demonstrated benefit across multiple tumor types, both as single agent or in combination with 
cytotoxic chemotherapy, and has been well tolerated.  Despite preliminary evidence of activity 
for antiangiogenic agents in BTC, no targeted agent has been approved in this setting, and there 
remains a high unmet need for new treatment options for this disease.
3.1.1.2.
Rationale for Exploration of Merestinib Combination Therapy in BTC
The tyrosine kinase receptor MET has been linked to the promotion of a metastatic and invasive 
tumor phenotype (Maulik et al. 2002).  Aberrant MET signaling, whether due to genetic lesions, 
transcriptional upregulation, or ligand-dependent autocrine or paracrine mechanisms, plays a key 
role in tumorigenesis and angiogenesis (Migliore and Giordano 2008).  Studies demonstrate that 
many types of human cancers, including gastric, colorectal, renal, breast, pancreatic, lung, 
cholangiocarcinoma, and hepatocellular carcinoma, have upregulated MET and/or elevated 
hepatocyte growth factor (HGF) expression.  In many cases, this aberrant expression correlates 
with a poor prognosis (reviewed in Birchmeier et al 2003; Comoglio et al. 2008).  Amplification 
of MET has also been demonstrated in tumor cells that have acquired resistance to treatments 
targeting other tyrosine kinase receptors, such as erlotinib and gefitinib (Bean et al. 2007; 
Engelman et al. 2007).

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MET receptor expression is a common feature of BTC with 50% to 60% of cholangiocarcinoma 
cases demonstrating high expression of MET by immunohistochemistry (IHC) and only about 
10% of cases demonstrating poor or no staining (Miyamoto et al. 2011; Thobe et al. 2013).  The 
frequency of MET expression does not appear to differ significantly between Asian and Non-
Asian cases and appears to occur at a stable rate, regardless of mutation rates for KRAS or 
IDH1/2.  In addition to supporting tumor biology, high MET expression may contribute to 
resistance to first-line therapy (Engelman 2007; Bean 2007; Dulak et al. 2011; Casado et al. 
2012).  Data from other tumor types suggest that cisplatin therapy results in selection of MET 
expressing cells and that cells with MET expression are resistant to cisplatin therapy (Sun and 
Wang 2011).  Improvements in response to cisplatin have been seen in combination with 
merestinib in cholangiocarcinoma models (Investigator’s Brochure [IB] for merestinib).  In 
cholangiocarcinoma cell line-derived xenograft models (EGI-1, SNU869 and SNU1196) and in
patient-derived cholangiocarcinoma xenograft tumor models [BIL001 (also known as CTG-
0011] and CTG-0399), concurrent treatment with merestinib and cisplatin resulted in enhanced 
suppression of tumor growth compared to that seen with cisplatin alone.
In addition to expressing MET, BTC tumors have been shown to have activation of AXL, 
activation of eIF4E, and activating ROS kinase fusion proteins (Gu et al. 2011; Yan et al. 2014; 
Fujimori et al. 2015).  Merestinib (LY2801653) is a potent and selective type II MET kinase 
inhibitor and has also been shown to be capable of inhibiting 13 MET mutations/variants and is 
an inhibitor of several other oncokinases including AXL, ROS, and eIF4E (Yan et al. 2013; 
Table JSBF.5).  Similar to high MET expression, high AXL expression may contribute to 
resistance to cisplatin (Hong et al. 2013). In the cholangiocarcinoma cell line-derived xenograft 
model SNU1196, AXL is very highly expressed.  In this model, concurrent treatment with 
merestinib and cisplatin resulted in enhanced suppression of tumor growth compared to that seen 
with cisplatin alone (merestinib IB). Preclinical testing suggests that increased antitumor activity 
could be achieved with the addition of merestinib to the combination of cisplatin and 
gemcitabine (merestinib Investigator Brochure).
Given the dysregulation of the MET, AXL, eIF4E, and ROS kinase pathways in BTCs, and 
based on the hypothesis that inhibition of MET or AXL could be used to sensitize tumors to 
cisplatin therapy or prevent resistance to cisplatin, Phase 1 testing of merestinib (Study I3O-MC-
JSBA [JSBA]) included testing in BTC as a single agent in refractory and advanced or metastatic 
patients, in combination with cisplatin after first-line therapy, and in combination with cisplatin 
and gemcitabine in first-line advanced or metastatic patients.  While enrollment to these cohorts 
has completed, final results are not yet available and testing is ongoing.  Among the BTC cohort 
receiving second-line treatment with merestinib and cisplatin, 1 patient has had a confirmed 
complete response (CR) and median PFS for the cohort has not yet been reached.  Among 6 first-
line CCA evaluable patients, 1 partial response (PR) and 2 stable disease (SD) have been 
reported.  In Study JSBA, treatment with merestinib alone or in combination has demonstrated a 
clinically acceptable safety profile.  Additional details are available in the merestinib IB.

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3.2.
Background
3.2.1. Ramucirumab
Ramucirumab (LY3009806) is a recombinant human monoclonal antibody (mAb) of the 
immunoglobulin G, subclass 1 (IgG1) that specifically binds to the extracellular domain of 
VEGF Receptor 2 with high affinity. This antibody potently blocks the binding of the VEGF 
ligand to VEGF Receptor 2, inhibits VEGF-stimulated activation of both VEGF Receptor 2 and 
p44/p42 MAP kinases, and neutralizes VEGF-induced mitogenesis of human endothelial cells.
Ramucirumab has been shown to block the interaction of VEGF and VEGF Receptor 2 (with a 
concentration that inhibits binding by 50% of approximately 1 nM), and to inhibit VEGF-
stimulated proliferation of endothelial cells and VEGF-induced migration of human leukemia 
cells. The results of these preclinical pharmacodynamic studies supported the initial 
investigation of ramucirumab in the treatment of solid tumors.
Clinical investigations with ramucirumab in solid tumors have resulted in 4 positive Phase 3 
trials, with 2 in gastric cancer (REGARD and RAINBOW), 1 in non-small cell lung cancer 
(NSCLC; REVEL), and 1 in metastatic colorectal cancer (CRC; RAISE).  Ramucirumab 
(Cyramza®) is approved in the United States, as a single agent or in combination with paclitaxel,
as a treatment for people with advanced or metastatic gastric or gastroesophageal junction 
adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or 
platinum-containing chemotherapy, in combination with docetaxel as a treatment for people with 
metastatic NSCLC whose cancer has progressed on or after platinum-based chemotherapy and in 
combination with FOLFIRI for the treatment of metastatic CRC with disease progression on or 
after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. In addition, the 
European Commission approved ramucirumab (Cyramza) in combination with paclitaxel and as 
a single agent when combination therapy is not appropriate, for people with advanced gastric 
cancer after prior chemotherapy.
3.2.2. Merestinib
Merestinib (LY2801653) is a type II ATP competitive, slow-off inhibitor that was designed in an 
effort to target MET and RON kinase.  Preclinical testing has demonstrated anti-proliferative and
anti-angiogenic activity of this compound.  Broad kinase screening against 400 kinases 
demonstrated potent restricted inhibition of a select group of oncokinases (Table JSBF.5 and 
Figure JSBF.1) (Yan et al. 2013).  Merestinib inhibits MET phosphorylation in HGF-stimulated 
H460 cells with an inhibitory concentration (IC50) of 35 nM (Yan et al. 2013).  It also inhibits 
MET phosphorylation in autocrine S114 cells and is active against 13 different activating mutant 
forms of MET with similar potency.  Merestinib inhibits macrophage-stimulating protein (MSP) 
induced RON (MST1R) phosphorylation in NIH3T3-RON cells with an IC50 of 11 nM.  In vitro, 
merestinib is also a potent inhibitor of the migration of human umbilical vein endothelial cells 
(HUVEC) and angiogenic cord formation in ASC1/EPC-D2 co-culture assays.  Merestinib 
inhibits the phosphorylation of ROS1, an oncogenic tyrosine kinase closely related to the 

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MET/RON family; in U118MG cells harboring the FIG-ROS1 translocation, merestinib inhibits 
phosphorylation of constitutively activated FIG-ROS1 fusion protein with an IC50 of 23 nM.
Table JSBF.5.
In Vitro Inhibitory Activity of Merestinib against MET and Other 
Kinases
Kinase
Biochemical Activity IC50 or Kd (nM)
Cell-Based Activitya IC50 (nM)
MET
4.7
35 – 52
MST1R (aka RON)
12
11
AXL
11
2
ROS1
43
23 – 170
MKNK1/2 
130 / 109
7
PDGFRA
620
41
FLT3
31
7
MERTK
0.8
10
TYRO3
1210
28
TEK (aka Tie2)
4
63
DDR1
0.95
0.1
DDR2
41
7
CSFR1
32
300
FLT1
76
>1000
FLT4
23
>316
TIE1
0.9.
>1000
KDR
53
347
RET
590
2000
Abbreviations;  IC50 = concentration producing 50% inhibition; Kd = dissociation constant.
a
Cell-based activity was cell proliferation or target inhibition.
Source: Yan et al. 2013

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Abbreviation:  IC50 = half maximal inhibitory concentration.
Source:  Yan et al. 2013
Figure JSBF.1.
Dendrogram of the in vitro cell-based activity of merestinib with 
IC50 less than 200 nM.
Table JSBF.6.
Merestinib In Vitro Inhibitory Activity Against MET-Activating 
Mutations in BaF3 Cells Cultured Without IL-3
MET mutation
IC50 (nM)
TPR-MET wild type
42
Y1230C 
54
D1228N 
111
V1092I 
12
M1250T 
119
V1188L 
23
L1195V 
248
K1244R 
77
M1131T 
208
V1220I 
18
S1040P 
53
H1106D 
33
G1119V
62
H1094Y
25
Abbreviations:  IC50 = half maximal inhibitory concentration; IL-3 = interleukin 3.
Source: Yan et al. 2013
Dose-dependent antitumor activities (measured by tumor volume reduction) of merestinib have 
been demonstrated in a number of human tumor xenograft models (Wu et al. 2013; Yan et al. 
IC50
1nM
10nM
100nM
1M

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2013; Kawada et al. 2014).  These included models that are MET, AXL, and or RON driven 
models. 
In addition to reducing tumor growth in multiple tumor xenograft models (MET autocrine 
U87MG glioblastoma model, MET amplified MKN45 gastric tumor model, and AXL over-
expression SNU-1196 cholangiocarcinoma model), merestinib treatment also resulted in a 
dramatic modulation of many angiogenesis parameters indicating a normalization of tumor 
vessels (a decrease in GLUT1 expression, an increase in pericyte coverage of vessels, decrease 
levels of hypoxia) (Yan et al. 2013; Yan et al. 2014). 
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 merestinib and ramucirumab are to be found 
in the IB for merestinib (LY2801653) and ramucirumab (LY3009806), respectively.  

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4.
Objectives and Endpoints
Table JSBF.7 shows the objectives and endpoints of the study.
Table JSBF.7.
Objectives and Endpoints
Objectives
Endpoints
Primary
Evaluate the efficacy, in terms of PFS, in patients with 
advanced or metastatic BTC, for

ramucirumab (8 mg/kg, IV) versus placebo, in 
combination with cisplatin (25 mg/m2, IV) and 
gemcitabine (1000 mg/m2, IV), on Days 1 and 8 of a 21-
day cycle.

merestinib (80 mg, oral each day) versus placebo, in 
combination with cisplatin (25 mg/m2, IV) and 
gemcitabine (1000 mg/m2, IV), on Days 1 and 8 of a 21-
day cycle.
PFS (objective progression or death), as determined 
by investigator assessment per RECIST 1.1.
Secondary
Evaluate the efficacy, in combination with cisplatin and 
gemcitabine, in terms of OS, for ramucirumab versus placebo 
and merestinib versus placebo. 
OS
Evaluate the efficacy, in combination with cisplatin and 
gemcitabine, in terms of ORR and DCR for ramucirumab 
versus placebo and merestinib versus placebo.
ORR and DCR

Safety profile of ramucirumab

Safety profile of  merestinib
The safety endpoints evaluated will include but are 
not limited to the following:

TEAEs, AESIs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and 
physical examinations

PK of ramucirumab

PK of merestinib

Minimum ramucirumab concentration in serum 

Postdose merestinib concentration in plasma
Immunogenicity of ramucirumab
Blood samples for immunogenicity testing will be 
collected to determine antibody production against 
ramucirumab.
Evaluate PRO measures of disease-specific symptoms, in 
combination with cisplatin and gemcitabine, for 
ramucirumab versus placebo and merestinib versus placebo.
Functional Assessment of Cancer Therapy 
Hepatobiliary Questionnaire (FACT-Hep)
EuroQol 5-Dimension 5-Level (EQ-5D-5L) 
Tertiary/Exploratory

To explore biomarkers relevant to ramucirumab or 
merestinib, angiogenesis, immune function, and the 
disease state, and to correlate these markers to clinical 
outcome.

Explore the relationship of pretreatment weight loss with 
primary and secondary treatment response outcomes.

Biomarker research may be assessed from 
tissue, whole blood, serum, and plasma 
samples, unless precluded by local regulations.
Abbreviations:  AESIs = adverse events of special interest; BTC = biliary tract cancer; DCR = disease control rate; 
IV = intravenous; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetics; PRO = patient-reported outcomes; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAEs = serious adverse events; TEAEs = treatment-emergent adverse events.

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5.
Study Design
5.1.
Overall Design
Study I3O-MC-JSBF (JSBF) is a global, multicenter, randomized, double-blind, Phase 2 study in 
patients with advanced or metastatic BTC who have had no prior therapy for advanced or 
metastatic BTC.
The primary objective is to compare the PFS in BTC patients treated with ramucirumab plus 
cisplatin and gemcitabine versus placebo plus cisplatin and gemcitabine and merestinib plus 
cisplatin and gemcitabine versus placebo plus cisplatin and gemcitabine.  To assess the primary 
objective, approximately 300 patients will be randomized, such that patients in each cohort (IV
and oral) will be allocated to receive investigational treatment or control in a 2:1 fashion:
Intravenous Treatment:

Arm A1: ramucirumab 8 mg/kg plus cisplatin (25 mg/m2) and gemcitabine 
(1000 mg/m2) intravenously on Days 1 and 8, every 21 days
or

Arm A2: placebo plus cisplatin (25 mg/m2) and gemcitabine (1000 mg/m2) intravenously 
on Days 1 and 8, every 21 days
Oral Treatment:

Arm B1: merestinib 80 mg orally each day, plus cisplatin (25 mg/m2, IV) and 
gemcitabine (1000 mg/m2, IV) on Days 1 and 8, every 21 days
or

Arm B2: placebo orally each day, plus cisplatin (25 mg/m2, IV) and gemcitabine 
(1000 mg/m2, IV) intravenously on Days 1 and 8, every 21 days
A cycle is defined as an interval of 21 days.  Treatment with all study drugs will be given in an 
outpatient setting.  Treatment will continue until there is evidence of disease progression or any 
other discontinuation criteria are met (Section 8).  Treatment with cisplatin and gemcitabine will 
be capped at a maximum of 8 cycles.  Treatment with the randomly assigned study therapy of 
ramucirumab, merestinib, or placebo will not be capped at a maximum number of cycles and 
should be continued until there is evidence of disease progression or any other discontinuation 
criteria are met.  During the planned treatment period, if one or more therapeutic agent is 
permanently discontinued for a reason other than progressive disease, then treatment with the 
other study agent(s) should continue and the patient should remain on study with full adherence 
to all protocol-related requirements.
Crossover between arms is not permitted.
All patients will be offered best supportive care, as determined appropriate by the investigator
and as not otherwise limited specifically within the protocol.

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Figure JSBF.2 illustrates the study design.
Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; 
IV = intravenous; OS = overall survival; PFS = progression-free survival; PO = oral.
Figure JSBF.2.
Illustration of study design.
5.2.
Number of Patients
The study will randomize approximately 300 patients such that patients in each of the IV cohorts
and the oral cohorts will be allocated to receive investigational treatment versus control in a 2:1
fashion, as described in Section 5.1.
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.  The 
end of study occurs after study completion and after the last patient has discontinued study 
treatment and completed the final follow-up visit (including the final follow-up visit for the 
continued access period, if applicable) or has been declared lost to follow-up.
5.4.
Scientific Rationale for Study Design
Study JSBF is designed as a randomized, double-blinded study to evaluate the safety and 
efficacy of 2 new potential treatments when each is individually combined with the current first-

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line standard of care for the treatment of advanced or metastatic BTC.  The study uses a 
standardized eligibility criteria and stratification to facilitate consistency of sample populations.  
The patients will be randomized such that patients in each of the IV cohorts and the oral cohorts
will be allocated to receive investigational treatment or control in a 2:1 fashion.  
5.5.
Justification for Dose
5.5.1. Cisplatin and Gemcitabine
All randomized patients on this study will receive treatment with cisplatin and gemcitabine 
according to the regimen that was used in the ABC-02 trial, which consisted of repeating cycles 
of cisplatin (25 mg/m2) followed by gemcitabine (1000 mg/m2) with each drug administered on 
Days 1 and 8 every 21 days for a maximum of 8 cycles (Valle et al. 2010).
5.5.2. Merestinib
The recommended dose of merestinib identified in Study JSBA for patients with BTC who 
received concurrent cisplatin and gemcitabine was 80 mg when given by mouth with food daily.
Merestinib 80 mg daily in combination with cisplatin and gemcitabine has demonstrated a 
clinically acceptable safety profile in Study JSBA. Plasma exposure of merestinib after repeated 
administration at this dose level observed in patients exceeds the concentration shown to produce 
efficacy in preclinical in vitro and in vivo models. In individuals across tumor types who have 
not tolerated the 80-mg dose concurrent with other therapy, a reduced dose of 40 mg daily has 
been shown to be acceptable.  Patients randomized to receive oral tablets will be randomized to 
receive merestinib or placebo at a starting dose of 80 mg daily.
5.5.3. Ramucirumab
Ramucirumab at a dose of 8 mg/kg on Day 1 and Day 8 on an every-21-day (3-week) schedule 
will be examined in this study.  This dose of ramucirumab is different from the approved dose 
regimens: 8 mg/kg every-2-week (gastric cancer and CRC) and 10 mg/kg every-3-week
(NSCLC). All approved indications are in second-line settings. 
Dose selection for Study JSBF is based on information obtained from exposure-response 
(efficacy and safety) findings from 4 Phase 3 studies: REGARD (gastric cancer, monotherapy), 
RAINBOW (gastric cancer, in combination with paclitaxel), REVEL (NSCLC, in combination 
with docetaxel), and RAISE (CRC, in combination with FOLFIRI) and safety experience from 
Phase 1 multiple ascending dose (MAD) studies (I4T-IE-JVBM [JVBM] and I4T IE-JVBN 
[JVBN]) (Cohn et al. 2015; Smit et al. 2015; Tabernero et al. 2015).
Efficacy
Exposure-efficacy response analyses performed on data obtained from REGARD, RAINBOW, 
REVEL, and RAISE demonstrated that an increase in exposure is associated with improvement 
in efficacy in terms of both OS and PFS over the ranges of exposures achieved by a dose of 
8 mg/kg every-2-week (REGARD, RAINBOW, and RAISE) or 10 mg/kg every-3-week 
(REVEL). 

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Safety
Weekly doses of ramucirumab ranging from 2 to 16 mg/kg were evaluated in the Phase 1 
Study JVBM.  An MTD was identified as 13 mg/kg/week.  Every-2-week (6 to 10 mg/kg) and 
every-3-week (15 to 20 mg/kg) dose regimens were evaluated in an additional dose-ranging 
study (Study JVBN).  All dose regimens in Study JVBN were well-tolerated and no MTD was 
identified in this study.
The ramucirumab dose regimen, 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks, 
demonstrated manageable safety profiles in all pivotal trials. Overall, the safety profiles of 
ramucirumab plus different combination therapies were largely consistent with the safety profiles 
of the individual treatment components and the combinations revealed no unexpected safety 
findings. Exposure-safety analyses indicated that an increasing ramucirumab exposure was 
correlated with increased incidence of Grade ≥3 hypertension in RAINBOW and REVEL, Grade 
≥3 neutropenia in RAINBOW and RAISE, Grade ≥3 leukopenia in RAINBOW, and Grade ≥3 
febrile neutropenia in REVEL. Of note, there were no Grade 4 or 5 hypertension events in 
RAINBOW or REVEL. Hypertension was managed primarily by the use of standard 
antihypertensive medication. Neutropenia and leukopenia are known risks with chemotherapies 
and are considered as clinically manageable. In addition, incidence of febrile neutropenia 
appeared to reach plateau at the third exposure quartile in REVEL. 
These exposure-efficacy and exposure-safety data indicate that there may be an opportunity to 
further enhance efficacy of ramucirumab while maintaining an acceptable safety profile using a 
dose regimen which can generate exposure higher than 8 mg/kg every-2-weeks or 10 mg/kg 
every-3-weeks regimens. Based on pharmacokinetic (PK) simulation, a dose regimen of 8 
mg/kg on Day 1 and Day 8 on an every-21-day (3-week) schedule was selected for Study JSBF 
for the following reasons:
1. This dose regimen may produce exposure that is approximately 33% higher than the 8 mg/kg 
every-2-weeks and approximately 60% higher than the 10 mg/kg every-3-weeks dose 
regimen and is therefore expected to produce better clinical efficacy outcomes relative to the 
either 8 mg/kg every-2-week or 10 mg/kg every-3-week regimen.
2. It is expected that ramucirumab-related adverse events (AEs) in the BTC indication may not 
be significantly increased using the selected ramucirumab dose of 8 mg/kg on Day 1 and 
Day 8 on an every-21-day (3-week) since the selected dose for Study JSBF is still 
approximately 60% lower than the maximum tolerated weekly dose identified in the Phase 1 
dose-escalation study, Study JVBM (13 mg/kg weekly).
3. In addition, Study JVCX studied the safety and tolerability in Japanese patients of 
ramucirumab at an IV dose of 8 mg/kg given on Days 1 and 8 of a repeating 3-week regimen 
in 3 separate 3-drug combinations, one with capecitabine and cisplatin and the other with S-1 
and oxaliplatin.  Interim findings from the study supported the safety of this dose and 
schedule of ramucirumab administration.

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In summary, the dosing regimen of ramucirumab 8 mg/kg on Day 1 and Day 8 every 21 days in 
combination with cisplatin and gemcitabine in Study JSBF is anticipated to produce a clinically 
acceptable benefit-risk profile in BTC patients.

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6.
Study Population
All patients meeting the eligibility requirements will be considered for enrollment regardless of 
race, religion, or gender. The investigator or the Sponsor will not grant exceptions to eligibility 
criteria.
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]
Are of an acceptable age to provide informed consent according to the local 
regulations and are at least 18 years of age.
[2]
Have an estimated life expectancy ≥3 months.
[3]
Have an Eastern Cooperative Oncology Group performance status of 0 or 1 at the 
time of randomization (refer to Appendix 7).
[4]
Have a histologically or cytologically confirmed diagnosis of non-resectable, 
recurrent, or metastatic biliary tract adenocarcinoma (intrahepatic or extrahepatic
cholangiocarcinoma, gallbladder cancer, or Ampulla of Vater).
[5]
Have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 on computed tomography (CT) or magnetic resonance 
imaging (MRI) assessments performed ≤ 28 days prior to Cycle 1 Day 1.
[6]
Have resolution of all clinically significant toxic effects of prior therapy to Grade ≤1 
by the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE), Version 4.0.
[7]
Have adequate biliary drainage (per investigator’s discretion), with no evidence of 
ongoing infection.
[8]
Have adequate organ function as determined by:
a.
Hepatic: Total bilirubin, aspartate transaminase (AST), and alanine transaminase (ALT) 
are all ≤ 3 times upper limit of institutional normal value (ULN) on 2 measurements
separated by at least 5 days. 
b. Renal: 
i.
Glomerular filtration rate (GFR) of ≥50 ml/min/1.73 m2.  GFR should be 
calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (refer to Appendix 6), or may be measured using 24 hour 
urine collection or clearance of exogenous filtration markers (such as iothalamate 
or 51-CrEDTA or Tc99m-DTPA).
ii.
The patient’s urinary protein is ≤1+ on dipstick or routine urinalysis. If urine 
dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine must 

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be collected and must demonstrate <2 g of protein in 24 hours to allow 
participation in the study.
c.
Hematologic:  
i.
Absolute neutrophil count (ANC) ≥1.5 x 109/L,
ii.
hemoglobin ≥9 g/dL (5.58 mmol/L; packed red blood cell transfusions are not 
allowed within 1 week prior to baseline hematology profile), and
iii.
platelets ≥ 100 x 109/L. 
d. Coagulation:  The patient must have adequate coagulation function as defined by 
International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT/aPTT) 
≤5 seconds above the ULN. Patients receiving low-dose anticoagulant therapy at 
prophylactic doses (such as prophylaxis with low-molecular weight heparin) are eligible,
provided that INR ≤1.5 and PTT/aPTT ≤5 seconds above the ULN.  Treatment with 
acetylsalicylic acid (aspirin) at a daily dose of ≤325 mg is permitted.
[9]
Males and females are sterile, postmenopausal, or compliant with a highly effective 
contraceptive method during study participation and for 3 months following the last 
dose of study drug.
[10] Female patients of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to first dose.
[11] The patient has provided signed informed consent and authorization for release of 
health information for research prior to any study-specific procedures and is 
amenable to compliance with protocol schedules and testing.
[12] Are willing to provide blood/serum/plasma and tumor tissue samples for research 
purposes. Submission of blood/serum/plasma and tumor tissue samples is 
mandatory for participation in this study, unless restricted per local regulations.  
Tumor tissue biopsies may be taken by either core needle or excisional biopsy.
In the event that the patient has available tumor tissue from a prior biopsy obtained 
within the preceding 28 days for which existing specimen is available and of 
sufficient amount, submission of this material may occur in lieu of a repeated 
biopsy.  
In the event that available tumor tissue is limited to cytology from brushing, the 
patient may be considered to be eligible if approval is granted by the Lilly clinical 
research physician (CRP)/clinical research scientist (CRS) following discussion 
between the investigator and the CRP/CRS.  
If a patient is being rescreened who has adequate tumor tissue that was already 
obtained in a prior screening window, approval may be granted by the Lilly 
CRP/CRS to excuse the patient from a repeated biopsy.
[13] Are able to swallow tablets. Patients who have a nontemporary gastric or enteral 
feeding tube may be permitted to participate in the study with prior approval from 
the Sponsor’s CRP/CRS.  

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6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] Previous systemic therapy for locally advanced or metastatic disease is not allowed.  
Transarterial chemoembolization (TACE) or radiotherapy, including use of 
radioactive beads, is not allowed unless otherwise addressed in the Exclusion 
Criterion 18.  The following previous treatments are allowed:
o
a non-curative operation (that is, R2 resection [with macroscopic residual disease] 
or palliative bypass surgery);
o
curative surgery with evidence of non-resectable disease relapse requiring 
systemic chemotherapy for which study participation will represent first line of 
chemotherapy;
o
adjuvant chemotherapy, provided neither gemcitabine nor cisplatin were used and 
the treatment was completed more than 6 months before trial entry.  Patients who 
received adjuvant gemcitabine and/or cisplatin greater than 12 months before 
relapse and study entry will be permitted.
o
photodynamic treatment, provided that there was clear evidence of disease 
progression at the local site or measurable and progressing disease is present at 
another site.
[15] Have a history of or have current hepatic encephalopathy of any grade, or ascites of 
Grade >1, or cirrhosis with Child-Pugh Stage B or higher.  
[16] Have ongoing or recent (≤6 months) hepatorenal syndrome
[17] Have had a major surgical procedure or significant traumatic injury including non-
healing wound, peptic ulcer, or bone fracture ≤28 days prior to randomization, or 
anticipate having a major surgical procedure during the course of the study. 
Randomization should only occur after complete wound healing.  Subcutaneous 
venous access device placement should not be considered a significant surgery, but 
should be placed greater than 7 days prior to randomization. 
[18] Have had radiation to any site (for example, bone) within 14 days prior to 
randomization. Palliative radiation to symptomatic metastatic sites (for example, 
bone) is permitted, provided it is performed >14 days prior to randomization.  If any 
tumor lesion is administered radiotherapy, then it cannot be considered for response 
assessment.
[19] Has documented brain metastases, leptomeningeal disease, or uncontrolled spinal 
cord compression. Screening of asymptomatic patients without history of central 
nervous system (CNS) metastases is not required.  However, patients with findings 
consistent with CNS malignancy or metastasis should be evaluated fully before 
study participation.  
[20] Have had any previous systemic therapy with VEGF inhibitors or VEGF-Receptor 
inhibitors (including investigational agents).

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[21] Are receiving therapeutic dose anticoagulation with warfarin, low-molecular-weight 
heparin, or similar agents (see also Inclusion Criterion 8d).
[22] Are receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs: 
for example, indomethacin, ibuprofen, naproxen, or similar agents) or other anti-
platelet agents (for example, clopidogrel, ticlopidine, dipyridamole, anagrelide). 
Aspirin use at doses up to 325 mg/day is permitted
[23] Symptomatic congestive heart failure (New York Heart Association III-IV are 
excluded, Class I and II are eligible), unstable angina pectoris, or symptomatic or 
poorly controlled cardiac arrhythmia.
[24] Within 6 months prior to randomization, have had any arterial thrombotic event, 
including myocardial infarction, unstable angina, cerebrovascular accident, or 
transient ischemic attack.
[25] Have an uncontrolled arterial hypertension with systolic blood pressure ≥150 or 
diastolic blood pressure ≥90 mm Hg despite standard medical management.
[26] Have a previous malignancy within 5 years of study entry or a concurrent 
malignancy. Patients with carcinoma in situ of any origin and patients with prior 
malignancies who are in remission and whose likelihood of recurrence is very low, 
as judged by the Lilly CRP/CRS in consultation with the treating investigator, are 
eligible for this study.  The approval by the CRP/CRS of such patients is required 
before these patients may be enrolled.
[27] The patient is currently enrolled in, or discontinued within the last 28 days from, a 
clinical trial involving an investigational product or non-approved use of a drug or 
device (other than the study drugs used in this study), or 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. 
Patients participating in surveys or observational studies are eligible to participate in 
this study.
[28] Have a history of gastrointestinal perforation and/or fistulae within 6 months prior 
to randomization.
[29] Have a known allergy or hypersensitivity reaction to any of the treatment 
components.
[30] Have a history of uncontrolled hereditary or acquired thrombotic disorder.
[31] Have uncontrolled metabolic disorders or other nonmalignant organ or systemic 
diseases or secondary effects of cancer that induce a high medical risk and/or make 
assessment of survival uncertain. Other severe acute or chronic medical or 
psychiatric condition or laboratory abnormality that may increase the risk associated 
with study participation or study drug administration, or may interfere with the 
interpretation of study results, and in the judgment of the investigator would make 
the patient ineligible for entry into this study.
[32] Have mixed hepatocellular biliary tract cancer histology.

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[33] Females who are pregnant or lactating.
[34] Have a QTc interval >470 msec as calculated be the Fridericia equation.
[35] The patient experienced any bleeding episode considered life-threatening, or any 
Grade 3 or 4 gastrointestinal/variceal bleeding episode in the 3 months prior to 
randomization requiring transfusion or endoscopic or operative intervention
6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be re-
screened, only after discussion with and permission from the Lilly CRP/CRS or designee.  Each 
time re-screening is performed, the individual must sign a new informed consent form (ICF) and 
will be assigned a new identification number.
Note that repeating 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. If a repeat screening laboratory value meets eligibility, it is 
recommended that the test is rechecked to confirm stability.

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7.
Treatments
7.1.
Treatments Administered
Table JSBF.8 shows the treatment regimens.
Table JSBF.8.
Treatment Regimens/Dosing Schedule
Arm
Study Druga,b
Dose
Route
Day (21-day Cycle)
Infusion Duration
A1
Ramucirumabc
8 mg/kg
IV
Days 1 and 8
over approx. 60 minutes
Cisplatin
25 mg/m2
IV
Days 1 and 8
over approx. 60 minutes
Gemcitabine
1000 mg/m2
IV
Days 1 and 8 
over approx. 30 minutes
A2
Placeboc
equivalent volume
IV
Days 1 and 8
over approx. 60 minutes
Cisplatin
25 mg/m2
IV
Days 1 and 8
over approx. 60 minutes
Gemcitabine
1000 mg/m2
IV
Days 1 and 8 
over approx. 30 minutes
B1
Merestinibd
80 mg
PO with food 
Each Day
N/A
Cisplatin
25 mg/m2
IV
Days 1 and 8
over approx. 60 minutes
Gemcitabine
1000 mg/m2
IV
Days 1 and 8 
over approx. 30 minutes
B2
Placebo
Similar appearing 
tablet(s) for dose
PO with food
Each Day
N/A
Cisplatin
25 mg/m2
IV
Days 1 and 8
over approx. 60 minutes
Gemcitabine
1000 mg/m2
IV
Days 1 and 8 
over approx. 30 minutes
Abbreviations:  IRR = infusion-related reaction; IV = intravenous; N/A = not applicable; PO = oral.
a
For Arm A administer ramucirumab/placebo (IV) before the administration of cisplatin.  For Arms A and B 
administer cisplatin before the administration of gemcitabine.  
b Treatment with all study drugs will be given in an outpatient setting.  Treatment will continue until there is 
evidence of disease progression or any other discontinuation criteria are met (Section 8).  Treatment with 
cisplatin and gemcitabine will be capped at a maximum of 8 cycles.  Treatment with the randomly assigned study 
therapy of ramucirumab, merestinib, or placebo will not be capped at a maximum number of cycles and should 
be continued until there is evidence of disease progression or any other discontinuation criteria are met.  During 
the planned treatment period, if one or more therapeutic agent is permanently discontinued for a reason other 
than progressive disease, then treatment with the other study agent(s) should continue and the patient should 
remain on study with full adherence to all protocol-related requirements.
c
IRRs may occur during or following administration of ramucirumab (placebo).  See Appendix 10 for a definition 
of IRRs.  For the first and second infusions:  IV administration of the next study drug should start only after at 
least a 1-hour observation period (after ramucirumab/placebo administration).  If there is no evidence of an IRR 
during the initial 2 infusions of ramucirumab/placebo, then no observation period is required for subsequent 
(third and later) treatment cycles, and IV administration of the next study drug can begin immediately after the 
infusion of ramucirumab/placebo.  In the event an IRR occurs thereafter, the 1-hour observation should be 
reinstituted.
d Merestinib should be administered in the morning for Cycle 1 Day 1.  Thereafter, tablets should be taken at 
approximately the same time each day, where evening administration is preferred.

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The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient/study site personnel/legal representative

verifying that instructions are followed properly 

maintaining accurate records of study treatment dispensing and collection

at the end of the study, returning all unused medication to Lilly, or its designee, 
unless Lilly and the investigator’s site have agreed all unused medication is to be 
destroyed by the site, as allowed by local law
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
7.1.1. Packaging and Labelling
Ramucirumab/placebo (IV) and merestinib/placebo (oral) will be provided by Lilly.
Commercial cisplatin and gemcitabine will be used (see Sections 7.1.1.3 and 7.1.1.4).
7.1.1.1.
Ramucirumab or Placebo (Intravenous)
Ramucirumab is a sterile, preservative-free solution for infusion of ramucirumab drug substance 
formulated in an aqueous solution at a concentration of 10 mg/mL (500 mg/50-mL vial).  The 
buffer contains 10 mM histidine, 75 mM sodium chloride, 133 mM glycine, and 
0.01% polysorbate 80.  The pH is 6.0.
Placebo is a sterile, preservative-free solution for infusion containing histidine buffer in a 50-mL 
vial to mimic the ramucirumab container and closure.  The buffer contains 10 mM histidine, 75
mM sodium chloride, 133 mM glycine, and 0.01% polysorbate 80.  The pH is 6.0.
All excipients used for the manufacture of ramucirumab (and placebo) are of pharmacopeial 
grade.  No animal-derived components are used in the manufacture of ramucirumab excipients.
7.1.1.2.
Merestinib or Placebo (Oral)
Merestinib will be supplied as 40-mg tablets for oral administration.  The tablets should be stored 
at room temperature according to the label and not crushed or dissolved.  Investigators should 
instruct patients to store the tablets in the original package and in a location inaccessible to 
children.
The placebo is a light blue, nonagon tablet, which is identical in appearance to the 40-mg 
merestinib tablet.
7.1.1.3.
Gemcitabine
Gemcitabine will be supplied in commercially available dosage forms and provided according to 
the country’s regulatory requirements.  Gemcitabine should be stored in accordance with the 
product information.

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7.1.1.4.
Cisplatin
Cisplatin will be supplied in commercially available dosage forms and provided according to the 
country’s regulatory requirements.  Cisplatin should be stored in accordance with the product 
information.
7.2.
Method of Treatment Assignment
Approximately 300 patients will be randomly assigned.  Patients who meet all criteria for 
enrollment will be randomly assigned such that patients in each of the IV cohorts and the oral 
cohorts will be allocated to receive investigational treatment or control in a 2:1 fashion within 
24 to 72 hours prior to Visit 1 (Day 1, Cycle 1).  Every attempt should be made to randomize the 
patient as close as possible to Day 1 of Cycle 1 and not more than 72 hours prior to Day 1.  
Assignment to treatment groups will be determined by a computer-generated random sequence
using an interactive Web response system (IWRS).
Randomization will be stratified by the following factors:

Primary Tumor Site (gall bladder versus intrahepatic cholangiocarcinoma versus
extrahepatic cholangiocarcinoma or Ampulla of Vater)

Geographic regions (North America or Europe versus Rest of World)

metastatic disease (yes versus no)
The chosen stratification factors have been identified as potentially important adverse prognostic 
factors or regional considerations in this disease.  Randomization will be performed separately 
within each of the strata (or cells) defined by all combinations of these 3 variables.
7.2.1. Selection and Timing of Doses
A cycle is defined as an interval of 21 days. Treatment with all study drugs will be given in an 
outpatient setting.  Treatment will continue until there is evidence of disease progression or any 
other discontinuation criteria are met (Section 8).  Treatment with cisplatin and gemcitabine will 
be capped at a maximum of 8 cycles.  Treatment with the randomly assigned study therapy of 
ramucirumab, merestinib, or placebo will not be capped at a maximum number of cycles and 
should be continued until there is evidence of disease progression or any other discontinuation 
criteria are met.  During the planned treatment period, if one or more therapeutic agent is 
permanently discontinued for a reason other than progressive disease, then treatment with the 
other study agent(s) should continue and the patient should remain on study with full adherence 
to all protocol-related requirements.
After Cycle 1, a treatment delay at the start of a cycle (Day 1) of ±7 days, because of holidays, 
weekends, inclement weather, or other justifiable events, will be permitted and not counted as a 
protocol violation.  After the start of a cycle, treatment should continue on schedule if possible, 
but a variance of ±3 days may be allowed to accommodate holidays, weekends, inclement 
weather, or other justifiable events.

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7.2.1.1.
Premedication
7.2.1.1.1. Premedication Prior to Administration of Ramucirumab/Placebo 
(Intravenous)
Prior to each infusion of ramucirumab/placebo (IV), premedicate all patients with a histamine H1 
antagonist, such as diphenhydramine hydrochloride (or equivalent).  Additional premedication 
may be provided at the investigator’s discretion.  All premedication administered must be 
adequately documented in the case report form (CRF).
See Table JSBF.11 for ramucirumab dose modifications and additional premedication 
requirements for patients who have experienced a prior ramucirumab infusion-related reaction 
(IRR).
7.2.1.1.2. Premedication Prior to Administration of Cisplatin and Gemcitabine
Sites should consult the most current manufacturer’s instructions for cisplatin and gemcitabine 
for complete prescribing information (including warnings, precautions, contraindications, and 
adverse reactions) and follow institutional procedures and local guidelines for the administration 
of each agent.  Premedication with hydration and prophylactic use of antiemetics for cisplatin is
recommended.  Investigators should follow American Society of Clinical Oncology (ASCO)
Guidelines for Antiemetics in Oncology or their local standards of care (Kris et al. 2006; Basch 
et al. 2011; Hesketh et al. 2015).
7.2.1.2.
Administration of Ramucirumab/Placebo (Intravenous)
The patient’s actual dose of ramucirumab/placebo (IV) will be determined by measuring the 
patient’s weight at the beginning of each cycle.  If the patient’s weight fluctuates by more than 
10% from the weight used to calculate the prior dose, the ramucirumab/placebo dose must be 
recalculated.  Recalculation of the ramucirumab/placebo (IV) dose for weight fluctuations of 
<10% is permitted but not required.  A 5% variance in the calculated total dose will be allowed 
for ease of dose administration.
For patients undergoing repeated palliative drainage procedures to remove pleural or peritoneal 
fluid, dry weight will be defined as weight obtained after the drainage procedure and before fluid 
reaccumulation.  In such circumstances, dry weight will be used for dose calculation, if obtained 
30 days prior to dose.  If no recent dry weight is available, actual weight will be used.
A patient may continue to receive ramucirumab/placebo (IV) until a criterion for discontinuation 
is met (as described in Section 8.1).
7.2.1.2.1. Treatment Requirements for Ramucirumab/Placebo (Intravenous)
Prior to each infusion of ramucirumab/placebo (IV), the patient must meet the criteria shown in 
Table JSBF.9.

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Table JSBF.9.
Criteria to Be Met Prior to Each Ramucirumab Administration
Urine protein

<2+ on dipstick or routine urinalysis for C1D1;
2+ on dipstick or routine urinalysis for subsequent infusionsa
-or-

<2 g on 24-hour urine collection
Hypertension

Hypertension is controlled
Wound healing

Any wound is fully healed
Ramucirumab-related toxicities and AEs 
(other than AESIs [see Section 7.4.1.2])

CTCAE (Version 4.0) Grade <2 or the patient’s baseline level, 
except for clinically insignificant AEs (such as alopecia), as 
determined by the investigator.
Abbreviations:  AE = adverse event; AESI = adverse event of special interest; C1D1 = Cycle 1 Day 1; 
CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009).
a
If urine protein =2+ on dipstick or routine urinalysis, refer to Table JSBF.11.
Ramucirumab infusions should be delivered in approximately 60 minutes.  The infusion rate 
should not exceed 25 mg/min.  Infusions >60 minutes are permitted in the following situations:
1. if needed in order to maintain an infusion rate 25 mg/min, or
2. if the patient previously experienced a ramucirumab IRR.  See Section 9.2.1.1 for dose 
modifications and premedication requirements.
7.2.1.3.
Administration of Merestinib/Placebo (Oral)
A flat dose of merestinib/placebo will be taken orally once daily in a 21-day cycle.  Merestinib 
should be administered in the morning for Cycle 1 Day 1.  Thereafter, tablets should be taken at 
approximately the same time each day, where evening administration is preferred.  If the patient 
chooses to take their dose in the mornings, dosing should be withheld on days scheduled for PK 
sampling (Day 1 and Day 8 on Cycles 1, 2, 4, 6 and 8), and be administered after the PK sample 
has been drawn (Appendix 4, Table APP.4.3).  The administration time and date of the dose 
preceding these PK sample draws should be captured by the clinic. 
Tablets must be taken with a meal or within 1 hour after a meal and should be taken with at least 
8 ounces (240 ml) of fluid.  As an example, a meal should consist of approximately 500 calories 
or more for a patient whose standard diet consists of 1500 to 1800 calories per day.
A patient may continue to receive merestinib/placebo (oral) until a criterion for discontinuation 
is met (as described in Section 8).
7.2.1.4.
Administration of Cisplatin
Administration of cisplatin chemotherapy has a high emetogenic potential.  While this potential 
may be decreased when administering lower doses of cisplatin the use of prophylactic and 
continuing antiemetic medications is recommended in this study.  Investigators should follow 
ASCO Guidelines for Antiemetics in Oncology or their local standards of care (Kris et al. 2006; 
Basch et al. 2011; Hesketh et al. 2015).
The cisplatin dose specified in this protocol should be administered according to local standard 
of care.  Suggested administration is on an outpatient basis as a 1.5-hour IV infusion (1 liter of 

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0.9% saline including cisplatin, 20 mmol of potassium chloride, and 8 mmol of magnesium 
sulfate over 1 hour followed by 500 ml of 0.9% saline over 30 minutes).  Cisplatin treatment 
should be administered on Days 1 and 8 and will repeat every 21 days.  Treatment with cisplatin 
may continue for a planned maximum of 8 cycles, or until a criterion for discontinuation is met 
(as described in Section 8).  The initial dose of cisplatin is 25 mg/m2.  This initial dose is to be 
followed as scheduled with recurring doses of cisplatin 25 mg/m2 IV unless dose modification is 
required (see Section 7.4.2).  The dose of cisplatin administered should be rounded to the nearest 
1 mg.
As a routine precaution, patients enrolled in this study are to be observed closely by the medical 
staff for any potential AEs for the duration of the infusion, in an area with resuscitation 
equipment and other agents (epinephrine, prednisone equivalents, etc.) available.  A nurse must 
be present in the immediate treatment area throughout the infusion and observation period.  A 
physician must be in close proximity to the patient treatment area.
7.2.1.5.
Administration of Gemcitabine
Patients will receive 1000 mg/m2 gemcitabine administered over approximately 30 minutes on 
Days 1 and 8 of each 21-day treatment cycle.  Treatment with gemcitabine may continue for a 
planned maximum of 8 cycles, or until a criterion for discontinuation is met (as described in 
Section 8).  Investigators should consult the approved gemcitabine product information for 
complete packaging and labeling information.
7.3.
Blinding
This is a double-blind study.  To preserve the blinding of the study, a minimum number of Lilly 
personnel will see the randomization table and treatment assignments before the study is 
completed.  Additionally, there are no anticipated or identified toxicities from ramucirumab or 
merestinib that would potentially result in unblinding to treatment assignment.
Unblinding of the study team will not occur until after the final analysis of the primary endpoint 
(PFS).  Following final analysis of the primary endpoint (PFS), investigators and patients may be 
unblinded to study treatment assignment (see Section 7.8).
7.3.1. Emergency Unblinding
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP/CRS prior to 
unblinding a patient’s treatment assignment unless this could delay emergency treatment of the 
patient.  If a patient’s treatment assignment is unblinded, Lilly must be notified immediately.
Emergency unblinding for AEs must be performed through the IWRS. All actions resulting in an 
unblinding event are recorded and reported by the IWRS.

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7.3.2. Inadvertent Unblinding
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur.  If an investigator, site 
personnel, or patient is inadvertently unblinded, the unblinding will not be sufficient cause for 
the patient to be discontinued from study treatment or excluded from study analyses.
Additionally, there may be ethical reasons for the patient to remain on the study treatment.  In 
the event of unblinding, the investigator must obtain specific approval from a Lilly CRP/CRS for 
the patient to continue in the study.
Unblinding of treatment to determine eligibility for a subsequent trial should not be deemed to 
constitute sufficient cause for emergency unblinding.
7.4.
Dosage Modification
Treatment for the first cycle should commence only if all the inclusion and exclusion criteria are 
met. For subsequent cycles, dose delay/modification is permitted as described in sections 
specific for ramucirumab/placebo (Section 7.4.1), merestinib/placebo (Section 7.4.2), cisplatin 
and gemcitabine (Section 7.4.3). Ramucirumab/placebo dose modifications are permanent; no 
dose escalations are allowed after dose reduction.
In the event of observed toxicities that may be associated with more than one agent (for example,
hepatic toxicity or unexpected hematologic toxicity) a temporal association should be evaluated 
to aid in assessment of drug relatedness and dose modification.  Other potentially reversible risk 
factors for the AE should be identified and addressed as appropriate.  For example, in the case of 
hepatic toxicity, patients should be evaluated for the need to undergo biliary drainage.  In the 
absence of temporal association or other potentially reversible or modifiable risks factors for the 
AE, for overlapping toxicities, consideration should be given to first reduce the dose of the 
investigational drugs and try to maintain the dose of gemcitabine and cisplatin.
Therapy with ramucirumab/placebo or merestinib/placebo should continue as scheduled if there 
is a delay or discontinuation of gemcitabine or cisplatin. Likewise, if there is a delay or 
modification of ramucirumab/placebo or merestinib/placebo due to toxicity, treatment with 
cisplatin and gemcitabine can continue as scheduled.  An attempt should be made to 
resynchronize administration with intravenous agents (that is, at Day 1 of the next normally 
scheduled cycle).  If clinically appropriate, the investigator can delay intravenous treatment 
components up to a maximum of 7 days to allow synchronized administration of agents.
7.4.1. Ramucirumab/Placebo (IV) Dose Modifications
This section provides instructions for ramucirumab/placebo dose modifications applicable to 
treatment Arm A.  The ramucirumab dose may need to be delayed and/or reduced if the patient 
experiences an AE, including adverse events of special interest (AESIs) and non-AESIs.
Table JSBF.10 presents the specific ramucirumab/placebo dose reductions.

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Table JSBF.10.
Ramucirumab/Placebo Dose Reductionsa
Starting dose
8 mg/kg
First dose reduction
6 mg/kg
Second dose reduction
5 mg/kg
a
Ramucirumab/Placebo dose reductions are allowed between cycles and within a given cycle.
Ramucirumab/placebo dose modifications are permanent; no dose escalations are allowed after
dose reduction.  Any patient who requires a ramucirumab/placebo dose reduction will continue 
to receive a reduced dose until discontinuation from ramucirumab/placebo or discontinuation 
from the study.
No dose reduction is required for the first instance of reversible, Grade 3 or 4 non-life-
threatening toxicity that is considered at least possibly related to treatment, provided that the AE 
recovered to Grade ≤1 or pretreatment level within 21 days. However, if the event required 
treatment delay for greater than 21 days or in the event of a second instance of the event, upon 
recovery (Grade ≤1 or pretreatment level), the dose should be reduced by one level 
(Table JSBF.10). Dose reductions may be warranted if worsening of symptoms or laboratory 
values is clinically significant in the opinion of the investigator and after discussion and approval 
of the Lilly CRP/CRS or designee.  At the discretion of the investigator, ramucirumab/placebo 
treatment may be delayed for up to 21 days for Grade 2 AEs that are reversible and not life-
threatening (dose reduction is not required).  Dose adjustments or delays are not required for 
Grade ≤2 alopecia, fatigue, or peripheral neuropathy.
If a toxicity related to ramucirumab/placebo does not resolve in the same treatment cycle, the
administration of ramucirumab/placebo can be delayed for up to 42 days (2 cycles).  If the
toxicity does not resolve within 42 days, ramucirumab/placebo will be discontinued. 
A total of up to 2 dose-level reductions are allowed during the study.  Any patient who has had 
2 ramucirumab/placebo dose reductions and who experiences an event that would cause a third 
dose reduction must be discontinued from ramucirumab/placebo.
7.4.1.1.
Ramucirumab/Placebo Dose Modifications for AESIs
Table JSBF.11 presents the criteria for ramucirumab/placebo dose modifications applicable if the 
patient experiences an AESI.  A list of the AESIs for ramucirumab is provided below:
Infusion-related reactions (IRRs)
Hypertension
Proteinuria
Arterial thromboembolic events (ATEs)
Venous thromboembolic events (VTEs)
Bleeding/hemorrhage
Gastrointestinal perforation 
Congestive heart failure
Wound healing complications
Fistula
Liver failure/liver injury
Reversible posterior leukoencephalopathy syndrome (RPLS)

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Table JSBF.11.
Dose-Modifications for Ramucirumab/Placebo Adverse Events of 
Special Interest
Adverse Event of Special Interest
Dose Modification
1.
Infusion-related reaction (Section 9.2.1.1)
1.a.

Infusion-related reaction - Grade 1 or 2
Reduce the infusion rate by 50% for the duration of the 
infusion and for all future infusions.
Prior to all future infusions of ramucirumab/placebo, 
premedicate with:

an intravenous histamine H1 antagonist, such as 
diphenhydramine hydrochloride,

dexamethasone or equivalent, and

acetaminophen
1.b.

Infusion-related reaction - Grade 3 or 4
Discontinue ramucirumab/placebo.
2.
Hypertension (Section 9.2.1.2)
2.a.

Hypertension (non-life-threatening and 
associated with symptoms) -
Grade 2 or 3
Delay ramucirumab/placebo until the hypertension is 
controlled with medication and is resolved to Grade <2.

If controlled with medication and resolved to Grade <2 
within 14 days, then resume ramucirumab/placebo at 
current dose.

If controlled with medication and resolved to Grade <2 
within 28 days, then resume ramucirumab/placebo at a 
reduced dose as shown in Table JSBF.10.

If not controlled with medication and not resolved to 
Grade <2 within 28 days, then discontinue 
ramucirumab/placebo.

Investigators have the discretion to consider the clinical 
circumstances of individual patients, especially 
involving borderline hypertension, and administer 
unchanged dose of ramucirumab/placebo for blood 
pressure up to systolic 160 mm Hg and diastolic 100 
mm Hg, if clinically appropriate.
2.b.

Uncontrolled hypertension, hypertensive 
crisis, or hypertensive encephalopathy -
Grade 4
Discontinue ramucirumab/placebo.
3.
Proteinuria (Section 9.2.1.3)
3.a.

Proteinuria =2+ (dipstick or routine 
urinalysis)a

Administer ramucirumab/placebo at the patient's current 
dose if clinically indicated.

Obtain 24-hour urine protein results within 3 days prior 
to the next ramucirumab/placebo dose.
o
If urine protein is <2 g/24 h, administer 
ramucirumab/placebo at the patient's current dose.
o
If urine protein is 2 g/24 h, modify the 
ramucirumab/placebo dose based on 24-hour 
collection.  See Proteinuria 2 g/24 h (24-hour 
urine collection), Line 3.c in this table.

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Dose-Modifications for Ramucirumab/Placebo Adverse Events of Special Interest (concluded)
Adverse Event of Special Interest
Dose Modification
3.b.

Proteinuria >2+ (dipstick or routine 
urinalysis)a

Delay ramucirumab/placebo dose for up to 28 days.
Obtain 24-hour urine protein results within 3 days prior to 
the next ramucirumab/placebo dose.
If urine protein is <2 g/24 h, no further dose delay or dose 
reduction is required.
3.c.

Proteinuria 2 g/24 h (24-hour urine 
collection)a
First or second occurrence:  delay ramucirumab/placebo 
until urine protein returns to <2 g/24 h.  Reduce 
ramucirumab/placebo dose, as shown in Table JSBF.10.
If urine protein remains 2 g/24 h after holding 
ramucirumab/placebo for 28 days, discontinue 
ramucirumab/placebo.
Third occurrence:  discontinue ramucirumab/placebo.
3.d.

Proteinuria >3 g/24 h or in the setting 
of nephrotic syndromea
Discontinue ramucirumab/placebo.
4.
Arterial thromboembolic events, venous 
thromboembolic events 
(Section 9.2.1.4.1) - Grade 3 or 4
Discontinue ramucirumab/placebo.
5.
Bleeding/hemorrhage (Section 9.2.1.5) -
Grade 3 or 4
Discontinue ramucirumab/placebo.
6.
Gastrointestinal perforation 
(Section 9.2.1.6)
Discontinue ramucirumab/placebo.
7.
Reversible posterior leukoencephalopathy 
syndrome (Section 9.2.1.7)
Discontinue ramucirumab/placebo.
8.
Congestive heart failure (Section 9.2.1.8) –
Grade 3 or 4
Discontinue ramucirumab/placebo.
9.
Fistula formation (Section 9.2.1.9)
Discontinue ramucirumab/placebo.
10.
Impaired wound healing (Section 9.2.1.10)
10.a.

Prior to planned surgery

Withhold ramucirumab/placebo.
10.b

After surgery

Resume ramucirumab/placebo based on clinical 
judgment (maximum delay is 28 days after the 
patient's previous dose).
10.c.

Wound-healing complications 
developed during study treatment

Delay ramucirumab/placebo dosing (for up to 28 days) 
until the wound is fully healed.
11.
Liver injury/liver failure (Section 9.2.1.11)
11.a.

Hepatic encephalopathy and/or 
hepatorenal syndrome 
Discontinue ramucirumab/placebo.
a
Perform dipstick or routine urinalysis within 3 days prior to each infusion of ramucirumab/placebo (see 
Table JSBF.9).  If 24-hour urine collection is also performed, the results of 24-hour urine collection should be 
used for clinical decision-making.
Refer to Section 9.2.1 for detailed information about AESIs for ramucirumab.

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7.4.1.2.
Ramucirumab/Placebo Dose Modifications for Non-AESIs
The ramucirumab/placebo dose may be modified if the patient experiences a Grade 3 clinical AE 
that meets all of the following conditions:

the AE is reversible and non-life-threatening

the AE is not an AESI

the AE is considered to be at least possibly related to ramucirumab

the AE resolves to Grade 1 or to the patient's pretreatment baseline level within 28 days
If the patient experiences Grade 4 fever or a Grade 4 laboratory abnormality, 
ramucirumab/placebo may be continued at the discretion of the investigator if the fever or 
laboratory abnormality resolves to Grade 1 or to the patient's pretreatment baseline level within 
28 days.
If a second instance of Grade 4 fever or Grade 4 laboratory abnormality occurs, resume 
ramucirumab/placebo at a lower dose, as shown in Table JSBF.10.
Patients who enter the study with symptoms or laboratory values equivalent to Grade 1 or 2 AEs 
should not have dose reductions related to the persistence or mild worsening of those symptoms 
or laboratory values; dose reductions may be warranted if worsening of symptoms or laboratory 
values is clinically significant in the opinion of the investigator.  Asymptomatic laboratory 
abnormalities should not result in dose delays, modifications, or discontinuation of 
ramucirumab/placebo unless determined by the investigator to be clinically significant or life-
threatening.
7.4.2. Gemcitabine and Cisplatin Dose Modifications
Treatment cycles will be repeated every 21 days.  Patients will receive gemcitabine (with 
cisplatin) on Days 1 and 8 or unless treatment is delayed due to toxicity requiring dose 
adjustment.  Gemcitabine and cisplatin dose adjustment for toxicity is summarized in 
Table JSBF.12.
Initiation of a new cycle with gemcitabine or cisplatin requires an absolute neutrophil count of at 
least 1000/µL, platelets of at least 100,000/µL, and resolution of nonhematologic toxicities to 
CTCAE v4.0 Grade 0, 1, or baseline (except alopecia and fatigue).  If these parameters are not 
met, then defer by 1 week.  If deferred by 2 consecutive weeks, then consider dose reduction.
Resolution of toxicity is required to occur within 3 weeks of the intended start of the cycle, 
otherwise gemcitabine and cisplatin therapy should be discontinued.  Patients discontinuing 
gemcitabine and/or cisplatin therapy may be allowed to continue with the other study treatments
if they are receiving clinical benefit.

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Table JSBF.12.
Gemcitabine and Cisplatin Dose Adjustment for Toxicity
Event
Gemcitabine Dose
Cisplatin Dose
In 
previous 
Cycle*
Febrile Neutropenia or 
Grade 4 ANC ≥ 7 days
Dose at 75% of prior dose.  Prior to treatment toxicity should have 
recovered to ≤ Grade 2 and ANC ≥1000/µL and Platelets ≥100,000/µL.
Consider growth factor support per ASCO guidelines.
Current 
or Prior 
Cycle
Cisplatin or Gemcitabine 
associated Grade 3-4 non-
hematologic AE
Treatment with gemcitabine and/or cisplatin should be deferred until 
recovery, and then continued with an appropriate dose reduction, 
adjustment of mitigatable factors, or discontinued as clinically indicated.
Bilirubin  > 1.6 mg/dL 
(>27 µmol/L)
Initiate gemcitabine dose at 800 
mg/m2. May reduce further for 
hematologic AEs as defined below
ANC 
(/µL)
Platelets 
(/µL)
Day 8
> 
1000 
And
≥ 
100,000
Dose at 100% of prior dose.  
Dose at 100% of prior dose.  
500 to 
1000
Or
50,000 to 
<100,000
Administer 75% of prior dose (25% 
dose reduction; if already receiving 
a 75% dose, reduce by a further 
25%); continue this reduced dose in 
next cycle.
Give 100% of dose.
<500
Or
<50,000
Hold for recovery.  At next cycle, 
restart at 75% of prior dose.
Hold for recovery.  At next cycle, 
restart at 75% of prior dose.
Abbreviations:  AE = adverse event; ANC = absolute neutrophil count; ASCO = American Society of Clinical 
Oncology.
Source: Meyerhardt et al. 2008 and Valle et al. 2010.
If a dose reduction to 75% has been made for gemcitabine or cisplatin and cell counts return to 
within normal limits, then the dose may be increased to 100% on the subsequent doses.
7.4.3. Merestinib /Placebo (Oral) Dose Modifications
The merestinib/placebo dose may be modified if the patient experiences a Grade 3 clinical AE 
that meets all of the following conditions:

the AE is reversible and non-life-threatening

the AE is considered to be at least possibly related to merestinib

the AE resolves to Grade 1 or to the patient's pretreatment baseline level within 28 days of 
merestinib/placebo treatment interruption
If the patient experiences Grade 4 fever or a Grade 4 hematologic laboratory abnormality, 
merestinib/placebo may be continued at the discretion of the investigator if the fever or 
laboratory abnormality resolves to Grade 1 or to the patient's pretreatment baseline level within 
7 days.
Patients treated with merestinib/placebo, are permitted to continue dosing of merestinib/placebo 
without dose reductions or interruptions in merestinib/placebo if they maintain an ANC ≥500/μL 

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and a platelet count of ≥25,000/μL, provided that the suppression of ANC and/or platelet counts 
is deemed to be related to cisplatin or gemcitabine therapy.
In the event that a patient experiences a merestinib/placebo-related toxicity requiring treatment to 
be held (as above) that resolves with treatment interruption, treatment may be resumed at a 
reduced dose of 40 mg.  No patient will have their merestinib/placebo dose reduced below 40 mg 
per day. At the start of the next cycle re-escalation to the original dose is acceptable in the 
absence of continuing toxicity.  However, if subsequent dose reduction is again required, the 
patient must be maintained at the reduced dose level for all remaining cycles.
If a patient has recurrence of the same toxicity at the 40-mg dose in the absence of other 
identifiable risk factors, then he/she will be discontinued from treatment. In the presence of 
other identifiable risk factors attempts should be made to mitigate those risks, if possible, before 
making the determination to discontinue merestinib/placebo therapy.
7.5.
Preparation/Handling/Storage/Accountability
Refer to the respective IBs for detailed information about preparation, handling, and storage of 
ramucirumab and merestinib.  Additional information is provided in the study pharmacy manual.
Refer to the manufacturer’s instructions for instructions on preparation, handling, and storage of 
cisplatin and gemcitabine.  Additional information for dosing is provided in the study pharmacy 
manual.
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
7.6.
Treatment Compliance
Ramucirumab/placebo (IV), cisplatin and gemcitabine will be administered only at the 
investigational sites by the authorized study site personnel.  As a result, treatment compliance is 
ensured.
Patient compliance with merestinib/placebo (oral) will be assessed at each visit by direct 
questioning and counting returned tablets.  A patient dosing diary may also be used to assist in 
collection of administration data related to the PK analysis.  Deviation(s) from the prescribed 
dosage regimen should be recorded on the CRF.  The patient must take 80% of the intended dose 
to be deemed compliant with study drug administration.  Similarly, a patient may be considered 
noncompliant if he or she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication.  Potential discontinuation of a patient due to 
study drug noncompliance will be discussed between the investigator and the Lilly CRP/CRS
before making the final determination for discontinuation.
7.7.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the CRF.  Concomitant medications (including over 

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the counter medications and supplements) and supportive care therapies must also be 
documented at the time of discontinuation and at the (30-day) Short-term Follow-up visit.
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment.
7.7.1. Supportive Care
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to all patients on this trial, with the intent to maximize quality of life.  
Patients will receive supportive care as judged by their treating physician.  If it is unclear 
whether a therapy should be regarded as supportive care, the investigator should consult the Lilly 
CRP/CRS or designee.
Details of interventions (for example, medications such as sedatives, antibiotics, analgesics, 
antihistamines, steroids, or erythropoietin), procedures (for example, paracentesis or 
thoracentesis), or blood products (for example, blood cells, platelets, or fresh frozen serum 
transfusions) must be recorded in the CRF.
Guidelines regarding the use of permitted supportive care agents (which include, but are not 
limited to, colony-stimulating factors (CSFs), erythropoiesis-stimulating agents, antidiarrheal 
agents, antiemetic agents, and analgesic agents) are presented in the following sections.
For Arm A, premedication and treatment of hypersensitivity (infusion-related) reactions is 
described in Section 9.2.1.1.
7.7.1.1.
Colony-Stimulating Factors
The use of G-CSF is permitted at the discretion of the investigator, based on ASCO (Smith et al. 
2015) and European Society for Medical Oncology (Crawford et al. 2010) guidelines.  G-CSF or 
similar agents are strongly recommended following Grade 3 or 4 neutropenia of duration >5 days 
or following any incidence of febrile neutropenia (ANC <1.0 × 109/L with a single temperature 
≥38.5°C) or a sustained temperature (≥38.0°C for >1 hour).
In addition, the use of prophylactic antibiotics such as ciprofloxacin may be considered for 
patients who may be susceptible to neutropenia or infections.  Ciprofloxacin 250 to 500 mg 
orally daily starting on Day 2 of a cycle for 7 to 10 days may be considered.
7.7.1.2.
Erythropoiesis-Stimulating Agents
The use of erythropoiesis-stimulating factors (for example, erythropoietin) is permitted at the 
discretion of the investigator based on ASCO guidelines (Rizzo et al. 2010).
7.7.1.3.
Antidiarrheal Agents
In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, loperamide, 
octreotide, and other antidiarrheals.  If diarrhea is severe (that is, requires IV hydration) and 
associated with fever or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics may be 

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prescribed.  Patients with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting should be considered for hospitalization for IV hydration and correction of electrolyte 
imbalance.
7.7.1.4.
Antiemetic Therapy
The routine use of standard antiemetics, including dexamethasone, 5-HT3 antagonists (such as 
granisetron or ondansetron), and NK1 antagonists as premedication and/or symptomatic 
management, should be administered as per the Multinational Association of Supportive Care in 
cancer and ASCO (Kris et al. 2006; Basch et al. 2011; Hesketh et al. 2015), or institutional 
guidelines.
7.7.1.5.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.  The chronic use of 
NSAIDs with a high risk of bleeding (for example, indomethacin, ibuprofen, naproxen, or 
similar agents) is strongly discouraged unless at the discretion and responsibility of the 
investigator after careful assessment of the individual bleeding risk of the patient.  If required, 
the chronic use of analgesic agents with no or low bleeding risk (for example, 
paracetamol/acetaminophen, metamizole, dipyrone, or propyphenazone) is recommended.
7.7.2. Prohibited Medication
No other chemotherapy, other anticancer therapy, immunotherapy, hormonal cancer therapy, 
radiation, surgery for cancer, or experimental medications will be permitted while patients are on 
study treatment.
Patients may not receive chronic antiplatelet therapy (for example, clopidogrel, ticlopidine, 
dipyridamole, and anagrelide).  Aspirin is permitted as per Section 7.7.3.
7.7.3. Restricted Therapies
Aspirin is permitted at doses ≤325 mg once daily.  Ongoing aspirin therapy at doses exceeding 
325 mg/day is not permitted.
Patients who develop venous thromboembolism during study therapy may continue study 
therapy and receive anticoagulation.  Patients who begin anticoagulation therapy during 
treatment on study must receive low-molecular-weight heparin (not oral anticoagulation).
Palliative radiation therapy is permitted after discussion with and agreement of the Lilly 
CRP/CRS or designee for irradiating small areas of painful metastases that cannot be managed 
adequately using systemic or local analgesics. Such areas must not be an identified target lesion 
and must not constitute progressive disease or meet RECIST criteria for progressive disease.  
Any symptomatic deterioration or clinical disease progression requiring, in the opinion of the 
investigator, other forms of specific antitumor systemic therapy, will be cause for discontinuation 
of study therapy.
Biliary stenting is permitted on study and should be recorded in the study CRF.

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Use of photodynamic therapy to manage biliary obstruction is permitted after discussion with 
and agreement of the Lilly CRP/CRS or designee for management of biliary obstruction.  Such 
areas must not be an identified target lesion and must not constitute progressive disease or meet 
RECIST criteria for progressive disease.
7.7.4. Other Study Conditions:  Surgery (or Procedure) during Study 
Treatment Period
If any surgery should be required during the study (palliative surgery or medically indicated by 
the investigator), the patient should undergo radiologic evaluation before surgery for 
documentation of disease status.  Elective, nonemergent surgery is strongly discouraged during 
study participation.  The time of study treatment interruption before surgery should be at least 
28 days following the last dose of ramucirumab/placebo or 4 days following the last dose of 
merestinib/placebo.  Timing of surgery following gemcitabine or cisplatin should be based on 
local practice or guidelines.  Patients may resume all study treatment no less than 28 days 
following surgery, provided there has been adequate recovery in the opinion of the investigator.  
Following surgery, radiological evaluation of disease is required prior to resumption of study 
treatment if treatment is not resumed within 3 weeks of treatment being held.
The additional radiologic evaluation before surgery should not reset the schedule of periodic 
radiographic evaluation for disease.  Patients undergoing surgery before disease progression 
should continue to be followed by imaging on their prior schedule.
7.7.5. Merestinib / Placebo (Oral) – Drug-Drug Interactions
Based on the available nonclinical data, there is a possible risk of clinical drug-drug interaction 
(DDI) when merestinib is coadministered with substrates of CYP2C19, 2C8, and 2C9.  In the 
absence of more data to refine the risk of interaction, caution is warranted in the concomitant use 
of LY2801653 with CYP2C19, 2C8, and 2C9 substrates known to have a narrow therapeutic 
range (CYP2C19: phenytoin, tricyclic antidepressants, tolbutamide; CYP2C8; CYP2C9: 
phenytoin).  When, in the investigators opinion, concomitant use of phenytoin, tricyclic 
antidepressants, or tolbutamide is indicated, use of these agents should be carefully monitored.
7.8.
Treatment after the End of the Study
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the final analysis for OS (approximately a total of 225 OS events in the 
study), as determined by Lilly.
Investigators will continue to follow Schedule of Activities (Section 2) for all patients until 
notified by Lilly that study completion has occurred.
Refer to Section 7.3 for unblinding that occurs after the final analysis of the primary endpoint 
(PFS).

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7.8.1. Continued Access
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks.  Placebo will no 
longer be administered, and crossover will not be permitted.
The continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
Lilly may allow patients to enroll in a “rollover” protocol to provide long-term continued access 
for patients enrolled in this study.  If a “rollover” protocol is used patients, must sign a new ICF 
before continued access is provided.
The patient’s continued access to ramucirumab or merestinib 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 JSBF.4).
Figure JSBF.3.
Continued access diagram.
Study Treatment Period
a Lilly will notify sites when the continued access period begins and ends. 
b Final analysis of overall survival.  Lilly will notify sites when study completion occurs.
c End of trial occurs at the last visit or last scheduled procedure for the last patient.
Study Completionb
Patient and investigator 
agree to discontinue  
study treatment
Study treatment
Continued access 
follow-up
(approximately 30 days)
Continued Access Perioda
End of Trialc

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Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be permanently 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

the patient is significantly noncompliant with study procedures and/or treatment

radiographic determination of disease progression

unacceptable toxicity

an intercurrent illness or change in the patient’s condition that renders the patient 
unsuitable for further treatment in the opinion of the investigator

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 should be permanently discontinued from ramucirumab or placebo (IV) for any of the 
following circumstances:

an unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient)

the patient has had 2 dose reductions of ramucirumab/placebo and experiences an AE that 
would cause a third dose reduction 

a Grade 3 or 4 infusion-related reaction that is clearly attributed to ramucirumab.

a Grade 3 or 4 arterial thrombotic event.

a Grade 3 or 4 venous thrombotic event that is considered to be life-threatening in the 
opinion of the investigator, or that cannot be adequately treated with anticoagulant 
therapy  

any pulmonary embolism or deep vein thrombosis occurring or intensifying during 
anticoagulant therapy

a Grade 3 or 4 bleeding or hemorrhagic event

gastrointestinal perforation or fistulae

any therapy-related event that is deemed life-threatening, regardless of NCI-CTCAE v 
4.0 grade

delay of ramucirumab/placebo >42 days (2 cycles) unless investigator considers 
continuation might be clinically beneficial for patient, is discussed with Sponsor 
physician and is appropriately documented

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
new occurrence of hepatic encephalopathy and/or hepatorenal syndrome.  In the event 
that study drug (ramucirumab or placebo) is not administered because of either of these 2 
conditions, re-treatment with study drug will not be permitted.

any Grade 3 or 4 events consistent with congestive heart failure (CHF)

Impaired Wound Healing: Discontinue ramucirumab/placebo if wound is not fully 
healed within 42 days of withholding ramucirumab.

Reversible Posterior Leukoencephalopathy Syndrome

urine protein level of 3 g/24 hours or in the setting of nephrotic syndrome

any Grade 4 (life-threatening) non-hematologic toxicity considered by the investigator to 
be possibly, probably, or definitely related to ramucirumab/placebo;
Patients should be permanently discontinued from merestinib or placebo (po) for any of the 
following circumstances:

1 dose reduction of merestinib/placebo and experiences an AE that would cause a second 
dose reduction

an unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient)

any toxicity considered clinically significant by the treating clinician that results in a 
delay of merestinib/placebo treatment >42 days (2 cycles), unless investigator considers 
continuation might be clinically beneficial for patient, is discussed with Sponsor 
physician and is appropriately documented

any Grade 4 (life-threatening) non-hematologic toxicity considered by the investigator to 
be possibly, probably, or definitely related to merestinib/placebo;
Patients should be permanently discontinued from cisplatin and gemcitabine for any of the 
following circumstances:

any event related to cisplatin and gemcitabine that is deemed life-threatening, regardless 
of NCI-CTCAE v. 4.0 grade

any toxicity considered clinically significant by the treating clinician (for example, ANC 
<1.0 109/L or platelets <75 x 109/L, gastrointestinal toxicity ≥Grade 2, serious electrolyte 
imbalance, etc.) and showing no sign of recovery despite adequate clinical intervention 
for more than 42 days
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/CRS 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/CRS to allow 
the inadvertently enrolled patient to continue in the study with or without study treatment.

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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 patient becomes pregnant during the study.  See Section 9.2 regarding regulatory 
reporting requirements on fetal outcome and breast-feeding

the investigator decides that the patient should be discontinued from the study

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 have end -of-study procedures performed as 
shown in the Schedule of Activities (Section 2).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he 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 any dose of 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.

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9.
Study Assessments and Procedures
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.
Section 2 provides the Schedule of Activities for this study.   Physical examinations and 
radiological assessments performed as part of routine clinical care may be used as baseline 
assessments if performed within the pre-treatment/pre-randomization windows specified in the 
schedule of events.
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
This study will be analyzed based on results of local (investigative site) radiologic assessments,
including dates of progression and death. Since radiographic imaging scans may be needed for
future regulatory purposes, or an independent review of all or a representative sample of scans
may be considered following the completion of PFS analysis, copies of all scans will be collected
throughout the study and stored centrally by a coordinating vendor designated by Lilly.
Investigative sites will send radiologic images routinely to Lilly (or designee) based on the
study-specified frequency. Lilly will collect and store tumor measurement images on all 
randomized patients.
Further details are provided in the manual of central radiology.
9.1.1. Efficacy Assessments at Baseline and During Study Treatment
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2).
Within 28 days prior to Cycle 1 Day 1, baseline tumor measurements will be performed on each 
patient.  Computed tomography (CT) scans, including spiral CT, and magnetic resonance 
imaging (MRI), are the preferred methods of measurement (CT scan thickness recommended to 
be 5 mm).  Intravenous and oral 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 intravenous and oral contrast).  A PET scan alone, or as part of a PET-CT,
may be performed for additional analyses but cannot be used to assess response according to 
RECIST v.1.1 (Eisenhauer et al. 2009).
All patients will be evaluated for response at these time points:

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
at baseline

every 6 weeks (±7 days) after randomization (regardless of treatment delays) during the 
Study Treatment Period, until disease progression OR study completion OR 14 months
after randomization, whichever occurs first

a confirmatory radiological scan is required after documented progression has occurred 
in the previous 4 to 6 weeks.
In addition, any patient whose disease has not progressed by 14 months after randomization 
(note that the patient may or may not still be on study treatment) will be evaluated for response at 
these time points:

every 12 weeks (±7 days) from 14 months after randomization, until disease progression 
OR study completion OR 3 years after randomization, whichever occurs first; then as per 
standard clinical practice after that.
Except when deemed not feasible in the opinion of the investigator because of the patient’s 
clinical status, imaging studies and tumor assessments will be performed as scheduled, even if 
therapy is delayed.  In the event that a patient is discontinuing study treatment due to clinical 
progression, attempts should be made to re-evaluate response by imaging prior to 
discontinuation.
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Radiological scan of the thorax and abdomen is required.  Imaging of the pelvis may also 
be considered depending on clinical presentation.
See Section 10.3.1 for definitions of the efficacy endpoints.
9.1.2. Efficacy Assessments During Postdiscontinuation Follow-Up
Postdiscontinuation follow-up will be conducted as described and shown in the Schedule of 
Activities (Section 2).
For patients who discontinue all study drugs without objectively measured progressive disease, 
continue to perform tumor assessment and imaging as follows:

every 6 weeks (±7 days) after randomization until disease progression OR study 
completion OR 14 months after randomization, whichever occurs first.

In addition, any patient whose disease has not progressed by 14 months after 
randomization will be evaluated for response every 12 weeks (±7 days) from 14 months 
after randomization, until disease progression OR study completion OR 3 years after 
randomization, whichever occurs first; then as per standard clinical practice after that.
After the patient has completed the confirmatory radiological scan, after documented 
radiographic disease progression, radiologic tests are no longer required, and the patient will be 
followed approximately every 3 months (7 days) until patient’s death, withdrawal of consent, or 
study completion (as defined in Section 7.8), whichever occurs first.  Whenever possible, 
survival follow-up is conducted in person. If an in-person visit is not possible, the site may 
confirm survival by contacting the patient directly via telephone.  

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9.1.3. Health Outcome/Quality of Life Measures
The assessment of patient-reported outcomes, including disease-specific symptoms and health 
status, will be assessed using the Functional Assessment of Cancer Therapy Hepatobiliary 
Questionnaire (FACT-Hep) and the EuroQol 5-Dimension 5-Level (EQ-5D-5L).  The 
instruments will be administered together with the FACT-Hep presented first, followed by 
presentation of the EQ-5D-5L.  Patients will complete the instruments only if the instruments 
have been translated into a language in which the patient is fluent and the translation has been 
validated.  Refer to the Study Schedule (Section 2) for the specific timing of these assessments.
9.1.3.1.
Functional Assessment of Cancer Therapy Hepatobiliary (FACT-Hep)
Questionnaire 
The FACT-Hep, is a patient self-reported questionnaire consisting of 2 sub-questionnaires:  1) 
the FACT-G that includes 27 general items to evaluate physical, social, emotional, and 
functional well-being; and 2) the 18-item Hepatobiliary Subscale (HepCS-18) for assessing 
disease-specific issues (Heffernan et al. 2002).
9.1.3.2.
EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
The EQ-5D-5L is a nonspecific and standardized instrument for use as a measure of self-reported 
health status (EuroQol Group 1990; Herdman et al. 2011).  Patients will complete the 5-level (no 
problems, slight problems, moderate problems, severe problems, and extreme problems), 
5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) 
questionnaire concerning their current health state.  A unique EQ-5D-5L health state is defined 
by combining 1 level from each of the 5 dimensions.  Additionally, patients will indicate their 
current health status by marking on a continuum ranging from 100 (best imaginable health state) 
to 0 (worst imaginable health state).
The EQ-5D-5L should be completed by the patient following completion of the FACT-Hep, 
before any extensive contact or consultation with study site personnel.
9.1.4. 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
The investigator will use Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 (NCI 2009) to assign AE terms and severity grades.
Investigators are responsible for:

monitoring the safety of patients in this study and for alerting Lilly or its designee to any 
event that seems unusual, even if this event may be considered an unanticipated benefit 
to the patient

the appropriate medical care of patients during the study

documenting their review of each laboratory safety report

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
following through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study treatment or the study, or that caused 
the patient to discontinue study treatment before completing the study.  The patient 
should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  Frequency of follow-up evaluation is left to the 
discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, study site personnel will record via CRF 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 procedure or study treatment via 
CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies. A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuations that result 
from AEs to Lilly or its designee via CRF, clarifying, if possible, the circumstances leading to 
the dose modification or discontinuation of treatment.
9.2.1. Adverse Events of Special Interest for Ramucirumab
Table JSBF.11 presents the criteria for dose modifications applicable if the patient experiences 
an AESI.  Contact the Lilly CRP/CRS if questions arise concerning AESIs.
9.2.1.1.
Infusion-Related Reactions
As with other monoclonal antibodies, IRRs may occur during or following 
ramucirumab administration.  Patients should be closely monitored for signs and symptoms 
indicative of an IRR from the initiation of the infusion in an area where resuscitation equipment 
and other agents (such as epinephrine and corticosteroids) are readily available.
A 1-hour observation period following the ramucirumab infusion is mandatory for the first 
2 infusions.  If the patient shows no evidence of an IRR with the first 2 infusions of 
ramucirumab, no observation period is required for subsequent infusions.  In the event an IRR 
occurs thereafter, the 1-hour observation should be reinstituted.
Symptoms of IRRs include rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, 
flushing, dyspnea, wheezing, hypoxia, and paresthesia.  In severe cases, symptoms include 
bronchospasm, supraventricular tachycardia, and hypotension.

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If the patient experiences a Grade 2 IRR, interrupt the infusion and treat the patient with 
anti-allergic medication.  If symptoms resolve, resume the infusion at a reduced rate (50%).
In the event of an IRR, blood samples will be collected for both PK and immunogenicity analysis 
at the following time points:  (i) as close as possible to the onset of the IRR, (ii) at the resolution 
of the IRR, and (iii) 30 days following the IRR.
9.2.1.1.1. Guidelines for Reporting IRRs
Any treatment-related IRRs are defined according to the CTCAE Version 4.0 definition (General 
Disorders and Administration Site Conditions).  Symptoms occurring during or following 
infusion of investigational therapy may also be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome (Immune System Disorders).  In the 
setting of symptoms occurring during or following infusion of investigational therapy, 
investigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.
9.2.1.2.
Hypertension
An increased incidence of severe hypertension (CTCAE Grade 3) has been reported in patients 
receiving ramucirumab as compared with placebo.  In most cases, hypertension was controlled 
using standard antihypertensive treatment.  Preexisting hypertension should be controlled before 
starting ramucirumab treatment.
Monitoring of blood pressure is required during ramucirumab therapy.  Every attempt should be 
made to control blood pressure to systolic <140 mm Hg and diastolic <90 mm Hg prior to 
starting treatment with ramucirumab.  Routine clinical and laboratory monitoring is required in 
patients who again develop hypertension or experience a deterioration in previous hypertension.
9.2.1.3.
Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGF Receptor 2 pathway, 
including ramucirumab.  Proteinuria has been associated with ramucirumab in clinical studies.  
The majority of events were Grade 1 or 2.  Monitoring for the development or worsening of 
proteinuria during ramucirumab therapy is required.  Discontinue ramucirumab if the patient 
experiences proteinuria >3 g/24 hours or nephrotic syndrome.
9.2.1.4.
Thromboembolic Events
9.2.1.4.1. Arterial Thromboembolic Events
Serious, sometimes fatal arterial thromboembolic events (ATEs), including myocardial 
infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, have been reported in 
clinical trials.
9.2.1.4.2. Venous Thromboembolic Events
Venous thromboembolic events (VTEs) are associated with cancer; however, the incidence of 
VTEs likely varies depending on the type of cancer, stage, and intensity of imaging.  
Additionally, VTEs have been associated with some antiangiogenic therapy, although the 

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incidence varies depending on the type of therapy, use of concomitant chemotherapy agents, and 
specific disease state.  VTEs have been reported from clinical studies investigating ramucirumab, 
particularly in the context of metastatic disease, or in regions adjacent to implanted venous 
access devices.
9.2.1.5.
Bleeding/Hemorrhage
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding.  Severe gastrointestinal (GI) hemorrhages, including fatal events, have been reported in 
patients with gastric cancer treated with ramucirumab in combination with paclitaxel.
Serious hemorrhagic AEs have been reported from clinical studies investigating ramucirumab.  
Hemorrhagic complications are associated with some malignancies (that is, variceal bleeding 
from portal hypertension in hepatocellular carcinoma, lower GI hemorrhag e from bowel 
metastases in ovarian carcinoma), although the rate of these complications varies considerably.  
As detailed in the ramucirumab IB, the incidences of hemorrhagic events to date, significant 
background incidence of bleeding in some malignancies, and use of concomitant antiplatelet 
therapy in some of the reported cases preclude any definitive association between bleeding and 
ramucirumab, although ongoing surveillance and identification (and exclusion) of patients with 
high bleeding risk remain essential and are detailed in the inclusion/exclusion criteria.
9.2.1.6.
Gastrointestinal Perforation
Patients with unresected (or recurrent) primary tumors or mesenteric or peritoneal disease who 
participate in this clinical study may be at increased risk for gastrointestinal perforation due to 
the nature of the disease.
An infrequent incidence of GI perforations has been associated with some antiangiogenic 
therapeutic agents, most specifically in the context of CRC (treated with combination regimens, 
including anti-VEGF antibodies and cytotoxic chemotherapy) and in advanced ovarian cancer.  
These events may be associated with extensive abdominal/peritoneal disease burden.  
Gastrointestinal perforation has been reported from clinical studies investigating ramucirumab.  
The incidences of these events to date and presence of significant comorbidities and risk factors 
preclude any definitive association with ramucirumab, although ongoing surveillance remains 
essential.  More information about GI perforation may be found in the IB.
9.2.1.7.
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical and radiologic 
syndrome typically consisting of reversible cortical neurological dysfunction and brain-imaging 
findings of subcortical edema involving the posterior circulation, particularly the occipital lobes 
(Hinchey et al. 1996).  The symptoms of RPLS most often include generalized seizures, 
headache, delirium, and cortical blindness, although these may vary significantly and 
occasionally include focal neurological deficits (Hinchey et al. 1996; Garg 2001; Lee et al. 
2008).  MRI represents the most reliable method for diagnosis (Lee et al. 2008).  Clinical 
symptoms and MRI abnormalities usually recover within days to weeks with proper 
management, although permanent neurologic dysfunction has been reported (Hinchey et al. 
1996; Tajima et al. 1999; Garg 2001; Lee et al. 2008).

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Across the ramucirumab clinical program, cases of RPLS have been reported.  Refer to the IB for 
the most current information,
Reversible posterior leukoencephalopathy syndrome should be identified and treated promptly in 
order to minimize potential for permanent neurological damage.  Treatment encompasses careful 
control of blood pressure, withdrawal of potentially causative medication, and administration of 
anticonvulsant agents to those experiencing seizures (Stott et al. 2005).
9.2.1.8.
Congestive Heart Failure
An increased risk of CHF has been associated with some antiangiogenic therapeutic agents, 
particularly in patients with metastatic breast cancer previously treated with anthracyclines.  A 
small number of CHF events (including fatal) were also reported in patients who had received 
ramucirumab after prior treatment with anthracyclines in the Phase 2 and Phase 3 studies.
Treatment with ramucirumab has the potential to enhance cardiotoxicity of agents within the 
anthracycline/anthracenedione class of chemotherapy medications.
Patients with risk factors should be closely monitored for signs and symptoms of CHF.
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease, such as preexisting coronary artery disease or CHF.  Ramucirumab should be 
discontinued in the event of any Grade 3 or 4 events consistent with CHF.
9.2.1.9.
Fistula Formation
Because fistula formation has been associated with antiangiogenic agents, patients may be at 
increased risk for the development of fistula when treated with ramucirumab.  Some fistulas can 
be resolved with surgical procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and Cleck 
2009).
9.2.1.10. Surgery and Impaired Wound Healing
Because ramucirumab is an antiangiogenic therapy, it may have the potential to adversely affect 
wound healing.  Ramucirumab did not impair wound healing in a study conducted in animals; 
however, the impact of ramucirumab on serious or nonhealing wounds has not been evaluated in 
humans.
9.2.1.11. Liver Failure and Other Significant Liver Injury
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  Patients with: 1) cirrhosis at a level of Child-Pugh 
Class B (or worse); or 2) cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis should not be enrolled in clinical trials with 
ramucirumab.  “Clinically meaningful ascites” is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.
9.2.2. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

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
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 CRF, 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.
9.2.3. 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 
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 

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and expedited reporting of SUSARs that are consistent with global regulations and associated 
detailed guidances.
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.
9.3.
Treatment of Overdose
Refer to the product label or investigator brochure of the overdosed agent for the most current 
information related to management of an overdose.
9.4.
Safety
9.4.1. Other Safety Measures
For each patient, ECGs, vital signs, laboratory tests, or other specified tests should be collected 
as shown in the Schedule of Activities (Section 2).  
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of study treatment should be reported to Lilly or its designee as an AE via 
CRF.
9.4.2. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
If a patient experiences an elevated ALT ≥5x ULN and elevated total bilirubin ≥2x ULN, clinical 
and laboratory investigation should be initiated by the investigator for possible causes based on 
the Lilly Hepatic Algorithm for Oncology Studies ( Appendix 11) and in consultation with the 
Lilly CRP/CRS.  Concurrently, patients should be evaluated for the need to undergo biliary 
drainage by stent placement.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities. To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests.  See Appendix 5.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring committee (DMC; an advisory group for 
this study formed to protect the integrity of data; refer to Section 10.3.6) can conduct additional 
analyses of the safety data.

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During the study, Lilly will perform a blinded review of all reports of deaths and SAEs to ensure 
completeness and accuracy.  If a death or other clinical AE is deemed serious, unexpected, and 
possibly related to study treatment, a limited number of Lilly Global Patient Safety 
representatives external to the study team will be unblinded for regulatory reporting and safety 
monitoring purposes.  These measures will preserve the integrity of the data collected during this 
study and minimize any potential for bias, while providing for appropriate safety monitoring.
9.5.
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected as shown in Appendix 4.
Blood samples will be drawn for all subjects in Arm A for the assessment of concentration of 
ramucirumab in serum.
Blood samples will be drawn for all subjects in Arm B for the assessment of concentration of 
merestinib and its metabolites in plasma. 
Blood samples will be drawn for all subjects in Arm A and Arm B for the assessment of plasma 
concentrations of total platinum derived from cisplatin and plasma concentrations of gemcitabine 
and its major metabolite.
A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon by the investigator and Lilly.
Drug concentration information that could unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalytical samples collected to measure study drug concentrations will be retained for a 
maximum of 1 year following the last patient visit for the study.
9.6.
Pharmacodynamics
Please refer to Section 9.8 below.
9.7.
Genetics
9.7.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in 
Appendix 4, where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research, either 
now or in the future.  Samples will be used to investigate variable response to ramucirumab 
and/or merestinib and to investigate genetic variants thought to play a role in BTC. 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 ERBs impose shorter time limits, at a facility selected by Lilly.  This retention 

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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 
ramucirumab and/or merestinib.
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 (PD), mechanism of action, variability of patient response 
(including safety), and clinical outcome.  Sample collection is incorporated into clinical studies 
to enable examination of these questions through measurement of biomolecules , including 
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular 
elements.  
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 ramucirumab or merestinib,
angiogenesis, immune function, and the disease state, and to correlate these markers to clinical 
outcome and/or for related research methods or validation of diagnostic tools or assays.
Required samples for biomarker research to be collected from all patients in this study are the 
following:
1.
blood samples (see Section 9.8.1)
2.
pretreatment tumor tissue (archived or newly biopsied ) (see Section 9.8.2)
Samples for biomarker research will be collected as specified in Appendix 4, where local 
regulations allow.  These samples are also described in the following sections.
It is possible that biomarker data for patients in the study has 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.
9.8.1. Samples for Nonpharmacogenetic Biomarker Research
Whole blood, serum, and EDTA 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 BTC, variable response to ramucirumab or 
merestinib, the mechanism of action of ramucirumab or merestinib, immune function, and/or for 
research-related methods, or validating 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.

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Samples will be retained for a maximum of 15 yea rs 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.  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 ramucirumab or merestinib or after ramucirumab or merestinib
become commercially available.
9.8.2. Tissue Samples for Research
Tumor tissue will be examined for biomarkers related to ramucirumab or merestinib, 
angiogenesis, immune function, and the disease state, and to correlate these markers to clinical 
outcome 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:

a newly obtained biopsy specimen during screening or an archived tumor sample obtained 
≤28 days before screening
Patients may be asked to undergo collection of an additional (optional) biopsy specimen and 
blood sample after treatment with ramucirumab and merestinib 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. 
Formalin-fixed paraffin-embedded tumor tissue obtained from the primary tumor or metastatic 
site should be provided as a block or unstained slides.  Due diligence should be used to make 
sure that tumor sample (not a normal adjacent or a tumor margin sample) is provided.  Pathology 
notes 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.
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 impose shorter time limits, at a facility 
selected by Lilly.  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 ramucirumab and merestinib or after ramucirumab or merestinib 
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.

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9.8.3. Immunogenicity Assessments
For patients in Arm A, blood samples for immunogenicity testing will be collected as shown in 
Appendix 4 to determine antibody production against ramucirumab.  Immunogenicity will be 
assessed by a validated assay designed to detect anti-drug antibodies in the presence of 
ramucirumab.  Antibodies may be further characterized and/or evaluated for their ability to 
neutralize the activity of ramucirumab.
Samples will be retained for a maximum of 15 years after last the patient visit for the study, or 
for a shorter period if regulations and ERBs/IRBs impose shorter time limits, at a facility 
selected by Lilly.  The duration allows Lilly to respond to future regulatory requests related to 
ramucirumab.
9.9.
Health Economics
Health Care Resource Use (HCRU) data collection will be scheduled on Day 1 of each 21-day 
cycle, beginning with Cycle 2 and covering the past 21 days.  Data collection will be done 
through a standard, or a study-specific CRF. Resource use data collection will, at a minimum,
include hospitalization episodes along with the corresponding lengths of stay, transfusions, 
concomitant medication, and any treatment-associated regimens, such as the administration of 
growth factors.

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10. Statistical Considerations
10.1. Sample Size Determination
The study will randomize 300 patients such that patients in each of the IV cohorts and the oral 
cohorts will be allocated to receive investigational treatment or control in a 2:1 fashion.  The 
primary analysis of PFS for the comparison of each investigational treatment to pooled control 
will be performed when a minimum of a total of 210 events in the study have been observed, 
assuming a 30% censoring rate in the study.  
Assuming a PFS hazard ratio of 0.70, this sample size yields approximately 80% statistical 
power to detect superiority of each investigational treatment over the pooled control with the use 
of a log-rank test, and a 1-sided type I error of 0.10, taking into account of the worst case 
scenario that same numbers of events are observed in an investigational treatment and pooled 
control.
The analysis of OS for the comparison of each investigational treatment to pooled control will be 
performed when a minimum of a total of 225 events in the study have been observed.  Assuming 
an OS hazard ratio of 0.75, this sample size yields approximately 68% statistical power to detect 
superiority of each investigational treatment over the pooled control with the use of a log -rank 
test and a 1-sided type I error rate of 0.10.
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. 
Per-protocol population: will include all randomized patients who receive at least 1 dose of 
study treatment and do not have any major protocol violations that could potentially affect the 
efficacy conclusions of the study.  This population will be defined in detail in the Statistical 
Analysis Plan (SAP) prior to database lock.
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 
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 treated patients who received at least 1 dose of 
study treatment and have at least 1 post baseline evaluable PK sample.
Biomarker population:  will include the subset of patients from the randomized population 
from whom a valid assay result has been obtained.

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10.3. Statistical Analyses
All tests of treatment effects will be conducted at a 1-sided alpha level of .1, unless otherwise 
stated.  Unless otherwise stated, 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 SAP and the clinical study report.  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
10.3.1. Efficacy Analyses
Progression-free survival is defined as the time from randomization until the first radiographic 
documentation of progression or death from any cause in the absence of progressive disease.  
Patients known to be alive and without disease progression will be censored at the time of the 
last adequate tumor assessment (a detailed PFS event/censoring scheme is provided in 
Table JSBF.13).  Progression-free survival will be compared between each investigational
treatment to pooled control using a log-rank test and 1-sided alpha level of 0.1.  The same 
comparison will also be conducted using 1-sided alpha level of 0.025.  The corresponding hazard 
ratio (HR) between treatment arms will be estimated using a Cox regression model (Cox 1972).  
Progression-free survival curves, median PFS, and PFS rates at various time points with 95% CI
for each treatment arm will be estimated using the Kaplan-Meier method (Kaplan and Meier 
1958).  Sensitivity analyses for PFS will be described in the SAP.
Overall survival is defined as the time from randomization until death from any cause.  If the 
patient is alive or lost to follow-up at the time of data analysis, OS data will be censored on the 
last date the patient is known to be alive.  Overall survival will be compared between each 
investigational treatment to pooled control using a log-rank test.  The corresponding HR between 
treatment arms will be estimated using a Cox regression model (Cox 1972). Overall survival 
curves, the median and survival rates at various time points with 95% CI, for each treatment arm 
will be estimated using the Kaplan-Meier method (Kaplan and Meier 1958).

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Table JSBF.13.
PFS Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Investigator assessed tumor progression or 
death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate radiological assessment 
or date of randomization (whichever is later)b
Unless
No baseline radiological tumor assessment 
available
Censored
Date of randomization
No adequate postbaseline radiological 
tumor assessment available and death 
reported after 2 scan intervals following 
randomizationb,c
Censored
Date of randomization
Tumor progression or death documented
immediately after 2 or more scan intervals 
following last adequate radiological tumor 
assessment or randomization (whichever is 
later)b,c
Censored
Date of last adequate radiological assessment 
or date of randomization (whichever is later)b
Abbreviations:  CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; SD = stable disease.
a
Symptomatic deterioration (that is, symptomatic progression that is not radiologically confirmed) will not be 
considered as tumor progression.
b
Adequate radiological tumor assessment refers to an assessment with one of the following responses:  CR, PR, 
SD, or PD.
c
Refer to the Statistical Analysis Plan for the definition of 2 scan intervals, including any adjustment for scan 
window.
Overall response rate is defined as the number of patients who achieve a best overall response of 
CR or PR divided by the total number of patients randomized to the corresponding treatment arm 
(ITT population).  The confirmation of CR and PR is not required.  The ORR, with 95% CI, will 
be summarized for each treatment arm and compared between each investigational treatment to 
pooled control using the Fisher’s exact test.
Disease control rate (DCR) is defined as the number of patients who achieve a best overall 
response of CR, PR, or SD divided by the total number of patients randomized to the 
corresponding treatment arm (ITT population).  The confirmation of CR and PR is not required.  
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6 to 8 weeks).  The DCR, with 95% CI, will be 
summarized for each treatment arm and compared between each investigational treatment to 
pooled control using the Fisher’s exact test.
Duration of response is defined as the time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date that disease is recurrent or objective 
progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the 
absence of objectively determined disease progression or recurrence.

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10.3.2. Health Outcome/Quality of Life Analyses
The main analysis will be conducted in the ITT population as defined in Section 10.2.  
Exploratory analyses of patient-reported outcomes (PROs) may be performed on subpopulations 
as appropriate.
For each instrument, the compliance rate 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.  
10.3.2.1. Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire
(FACT-Hep)
FACT-Hep scores and their change from baseline will be summarized descriptively at each 
assessment time point.  The change from baseline in FACT-Hep scores will be evaluated to 
investigate statistically significant differences between ramucirumab and placebo and between 
merestinib and placebo.
A mixed model repeated measure analysis model will be applied to evaluate trajectories of pre-
specified scores, domains, and items to investigate differences between ramucirumab and 
placebo and between merestinib and placebo; the model will include time, treatment, and the 
interaction of time and treatment.  Time to deterioration (TtD) of selected scores, domains, and 
items will be characterized using the Kaplan-Meier method; between-treatment arm comparisons 
will be estimated using the Cox proportional hazards models (Cox 1972). Analysis details will 
be presented in the SAP.
10.3.2.2. EuroQol 5-Dimension 5-Level (EQ-5D-5L)
For the EQ-5D-5L patient responses, based on their experiences during that day, the first 5 EQ-
5D items form a 5-digit code uniquely identifying 1 of the 3125 possible health states.  These 
unique 5-digit health states serve only as an index, or locator, into a pre-selected, country-
specific value set to assign a utility value to this particular EQ-5D descriptive profile.  These 
utility values are applied to the OS estimate for the estimation of quality-adjusted-life-years 
(QALYs) that are used to inform economic evaluations of health care interventions.  No 
inference on these descriptive measures was intended by the questionnaire developers.  
Nonetheless, descriptive presentation of these data will be provided, by visit and by treatment, 
and will include numbers and proportions of responders on each of the 5 dimensions across each 
of the 5-level categorical responses (that is, mobility, self-care, usual activity, pain/discomfort, 
and anxiety/depression).  The visual analogue scale (VAS) will be scored from 0 (worst 
imaginable health state) through 100 (best imaginable health state) to represent the patient’s self-
report concerning how bad or how good their health was during that day.  For both, the VAS 
scores and the produced utility values descriptive statistics will include a measure of the central 
tendency and a measure of dispersion (that is, these can be mean values and standard deviations 
[or standard errors, or 95% CIs] or if the data are skewed, median values and the 25th and 75th
percentiles).  Completion compliance of the EQ-5D-5L questionnaires will be described by 
assessment time point (including baseline, on-study, and short-term follow-up) by the number 

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and percentage of patients who filled out a questionnaire (per patient, at least 1 question 
answered) over number of patients who are expected to complete the questionnaire at that time 
point.  Reasons for noncompliance will be summarized.
10.3.3. Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA) Version 18.0 (or higher) will be 
used when reporting AEs by MedDRA terms.  The MedDRA Lower Level Term (LLT) will be 
used in the treatment-emergent computation.  Treatment-emergent adverse events will be 
summarized by System Organ Class (SOC) and by decreasing frequency of Preferred Term (PT) 
within SOC.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

SAEs, including possible relationship to study drug

AEs leading to dose adjustments

discontinuations from study treatment due to AEs or death

treatment-emergent abnormal changes in laboratory values

treatment-emergent abnormal changes in vital signs 
10.3.4. Other Analyses
10.3.4.1. Immunogenicity Analysis
The number and percentage of patients with positive anti-ramucirumab antibodies will be 
summarized.  Any relationship with the occurrence of an IRR and positive anti-ramucirumab 
antibodies may be explored.
10.3.4.2. 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.
10.3.4.3. 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. 
10.3.4.4. Concomitant Therapy
A summary of prior and concomitant medications by treatment arm will be reported.

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10.3.4.5. Postdiscontinuation Anticancer Therapy
The numbers and percentages of patients receiving postdiscontinuation 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.
10.3.4.6. 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.
For IV arm only, study treatment will be administered at the investigator site, therefore treatment 
compliance is assured.
For oral arm only, 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.  Study treatment taken will be derived from the difference between the total number 
of tablets dispensed and returned over the course of the patient’s treatment.
10.3.4.7. Pharmacokinetics
Ramucirumab Cmin and concentrations at 1 hour post end of infusion (approximately Cmax) in 
serum will be summarized by descriptive statistics. Additional analysis utilizing the population 
PK approach may also be conducted if deemed appropriate.
Merestinib plasma concentrations will be summarized by descriptive statistics. Additional 
analysis utilizing the population PK approach may also be conducted if deemed appropriate.
The relationship between ramucirumab or merestinib exposure and selected efficacy and safety 
outcomes may be explored.
Plasma concentrations of total platinum derived from cisplatin and plasma concentrations of 
gemcitabine and its major metabolite will be summarized by descriptive statistics.  
10.3.4.8. Healthcare Resource Utilization
Hospitalizations, transfusions, and emergency room visits, during the study and at the 30-day 
visit, will be summarized descriptively by treatment arm.
10.3.5. 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. 
10.3.6. Interim Analyses
One interim analysis of safety will be conducted after a total of at least 75 evaluable patients 
have completed Cycle 1.  The interim analysis will be conducted to assess safety.  
An assessment committee (AC) will be established to conduct safety reviews. The membership, 
roles, and responsibilities of the AC are defined in the AC Charter.  Blinded Lilly study team 

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members will not be part of the AC.  The AC members will review unblinded safety data at the 
prespecified time point to determine whether there are sufficient safety concerns to justify 
modifying the study or the termination of study treatment and/or enrollment.  Only the AC and 
statistical analysis center are authorized to evaluate unblinded interim safety analyses.  Study 
sites will receive information about interim results only if they need to know for the safety of 
their patients.
Details of the unblinding plan will be described in the Assessment Committee Charter.  
Unblinding details are specified in the unblinding plan section of the SAP or in a separate 
unblinding plan document.
A limited number of preidentified individuals may gain access to the limited unblinded data, as 
specified in the unblinding plan, prior to the interim or final database lock, in order to initiate the 
final population PK/PD model development processes for interim or final analyses.  Information 
that may unblind the study during the analyses will not be reported to study sites or blinded study 
team until the study has been unblinded.

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AM, ColliganB, Douglass L, Carter J, Walgren RA. Prevalence of MET expression, activating 
mutations of KRAS and IDH1/2, and ROS1 fusions in cholangiocarcinoma patient tumor 
samples [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association 
for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. 
Abstract nr 2339.
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, 
Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. 
Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 
2010;362(14):1273-1281.
Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, Morris K, Duggan M, Cunningham D, 
Anthoney DA, Corrie P, Madhusudan S, Maraveyas A, Ross PJ, Waters JS, Steward WP, 
Rees C, Beare S, Dive C, Bridgewater JA. Cediranib or placebo in combination with cisplatin
and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a 
randomised phase 2 trial. Lancet Oncol. 2015 Aug;16(8):967-978.
Wu W, Bi C, Credille KM, Manro JR, Peek VL, Donoho GP, Yan L, Wijsman JA, Yan SB, 
Walgren RA.  Inhibition of tumor growth and metastasis in non-small cell lung cancer by 
LY2801653, an inhibitor of several oncokinases, including MET. Clin Cancer Res. 
2013;19(20):5699-5710.
Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek 
BW, Manro JR, Shih C, Stewart JA, Stewart TR, Stout SL, Uhlik MT, Um SL, Wang Y, 
Wu W, Yan L, Yang WJ, Zhong B, Walgren RA.  LY2801653 is an orally bioavailable multi-
kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and 
displays anti-tumor activities in mouse xenograft models.  Invest New Drugs. 
2013;31(4):833-844.

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Yan SB, Um SL, Peek VL, Thobe MN, Credille KM, Stephens JR, Manro JR, Ballard DW, 
Baker JA, Cook JD, Konicek BW, Graff JR, Holzer TR, Walgren RA. Preclinical evaluation 
of LY2801653, an orally bioavailable small molecule oncokinase inhibitor, in 
cholangiocarcinoma models. American Association for Cancer Research. 2014. Abstract 4403.
Yi JH, Thongprasert S, Lee J, Doval DC, Park SH, Park JO, Park YS, Kang WK, Lim HY. A 
phase II study of sunitinib as a second-line treatment in advanced biliary tract carcinoma: a 
multicentre, multinational study. Eur J Cancer. 2012;48:196-201.
Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S et al. Clinicopathological and 
prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J 
Cancer. 2008;98(2):418-425.
Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, 
Clark JW, Abrams TA, Chan JA, Enzinger PC, Bhargava P, Kwak EL, Allen JN, Jain SR, 
Stuart K, Horgan K, Sheehan S, Fuchs CS, Ryan DP, Sahani DV. Efficacy and safety of 
gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of 
changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol.
2010;11(1):48-54.

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Appendix 1.
Abbreviations and Definitions
Term
Definition
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.
AESI
adverse events of special interest
ALT
alanine transaminase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate transaminase
ATE
arterial thromboembolic event
blinding/masking
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment.  Unless otherwise specified, blinding will remain in effect until final database 
lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.  
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
BTC
biliary tract cancer
CHF
congestive heart failure
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CNS
central nervous system
collection database
a computer database where clinical trial data are entered and validated.
CR
complete response
CRC
colorectal cancer
CRF
case report form

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CRP/CRS
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
[CRS], global safety physician, or other medical officer.
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DDI
Drug-drug interaction
DMC
data monitoring committee
ECG
electrocardiogram
effective method of 
contraception
male condom with spermicide, female condom with spermicide, diaphragm with 
spermicide, cervical sponge, or cervical cap with spermicide.
bilateral tubal ligation, male condom with spermicide, intrauterine device that has been in 
place for at least 3 months before the first dose of study treatment, or an oral contraceptive 
pill taken for at least 3 months before the first dose of study treatment.
Also see the definition of highly effective method of contraception.
enroll
The 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.
EQ-5D-5L
EuroQol 5-Dimension 5 Level
end of study
End of study is the date of the last visit or last scheduled procedure for the last patient.
ERB/IRB
ethical review board/institutional review board:  /A board or committee (institutional, 
regional, or national) composed of medical and nonmedical members whose responsibility 
is to verify that the safety, welfare, and human rights of the patients participating in a 
clinical study are protected.
FACT
Functional Assessment of Cancer Therapy
FACT-Hep
FACT Hepatobiliary Questionnaire
GCP
good clinical practice
GFR
glomerular filtration rate
GI
gastrointestinal
HGF
hepatocyte growth factor
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), total abstinence, 
or vasectomy.
Also see the definition of effective method of contraception.

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IB
investigator’s brochure
IC50
inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IgG1
immunoglobulin G, subclass 1
INR
International Normalized Ratio
IV
intravenous
interim analysis
An interim analysis is an analysis of clinical trial data conducted before the final reporting 
database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to gain 
further information about the authorized form.
IRR
infusion-related reaction
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
MedDRA
Medical Dictionary for Regulatory Activities
MET
mesenchymal-epithelial transition factor
MVD
microvascular density
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
OS
overall survival
PET
positron emission tomography
PFS
progression-free survival

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PK
pharmacokinetic(s)
PO
oral
PR
partial response
PRO
patient-reported outcomes
PTT/aPTT
partial thromboplastin time /activated partial thromboplastin time
QTc 
corrected QT interval
randomize
the process of assigning patients to an experimental group on a random basis
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event
SAP
Statistical Analysis Plan
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
Study completion
This study will be considered complete following the final analysis of overall survival is 
performed), as determined by Lilly.  
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.
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event

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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.
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 IB 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.

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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 investigator will sign the final clinical study report for this study, indicating agreement, to 
the best of his or her knowledge, with the analyses, results, and conclusions of the report.
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 investigator with the most enrolled patients will serve as the clinical study report 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the clinical study report coordinating investigator.
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.

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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.
Electronic patient-reported outcome (ePRO) measures (for example, a rating scale) are entered 
into an ePRO instrument (for example, personal data assistant [PDA], or by means of IWRS) at 
the time that the information is obtained.  In these instances where there is no prior written or 
electronic source data at the site, the ePRO instrument record will serve as the source.
If ePRO records are stored at a third-party site, investigator sites will have continuous access to 
the source documents during the study and will receive an archival copy at the end of the study 
for retention.
Any data for which the ePRO instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
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 
database system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
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, 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 judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 3.
Clinical Laboratory Tests
Randomization and treatment decisions will be based on local laboratories.  For each local 
chemistry blood draw, samples for central laboratory shipment should be collected as well.

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Hematologya: (local laboratory only)
Clinical Chemistrya,c: (local and central 
laboratory)
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total bilirubin
Mean cell volume  (MCV)
Direct bilirubin
Mean cell hemoglobin concentration (MCHC)
Alkaline phosphatase
Leukocytes (WBC)
Alanine aminotransferase (ALT)
Neutrophils, segmented
Aspartate aminotransferase (AST)
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatinine
Eosinophils
Magnesium
Basophils
Calcium
Platelets
Glucose, non-fasting
Albumin
Urinalysis (Local)a:
LDH
Routine dipstick measurements, and if clinically 
indicated, microscopic analysis.  If urine dipstick or 
routine analysis indicates proteinuria ≥2+ at 
evaluations, a 24-hour urine collection (to assess 
protein) must be obtained.
Chloride
Serum Thyroid Function Tests (central)
TSH
Free thyroxine (T4)
Free triiodothyroxine (T3)
Tumor Markers (central)
Carbohydrate antigen 19-9 (CA19-9)
Carcinoembryonic antigen (CEA)
CA 125
Exploratory Biomarkers/Otherb: (central 
laboratory only)
Anti-ramucirumab antibody
Ramucirumab concentrations in serum
Pregnancy Test: (local laboratory only)
(females only)a,d
Coagulation Tests: (local laboratory only)a:
Prothrombin time (PT or INR)
Partial thromboplastin time (PTT)
Abbreviations:  β-hCG = beta human chorionic gonadotropin; RBC = red blood cells; TSH = thyroid-stimulating 
hormone; WBC = white blood cells; WOCBP = women of childbearing potential.
a
Assayed by Investigator designated (local) laboratory.  For Arms A and B, perform urinalysis at baseline and 
short-term follow-up visit.  During the treatment period, perform urinalysis for Arm A.
b
Assayed by Sponsor-designated (central) laboratory.
c
Investigator-designated (local) laboratory results are to be used for on-study dosing decisions.  Samples must also 
still be submitted for testing by the Sponsor-designated central laboratory but will not be used to make treatment 
decisions.
d
Serum pregnancy test in WOCBP will be done at baseline; thereafter, serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of β-hCG) to be performed.

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Appendix 4.
Sampling Schedule for Genetics/ 
Biomarkers/Immunogenicity/Pharmacokinetics/ 
Pharmacodynamics
It is essential that the exact infusion start and stop times (actual clock readings), as well as 
infusion parameters (such as, type of infusion pump, flow rate settings) are recorded.  The exact 
time of collection of each venous blood sample will be based on the clock used to record 
infusion times.  It is essential that the pharmacokinetic blood samples not be withdrawn from the 
same site as the drug infusion.
Table APP.4.1.
Sampling Schedule for Genetics/Biomarkers/Pharmacodynamics
(Arms A and B)
Scree
ning
Cycle 1 Day 1
Cycle 1 
Day 8
6 weeks 
post-
treatment
12 weeks 
post-
treatment
24-X 
weeks 
post-
treatment
Short-
Term 
Follow-
Up
Before 
dosing
End of 
study day
Pharmacogenetics 
(PGx) samplea
X
Mandatory tumor 
tissueb
X
Whole bloodc
X
X
X
X
X
X
X
X
Plasmac
X
X
X
X
X
X
X
X
Serumc
X
X
X
X
X
X
X
X
a
A pretreatment blood sample is preferred; however, the whole blood sample for genetic analysis may be 
collected at a later time point if necessary.
b Collection of a fresh tumor biopsy tumor tissue during screening is required unless an archived tumor sample is 
available that was obtained ≤28 days prior to screening.  Previously archived formalin-fixed paraffin-embedded 
tumor tissue obtained from the primary tumor or metastatic site should be provided as a whole block or unstained 
slides.
c
Whole blood, plasma, and serum samples for exploratory purposes should be obtained during screening, on 
Cycle 1 Day 1 (before dosing and at the end of study day), on Cycle 1 Day 8, and then to coincide within 7 days 
of the  Radiological Tumor Assessment at 6  and 12 weeks, and then every 12 weeks thereafter.

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Table APP.4.2.
Pharmacokinetic and Immunogenicity, Schedule (Arm A)
Visit
Time Pointa
Window
Ramucirumab
PKb
IKb
Cycle 1 
Day 1
Prior to infusion
Within 7 days Prior to 
infusion
X
X
Cycle 1 
Day 1
1 hr post end-of-infusion
1 to 1.5 hours after the end 
of the infusion
X
Cycle 1 
Day 8
Prior to infusion
Within 3 days prior to 
infusion
X
Cycle 2 
Day 1
Prior to infusion
Within 3 days prior to 
infusion
X
Cycle 3 
Day 1
Prior to infusion
Within 3 days prior to 
infusion
X
X
Cycle 3 
Day 1
1 hr post end-of-infusion
1 to 1.5 hours after the end 
of the infusion
X
Cycle 4 
Day 1
Prior to infusion
Within 3 days prior to 
infusion
X
Cycle 5 
Day 1
Prior to infusion
Within 3 days prior to 
infusion
X
Cycle 7 
Day 1
Prior to infusion
Within 3 days prior to 
infusion
X
Cycle 9 
Day 1
Prior to infusion
Within 3 days prior to 
infusion
X
Cycle 9 
Day 1
1 hr post end-of-infusion
1 to 1.5 hours after the end 
of the infusion
X
Cycle 13 
Day 1
Prior to infusion
Within 3 days prior to 
infusion
X
Short-term 
follow-up
Follow-up
Anytime during the follow-
up visit
X
X
Abbreviations:  IK = immunogenicity; IRR = infusion-related reaction; PK = pharmacokinetics.
a
Relative to ramucirumab or placebo infusion.
b
In the event of an IRR, blood samples will be collected for both PK and IK analysis at the following time points:  
(i) as soon as possible after the onset of the IRR, (ii) at the resolution of the IRR, and (iii) 30 days following the 
IRR.

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Table APP.4.3.
Pharmacokinetic Schedule (Arm B)
Visit
Cycle/Day 
Time
Merestinib PK (plasma 
concentration)
C1 D8a
C1 D8a
Morning
X
C2,4,6,8 D1a
C2,4,6,8 D1
Morning 
X
C2,4,6,8 D8a
C2,4,6,8 D8
Morning
X
Abbreviations:  C = cycle; D = day; PK = pharmacokinetic(s).
a
If patient has not taken drug on the evening before a visit, it should be taken after the PK sample has been drawn. 
Note:  It is essential that the dosing dates, dosing times, draw dates and draw times are accurately recorded.  Timing 
of outpatient doses administered on Day 7 and Day 21 of every cycle should be recorded by the clinic. 
Table APP.4.4.
Pharmacokinetic Schedule (Arm A + Arm B)
Visit
Time Point
Window
PK
Gemcitabine
Cisplatin
Cycle 3 Day 1
Prior to cisplatin 
infusion
Within 30 min prior to 
cisplatin  infusion
X
end-of-cisplatin-
infusion
Within 10 min after the end 
of cisplatin infusion
X
Prior to gemcitabine 
infusion
Within 30 min prior to 
gemcitabine infusion
X
end-of-gemcitabine-
infusion
Within 10 min after the end 
of gemcitabine infusion
X
Cycle 3 Day 8
Prior to cisplatin 
infusion
Within 30 min prior to 
cisplatin  infusion
X
end-of-cisplatin-
infusion
Within 10 min after the end
of cisplatin infusion
X
Prior to gemcitabine 
infusion
Within 30 min prior to 
gemcitabine infusion
X
end-of-gemcitabine-
infusion
Within 10 min after the end 
of gemcitabine infusion
X
Abbreviation:  PK = pharmacokinetics.
Note:  It is essential that the dosing dates, dosing times, draw dates, and draw times are accurately recorded.

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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
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
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 laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 6.
Creatinine Clearance Formula
The CKD-EPI Creatinine Equation (2009)
The CKD-EPI creatinine equation is based on the same 4 variables as the MDRD Study equation, 
but uses a 2-slope spline to model the relationship between estimated GFR and serum creatinine, 
and a different relationship for age, sex and race.  The equation was reported to perform better 
and with less bias than the MDRD study equation, especially in patients with higher GFR .  This 
results in reduced misclassification of CKD.  As of November 2009, very few clinical 
laboratories report the estimated GFR using the CKD-EPI creatinine equation.  In the future, 
other GFR estimating equations may outperform CKD-EPI.
The CKD-EPI creatinine equation is: 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med.
2009;150:604-612. 

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Appendix 7.
ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to 
carry out any work activities.  Up and about more than 
50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours
4
Completely disabled.  Cannot carry on any selfcare.  
Totally confined to bed or chair
5
Dead.
Source:  Oken et al. 1982.

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Appendix 9.
Permitted and Prohibited Concomitant 
Therapy (Arm A)
Below is a table of medications and drug classes that either have restricted use (see the 
Conditions for Use column and referenced guidelines) or are not permissible for use while the 
patient is on Arm A of the study.
Therapy
As 
Needed
Chronic 
Use
Conditions for Use
Anticoagulants other 
than warfarin
no
no
Use of warfarin is prohibited.  Refer to Inclusion Criterion [8]d
and Exclusion Criterion 21.
Biologic response 
modifiers
no
no
Chemotherapy
no
no
Colony-stimulating 
factors
yes
no
Follow local guidelines.
Erythroid growth 
factors
yes
no
Follow local guidelines.
Experimental 
medicines
no
no
Investigational agents
no
no
NSAIDs
yes
no
Chronic use of aspirin up to 325 mg/day is permitted. 
Radiotherapy
yes
no
Palliative radiotherapy during the study, if clinically indicated, 
can be considered after consultation with the Lilly CRP/CRS.
Abbreviations:  CRP = (Lilly) clinical research physician; CRS = (Lilly) clinical research scientist; 
NSAIDs = nonsteroidal anti-inflammatory drugs.

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Appendix 10.
NCI-CTCAE v 4.0 Infusion-Related 
Reactions
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Infusion-
related 
reaction
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
nonsteroidal 
anti-inflammatory drugs 
[NSAIDs], narcotics, IV
fluids); prophylactic 
medications indicated for 
≤ 24 h
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition:  A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Allergic 
reaction
Transient flushing 
or rash, drug fever 
<38°C (<100.4°F); 
intervention not 
indicated
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics); 
prophylactic medications 
indicated for ≤ 24 h
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition:  A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition:  A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
like substances from mast cells, causing a hypersensitivity immune response.  Clinically, it presents with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness and may lead to death.
Cytokine 
release 
syndrome
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV
fluids); prophylactic 
medications indicated for 
≤ 24 h
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
pressor or 
ventilator 
support 
indicated
Death
Definition:  A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by 
the release of cytokines from the cells.
Abbreviations:  IV = intravenous(ly); NSAIDs = nonsteroidal anti-inflammatory drugs.

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Appendix 11.
Hepatic Monitoring Algorithm for Patients 
in Oncology Clinical Trials

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Appendix 12.
Protocol Amendment I3O-MC-JSBF(a) 
Summary: Randomized, Double-Blind, Phase 2 Study of 
Ramucirumab or Merestinib or Placebo plus Cisplatin 
and Gemcitabine as First-Line Treatment in Patients 
with Advanced or Metastatic Biliary Tract Cancer
Overview
Protocol I3O-MC-JSBF, Randomized, Double-Blind, Phase 2 Study of Ramucirumab or 
Merestinib or Placebo plus Cisplatin and Gemcitabine as First-Line Treatment in Patients with 
Advanced or Metastatic Biliary Tract Cancer, has been amended.  The new protocol is indicated 
by amendment (a) and will be used to conduct the study in place of any preceding version of the 
protocol.
Changes were made to this protocol based on regulatory authority feedback, from the US FDA.   
Additionally, minor changes were made in Sections 7.1.1.3, 7.1.1.4, and 7.2.1.5 to provide 
clarity to the site personnel.
The overall main changes made to this protocol are as follows:

Table JSBF.2 (Treatment Period) is amended to include a full chemistry profile on Day 8 of 
each study Cycle during Cycles 1 through 8.  Thereafter, collection for testing of a full 
chemistry profile on Day 8 of each study cycle is optional as clinically indicated at the 
discretion of the treating investigator.

Table JSBF.1 (Schedule of Screening Activities), Table JSBF.2 (Treatment Period), and 
Table JSBF.3 (Postdiscontinuation Follow-Up Schedule) are amended to include testing of 
serum TSH, free thyroxine (T4), and free triiodothyronine (T3).  Testing is added to baseline 
assessment, Cycle 8, the short-term follow-up visit, and as clinically indicated at the 
discretion of the treating investigator.

Text has been added to Section 10.1 (Sample Size Determination) related to analysis of OS 
for the study.

Text has been added to Section 7.4 (Dose modification) as guidance for investigators to make
attributions for the purpose of dose modifications, in the event of observed toxicities that 
may be associated with more than one agent.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of double underscore.
Section 2.  Schedule of Activities

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Table 1.  Schedule of Screening Activities I3O-MC-JSBF 
 
 
Baseline 
 
Cycle 
BL 
Notes 
Visit 
0 
Relative Day Prior to Cycle 1 Day 
1 
28 
14 
7 
Procedure 
Category 
Prot. Ref. 
Procedure 
 
 
 
Laboratory/ 
Diagnostic Tests 
6.1, 
Appendix 3 
Serum Chemistry profile 
 
X 
 
Two measurements are required that are separated by at least 5 days.  Serum chemistry to include 
TSH, free thyroxine (T4), and free triiodothyronine (T3). 
Abbreviations:  …TSH = thyroid-stimulating hormone;…. 
 
 
Table 2.  Treatment Period, I3O-MC-JSBF 
 
 
 
Treatment Period 
 
 
 
Study Period 
 
 
 
 
 
 
 
 
Notes 
 
 
 
Cycle (21-day cycle) 
1-8 
9+
 
 
Relative Day within 
Cycle) 
1 
2-7 
8 
9-21 
1 
2-7 
8a 
9-21 
Procedure 
Category 
Protocol 
Section 
Procedure 
 
 
 
 
 
 
 
 
Laboratory/ 
Diagnostic 
Tests 
Appendix 3 
Full chemistry profile 
X 
 
X 
 
X 
 
 
 
Assessments performed within 3 days prior to Day 1 of the 
cycle may be used for treatment decisions, if the results are 
deemed still clinically valid by the treating investigator.  Day 8 
chemistry to be collected during Cycles 1 through 8.  
Thereafter, Day 8 collections will be optional as clinically 
indicated at the discretion of the treating investigator. 
In Cycle 8, serum chemistry on any day in the cycle to include 
TSH, free thyroxine (T4), and free triiodothyronine (T3). 
Abbreviations:  …TSH = thyroid-stimulating hormone;…. 
 

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Table 3.  Postdiscontinuation Follow-Up Schedule, I3O-MC-JSBF
Postdiscontinuation Follow-up
Cycle
Short-term 
Follow-up
Long-term 
Follow-up
Notes
Visit
801
802-8XX
Duration
Refer to 
footnote for 
duration
Refer to 
footnote for 
duration
Procedure 
Category
Protocol 
Reference
Procedure
Laboratory/
Diagnostic 
Tests
Appendix 3
Chemistry
X
Serum chemistry to include TSH, free thyroxine (T4), and free triiodothyronine (T3).
Abbreviations:  …TSH = thyroid-stimulating hormone;….

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7.1.1.3.  Gemcitabine
Gemcitabine will be supplied in commercially available dosage forms and provided according to 
the country’s regulatory requirements.  Gemcitabine should be stored in accordance with the 
package insert product information.
7.1.1.4.  Cisplatin
Cisplatin will be supplied in commercially available dosage forms and provided according to the 
country’s regulatory requirements.  Cisplatin should be stored in accordance with the package 
insert product information.
7.2.1.5.  Administration of Gemcitabine
Patients will receive 1000 mg/m2 gemcitabine administered over approximately 30 minutes on 
Days 1 and 8 of each 21-day treatment cycle.  Treatment with gemcitabine may continue for a 
planned maximum of 8 cycles, or until a criterion for discontinuation is met (as described in 
Section 8).  Investigators should consult the approved gemcitabine package insert product 
information for complete packaging and labeling information.
7.4.  Dosage Modification
In the event of observed toxicities that may be associated with more than one agent (for example, 
hepatic toxicity or unexpected hematologic toxicity) a temporal association should be evaluated 
to aid in assessment of drug relatedness and dose modification.  Other potentially reversible risk 
factors for the AE should be identified and addressed as appropriate.  For example, in the case of 
hepatic toxicity, patients should be evaluated for the need to undergo biliary drainage.  In the 
absence of temporal association or other potentially reversible or modifiable risks factors for the 
AE, for overlapping toxicities, consideration should be given to first reduce the dose of the 
investigational drugs and try to maintain the dose of gemcitabine and cisplatin.
10.1.  Sample Size Determination
The analysis of OS for the comparison of each investigational treatment to pooled control will be 
performed when a minimum of a total of 225 events in the study have been observed.  Assuming 
an OS hazard ratio of 0.75, this sample size yields approximately 68% statistical power to detect 
superiority of each investigational treatment over the pooled control with the use of a log-rank 
test and a 1-sided type I error rate of 0.10.
Attachment 3.  Clinical Laboratory Tests
Serum Thyroid Function Tests (central)
TSH
Free thyroxine (T4)
Free triiodothyroxine (T3)
Abbreviations:  …TSH = thyroid-stimulating hormone;….

Leo Document ID = 5d184a92-4920-47c9-b069-c7d97cde7b20
Approver: 
Approval Date & Time: 30-Mar-2016 14:48:16 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Mar-2016 15:46:23 GMT
Signature meaning: Approved
PPD
PPD