A Phase 1b/2 Study of Ramucirumab in Combination With LY2875358 in Patients With Advanced Cancer
Phase: PHASE1
Conditions: Advanced Cancer, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Hepatocellular Cancer, Renal Cell Carcinoma, Non-Small Cell Lung Cancer
Sponsor: Eli Lilly and Company

Title: A Phase 1b/2 Study of Ramucirumab in Combination with LY2875358 in Patients with 
Advanced Cancer. 
NCT ID: NCT02082210 
Document Approval Date: 13 Mar 2015 

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1.
Protocol I4C-MC-JTBF(b)
A Phase 1b/2 Study of Ramucirumab in Combination with 
LY2875358 in Patients with Advanced 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 
ramucirumab (IMC-1121B; LY3009806) and LY2875358, unless such persons are bound 
by a confidentiality agreement with Eli Lilly and Company or its subsidiaries.  This 
document and its associated attachments are subject to United States Freedom of 
Information Act (FOIA) Exemption 4.
Generic Names:  Ramucirumab (IMC-1121B; LY3009806) and LY2875358
This Phase 1b/2 study is a multicenter, non-randomized, open-label, dose escalation study 
to determine a recommended schedule and dose range for LY2875358 that may be safely 
administered in combination with a fixed regimen of ramucirumab to patients with advanced 
and/or metastatic cancer (Part A), followed by tumor-specific expansion cohorts for gastric 
or gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, or renal cell 
cancer for dose confirmation and exploration of clinical activity (Part B).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol  Approved by Lilly:  28 October 2013
Amendment (a) Approved by Lilly:  15 September 2014
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 13-Mar-2015 GMT

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2.
Synopsis
This Phase 1b/2 study is a multicenter, nonrandomized, open-label, dose-escalation study to 
determine a recommended schedule and dose range for LY2875358 that may be safely 
administered in combination with a fixed regimen of ramucirumab to patients with advanced 
and/or metastatic cancer (Part A), followed by tumor-specific expansion cohorts for gastric or
gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, renal cell cancer patients, 
or non-small cell lung cancer for dose confirmation and exploration of clinical activity (Part B). 
During the first cycle (28 days), the dose-limiting toxicities will be assessed and potential 
chronic toxicity will be evaluated for the entire treatment period.

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3.
Table of Contents
A Phase 1b/2 Study of Ramucirumab in Combination with 
LY2875358 in Patients with Advanced Cancer
Section
Page
1.
Protocol I4C-MC-JTBF(b)  A Phase 1b/2 Study of Ramucirumab in 
Combination with LY2875358 in Patients with Advanced Cancer.......................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................3
4.
Abbreviations and Definitions...........................................................................................10
5.
Introduction ......................................................................................................................15
5.1.
MET Activation by Anti-angiogenic Therapy...............................................................15
5.2.
Introduction to Study Drugs .........................................................................................16
5.2.1.
Ramucirumab.......................................................................................................16
5.2.1.1.
Ramucirumab and Gastric or GEJ Adenocarcinoma........................................17
5.2.1.2.
Ramucirumab and Hepatocellular Cancer .......................................................17
5.2.1.3.
Ramucirumab and Renal Cell Carcinoma .......................................................18
5.2.1.4.
Ramucirumab and Non-Small Cell Lung Cancer ............................................18
5.2.2.
LY2875358..........................................................................................................19
5.3.
Rationale for Study I4C-MC-JTBF...............................................................................20
5.3.1.
Rationale for Amendment (a)...............................................................................21
5.3.2.
Rationale for Amendment (b)...............................................................................21
6.
Objectives.........................................................................................................................22
6.1.
Primary Objective ........................................................................................................22
6.2.
Secondary Objectives...................................................................................................22
6.3.
Exploratory Objective ..................................................................................................22
7.
Study Population...............................................................................................................23
7.1.
Inclusion Criteria..........................................................................................................23
7.2.
Exclusion Criteria ........................................................................................................25
7.3.
Rescreening..................................................................................................................27
8.
Investigational Plan...........................................................................................................28
8.1.
Summary of Study Design............................................................................................28
8.1.1.
Sample Size .........................................................................................................30
8.1.2.
Rationale for Selection of Dose............................................................................32
8.1.3.
Study Completion and End of Trial......................................................................33
8.2.
Discontinuations ..........................................................................................................33
8.2.1.
Discontinuation of Patients...................................................................................33

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8.2.2.
Discontinuation of Study Sites .............................................................................35
8.2.3.
Discontinuation of the Study................................................................................35
9.
Treatment..........................................................................................................................36
9.1.
Materials and Supplies .................................................................................................36
9.1.1.
Ramucirumab.......................................................................................................36
9.1.2.
LY2875358..........................................................................................................36
9.2.
Study Drug Administration ..........................................................................................36
9.2.1.
Ramucirumab Dosing Schedule............................................................................37
9.2.1.1.
Premedication for Ramucirumab.....................................................................37
9.2.2.
LY2875358 Dosing Schedule...............................................................................37
9.2.2.1.
Dose Escalation of LY2875358 in Part A .......................................................37
9.2.2.2.
Dose-Limiting Toxicity Determination ...........................................................38
9.2.2.3.
Dose Escalation Method and Maximum Tolerated Dose 
Definition .......................................................................................................39
9.2.2.4.
Dose Confirmation of LY2875358 in Part B...................................................39
9.2.3.
Dose Adjustments and Delays..............................................................................40
9.2.3.1.
Infusion-Related Reaction ..............................................................................40
9.2.3.2.
Treatment Guidelines and Dose Modifications for 
Ramucirumab-specific Adverse Events...........................................................44
9.2.3.2.1.
Hypertension ............................................................................................44
9.2.3.2.2.
Proteinuria ................................................................................................45
9.2.3.2.3.
Thromboembolic Events...........................................................................45
9.2.3.2.4.
Bleeding (Hemorrhagic) Events................................................................46
9.2.3.2.5.
Gastrointestinal Perforations.....................................................................46
9.2.3.2.6.
Congestive Heart Failure in Patients Who Received 
Ramucirumab in Combination With Mitoxantrone or 
Following Prior Anthracycline Therapy ....................................................46
9.2.3.2.7.
Surgery and Impaired Wound Healing ......................................................47
9.2.3.2.8.
Liver Injury/Liver Failure .........................................................................47
9.2.3.2.9.
Reversible Posterior Leukoencephalopathy Syndrome ..............................47
9.2.3.3.
Treatment Guidelines for LY2875358-Specific Adverse 
Events ............................................................................................................48
9.3.
Method of Assignment to Treatment ............................................................................49
9.4.
Blinding .......................................................................................................................49
9.5.
Concomitant Therapy...................................................................................................49
9.6.
Treatment Compliance .................................................................................................50
9.6.1.
Evaluable Patients................................................................................................51
10.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................52

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10.1. Safety Evaluations........................................................................................................52
10.1.1.
Safety Data Collection and Review ......................................................................52
10.1.2.
Adverse Events ....................................................................................................52
10.1.2.1.
Serious Adverse Events ..................................................................................54
10.1.2.1.1.
Adverse Event and Serious Adverse Event Reporting ...............................55
10.1.2.1.2.
Prior to Administration of Study Drug(s) ..................................................55
10.1.2.1.3.
On Therapy...............................................................................................55
10.1.2.1.4.
Follow-Up Visit........................................................................................55
10.1.2.1.5.
Suspected Unexpected Serious Adverse Reactions....................................56
10.1.2.2.
Summary of Adverse Event/Serious Adverse Event 
Reporting Guidelines......................................................................................56
10.1.3.
Other Safety Measures .........................................................................................56
10.1.3.1.
Electrocardiograms.........................................................................................56
10.1.4.
Safety Monitoring ................................................................................................57
10.1.5.
Complaint Handling.............................................................................................57
10.2. Sample Collection and Testing.....................................................................................58
10.2.1.
Samples for Study Qualification and Health Monitoring.......................................58
10.2.2.
Samples for Biomarker Research..........................................................................59
10.2.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................60
10.2.3.1.
Pharmacokinetic Samples...............................................................................60
10.2.4.
Samples for Immunogenicity Research.................................................................61
10.3. Efficacy Evaluations ....................................................................................................61
10.4. Procedure/Sampling Compliance..................................................................................62
11.
Data Management Methods...............................................................................................63
11.1. Data Quality Assurance................................................................................................63
11.2. Data Capture Systems ..................................................................................................63
11.2.1.
Case Report Form ................................................................................................63
11.2.2.
Ancillary Data......................................................................................................64
12.
Data Analyses...................................................................................................................65
12.1. General Considerations ................................................................................................65
12.2. Patient Disposition .......................................................................................................65
12.3. Patient Characteristics ..................................................................................................65
12.4. Safety Analyses............................................................................................................66
12.5. Pharmacokinetic Analyses............................................................................................66
12.6. Efficacy........................................................................................................................67
12.7. Biomarker Analyses.....................................................................................................67
12.8. Interim Analyses ..........................................................................................................67

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13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................69
13.1. Informed Consent.........................................................................................................69
13.2. Ethical Review.............................................................................................................69
13.3. Regulatory Considerations ...........................................................................................69
13.3.1.
Investigator Information.......................................................................................70
13.3.2.
Protocol Signatures ..............................................................................................70
13.3.3.
Final Report Signature .........................................................................................70
14.
References ........................................................................................................................71

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List of Tables
Table
Page
Table JTBF.1.
Simon’s Optimal Two-stage Design Parameters for Each Cohort...................32
Table JTBF.2.
Previously Observed Landmark Disease Control for Each Cohort..................32
Table JTBF.3.
NCI-CTCAE Version 4 Infusion-Related Reactionsa.....................................42
Table JTBF.4.
Adverse Event and Serious Adverse Reporting Guidelines for Study 
JTBF .............................................................................................................56

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List of Figures
Figure
Page
Figure JTBF.1.
Study design for I4C-MC-JTBF.....................................................................28

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JTBF Study Schedule ......................................................................75
Attachment 2.
Protocol JTBF Clinical Laboratory Tests .......................................................81
Attachment 3.
Protocol JTBF Hepatic Monitoring Tests for Treatment Emergent 
Abnormality ..................................................................................................82
Attachment 4.
Protocol JTBF Pharmacokinetic and Pharmacodynamic Sampling 
Schedule........................................................................................................83
Attachment 5.
Protocol JTBF Recommendations for Reporting 
Serious Adverse Events .................................................................................86
Attachment 6.
Protocol JTBF ECOG Performance Status.....................................................87
Attachment 7.
Protocol JTBF Sampling Summary................................................................88
Attachment 8.
Protocol JTBF RECIST Criteria 1.1...............................................................90
Attachment 9.
Protocol Amendment I4C-MC-JTBF(b) Summary:  A Phase 1b/2 Study 
of Ramucirumab in Combination with LY2875358 in Patients with 
Advanced Cancer...........................................................................................97

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4.
Abbreviations and Definitions
Term
Definition
AE
Adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
AUCτ,ss
area under the concentration-time curve during the dosing interval at steady 
state
audit
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s).
BP
blood pressure
BSC
best supportive care
CHF
congestive heart failure
CI
confidence interval
CL
systemic clearance
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.
complaint
Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.

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confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
CR
complete response
CRF/eCRF
case report form/electronic case report form: Sometimes referred to as clinical 
report form, a printed or electronic form for recording study participants’ data 
during a clinical study, as required by the protocol.
CRP
clinical research physician
CRS
clinical research scientist
Css,max
maximum concentration at steady state
Css,min
minimum concentration at steady state
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DCSI
Development Core Safety Information
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last 
patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least one dose of study treatment.
enter
Patients who are entered in the trial are those who have signed the informed 
consent form directly 
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.
FDG-PET
2-deoxy-2[F-18]fluoro-D-glucose positron emission tomography
FFPE
formalin-fixed paraffin-embedded
FISH
fluorescence in-situ hybridization

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GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factors
GEJ
gastroesophageal junction
GI
gastrointestinal
HGF
hepatocyte growth factor 
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IHC
immunohistochemistry
Informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the 
trial that are relevant to the patient’s decision to participate.  Informed consent 
is documented by means of a written, signed and dated informed consent form 
(ICF).
INR
International Normalized Ratio
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for datalock.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used 
as a reference in a clinical trial.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a 
study is conducted by a team of individuals at a study site, the investigator is the 
responsible leader of the team and may be called the principal investigator.
IV
intravenous(ly)
Lilly Safety System
(LSS)
Global safety database that tracks and reports serious adverse and spontaneous 
events occurring while using a drug/drug delivery system.
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MET
mesenchymal epithelial transition factor
MET ECD
extracellular cleaved domain of MET

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monitor
A person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local SOPs (if any), and global Medical SOPs.  
Monitors are trained on the investigational product(s), the protocol, informed 
consent document, any other written information provided to subjects, relevant 
SOPs, International Conference on Harmonisation Good Clinical Practice 
guidelines (ICH-GCP), and all applicable laws (for example, privacy and data 
protection) and regulations. 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NSAID
non-steroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
ORR
overall response rate 
OS
overall survival
patient
A subject with a defined disease.
PCR
polymerase chain reaction
PD
pharmacodynamic
PFS
progression-free survival
PK
pharmacokinetic(s)
PlGF
placental growth factor
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
QTc
corrected QT
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.

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re-screen
To screen a patient who was previously declared a screen failure for the same 
study
RP2D
recommended Phase 2 dose
RPLS
reversible posterior leukoencephalopathy syndrome
RR
response rate
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.  In this 
study, screening involves invasive or diagnostic procedures and/or tests (for 
example, scans, blood draws).  For this type of screening, informed consent for 
these screening procedures and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study.
screen failure
A patient who does not meet one or more criteria required for participation in a 
trial
SD
stable disease
SE
standard error
sponsor
The party who takes responsibility for the initiation, management and/or 
financing of a clinical study.
study completion
This study will be considered complete following the final analysis.  
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
TMDD
Target-Mediated Drug Disposition
TPO
third-party organization
ULN
upper limit of normal
V
volume of distribution
VEGF
vascular endothelial growth factor
VEGFR-2
vascular endothelial growth factor receptor-2
VTE
venous thromboembolic event

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A Phase 1b/2 Study of Ramucirumab in Combination with 
LY2875358 in Patients with Advanced Cancer
5.
Introduction
5.1.
MET Activation by Anti-angiogenic Therapy
Most angiogenesis inhibitors used in the treatment of cancer block the actions of vascular 
endothelial growth factor (VEGF) or its receptor, vascular endothelial growth factor receptor-2
(VEGFR-2), which is overexpressed in the majority of human cancers. Treatment with anti-
VEGF or VEGFR-2 monoclonal antibodies (mAbs) delays progression and prolongs the survival 
of patients (Ferrara and Kerbel 2005; Ellis and Hicklin 2008; Fuchs et al. 2013). However, 
inhibition of VEGF signaling is accompanied by increased invasiveness and metastasis in some 
preclinical models (Rubenstein et al. 2000; Casanovas et al. 2005; Ebos et al. 2009; Paez-Ribes 
et al. 2009). The mechanism of the exaggerated aggressiveness is unknown, but contributing 
factors could be vessel pruning, hypoxia, and increased expression of the mesenchymal epithelial 
transition factor (MET), the tyrosine kinase receptor for the hepatocyte growth factor (HGF) 
(Bottaro and Liotta 2003; Pennacchietti et al. 2003). The HGF/MET pathway promotes tumor 
cell motility, proliferation, survival, invasion, and metastasis (Benvenuti and Comoglio 2007; 
Trusolino et al. 2010). Mesenchymal epithelial transition factor is overexpressed, activated, 
amplified, or mutated in a wide variety of solid tumors (Graveel et al. 2009; Ponzo et al. 2009;
Trusolino et al. 2010), is correlated with poor prognosis (Ghoussoub et al. 1998; Lengyel et al. 
2005; Sawada et al. 2007; Kong et al. 2009), and is thought to contribute to a tumor’s 
aggressiveness and resistance to therapy (Lai et al. 2009; Xu et al. 2010). 
Preclinical animal studies recently demonstrated that MET expression is upregulated in response 
to anti-angiogenic treatment (Piao et al. 2013). The highest upregulation was seen in tumors that 
become resistant to anti-angiogenic therapy. Invasion and metastasis promoted by selective 
inhibition of VEGF signaling can be reduced by the concurrent inhibition of MET.  Inhibition of 
VEGF signaling by function-blocking antibodies slows tumor growth but increases intratumoral 
vascular pruning, hypoxia, HIF-1α accumulation, MET activation, and change to a more 
mesenchymal tumor cell phenotype favoring a more aggressive tumor biology. In particular, 
hypoxia is known to increase MET expression in tumor cells through HIF-1α binding sites on the 
c-Met promoter (Pennacchietti et al. 2003). This phenotype of heightened tumor aggressiveness 
did not occur when MET inhibitors were co-administered with an anti-VEGF antibody or with 
sunitinib. The simultaneous pharmacological inhibition of MET and VEGF signaling not only 
slowed tumor growth but also reduced invasion and metastasis (Sennino et al. 2012). Concurrent 
inhibition of MET and VEGF signaling substantially prolonged the survival of mice over vehicle 
or anti-VEGF antibody alone (Sennino et al. 2012). 
Similar to the reported literature, preclinical studies with the murine equivalent of the VEGFR-2 
targeting antibody ramucirumab, DC-101, and the MET targeting humanized antibody
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xenograft model (data on file). This cumulative evidence from preclinical models provides a 
clear rationale for simultaneous inhibition of MET and VEGF signaling as a potential therapeutic 
strategy, and fosters the hypothesis that the addition of LY2875358 to ramucirumab 
(LY3009806, IMC-1121B; hereafter referred to as ramucirumab) might counteract the 
emergence of a more aggressive phenotype induced by MET upregulation in response to anti-
angiogenic treatment by ramucirumab. 
This Phase 1b/2 study (I4C-MC-JTBF [JTBF]) will evaluate a recommended schedule and dose
range for LY2875358 that may be safely administered in combination with ramucirumab to
patients with advanced and/or metastatic cancer (Part A), followed by tumor-specific expansion 
cohorts for gastric or gastroesophageal junction (GEJ) adenocarcinoma, hepatocellular 
carcinoma (HCC), renal cell cancer or non-small cell lung cancer (NSCLC) patients for dose 
confirmation and exploration of clinical activity (Part B). The tumor types for expansion cohorts 
were selected based on clinical activity observed in Phase 2 or 3 trials for ramucirumab 
monotherapy in these tumor types, as outlined in Section 5.2.1; these tumors are also ones in 
which there exists preclinical and clinical evidence indicating that VEGFR-2 and MET signaling 
contribute to cancer pathogenesis.
5.2.
Introduction to Study Drugs
Both ramucirumab and LY2875358 have been previously evaluated as monotherapy in separate 
clinical studies, and a recommended schedule and dose range for monotherapy has been 
determined for each of the 2 antibodies.  Detailed information about the characteristics of 
ramucirumab and LY2875358 are provided in the respective Investigator’s Brochures (IBs).  The 
following sections provide a summary of the information most relevant to this Phase 1b/2 study
(JTBF).
5.2.1. Ramucirumab
Ramucirumab is a recombinant human immunoglobulin G, subclass 1 mAb that specifically 
binds to the extracellular domain of VEGFR-2 with high affinity.  This antibody potently blocks 
the binding of VEGF ligands to VEGFR-2, inhibits VEGF-stimulated activation of both 
VEGFR-2 and p44/p42 MAP kinases, and neutralizes VEGF-induced proliferation and migration 
of human endothelial 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 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, and in 
combination with docetaxel as a treatment for people with metastatic NSCLC whose cancer has 
progressed on or after platinum-based chemotherapy.  In addition, the European Commission 

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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.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of ramucirumab may be found in the IB.  Information on AEs expected to 
be related to ramucirumab may be found in Section 7 (Development Core Safety Information
[DCSI]) of the IB.  Information on serious adverse events (SAEs) expected in the study 
population independent of drug exposure and that will be assessed by the sponsor in aggregate, 
periodically during the course of the study, may be found in Section 6 (Effects in Humans) of the 
IB.
5.2.1.1. Ramucirumab and Gastric or GEJ Adenocarcinoma
Study I4T-IE-JVBD (JVBD; also known as REGARD) was the pivotal study comparing 
ramucirumab plus best supportive care (BSC) versus placebo plus BSC in the treatment of 
advanced gastric or GEJ adenocarcinoma following disease progression during or following 
first-line platinum- or fluoropyrimidine-containing combination therapy (Fuchs et al. 2013).  
Study JVBD was a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled 
study that examined single-agent ramucirumab 8 mg/kg given every 2 weeks (Q2W) in 
combination with BSC in patients with histologically or cytologically confirmed metastatic or 
locally recurrent, unresectable gastric or GEJ adenocarcinoma. A total of 355 patients were 
randomized in a 2:1 ratio to receive ramucirumab plus BSC or placebo plus BSC.  The study met 
its primary endpoint of overall survival (OS), demonstrating a statistically significant and 
clinically relevant improvement with ramucirumab. Ramucirumab, as a single agent, reduced 
the risk of death in this population by 22% (hazard ratio [HR] = 0.776; 95% confidence interval 
[CI], 0.603-0.998; p=0.0473), resulting in a 37% longer median OS in the ramucirumab arm than 
in the placebo arm (5.2 months vs. 3.8 months, respectively).  Improvement in OS with 
ramucirumab was accompanied by statistically significant improvements over placebo in median 
progression-free survival (PFS) and PFS at 12 weeks.  Treatment with ramucirumab significantly 
reduced the risk of disease progression or death by 52% (HR = 0.483; 95% CI, 0.376-0.620; 
p<0.0001), resulting in a 62% longer median time to disease progression in the ramucirumab arm 
than in the placebo arm (2.1 months vs. 1.3 months, respectively). Progression-free survival at 
12 weeks was 40.1% in the ramucirumab arm and 15.8% in the placebo arm (p<0.0001). No 
difference in terms of response rate (RR) were observed between the 2 treatment arms (3% RR
for both arms). Rates of hypertension were higher in the ramucirumab arm than in the placebo 
arm (16% vs. 8%, respectively), whereas rates of other AEs were mostly similar between 
treatment arms (94% vs. 88%, respectively). Ramucirumab is the first biological treatment given 
as a single drug that has survival benefits in patients with advanced gastric or GEJ 
adenocarcinoma progressing after first-line chemotherapy.
5.2.1.2.
Ramucirumab and Hepatocellular Cancer
In the Phase 2 Study I4T-IE-JVBQ (JVBQ), patients with unresectable HCC who had not 
received prior systemic anticancer therapy were enrolled to assess the efficacy and safety of 
ramucirumab as first-line therapy (Zhu et al. 2013).  A total of 42 adult patients received 

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ramucirumab 8 mg/kg Q2W until disease progression or limiting toxicity in this single-arm 
study. The primary endpoint was PFS; secondary endpoints included objective RR and OS. The 
median PFS was 4.0 months (95% CI, 2.6-5.7]). The RR was 9.5% (95% CI, 2.7-22.6) (4/42 
patients had a partial response [PR]), and the median OS was 12.0 months (95% CI, 6.1-19.7). 
For patients with Barcelona Clinic Liver Cancer stage C disease, the median OS was 4.4 months 
(95% CI, 0.5-9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1-
23.5) for patients with Child-Pugh A cirrhosis. Treatment-related Grade ≥3 toxicities included 
hypertension (14%), gastrointestinal (GI) hemorrhage and infusion-related reactions (7% each), 
and fatigue (5%). There was 1 treatment-related death (GI hemorrhage). After treatment with 
ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a 
transient decrease in soluble VEGFR-2.
A randomized, controlled Phase 3 trial (Study I4T-IE-JVBF; Study JVBF, also known as 
REACH) of ramucirumab monotherapy versus placebo in a second-line setting (post-sorafenib) 
for advanced HCC is currently ongoing (NCT01140347). Study JVBF is a global, randomized, 
double-blind Phase 3 study of ramucirumab plus BSC compared to placebo and BSC as a 
second-line treatment in patients with HCC who have been previously treated with sorafenib in 
the first-line setting.  The study did not meet its primary endpoint of OS; although the OS results 
favored the ramucirumab arm, they were not statistically significant.  Encouraging single-agent 
ramucirumab activity was observed, with meaningful improvements in key secondary endpoints 
of PFS, objective response rate (ORR), and time to progression (TTP).
5.2.1.3.
Ramucirumab and Renal Cell Carcinoma
Multi-targeted tyrosine kinase inhibitors (TKIs) have antitumor activity in metastatic renal cell 
carcinoma. Resistance to these agents develops frequently and their use is often limited by 
intolerance (Sternberg et al. 2010; Rini et al. 2011). Study I4T-IE-JVBP (JVBP) investigated the
clinical efficacy and safety of ramucirumab in patients with TKI-resistant/intolerant metastatic 
renal cell carcinoma (Garcia et al. 2013). In this single-arm Phase 2 trial, patients received 
ramucirumab 8 mg/kg Q2W until disease progression or intolerable toxicity. The majority of 
patients (89.7%) had received prior sunitinib, either as the only prior TKI or prior to/following 
sorafenib. The primary endpoint was RR. Thirty-nine renal cell carcinoma patients received 
ramucirumab monotherapy. The RR was 5.1% (95% CI, 0.6%-17.3%). The 12-week disease 
control rate (DCR) was 64.1% (95% CI, 47.2%-78.8%). Median PFS and OS were 7.1 months 
(95% CI, 4.1-9.7) and 24.8 months (95% CI, 18.9-32.6), respectively. Grade 3 or higher AEs
occurring in ≥5% of patients included Grade 3 hypertension (7.7%) and proteinuria (5.1%). 
There was 1 on-study death from multi-organ failure. Although the study did not meet its 
primary endpoint of ≥15% RR, ramucirumab was associated with evidence of antitumor activity 
in patients with TKI-resistant/intolerant metastatic renal cell carcinoma. Ramucirumab was safe 
and well tolerated in the study.
5.2.1.4.
Ramucirumab and Non-Small Cell Lung Cancer
Ramucirumab was studied in a pivotal randomized, double-blind, Phase 3 study for NSCLC
patients (Study JVBA; also known as REVEL). The REVEL study evaluated the efficacy and 
safety of ramucirumab plus docetaxel versus placebo plus docetaxel in the second-line treatment 

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of Stage IV nonsquamous and squamous NSCLC following disease progression after one prior
platinum-based therapy (Perol et al. 2014).  A total of 1,253 patients (26.2% squamous) were 
randomized in a 1:1 ratio to receive docetaxel 75 mg/m2 in combination with either ramucirumab
10 mg/kg or placebo on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, 
or death. The study met its primary endpoint of OS, demonstrating a statistically significant and 
clinically relevant improvement for the ramucirumab combination arm. The OS HR was 0.857 
(95% CI 0.751, 0.98; P=0.0235) with a median OS of 10.5m for ramucirumab plus docetaxel 
versus 9.1m for docetaxel. The OS was longer for ramucirumab plus docetaxel in most patient 
subgroups, including squamous and non-squamous histology. Secondary efficacy endpoints 
included PFS and ORR.  The HR for PFS was 0.762 (P<0.0001) with a median PFS of 4.5 
months for ramucirumab plus docetaxel versus 3.0 months for docetaxel. The ORR was 22.9% 
for ramucirumab plus docetaxel and 13.6% for docetaxel (p<0.001). The patient characteristics
were balanced between both arms. Grade ≥3 AEs occurring in >5% of patients on ramucirumab 
plus docetaxel were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), 
fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and 
pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as 
was pulmonary hemorrhage (any grade; all patients: 2.1% vs. 1.6%; squamous patients: 3.8% 
vs. 2.4%).  In conclusion, REVEL demonstrated a statistically significant improvement in ORR, 
PFS, and OS for ramucirumab in combination with docetaxel versus docetaxel in NSCLC 
patients with Stage IV NSCLC as second-line treatment after platinum-based therapy.   
5.2.2. LY2875358
LY2875358 is a humanized immunoglobulin G, subclass 4 bivalent mAb that can block 
signaling of the HGF/MET pathway via 2 modes of action. LY2875358 blocks ligand-dependent 
and ligand-independent MET signaling as demonstrated in preclinical studies described in the IB. 
Ligand-dependent activation of the MET pathway is impaired upon binding of LY2875358 to 
MET by limiting HGF interaction with the receptor. In addition, binding of LY2875358 to MET 
causes receptor internalization and degradation of MET resulting in suppression of ligand-
independent activation of MET.
LY2875358 has been evaluated in the first-in-human Phase 1 Study I4C-MC-JTBA (JTBA) and 
the Phase 1 Study I4C-JE-JTBD (JTBD) in Japanese patients, with the primary objective being 
to determine a recommended Phase 2 dose (RP2D) range of LY2875358 as monotherapy and in 
combination with erlotinib.  In both studies, LY2875358 was administered intravenously (IV) 
Q2W using a flat dosing scheme at doses of up to 2000 mg as monotherapy and in combination 
with erlotinib. As of 18 March 2014, cumulatively 184 subjects have received LY2875358 in 
the 6 ongoing clinical trials, including 123 patients receiving LY2875358 monotherapy.  No 
dose-limiting toxicities (DLTs) have been reported for either LY2875358 monotherapy or for 
combination therapy with erlotinib in in the dose escalation Studies JTBA and JTBD.  The most 
frequently reported treatment-emergent adverse events (TEAEs) possibly related to LY2875358 
monotherapy across all studies within the LY2875358 clinical program include fatigue (16.3%),
nausea (9.8%), diarrhea (5.7%), and peripheral edema (5.7%). A total of 7 possibly related 
TEAEs (≥Grade 3) for LY2875358 monotherapy were reported:  2 events of fatigue and 1 event 

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each of peripheral edema, pancreatitis, anemia, nausea, and hyponatremia. A total of 87 SAEs 
have been reported in the Lilly Safety System (LSS) database in Studies JTBA and JTBD as of 
18 March 2014.  Of these SAEs, 5 were considered possibly related to LY2875358 by either the 
investigator or the sponsor, including 1 event each of thrombocytopenia, pancreatitis, dyspnea, 
pyrexia, and peripheral edema in a patient with pre-existing edema. 
The RP2D range of LY2875358 was determined in Study JTBA and JTBD to be between 700-
2000 mg IV Q2W for monotherapy. For Phase 2 studies, a dose of 750 mg Q2W was selected 
because this dose is predicted to saturate MET receptors in patients with cancer and achieve 
exposures sufficient to yield maximal MET inhibition and tumor growth inhibition in vivo.
In Study JTBA, a durable confirmed PR according to Response Evaluation Criteria in Solid 
Tumors (RECIST) has been observed for LY2875358 monotherapy in a patient with metastatic 
transitional cell carcinoma enrolled at 700 mg LY2875358 in the dose-escalation segment (data 
on file).  Five additional patients (21.7%) demonstrated stable disease (SD) as their best overall 
response for LY2875358 monotherapy in the dose escalation portion of Study JTBA. 
Study JTBA has been amended and is currently enrolling patients in 5 different tumor-specific 
expansion cohorts for dose confirmation of LY2875358 monotherapy at 2000 mg Q2W,
including cohorts for renal cancer and HCC patients (approximately 15 patients each). In the 
renal cell cancer cohort, 3 out of 15 evaluable patients demonstrated SD as their best response,
including a papillary renal cancer patient who has been on study for 12 months as of October
2013 (data on file).  Further durable, confirmed PRs for LY2875358 monotherapy have been 
observed in a patient enrolled in the HCC cohort and for a patient in the uveal melanoma with 
liver metastases cohort. No data are so far available for LY2875358 monotherapy in gastric 
cancer patients, as the Asian gastric cancer patient study for LY2875358 monotherapy (Study 
I4C-JE-JTBE) is pending analysis. 
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) for ramucirumab and LY2875358 may be found in the respective molecule 
IBs.  Information on AEs expected to be related to the investigational products may be found in 
Section 7 DCSI of the respective IBs.  Information on SAEs expected in the study population 
independent of drug exposure and that will be assessed by the sponsor in aggregate, periodically 
during the course of the study, may be found in Section 6 (Effects in Humans) of the respective 
IBs. 
5.3.
Rationale for Study I4C-MC-JTBF
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and
applicable regulatory requirements. Given these requirements, the rationale for this study is
based on the following:

Published preclinical data supporting the concept of blocking MET signaling to
counteract the emergence of a more aggressive phenotype induced by MET upregulation 
in response to anti-angiogenic treatment 

The clinical efficacy observed for ramucirumab in gastric, hepatocellular, renal cell and 
non-small cell lung cancers

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
in Phase 2 and/or Phase 3 studies  

The initial clinical activity of LY2875358 monotherapy with PRs and SDs in 
advanced/metastatic cancer patients in Phase 1 studies

The favorable safety profile of ramucirumab and LY2875358 as monotherapies in 
clinical studies.
Study I4C-MC-JTBF (JTBF) will test the hypothesis of whether LY2875358 may be safely 
administered in combination with ramucirumab.  It will further explore the antitumor activity of 
the combination in specific tumor types. To this end, advanced and/or metastatic cancer patients 
will receive increasing doses of LY2875358 (750-2000 mg Q2W) to determine a recommended 
schedule and dose range for LY2875358 in combination with a fixed regimen of ramucirumab 
8 mg/kg Q2W (Part A), followed by tumor-specific expansion cohorts for gastric or GEJ 
adenocarcinoma, hepatocellular carcinoma, renal cell or non-small cell lung cancer patients for 
dose confirmation and exploration of clinical activity (Part B). Given the safety profile of 
ramucirumab and LY2875358 as monotherapies, the potential benefits of this study are expected 
to outweigh the potential risks.
5.3.1. Rationale for Amendment (a)
The primary rationale for amendment (a) is to add a further expansion cohort for NSCLC to Part 
B of study JTBF as outlined in Section 8.1 of the initial protocol. Ramucirumab demonstrated 
clinical benefit in NSCLC patients in a recently published Phase 3 study when combined with 
docetaxel (Perol et al. 2014; see Section 5.2.1.4). Since the rationale of a more aggressive 
phenotype induced by MET upregulation in response to anti-angiogenic treatment is also 
pertinent to NSCLC, the documented clinical efficacy of ramucirumab in NSCLC supports the 
addition of a further expansion cohort to evaluate the combination of ramucirumab and 
LY2875358 in NSCLC. 
In addition, some minor editorial changes have been made throughout the protocol to improve 
clarity and practicability of the protocol and secure alignment with the intended study design.
5.3.2. Rationale for Amendment (b)
The rationale for amendment (b) is to modify Exclusion Criterion [28] and allow patients 
previously treated with ramucirumab to enroll in Part B1 (Gastric or GEJ adenocarcinoma) and 
Part B4 (NSCLC) cohorts reflecting the approval of ramucirumab for those tumors since 
initiation of the study.
Minor editorial changes have been made throughout the protocol to improve clarity and 
practicability of the protocol, secure alignment with the intended study design, and update 
information available for study drugs.

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6.
Objectives
6.1.
Primary Objective
The primary objective of this study is to determine a recommended schedule and dose range for
LY2875358 that may be safely administered in combination with a fixed regimen of 
ramucirumab to patients with advanced and/or metastatic cancer.
As a co-primary objective for Part B, this study will evaluate preliminary antitumor activity 
observed with LY2875358 in combination with a fixed regimen of ramucirumab, in tumor-
specific expansion cohorts, in terms of overall response rate (ORR).
6.2.
Secondary Objectives
The secondary objectives of this study are:

To characterize the safety and toxicity profile of LY2875358 in combination with a fixed 
regimen of ramucirumab 

To evaluate the pharmacokinetics (PK) of ramucirumab and LY2875358 when given in 
combination

To document any antitumor activity observed with LY2875358 in combination with a 
fixed regimen of ramucirumab 

To evaluate incidence and levels of antitherapeutic antibodies against ramucirumab and 
LY2875358 when given in combination.
6.3.
Exploratory Objective
The exploratory objectives of this study are:

To evaluate tumor tissue and blood for biomarkers related to the VEGF and MET
signaling pathway and tumor biology of the respective tumor types enrolled in the study, 
which may include but are not necessarily limited to tumor expression (eg, MET and 
VEGFR-2) and circulating biomarker (eg, VEGF-A, HGF, extracellular cleaved domain 
of MET [MET ECD]) and their potential association with the objectives of the study 
(including PK/pharmacodynamic [PD] biomarker relationship)

To evaluate antitumor activity based on functional tumor imaging examinations, 
including but not limited to 2-deoxy-2[F-18]fluoro-D-glucose positron emission 
tomography (FDG-PET) or other relevant modalities.

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7.
Study Population
Patients will undergo screening and baseline procedures per the Study Schedule (see 
Screening/Baseline Assessments, Attachment 1). Study inclusion and exclusion criteria will be 
applied per Sections 7.1 and 7.2. Individuals who do not meet the criteria for participation in this 
study (screen failure) may be re-screened as needed after discussion with the clinical research 
physician (CRP) or designee (Section 7.3). Prospective approval of protocol deviations to 
recruitment and enrollment criteria, also known as protocol waivers or exemptions, are not 
permitted.
7.1.
Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
[1]
Patients must have histological or cytological confirmed diagnosis of the
following tumor types that is advanced and/or metastatic cancer and must be, 
in the judgment of the investigator, an appropriate candidate for experimental 
therapy after available standard therapies have failed, or for whom standard 
therapy would not be appropriate.

Part A: 
o
Any type of solid tumor (“all comer”)

Part B: 
o
Part B1:  Gastric or GEJ adenocarcinoma
o
Part B2:  Hepatocellular cancer (excluding fibrolamellar carcinoma)
o
Part B3:  Renal cell carcinoma (any histology)
o
Part B4: Non-small cell lung cancer (squamous or non-squamous)
[2]
Have at least 1 measurable lesion outside of the central nervous system (CNS)
whose presence is assessable using standard techniques by RECIST version 
1.1 (Eisenhauer et al. 2009).  For patients with prior radiation therapy, 
measurable lesions must be outside a previous radiotherapy field if they are 
the sole site of disease, unless disease progression has been documented at 
that site since radiation.
[3]
Availability of a tumor sample taken prior to study treatment but after 
progression (or discontinuation) on the most recent line of systemic tumor 
therapy (“post-progression tumor sample”) or willing to undergo a tumor 
biopsy pre-study treatment (mandatory). Tumor sample requirements are 
described in Section 10.2.1.  
Tumor tissue (formalin-fixed paraffin-embedded [FFPE] blocks) or unstained 
slides from any time since diagnosis of the tumor disease (ie, archival tumor 
samples) will be requested but are not required (optional).

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[4]
Have a performance status of 2 on the Eastern Cooperative Oncology Group 
(ECOG) scale in Part A and 1 on the ECOG scale in Part B (Attachment 6).
[5] Have adequate organ function, as demonstrated by:

Hematologic:  Absolute neutrophil count (ANC) 1.5 x 109/L, platelets 75 x 
109/L, and hemoglobin 8 g/dL. Transfusions are not allowed within 14 days 
of the first dose of study drug to reach defined platelets, or hemoglobin values

Hepatic:  Bilirubin 1.5 times upper limits of normal (ULN), alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST) 2.5 times 
ULN.  Patients with hepatic metastases or hepatocellular carcinoma: Bilirubin 
≤3.0 mg/dL and ALT and AST 5 times ULN

Renal:  Serum creatinine, 1.5 times ULN or calculated creatinine clearance 
>30 mL/min

Coagulation:  Adequate coagulation function, as defined by International 
Normalized Ratio (INR) ≤1.5, prothrombin time (PT) and partial 
thromboplastin time/activated partial thromboplastin time (PTT/aPTT) ≤1.5 
times ULN.
[6]
Routine urinalysis showing ≤1+ protein or protein/creatinine ratio <0.5.  For 
proteinuria ≥2+ or urine protein/creatinine ratio ≥0.5, 24-hour urine must be 
collected and the level must be <1 g of protein in 24 hours for patient 
enrollment.
[7]
Have discontinued all previous cancer therapies and any agents that have not 
received regulatory approval for any indication, for at least 21 days or 5 half-
lives prior to study enrollment, whichever is shorter, and recovered from the 
acute effects for therapy (toxic effects of prior locoregional therapy, surgery, 
or other treatment-related toxicity resolved to baseline or Grade 1). Patients 
must have discontinued mitomycin-C or nitrosourea therapy for at least 42 
days. 
[8]
Have given written informed consent prior to any study-specific procedures.
[9]
Have an estimated life expectancy, in the judgment of the investigator, that 
will permit the patient to complete 8 weeks (2 cycles) of treatment.
[10] Males and females with reproductive potential:  Must agree to use medically 
approved contraceptive precautions during the study and for at least 3 months
following the last dose of study drug. 
Females with childbearing potential must have had a negative serum 
pregnancy test 7 days before the first dose of study drug and must not be 
breast-feeding.
[11] Are ≥18 years of age
[12] Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures

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7.2.
Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[13]
Have serious pre-existing medical conditions (at the discretion of the 
investigator, such as severe acute or chronic medical condition or laboratory 
abnormality that may increase the risk associated with study participation)
[14]
Have a history of hypertensive crisis or hypertensive encephalopathy or 
current poorly controlled hypertension (blood pressure [BP] systolic ≥150 
mmHg and/or diastolic ≥95 mmHg) despite standard medical management.
[15]   Patient has experienced any arterial thromboembolic event (ATE), including 
myocardial infarction, unstable angina pectoris, cerebrovascular accident, or 
transient ischemic attack, within 6 months prior to receiving study drugs.
[16]    Have a history of deep vein thrombosis, pulmonary embolism, or any other 
significant thromboembolic event (venous port or catheter thrombosis or 
superficial venous thrombosis are not considered “significant”) during the 
3 months prior to receiving study drugs. Patients with chronic portal vein 
thrombosis who are asymptomatic and not considered to need anti-coagulation 
therapy are eligible. 
[17]  Are receiving therapeutic anticoagulation with warfarin, low-molecular-
weight heparin, or similar agents.  Patients receiving prophylactic, low-dose
anticoagulation therapy are eligible provided that they are on low-molecular-
weight heparin or oral Xa inhibitors or it is medically appropriate at the 
investigator’s judgment that patients are switching to low-molecular-weight 
heparin or oral Xa inhibitors before initiation of study therapy. 
Patients on prophylactic anticoagulation therapy with unresected primary 
tumors or luminal tumor recurrence following resection are eligible, provided 
that the tumor does not present a significant bleeding risk in the opinion of the 
investigator or consulting gastroenterologist.
[18] The patient is receiving chronic therapy with nonsteroidal anti-inflammatory 
drugs (NSAIDs; eg, indomethacin, ibuprofen, naproxen, or similar agents) or 
other antiplatelet agents (eg, clopidogrel, ticlopidine, dipyridamole, and 
anagrelide).  Aspirin use at doses up to 325 mg/day is permitted.
[19]
Have significant bleeding disorders, vasculitis, or had a significant bleeding 
episode from the GI tract within 3 months prior to receiving study drugs 
[20]
Have a history of GI perforation and/or fistulae within 6 months prior to 
receiving study drugs 
[21]
Have congestive heart failure (CHF) New York Heart Association class ≥3 or 
symptomatic or poorly controlled cardiac arrhythmia.

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[22]
Have undergone major surgery within 28 days prior to receiving study drugs, 
or have had a central venous access device placement within 7 days prior to 
receiving study drugs or major surgical procedures are planned.
[23] Have a serious or nonhealing wound, peptic ulcer, or bone fracture within 
28 days prior to receiving study drugs.
[24]  Have an known active fungal, bacterial, and/or known viral infection 
including:

human immunodeficiency virus (screening is not required)

viral hepatitis A (screening is not required)

hepatitis B or C (screening is required-documentation of a negative test result 
within 6 months must be available for hepatitis B surface antigen and hepatitis C 
[antibodies or ribonucleic acid according to local standard]).  Hepatocellular 
cancer patients with chronic viral (B or C) hepatitis are eligible if they retain 
adequate liver function determined by Child-Pugh Stage A.
[25]
Have liver cirrhosis with a Child-Pugh Stage of B or C
[26]
Have symptomatic CNS malignancy (with the exception of medulloblastoma) 
or metastasis (baseline contrasted computed tomography [CT] of the head or 
magnetic resonance imaging [MRI] of the brain required in all patients. For 
those patients with known CNS metastases, ongoing CNS surveillance using 
the same modality is required at half the frequency as extra-CNS imaging). 
Patients with treated CNS metastases are eligible for this study if they were 
adequately treated and currently not requiring corticosteroids and/or 
anticonvulsants for its treatment, and their disease is asymptomatic and 
radiographically stable for at least 30 days.  Patients with unequivocally 
documented leptomeningeal metastases are excluded.
[27] Have corrected QT (QTc) interval of >470 msec on screening 
electrocardiogram (ECG) at several consecutive days of assessment
[28]   Have received previous treatment with ramucirumab or LY2875358, except 
for patients enrolled in Cohort B1 (Gastric or GEJ adenocarcinoma) and B4 
(NSCLC) who may have received previous ramucirumab treatment.  
[29]   Known hypersensitivity to any of the treatment components of ramucirumab 
or LY2875358.
[30]  Have a second primary malignancy that, in the judgment of the investigator 
and sponsor, may affect the interpretation of results.
[31]   Are pregnant or breastfeeding.

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[32] Have received treatment within 28 days of the initial dose of study drug with 
an investigational product or non-approved use of a drug or device (other than 
the study drug/device used in this study) for non-cancer indications or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.  
[33]   For Part B4 (NSCLC) only:

The patient has radiologically documented evidence of major blood 
vessel invasion or encasement by cancer. 
For squamous cell histology or for centrally located mediastinal 
masses (<30 mm from the carina) identified by CT scan or chest X-
ray, the patient must undergo an MRI of the chest or intravenous 
contrast CT scan prior to study treatment, to exclude major airway or 
blood vessel invasion by cancer.

Patients with a history of gross hemoptysis (defined as bright red 
blood or ≥1/2 teaspoon) within 2 months prior to study treatment.

The patient has radiographic evidence of intratumor cavitation,
regardless of tumor histology.
7.3.
Rescreening
A patient who fails screening is allowed to screen again after signing a new informed consent
form (ICF) and being assigned a new patient number under the conditions specified in this
section.
The following patients may be eligible for rescreening for any of the following circumstances:

Patients who have become eligible to enroll in the study as the result of a protocol
amendment

Patients whose status has changed such that the eligibility criterion that caused the patient
to screen fail, would no longer cause the patient to screen fail again (eg, unexpected 
surgery during the screening period that causes a screen failure but is no longer relevant 
following recovery from surgery)

Patients who complete screening and meet all inclusion and exclusion requirements but 
are unable to be enrolled due to extenuating circumstances (eg, severe weather, death in 
family, child illness).
A patient for whom a tumor sample from prior to study treatment but after progression (or 
discontinuation) to the most recent line of systemic tumor therapy was available, but fails 
screening for other reasons, will not need to resubmit another tumor sample if screened again,
provided the original sample was adequate to perform the protocol required tests.

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8.
Investigational Plan
8.1.
Summary of Study Design
Study JTBF is a nonrandomized, open-label, dose-escalation, multicenter Phase 1b/2 study that
consists of 2 parts:

Part A: Dose escalation part with increasing doses of LY2875358 (750-2000 mg 
Q2W) to determine a recommended schedule and dose range for LY2875358 that may 
be safely administered in combination with a fixed regimen of ramucirumab 8 mg/kg 
Q2W to patients with advanced and/or metastatic cancer.

Part B: Tumor-specific expansion cohorts in patients with gastric or GEJ
adenocarcinoma, hepatocellular carcinoma, renal cell cancer or NSCLC (approximately 
15 patients each) for dose confirmation of LY2875358 in combination with a fixed 
regimen of ramucirumab 8 mg/kg Q2W and exploration of clinical antitumor activity
(Figure JTBF.1).
Abbreviations:  HCC = hepatocellular carcinoma; NSCLC = non-small cell lung cancer; PD = pharmacodynamics; 
PK = pharmacokinetics; pt = patient; Q2W = every 2 weeks; Ram = ramucirumab; RCC = renal cell cancer. 
Figure JTBF.1.
Study design for I4C-MC-JTBF.
In Part A, dose escalation of LY2875358 will follow a 3+3 dose escalation scheme to determine 
a recommended schedule and dose of LY2875358 in combination with a fixed regimen of 
ramucirumab 8 mg/kg Q2W. The dose of ramucirumab 8 mg/kg Q2W has been used for 
ramucirumab Phase 2 and 3 studies in gastric/GEJ, hepatocellular carcinoma, and renal cell 
cancer patients. Patients will be enrolled in cohorts of at least 3 patients.  Eligible patients will 
receive ramucirumab as a 60-minute IV infusion followed by LY2875358 as a 90-minute IV 
infusion on Days 1 and 15 of a 28-day cycle. LY2875358 will be administered after a minimum 

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of a 60-minute observation period (minimum of 30-minute observation period in Cycle 2 and 
beyond) after the end of the ramucirumab infusion on Days 1 and 15 of a 28-day cycle.  If it is 
determined that a reduced LY2875358 infusion time is safe and feasible, the investigators will be 
notified in writing and the pharmacy manual updated to reflect the change.  Both LY2875358 
dose levels intended to be evaluated in Part A (ie, 750 and 2000 mg LY2875358 flat-dose) have 
been determined in the Phase 1 Study JTBA to be safe and biologically active, and are further 
studied in currently ongoing Phase 2 studies as monotherapy or in combination regimens.  
Dose escalation of LY2875358 will be guided primarily by safety assessments during Cycle 1
(28 days); available PK and PD biomarker data may also be used as a secondary consideration. 
Blood samplings are being performed at expected time of maximal plasma concentration of 
ramucirumab and LY2875358, and up to 24 hours after the end of infusion of both antibodies to 
evaluate the PK profile of ramucirumab and LY2875358 when given in combination. The 
sponsor and the investigators will review and discuss all available patient safety data prior to 
dose escalation. If appropriate, intermediate LY2875358 dose level (or below the LY2875358 
starting dose of 750 mg) may be explored after discussion between the sponsor and the 
investigator. The decision will be documented in writing.
Part B is intended to confirm safety and tolerability of LY2875358 in combination with a fixed 
regimen of ramucirumab 8 mg/kg Q2W and to explore preliminary efficacy of the combination 
treatment in 4 tumor-specific expansion cohorts (approximately 15 patients each):

Part B1: Advanced gastric or GEJ adenocarcinoma

Part B2:  Advanced hepatocellular carcinoma 

Part B3:  Advanced renal cell carcinoma (all histologies).

Part B4:  Advanced NSCLC (squamous or non-squamous)
Part B will be opened after an interim analysis of Part A data. The dose and schedule of 
LY2875358 in Part B for combination with the fixed regimen of ramucirumab 8 mg/kg Q2W 
will be defined based upon safety, PK/PD, and antitumor activity observed in Part A. The 
sponsor, in collaboration with the investigators, will review Part A results prior to determining 
the recommended schedule and dose of LY2875358 to be studied in Part B. The decision will be 
documented in writing and a written notification will be sent to the Institutional Review Board 
(IRB) prior to enrollment of patients into Part B. No amendment will be required. If indicated 
by safety, PK/PD and/or emerging clinical data, the recommended schedule and dose of 
LY2875358 and ramucirumab in Part B might be individually adjusted for each tumor cohort
following written notification by the sponsor. For patient enrolled in Part B4 (that is NSCLC), 
careful patient selection, based on anatomical factors of large size, vessel encasement and tumor 
cavitation, and continuous patient monitoring is required.  
To explore potential biomarkers predicting clinical activity for the combination of ramucirumab 
and LY2875358, availability of tumor samples taken prior to study treatment but after 
progression (or discontinuation) on the most recent line of systemic tumor therapy (or 
willingness to undergo a pre-study treatment tumor biopsy) will be mandatory for patients in 
Parts A and B. This “post-progression tumor sample” may be evaluated for biomarkers related 

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to the VEGF and MET signaling pathway and tumor biology of the respective tumor types 
enrolled in the study, which may include but is not necessarily limited to MET
expression/amplification and VEGFR-2.  In addition, tumor tissue from any time since diagnosis 
of the tumor (ie, archival tumor samples) will be requested (optional) to explore any relationship 
between clinical activity and biomarker status based on the archival tissue versus the mandatory
“post-progression tumor sample.” The analysis of both type of tumor samples is expected to 
critically inform any tailoring strategy for the further development of a ramucirumab and 
LY2875358 combination treatment. 
Moreover, blood samples for exploratory biomarker analysis will be collected throughout this 
study which may be assessed for circulating biomarker (ie, VEGF-A, HGF, MET ECD) and their 
potential association with the objectives of the study. 
The protocol for Study JTBF may be amended (eg, prior to commencement of Part B, which may
include respecification of the selected tumor types for Part B. Depending on the safety and
tolerability of ramucirumab in Part A, and the results of ongoing clinical and preclinical studies 
for ramucirumab and LY2875358 in combination with standard of care therapies, further 
treatment arms in Part B may be added by a protocol amendment.
The planned duration of treatment is not fixed. At the end of the first treatment cycle, each 
patient will be clinically evaluated for safety by the investigator before being permitted to
receive the next treatment cycle. Eligible patients will receive 2 cycles of ramucirumab and 
LY2875358, unless 1 or more of the criteria for discontinuation (per Section 8.2.1) are met. 
Patients who have completed 2 cycles and are receiving clinical benefit may remain on study,
provided they have not met any criteria for discontinuation (per Section 8.2.1).
Refer to Attachment 1 for the Study Schedule.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
GCP and International Conference on Harmonisation (ICH) guidelines, and applicable regulatory 
requirements.
8.1.1. Sample Size
To determine a recommended schedule and dose range of LY2875358 in combination with 
ramucirumab that may be safely administered to patients with advanced and/or metastatic cancer, 
an adequate patient sample size is required.  A sufficient sample size will allow for an accurate 
evaluation of the relationship between exposure and toxicity, as well as an evaluation of the 
relationship between exposure and pharmacological effects using descriptive statistics and 
appropriate modeling techniques, if data warrant.  This sample size is estimated to be a total of 
approximately 70 patients (6-12 [Part A] + 60 [Part B]).
For Part A, following a 3+3 dose escalation scheme, the sample size calculation assumes that 
cohorts will include 3 to 6 patients. If 2 cohorts for the intended 2 dose levels for LY2875358 (ie,
750 and 2000 mg) are needed to determine a recommended dose range for LY2875358 in 
combination with ramucirumab, then approximately 6-12 patients will be enrolled in Part A. To
ensure accurate evaluation of safety, tolerability, or PK/PD biomarkers, additional patients may

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be enrolled during Part A if deemed appropriate based on agreement between the investigators 
and the sponsor.
For Part B, the sample size of approximately 15 patients per expansion cohort was selected to 
allow adequate confirmation of safety and tolerability of LY2875358 in combination with 
ramucirumab and to identify evidence of preliminary clinical activity worthy of further 
investigation in Phase 2, analogous to the first stage of a Simon’s two-stage design. If the true 
clinical RR according to RECIST for the combination of ramucirumab and LY2875358 in 1 of 
the tumor types selected is 10%, then there is a 79% chance of observing at least 1 patient with a 
clinical response, which might warrant further study of the regimen. On the other hand, if the 
true RR is close to the RR of ramucirumab monotherapy (for example, 3% in REGARD), then 
there is a 36.7% chance of incorrectly concluding that the regimen merits further study. In 
addition, variable response to treatment due to genetic variation can be measured based on 
patients’ post-progression tumor samples. It is assumed that 50% of the study population is
expected to be biomarker positive, and the true response rates are 40% and 3% in the biomarker 
positive and biomarker negative group respectively. Since the observed number of biomarker 
positive patients can vary, the sample size of 15 would give us a weighted average power of 40%
(i.e. each power is weighted by its associated probability of observed number of biomarker 
positive patients) based on 2-sided type 1 error rate of 20% to detect statistically significant 
dependence between biomarker status and clinical response, suggesting the potential clinical 
utility of the biomarker for identifying the most appropriate target population.
In case of significant clinical activity in any of the tumor-specific expansion cohorts, further 
patients may be added to enroll up to approximately 45 patients per cohort to further characterize 
the safety and explore preliminary clinical activity of LY2875358 in combination with a fixed 
regimen of ramucirumab treatment, if deemed appropriate after discussion and mutual agreement 
between the investigators and the sponsor. A sample size of 45 would give us a weighted 
average power of 83% based on 2-sided type 1 error rate of 5% to detect the significant 
dependence between biomarker status and clinical response as above. The criterion of 
significant clinical activity may vary based on tumor-specific response rates or landmark disease 
control. Table JTBF.1 summarizes the parameters of Simon’s optimal two-stage design for each 
cohort. The uninteresting RR of Gastric/GEJ, HCC, RCC are referenced from previous trials 
JVBD, JVBQ and JVBP. The uninteresting RR of NSCLC is based on the RR in the second-line 
docetaxel arm (Scagliotti et al. 2011). Alternatively, disease control may be considered in order 
to proceed with enrollment up to 45 patients per cohort if deemed appropriate. Table JTBF.2
summarizes landmark disease control and landmark disease control considered of interest to 
enroll up 45 patients per cohort. Such decisions will be documented in writing following 
discussions between the investigators and the sponsor, and a written notification will be sent to 
the IRB prior to enrollment of further patients. 

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Table JTBF.1.
Simon’s Optimal Two-stage Design Parameters for Each Cohort
Tumor Type
Uninteresting 
RR
Favorable 
RR
1-sided type 1 
error rate
Power
n1
n
r1
r
Gastric/GEJ
3%
10%
0.15
0.7
14
45
1
3
HCC
10%
22%
0.1
0.75
14
42
2
7
RCC
5%
12%
0.15
0.7
13
45
1
4
NSCLC
8.5%
22%
0.1
0.8
14
41
2
6
Abbreviations: GEJ = gastroesophageal junction; HCC = hepatocellular carcinoma; n1 = number of patients enrolled
in the first stage; n = total number of patients enrolled; NSCLC = non=small cell lung cancer; r1 = number of 
responses required to proceed to the second stage; r = total number of responses required for further investigation of 
the drug; RCC = renal cell carcinoma; RR = response rate.
Table JTBF.2.
Previously Observed Landmark Disease Control for Each Cohort
Tumor Type
Observed Landmark
Landmark of Interest
Gastric/GEJ
12-weeks PFS 40%
60%
HCC
4-mos PFS 50%
75%
RCC
7.1-mos PFS 50%
75%
NSCLC
3-mos PFS 50%
75%
Abbreviations: GEJ = gastroesophageal junction; HCC = hepatocellular carcinoma; mos = months; NSCLC = non-
small cell lung cancer; PFS = progression-free survival; RCC = renal cell carcinoma
8.1.2. Rationale for Selection of Dose
In this study, ramucirumab will be administered at a fixed regimen of 8 mg/kg in combination 
with LY2875358 at a dose range of 750-2000 mg, both administered Q2W.  
The ramucirumab dose and schedule of 8 mg/kg Q2W IV infusion is the same as those for which 
safety and clinical efficacy have been demonstrated in Phase 2 and/or Phase 3 studies in gastric 
and GEJ adenocarcinoma, hepatocellular carcinoma, and renal cell cancer patients.
The LY2875358 dose range of 750-2000 mg administered as an Q2W IV infusion combination 
with ramucirumab was selected based on the safety and PK profile established for LY2875358
monotherapy in the Phase 1 Study JTBA and in preclinical in vivo efficacy studies.  A Target-
Mediated Drug Disposition (TMDD) model adequately fit the human PK data from the Study 
JTBA dose escalation and was used to simulate the dose range of 700-2000 mg Q2W.  In this 
dose range, non-receptor-mediated clearance predominates, suggesting that receptors (MET) are 
saturated.  Also, based on the simulations of LY2875358 PK of 750 mg Q2W, 100% of the 
population is predicted to have a minimum concentration at steady state (Css,min) ≥50 g/mL, 
which is the Css,min associated with maximal tumor growth inhibition in the ligand-independent 
xenograft model MKN45.  Furthermore, based on in vivo target inhibition studies, MET 

I4C-MC-JTBF(b) Phase 1 Oncology Protocol
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inhibition at the level of the tumor would be maximized at a dose of 750 mg Q2W.  In addition, 
PRs were observed in Study JTBA in the 700- to 2000-mg dose range.  Two patients who 
received doses of 700 mg and 2000 mg as monotherapy achieved a PR (data on file).  Two 
patients who received LY2875358 in combination with erlotinib achieved a PR, 1 each at doses 
of 700 mg and 2000 mg.  Therefore, LY2875358 exposures achieved by 700-2000 mg Q2W are 
expected to be sufficient to prevent HGF binding and signaling, reduce expression of MET, and 
inhibit MET-driven growth of solid tumors.  
Patients enrolled in this study will be closely monitored for safety and tolerability of the 
combination of ramucirumab and LY2875358.  Dose escalation following a 3+3 dose escalation 
scheme in Part A will be only allowed after evaluation of all safety data.  In addition, available 
PK/PD results will be reviewed prior to dose escalation.
8.1.3. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the final analysis.  “End of trial” refers to the date of the last visit or last 
scheduled procedure for the last patient.
8.2.
Discontinuations
8.2.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified. A discussion must occur between 
the sponsor CRP/clinical research scientist (CRS) and the investigator to determine whether the 
patient may continue in the study, with or without investigational product. Inadvertently 
enrolled patients may be maintained in the study and on investigational product when the Lilly 
CRP/CRS agrees with the investigator that it is medically appropriate for that patient. The 
patient may not continue in the study with or without investigational product if the Lilly 
CRP/CRS does not agree with the investigator’s determination that it is medically appropriate for 
the patient to continue. The investigator must obtain documented approval from the Lilly 
CRP/CRS to allow the inadvertently enrolled patient to continue in the study with or without 
investigational product.
Patients will be discontinued from the study drug(s) in the following circumstances:

The patient has evidence of progressive disease. 
o
NOTE:  In select cases, after discussion with the sponsor, treatment beyond 
progression may be permissible if the patient is thought to be deriving ongoing 
benefit from the study therapy. For instance, local therapies, such as radiation 
treatment to control isolated areas of CNS progression, may be permissible 
provided study drugs are held on the days of local therapy. Additional systemic 
therapy, however, is not allowed.  This option is contingent upon study drug 

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availability.  Patients may continue until they fulfill another one of the criteria for 
study discontinuation.

The patient experiences unacceptable toxicity that is deemed related to study drug(s) (eg, 
a persistent moderate toxicity that is intolerable to the patient).

The patient experiences a Grade 3 or 4 infusion-related reaction related to study drug(s)
The patient should be permanently discontinued from ramucirumab for any of the 
following events (see Section 9.2.3.2):
o
Grade 4 hypertension or persistent/recurrent hypertension 
o
Grade 4 proteinuria or persistent/recurrent proteinuria >3 g/24 hours 
o
Grade 3 or 4 ATE
o
Grade 3 or 4 venous thromboembolic event (VTE) considered by the investigator 
to be life-threatening, or symptomatic and not adequately treated by 
anticoagulation therapy.
o
Pulmonary embolism/deep vein thrombosis occurs or intensifies during 
anticoagulant therapy
o
Grade 3 or 4 bleeding or hemorrhagic event
o
GI perforation
o
Grade 3 or 4 events consistent with CHF
o
New occurrence of hepatic encephalopathy and/or hepatorenal syndrome resulting 
from liver cirrhosis 
o
Reversible posterior leukoencephalopathy syndrome (RPLS)
o
Any event which would warrant ramucirumab to be modified by >2 dose 
reductions or to be held for >2 consecutive doses (approximately 28 days; see 
definition in Section 9.2.3).  In situations where >2 consecutive doses have been 
missed, events related to the missed doses have resolved, and there is evidence of 
ongoing disease control, continuation of ramucirumab and/or LY2875358 may be 
considered and must be discussed with the Lilly clinical team.

The patient should be permanently discontinued from LY2875358 for any of the 
following events (see Section 9.2.3.3):
o
Concomitant elevation of AST/ALT and bilirubin that is deemed related to 
LY2875358, as defined in Section 9.2.3.3
o
Any event, which would warrant LY2875358 to be held for >2 consecutive doses 
(approximately 28 days; see definition in Section 9.2.3).  
NOTE:  If 1 of the 2 investigational study drugs need to be discontinued permanently due 
to treatment-related toxicity specifically attributable to one of the study drugs (eg, 
ramucirumab-related hypertension), the patient may continue treatment with the other 
study drug at the investigator´s discretion and following a discussion with the Lilly 
clinical team, as long as the patient is receiving therapeutic benefit in the opinion of the 
investigator and is not fulfilling any of the criteria for study discontinuation. This option 
is contingent upon study drug availability

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Patients will be discontinued from the study in the following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

Investigator/Physician Decision
o
The investigator/physician decides that the patient should be discontinued from 
the study or study drug(s)
o
If 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 the study drug(s) must occur prior to introduction of the 
other agent

Patient Decision
o
The patient requests to be discontinued from the study or study drug

Sponsor Decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP

The patient is significantly noncompliant with study procedures and/or treatment (Section 
9.6).
The reason for and date of discontinuation will be collected for all patients.  The Date of 
Discontinuation (for any of the above reasons) from study treatment is to be reported on the 
electronic case report form (eCRF).  Patients who discontinue will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
8.2.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for any scientific, medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.
8.2.3. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges it necessary for any scientific, medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.

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9.
Treatment
9.1.
Materials and Supplies
9.1.1. Ramucirumab
Ramucirumab, provided by Lilly, is a sterile, preservative-free solution for infusion 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.  
Ramucirumab is a clear or slightly opalescent and colorless or pale yellow liquid without visible 
particles.  The pH is 6.0.  The osmolality is 285 mmol/kg.  
Ramucirumab must be stored under refrigeration at 2°C to 8°C  with protection from direct light. 
DO NOT FREEZE AND/OR SHAKE RAMUCIRUMAB. Stability studies have demonstrated 
that the drug product can withstand transient excursion to room temperature without adverse 
effect; however, storage at this temperature is not recommended.
9.1.2. LY2875358
LY2875358 will be provided by Lilly as investigational product. LY2875358 for injection is a 
lyophilized product supplied in glass vials containing 75 mg of LY2875358. This product is 
reconstituted with 3.2 mL of sterile water for injection, resulting in 25 mg/mL of LY2875358.  
The reconstituted formulation is stable for up to 6 hours at room temperature. For further 
instructions, please refer to the pharmacy binder.
LY2875358 should be stored within the temperature range stated on the label.
Clinical study materials will be labeled according to the country’s regulatory requirements. 
9.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agents and planned duration of each 
individual’s treatment to the site personnel

verifying that instructions are followed properly

maintaining accurate records of study drug dispensation, destruction, and collection, and

returning or destroying all unused medication to Lilly or its designee at the end of the 
study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drugs so that the situation can be assessed.
Eligible patients will receive 2 cycles of study drugs, unless 1 or more of the criteria for
discontinuation (per Section 8.2.1) are met. Patients who have completed 2 cycles and are 
receiving clinical benefit may remain on study provided they have not met any criteria for study 

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discontinuation (per Section 8.2.1). If tolerated, ramucirumab and LY2875358 infusions should 
be administered on the same day to keep the schedule of both study drugs synchronized.  
9.2.1. Ramucirumab Dosing Schedule
Ramucirumab will be dosed at 8 mg/kg and administered as a 1-hour IV infusion prior to the 
administration of LY2875358 on Days 1 and 15 of a 28-day cycle in Part A and B of this study.  
The infusion rate of ramucirumab should not exceed 25 mg/min.
9.2.1.1.
Premedication for Ramucirumab
Premedication is recommended prior to infusion of ramucirumab.  Recommended premedication 
agents include histamine H1 antagonists such as diphenhydramine hydrochloride 50 mg (or 
equivalent).  Additional premedication may be provided at the investigator’s discretion.  
Premedication must be provided in the setting of a prior Grade 1-2 infusion-related reaction, as 
detailed in Section 9.2.3.1.  All premedication administered must be adequately documented on
the eCRF.
9.2.2. LY2875358 Dosing Schedule 
LY2875358 will be administered after a minimum of a 60-minute observation period (minimum 
of 30-minute observation period in Cycle 2 and beyond) following the end of the ramucirumab 
infusion on Days 1 and 15 of a 28-day cycle. LY2875358 will be administered as an IV infusion 
using either a central or a peripheral venous line.  No in-line, sterile, nonpyrogenic filter should 
be used. To ensure that the total dose of LY2875358 will be administered, the line should be 
flushed at the end of the infusion (see pharmacy instructions). The LY2875358 infusion,
including the flushing of the line, should be administered over a period of approximately 90
minutes. If it is determined that a reduced LY2875358 infusion time is safe and feasible, the 
investigators will be notified in writing and the pharmacy instructions will be updated to reflect 
the change.  
No premedication is recommended prior to infusion of LY2875358.  Premedication may be 
provided at the investigator’s discretion.  Premedication must be provided in the setting of a prior 
Grade 1-2 infusion-related reaction, as detailed in Section 9.2.3.1.  All premedication 
administered must be adequately documented on the eCRF.  
9.2.2.1.
Dose Escalation of LY2875358 in Part A
In Part A, dose levels of LY2875358 previously tolerated as monotherapy and in combination 
with erlotinib in Study JTBA will be administered following the proposed dose escalation 
scheme below:  
Dose level 1:  LY2875358 750-mg flat dose as a 90-minute IV infusion after a minimum of a 60-
minute observation period (minimum of 30-minute observation period in Cycle 2 
and beyond) following the end of the ramucirumab 8-mg/kg infusion on Days 1 
and 15 of a 28-day cycle  
Dose level 2: LY2875358  2000-mg flat dose as a 90-minute IV infusion after a minimum of a 
60-minute observation period (minimum of 30-minute observation period in Cycle 
2 and beyond) following the end of the ramucirumab 8-mg/kg infusion on Days 1 
and 15 of a 28-day cycle  

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Dose escalation will be guided primarily by safety assessments, in particular AEs, during Cycle 
1. By nature of being a dose escalation study, data will be evaluated on an ongoing basis to 
determine a recommended schedule and dose range of LY2875358 that may be safely 
administered in combination with ramucirumab on Days 1 and 15 of a 28-day cycle.
The sponsor and investigators will review and discuss all patient safety data prior to dose 
escalation.  In addition, if available at the time of dose escalation decision, PK results will be 
used as secondary/supporting data for dose escalation. Intermediate dose levels for LY2875358 
(or a dose below the starting dose) may be considered based on appearance of toxicity or PK/PD 
modeling, if deemed appropriate by agreement between the investigators and the sponsor. If 
during the dose escalation, a new sequence of drug administration (eg, inverse order of 
administration or sequential dosing of the study drugs on separate days) should be indicated for 
safety or PK reasons, or preclinical data suggest that this may pose a better regimen, then the 
investigators together with the sponsor will decide on this change and inform the ERBs in 
writing. No protocol amendment will be required.
No dose escalation can occur without prior discussion and agreement between the investigator 
and the Lilly CRP/CRS; the decision will be documented in writing.  Based on the ongoing 
safety reviews, modifications to the dose escalation strategy or other design elements may be 
made via protocol amendment to ensure patient safety. Intrapatient dose escalation will not be 
permitted in this study. 
For assessment of toxicity the standard scoring system, Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0, established by the National Cancer Institute (NCI) (NCI 
2010) will be used. A minor version of CTCAE Version 4.0 (eg, CTCAE Version 4.03) may be 
used for this study.  Minor updates to CTCAE Version 4.0 will not necessitate a protocol 
amendment, and the use of an updated CTCAE Version 4.0 will not be considered a protocol 
violation. Any AEs related to study drugs will be considered as toxicities.
9.2.2.2.
Dose-Limiting Toxicity Determination
Dose-limiting toxicity is defined as an AE during Cycle 1 that is possibly, probably, or definitely
related to treatment with LY2875358 in combination with a fixed regimen of ramucirumab and 
fulfills any 1 of the following criterion using the NCI CTCAE Version 4.03:

Grade 3 non-hematological toxicity. Exceptions will be made for:
nausea, vomiting, diarrhea, constipation, or skin rash that persists for ≤3 
days following appropriate supportive care intervention
Grade 3 hypertension in which systolic BP ≥160 mmHg and/or diastolic 
BP ≥100 mmHg persist <7 days after intensified antihypertensive therapy 
is initiated

Grade 4 hematological toxicity of ≥7 days duration

≥Grade 3 thrombocytopenia with ≥Grade 2 bleeding

Any febrile neutropenia

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
Any other significant toxicity deemed by the primary investigator and Lilly
clinical research personnel to be dose-limiting (eg, any toxicity that is possibly 
related to the study medication that requires the withdrawal of the patient from the 
study during Cycle 1).
Infusion-related reactions (including hypersensitivity reactions and anaphylaxis) should not be 
considered as DLTs unless the investigator or Lilly medical monitor provides compelling 
rationale to support their inclusion as a DLT.
Patients in Part A (Cycle 2 or greater) and Part B will be evaluated on an ongoing basis for AEs.
In these patients, a DLT-equivalent toxicity will be defined based on trends of any clinical 
significant toxicity deemed by the study investigators and Lilly clinical research personnel to be 
dose-limiting and related to study drug(s)s. The investigators and Lilly CRP/CRS will have to 
agree as to whether such AEs are considered as DLT-equivalent.
9.2.2.3.
Dose Escalation Method and Maximum Tolerated Dose Definition
In this study, a 3+3 dose-escalation paradigm will be utilized.  If 1 patient, at any dose level, 
experiences a DLT during the DLT period (Cycle 1), then up to 3 additional patients will be 
enrolled at that dose level.  If a DLT is observed in ≥2 out of 6 patients at any dose level, dose 
escalation will cease and either the previous dose level will be declared the maximum tolerated 
dose (MTD) or, following discussions between the investigators and the sponsor, additional 
patients may be treated at intermediate doses between the previous and the current dose levels.
The first patient enrolled in Part A in this study will be observed for a DLT (as defined in 
Section 9.2.2.2) during the first 14 days of Cycle 1, before subsequent patients are treated at that 
dose level. If the first patient does not experience a DLT during this period, subsequent patients 
may be concurrently enrolled at the initial cohort. In subsequent cohorts, all patients may be 
enrolled concurrently.
9.2.2.4.
Dose Confirmation of LY2875358 in Part B
Once a recommended schedule and dose range of LY2875358 that may be safely administered in 
combination with ramucirumab on Days 1 and 15 of a 28-day cycle has been determined in Part 
A, the tumor expansion portion of the study (Part B) will be opened.  Approximately 15 patients 
in each of the 4 specified tumor types will be enrolled (approximately 60 patients in total).  The 
dose and schedule of LY2875358 in Part B for combination with the fixed regimen of  
ramucirumab 8 mg/kg Q2W will be defined based upon safety, PK/PD, and antitumor activity 
observed in Part A.  The sponsor, in collaboration with the investigators, will review Part A 
results prior to determining the recommended schedule and dose of LY2875358 to be studied in 
Part B. The decision will be documented in writing and a written notification will be sent to the 
IRB prior to enrollment of patients into Part B. No amendment will be required.  If indicated by 
safety, PK/PD, and/or emerging clinical data, the recommended schedule and dose of 
LY2875358 and ramucirumab in Part B might be individually adjusted for each tumor cohort
following written notification by the sponsor. 

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9.2.3. Dose Adjustments and Delays
In Cycle 1, no dose adjustments, or delays of ramucirumab and/or LY2875358 will be allowed 
(ie, DLT assessment period), except in case of any DLT.
In Cycle 2 or beyond, if a patient experiences a toxicity warranting a dosing delay in the 
investigator´s opinion, ramucirumab and/or LY2875358 dosing may be held for up to 2 
consecutive doses (approximately 28 days) to allow sufficient time for recovery from the toxicity.
This approximate 28-day time period begins on the day that the next dose of study treatment 
should have been administered but was withheld for toxicity. If both study drugs were held due 
to a toxicity, study treatment with both study drugs should be resumed as soon as that toxicity is 
resolved, provided that the patient did not meet any discontinuation criteria.
In case the toxicity is specifically attributable to 1 of the 2 experimental study drugs in the 
opinion of the investigator (eg, ramucirumab-related hypertension), the patient may continue to 
receive the other study drug following the regularly scheduled Q2W treatment time points (eg,
LY2875358). In this setting, treatment of the withheld study drug (eg, ramucirumab) should be 
resumed at the next regularly scheduled Q2W treatment time point of the continued study drug 
(eg, LY2875358) following the resolution of the event causing the hold. Make-up doses of the 
withheld study drug occurring between regularly scheduled Q2W treatment time points are not 
permitted in order to keep the administration of both study drugs synchronized to the same study 
days (ie, Day 1 or 15 of a cycle). In situations where >2 consecutive doses have been missed, 
events related to the missed doses have resolved, and there is evidence of ongoing disease 
control, continuation of ramucirumab and/or LY2875358 may be considered and must be 
discussed with the Lilly clinical team.
It is recognized that, in the course of clinical cancer care, it is not always possible to schedule 
therapeutic infusions precisely 2 weeks following a prior infusion (ie, because of holidays, travel 
difficulties, or other circumstances). Accordingly, study drug infusions administered within the 
timing window as indicated in the Study Schedule (see Attachment 1) relative to the regularly
scheduled Q2W treatment time point will be considered acceptable. Moreover, in Cycle 3 or 
beyond, ramucirumab and LY2875358 dosing may be delayed for up to approximately 14 days 
because of holidays, weekends, inclement weather, or other justifiable events, and not counted as 
a protocol violation. This approximate up to 14-day time period begins on the day that the next 
dose of study treatment should have been administered. In order to keep the administration of 
both study drugs synchronized, the next dose of ramucirumab and LY2875358 should be 
administered at the same study day to continue the regularly scheduled Q2W treatment time 
points.
In the event of dosing delays or missed doses, disease assessment and imaging studies should be 
undertaken according to the original study schedule, regardless of the actual number of on-study 
treatments received.
9.2.3.1. Infusion-Related Reaction
As with other mAbs, infusion-related reactions may occur during or following ramucirumab 
and/or LY2875358 administration. Patients should be closely monitored for signs and symptoms

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indicative of an infusion-related reaction, starting with the initiation of the infusion until at least
30 minutes after the infusion. Monitoring should be performed in an area where resuscitation
equipment and other agents (eg, epinephrine, corticosteroids) are readily available (Table 
JTBF.3).
Any treatment-related infusion-related reactions are defined according to the NCI-CTCAE 
Version 4.03 definition (“General disorders and administration site conditions” section).  
Symptoms occurring during or following infusion of investigational product may also be defined 
according to AE categories such as allergic reaction, anaphylaxis, or cytokine release syndrome 
(“Immune system disorders” section).  In the setting of symptoms occurring during or following 
infusion of the study drugs, 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.

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Table JTBF.3.
NCI-CTCAE Version 4 Infusion-Related Reactionsa
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 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hours
Prolonged (eg, 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 
(eg, antihistamines, 
NSAIDs, narcotics); 
prophylactic medications 
indicated for ≤24 hours
Prolonged (eg, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for clinical 
sequelae (eg, 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 (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hours
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
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; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.03; NSAID = nonsteroidal anti-inflammatory drug.
a
Premedication must be provided in the setting of a prior Grade 1-2 infusion-related reaction.

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Consistent with usual medical practice, selected parenteral medications may be utilized for 
Grade 2 allergic/hypersensitivity reaction as detailed below.  The sponsor physician or designee 
should be contacted immediately if questions arise concerning the grade of the reaction.  The 
following are treatment guidelines for infusion-related reactions:
Grade 1

Slow the infusion rate by 50% for the duration of the infusion and all subsequent 
infusions. 

Monitor the patient for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV 
(or equivalent); additional premedication may be administered at the investigator’s 
discretion.
Grade 2

Stop the infusion.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), acetaminophen 
650 mg orally for fever, and oxygen.

Resume the infusion at 50% of the prior rate for the duration of the infusion and all 
subsequent infusions once the infusion-related reaction has resolved or decreased to 
Grade 1; the infusion duration should not exceed 2 hours for each of the study drugs

Monitor for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV 
(or equivalent); additional premedication may be administered at the investigator’s 
discretion.

For a second Grade 1 or 2 infusion-related reaction, administer dexamethasone 8-10 mg 
IV (or equivalent); then, for subsequent infusions, premedicate with diphenhydramine 
hydrochloride 50 mg IV (or equivalent), acetaminophen 650 mg orally, and 
dexamethasone 8-10 mg IV (or equivalent).
Grade 3

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone   
8-10 mg IV (or equivalent), bronchodilators for bronchospasm, and other 
medications/treatment as medically indicated.

Patients who have a Grade 3 infusion-related reaction will not receive further 
investigational product causing this infusion-related reaction.
Grade 4

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone   
8-10 mg IV (or equivalent), and other medications/treatment as medically indicated.

Give epinephrine or bronchodilators as indicated.

Hospital admission for observation may be indicated.

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
Patients who have a Grade 4 infusion-related reaction will not receive further 
investigational product causing this infusion-related reaction.
If a patient should have an infusion-related reaction to the study drugs, all attempts should be 
made to obtain blood samples for both immunogenicity and PK analysis as close to the onset of 
the event as possible, at the resolution of the event, and 30 days following the event.
9.2.3.2. Treatment Guidelines and Dose Modifications for Ramucirumab-specific 
Adverse Events 
Dose modifications of ramucirumab are permitted in the setting of non-life-threatening,
reversible Grade 3-4 clinical AEs (eg, fever) considered to be at least possibly related to 
ramucirumab. 

For toxicities that resolve to Grade ≤1 or baseline, ramucirumab may be re-administered 
at a dose of 8 mg/kg  

If a second instance of such an event occurs, ramucirumab should be subsequently re-
administered at a dose of 6 mg/kg Q2W.

A second dose reduction to 5 mg/kg Q2W is permitted for this level of event (Grade 3-4).
Any further dose reduction of ramucirumab below 5 mg/kg is not permitted, and if the criteria 
for a ramucirumab dose reduction are met for patients at 5 mg/kg ramucirumab Q2W, 
ramucirumab must be discontinued. If the dose of ramucirumab is reduced, subsequent dose 
increases are not permitted. If a patient’s dose is reduced or treatment is discontinued as a result 
of an AE, study site personnel must clearly report the circumstances and data leading to any such 
dosage reduction or discontinuation of treatment.
Patients who enter the study with symptoms or laboratory values equivalent to NCI-CTCAE 
Version 4.03 Grade 1-2 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 Grade 3-4 laboratory abnormalities should not result in dose 
interruptions, modifications, or discontinuation of study therapy unless determined to be 
clinically significant by the investigator (or unless otherwise specified in the study protocol).
9.2.3.2.1. Hypertension
The following are treatment guidelines for hypertension that develops during the study.
Grade <3

If the hypertension is not associated with symptoms, continue ramucirumab and initiate 
antihypertensive therapy.

If the hypertension is associated with symptoms, hold ramucirumab until symptoms 
resolve and initiate antihypertensive therapy.

If ramucirumab is held more than once for hypertension (ie, symptomatic hypertension, 
markedly elevated BP unresponsive to antihypertensive therapy), the dose of 
investigational product should be reduced upon re-treatment to 6 mg/kg Q2W.  A second 

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dose reduction to 5 mg/kg Q2W should be undertaken if an additional postponement of 
ramucirumab is required.
Grade 3 (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg; medical intervention indicated; 
more than 1 drug or more intensive therapy than previously used indicated)

For Grade 3 hypertension not associated with symptoms, continue ramucirumab with 
more intensive antihypertensive therapy.  If systolic BP remains ≥160 mmHg or diastolic 
BP remains ≥100 mmHg >3 weeks after initiation of additional antihypertensive therapy, 
hold ramucirumab while continuing appropriate antihypertensive therapy.

If the hypertension is associated with symptoms, hold ramucirumab while continuing 
appropriate antihypertensive therapy.

If ramucirumab is held more than once for hypertension (ie, symptomatic hypertension, 
markedly elevated BP unresponsive to antihypertensive therapy), the dose of 
ramucirumab should be reduced upon re-treatment to 6 mg/kg Q2W.  A second dose 
reduction to 5 mg/kg Q2W should be undertaken if an additional postponement of 
investigational product is required.
Grade 4 or refractory

Patients with Grade 4 hypertension (life-threatening consequences, eg, malignant 
hypertension, transient or permanent neurologic deficit, hypertensive crisis, or urgent 
intervention indicated) or patients whose hypertension is poorly controlled (>160 mmHg 
systolic BP or >100 mmHg diastolic BP for >4 weeks) despite appropriate oral 
medication (>2 oral agents at MTD) will be discontinued from ramucirumab.
9.2.3.2.2. Proteinuria
If, while receiving ramucirumab, a patient has proteinuria ≥2+ per a dipstick or routine urinalysis 
test, ramucirumab will continue as scheduled, and a 24-hour urine collection will be conducted 
prior to the subsequent scheduled treatment cycle.  If the protein level is <2 g/24 hours, the 
patient will continue on ramucirumab at the same dose without interruption.  If the protein level 
is 2 to 3 g/24 hours, ramucirumab for the subsequent cycle will be held for 2 weeks and a 24-
hour urine collection will be repeated.  Treatment with ramucirumab will resume at a reduced 
dose level (6 mg/kg Q2W) once the protein level returns to <2 g/24 hours.  A second dose 
reduction of ramucirumab to 5 mg/kg every 2 weeks is permitted if proteinuria >2 g/24 hours 
recurs.  Ramucirumab will be discontinued if the protein level is >3 g/24 hours, if there is a third 
occurrence of proteinuria >2 g/24 hours, or if the protein level does not return to <2 g/24 hours 
within 2 weeks.
9.2.3.2.3. Thromboembolic Events
Investigators should perform all testing required to fully characterize arterial or venous
thromboembolic/vascular events. The incidence and type of thromboembolic/vascular events 
will be collected and reported. Ramucirumab should be discontinued in the event of any Grade 
3-4 ATE or VTE that is considered by the investigator to be life-threatening, or symptomatic and 
not adequately treated by anticoagulation therapy. Ramucirumab may be continued in the setting 

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of an incidentally diagnosed, asymptomatic deep vein thrombosis or pulmonary embolism, or 
following these events when symptoms have resolved with the institution of anticoagulation 
therapy.  Ramucirumab should also be discontinued in the setting of a deep vein thrombosis or
pulmonary embolism that occurs or intensifies while the patient is receiving therapeutic
anticoagulation therapy.
9.2.3.2.4. Bleeding (Hemorrhagic) Events
Serious bleeding (hemorrhagic) AEs have been reported from clinical studies investigating 
ramucirumab.  Hemorrhagic complications are associated with some malignancies (ie, variceal
bleeding from portal hypertension in hepatocellular carcinoma, lower GI hemorrhage 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. Ramucirumab should be discontinued in the event of any 
Grade 3 or 4 bleeding (hemorrhagic) event.
9.2.3.2.5. Gastrointestinal Perforations
An infrequent incidence of GI perforations has been associated with some anti-angiogenic
therapeutic agents, most specifically in the context of colorectal cancer (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 ramucirumab IB.  
Ramucirumab should be discontinued in the event of a GI perforation.
9.2.3.2.6. Congestive Heart Failure in Patients Who Received Ramucirumab in
Combination With Mitoxantrone or Following Prior Anthracycline
Therapy
An increased risk of CHF has been associated with some anti-angiogenic therapeutic agents,
particularly in patients with metastatic breast cancer previously treated with anthracyclines or
with other risk factors for CHF, including prior radiotherapy to the left chest wall. Findings have
ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF 
requiring treatment or hospitalization. Caution should be exercised when treating patients with 
clinically significant cardiovascular disease such as preexisting coronary artery disease or CHF.  
Patients with symptomatic CHF, unstable angina pectoris, or symptomatic or poorly controlled 
cardiac arrhythmia should not be enrolled in clinical trials with ramucirumab. Ramucirumab
should be discontinued in the event of any Grade 3-4 events consistent with CHF.

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9.2.3.2.7. Surgery and Impaired Wound Healing
Surgery and impaired wound healing have been observed with some anti-angiogenic agents.  
Ramucirumab will not be administered to patients who have undergone major surgery within 28 
days prior to initiation of study treatment or who have undergone central venous access device 
placement within 7 days prior to receiving study drugs. Patients with postoperative and other 
nonhealing wound complications are excluded, as are patients for whom major surgical 
procedures are planned.
9.2.3.2.8. Liver Injury/Liver Failure
An independent data monitoring committee (IDMC) for Study I4T-IE-JVBF (JVBF) a 
randomized, blinded study evaluating ramucirumab versus placebo in hepatocellular carcinoma 
following prior sorafenib therapy recommended modifications following an 02 August 2012 
meeting. This was the fifth meeting of the IDMC for this study (the prior meetings had 
concluded with recommendations to continue this study without modifications), and occurred at 
the request of the sponsor to investigate a potential association of liver failure and other events of 
severe liver injury with ramucirumab. The IDMC reviewed unblinded safety data from 400 
patients who had been treated with either ramucirumab or placebo. The data cut-off date of this 
safety review was 18 July 2012. In review of the safety data, the IDMC noted that death rates 
related to study medication were in the expected range for patients with hepatocellular carcinoma 
and cirrhosis. However, the IDMC observed a numeric imbalance of liver-related AEs, 
specifically for hepatic encephalopathy, between the 2 treatment arms. Based on this safety 
finding, the IDMC specifically addressed hepatic encephalopathy, hepatorenal syndrome, and 
ascites in the context of cirrhosis, exclusive of other etiologies of these diagnoses.
The IDMC recommended continuing Study JVBF with modifications.  These modifications 
included:  (a) exclusion of patients with Child-Pugh B cirrhosis (or worse), (b) exclusion of 
patients with cirrhosis (any degree) and a history of hepatic encephalopathy or clinically 
meaningful ascites resulting from cirrhosis, and (c) an additional criteria for discontinuation of 
study drug (ramucirumab or placebo) for patients with new occurrence of hepatic 
encephalopathy and/or hepatorenal syndrome resulting from liver cirrhosis. Although the 
IDMC's recommendations are specific to Study JVBF, Lilly has chosen to implement these 
recommendations for ongoing Lilly-sponsored studies in which patients are receiving 
ramucirumab. Ramucirumab should be discontinued following a new occurrence of hepatic 
encephalopathy and/or hepatorenal syndrome resulting from liver cirrhosis.
9.2.3.2.9. Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome 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). Magnetic resonance 
imaging represents the most reliable method for the diagnosis (Lee et al. 2008). Clinical 
symptoms and MRI abnormalities usually recover within days to weeks with proper 

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management, although permanent neurologic dysfunction has been reported (Hinchey et al. 
1996; Tajima et al. 1999; Garg 2001; Lee et al. 2008). Reversible posterior leukoencephalopathy 
syndrome has been associated with multiple clinical conditions, including hypertensive
encephalopathy, eclampsia, and renal failure with hypertension, as well as the use of both
immunosuppressive and cytotoxic drugs (Garg 2001; Marinella and Markert 2009). More
recently, RPLS has been associated with the use of the anti-VEGF agent bevacizumab, as
described in the prescribing information for this agent (Marinella and Markert 2009; Avastin 
package insert, 2011).
While the precise pathogenesis of RPLS has not been established, the pathophysiology may
involve impaired cerebrovascular autoregulation leading to blood-brain barrier disruption and
vasogenic edema (Schwartz 1996). Although the pathogenesis of RPLS appears to be
multifactorial, drug-induced endothelial damage and acute hypertension are frequently proposed
causes of cerebrovascular dysfunction in RPLS (Marinella and Markert 2009).
Reversible posterior leukoencephalopathy syndrome should be identified and treated promptly in 
order to minimize potential for permanent neurological damage. Treatment encompasses careful 
control of BP, withdrawal of potentially causative medication, and administration of 
anticonvulsant agents to those experiencing seizures (Stott et al. 2005). As of 31 December 
2012, 1 SAE of RPLS has been reported in the double-blind, randomized, placebo-controlled 
Phase 3 colorectal cancer Study I4T-MC-JVBB (JVBB). The event was determined to be related 
to administration of all study drugs, including blinded investigational drug product (the treatment 
assignment for this patient remains blinded). Because hypertension is an identified risk for 
ramucirumab, investigators should control BP in accordance with the guidelines in the 
ramucirumab IB and in relevant sections of the study protocol (Section 9.2.3.2.1). In addition, 
investigators should consider a diagnosis of RPLS in the setting of seizures, headache, nausea, 
delirium, visual changes, and/or other unexplained neurological symptoms, especially in 
combination with hypertension and MRI findings of hyperintensity on T2-weighted and fluid 
attenuated inversion recovery images. If the diagnosis of RPLS is confirmed, ramucirumab
should be permanently discontinued.
9.2.3.3.
Treatment Guidelines for LY2875358-Specific Adverse Events 
Intrapatient dose adjustments of LY2875358 will not be permitted in this study.
In Cycle 2 or beyond, patients who experience any Grade 3 or greater toxicity related to 
LY2875358 therapy should have LY2875358 therapy held for up to 2 consecutive doses  
(approximately 28 days) to allow sufficient time for recovery from the toxicity. This 
approximate 28-day time period begins on the day that the next dose of LY2875358 should have 
been administered but was withheld for toxicity. Patients who do not recover within this time 
period from this LY2875358-related toxicity to a level that, in the opinion of the investigator, is 
reasonable to allow for continuation of LY2875358 treatment, should discontinue further 
LY2875358 treatment. 
Patients who experience a concomitant elevation of AST/ALT >3 times ULN and bilirubin >2 
times ULN related to LY2875358 and who lack a natural disease state known to cause liver

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enzyme elevation (eg, hepatic metastases) should be permanently discontinued from LY2875358 
treatment. Only patients who have experienced a clinical benefit from study therapy may, at the 
discretion of the investigator, be re-challenged with LY2875358 after recovery from concomitant 
elevation of AST/ALT >3 times ULN and bilirubin >2 times ULN related to LY2875358.
Patients enrolled in Part B will undergo ongoing safety monitoring per tumor-specific expansion 
cohorts. If DLT-equivalent toxicities (Section 9.2.2.2) have been identified for a particular 
tumor-specific expansion cohort, LY2875358 dose de-escalation for all patients in this tumor-
specific expansion cohort (or, if appropriate, in all cohorts) will be discussed between the 
investigators and the sponsor.  The decision will be documented in writing and provided to 
IRBs/ERBs in writing. No amendment will be required.
9.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive ramucirumab and 
LY2875358 in this study.  Before each patient’s enrollment into the study, an eligibility check 
must be conducted between the investigational site and the Lilly clinical research personnel to 
confirm that each patient meets all enrollment criteria.  Upon confirmation of eligibility, the 
sponsor will confirm the dose and identification number assignment and cohort for each patient.  
No dose escalations (ie, to the next cohort) can occur without prior discussion and agreement 
with the responsible Lilly CRP or CRS. 
If investigators have eligible patients who have consented concurrently to Part A, more than 3
patients may be entered at a particular dose level, provided that accrual has not ceased due to 
excessive toxicity.  This enrollment procedure is allowed because of the advanced disease state 
of this patient population and the screening involved in defining eligibility.  This event should be 
approved by the sponsor following discussions with the investigators.
9.4.
Blinding
This is an open-label study.
9.5.
Concomitant Therapy
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study, with the following 
exceptions:  

Palliative radiotherapy of ≤14 calendar days in Cycles 2 and beyond following 
discussions between the investigators and the sponsor (eg, a solitary [non-skull] skeletal 
metastasis), as long as the patient has not developed another reason for study 
discontinuation

Patients on stable doses of bisphosphonates or denosumab are allowed to continue.
These agents should not be initiated within the 4 weeks prior to study enrollment or at 
any point while on the study

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
In select cases, after discussion with the sponsor, local therapies (such as radiation 
treatment to control isolated areas of CNS progression) may be permissible provided 
study drugs are held on the days of local therapy).
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study.  Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the eCRF.  
Replacement hormonal therapy initiated before study entry will be allowed.
Patients should receive full supportive care. The routine use of granulocyte colony stimulating 
factors (G-CSF) is not permitted during this study. If clinically indicated, the use of G-CSF is 
permitted during investigational therapy at the discretion of the investigator.  G-CSF or similar 
agents are recommended following Grade 3 or 4 neutropenia of duration >5 days or following 
any incidence of febrile neutropenia (ANC <1.0 × 109/L with temperature ≥38.5°C).
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to American Society of Clinical Oncology guidelines (Rizzo 
et al. 2008). 
The use of analgesic agents is permitted at the discretion of the investigator.  The chronic use of 
antiplatelet therapy (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, 
anagrelide, triflusal, or similar agents) and 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.  Chronic use of analgesic agents with no or low bleeding risk (for 
example, paracetamol/acetaminophen, metamizole, dipyrone, or propyphenazone) is acceptable. 
Patients receiving therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or 
similar agents are excluded from participation.  Anticoagulant therapy may be instituted during 
the course of treatment on study as detailed in Section 9.2.3.2.3 (following an asymptomatic or 
treatable deep vein thrombosis or pulmonary embolism), provided that no evidence of portal 
hypertension (including splenomegaly) or any prior history of variceal bleeding exists.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
9.6.
Treatment Compliance
Ramucirumab and LY2875358 will be administered IV at the investigational site, under the 
direction of the investigator.  As a result, patient’s compliance with study drug administration is 
ensured.  Patients should attend scheduled clinic visits and must comply with study criteria under 
their control.  Deviation(s) from the prescribed dosage regimen should be recorded on the eCRF.  
Potential discontinuation of a patient due to study noncompliance (not attending the scheduled 
visits; see Attachment 1) will be discussed between the investigator and the Lilly CRP/CRS 
before the final determination is made to discontinue the patient.

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9.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drugs will be replaced and will not 
be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug, regardless of whether they are deemed 
evaluable for the assessment of a dose level.
Any patient who is discontinued from the study before completing the first cycle of ramucirumab 
and LY2875358 treatment will be deemed non-evaluable for assessment of a dose level, unless it 
can be documented whether the patient did or did not experience a DLT during Cycle 1.
If a patient is noncompliant during Cycle 1 due to reasons other than drug-related toxicity, he or 
she will be considered nonevaluable and may be replaced. Nonevaluable patients may be 
replaced to ensure that at least 3 patients complete 1 cycle of therapy at each dose level, unless 
accrual to that cohort has stopped due to a DLT. Patients who are not evaluable for PK, but who 
complete 1 cycle of therapy, may be replaced upon consultation with the investigator(s) and the 
Lilly CRP/CRS to ensure adequate PK data, unless accrual to that cohort has stopped due to a 
DLT.

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10. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
10.1. Safety Evaluations
The safety and tolerability of ramucirumab and LY2875358 have been separately assessed in 
clinical studies, and the results from these studies are detailed in the respective IBs.  This Phase 
1b/2 study contains detailed safety monitoring that will permit initial characterization of the 
safety profile of the combined administration of ramucirumab and LY2875358 in patients with 
advanced or metastatic cancer.  Study procedures and their timing, including collection of blood, 
urine, and tumor samples, are described in the Study Schedule (Attachment 1).
Standard laboratory tests, including chemistry, hematology, coagulation, and urinalysis panels, 
will be performed.  A urine or serum pregnancy test will be administered if applicable.  Other 
clinical laboratory tests will also be collected.  Attachment 2 lists the specific tests that will be 
performed for this study.
10.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into 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 investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  Table 
JTBF.4 presents a summary of AE and SAE reporting guidelines.  Table JTBF.4 also shows 
which database or system is used to store AE and SAE data.
10.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
vital sign measurements, and so on, that occur should also be reported to Lilly or its designee as 

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an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect.
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using NCI-CTCAE Version 4.03.
The NCI-CTCAE Version 4.03 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  Any minor version of 
NCI-CTCAE Version 4.03 (eg, Version 4.0X) may be used for this study.  Minor NCI-CTCAE 
Version 4.03 updates will not necessitate a protocol amendment. For AEs without matching 
terminology within the NCI-CTCAE Version 4.03 criteria, the investigator will be responsible 
for selecting the appropriate system organ class and assessing severity grade based on the 
intensity of the event.  Note that both CTCAE term (actual or coded) and severity grade must be 
selected by study site personnel and collected on the eCRF.  This collection is in addition to 
verbatim text used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
Cases of pregnancy that occur during maternal or paternal exposures to study drugs should be 
reported.  Data on fetal outcome and breastfeeding should be collected, if feasible, for regulatory
reporting and drug safety evaluation.
Upon documentation of pregnancy, the patient must be removed from the study and treatment 
with study drug(s) must be stopped immediately.
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition 
all AEs related to protocol procedures are reported to Lilly or designee.
If a patient's dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment. 
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and/or study drug via eCRF. The investigator 
decides whether he or she interprets the observed AEs as related to either study disease, study 
medication, study procedure, or other concomitant treatment or pathologies.  To assess the 
relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

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
Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
10.1.2.1. Serious Adverse Events
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs.  Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (ie, 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 SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-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.  
If an investigator becomes aware of SAEs occurring to a patient after the patient’s participation 
in the trial has ended, and the investigator believes that the SAE is related to a protocol

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procedure or study drug, the investigator should report the SAEs to the sponsor, and the SAEs 
will be entered in the LSS.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
10.1.2.1.1. Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
LSS.
10.1.2.1.2. Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the informed consent form.  For patients who do not enroll 
in the trial (ie, have not received at least 1 dose of ramucirumab and/or LY2875358), only AEs 
and SAEs related to protocol procedures are required to be collected. 
10.1.2.1.3. On Therapy
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study drug 
to when he/she receives the last dose of study drug.
10.1.2.1.4. Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
during the follow-up visit (Visit 801) must be reported to Lilly or its designee.  The initial 
follow-up period (V801) starts following the last dose of LY2875358.  At the follow-up visit
(V801) (30 ± 3 days after last dose of LY2875358) the patient will be required to have specific 
safety assessments (Attachment 1).  
Following the safety assessments, which mark the end of the follow-up visit (Visit 801), the 
patient will be discontinued from the study, unless there is an ongoing AE or SAE that is 
possibly related to study drug(s).  In this instance, the patient should be followed until the event 
is resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.
If it is deemed to be in the best interest of the patient to start a new anticancer treatment prior to 
the scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this 
case, the follow-up assessments should be completed prior to the initiation of the new therapy.
After the follow-up visit (Visit 801), AEs are not required to be reported unless the investigator 
feels the AEs were related to either study drug(s) or a protocol procedure. If an investigator 
becomes aware of an SAE believed to be related to protocol procedures or study drug(s), the
investigator should report the SAE to the sponsor, and the SAE will be entered in the LSS.

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10.1.2.1.5. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the
DCSI of the IB and that the investigator identifies as related to study drug or procedure.  The US
21 CFR 312.32, the EU 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 and expedited reporting of 
SUSARs that are consistent with global regulatory regulations and the associated detailed 
guidances.
10.1.2.2. Summary of Adverse Event/Serious Adverse Event Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JTBF.4.
Table JTBF.4.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study JTBF
Timing
Types of AEs/SAEs 
Reported 
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of 
informed consent and ends just 
before the first dose of study 
drug)
Pre-existing conditions
All AEs
All SAEs regardless of 
relatedness 
x
x
x
x
On therapy
(Starts at first dose of study 
drug[s] and ends at last dose of 
study drug[s])
All AEs
All SAEs regardless of 
relatedness
x
x
x
Follow-up Visit (Visit 801)
(Starts just after the last dose of 
study drug[s] and ends when 
end of study safety assessments 
are completed 30 ± 3 days after 
last dose of study drug[s]) 
All AEs
All SAEs regardless of 
relatedness
x
x
x
Subsequent follow-up visits, if 
necessary for patient 
monitoring 
Ongoing AEs possibly 
related to study drug(s), or 
protocol procedures
All SAEs related to protocol 
procedures or study drug(s)
x
x
x
Patient no longer on study
All SAEs related to protocol 
procedures or study drug of 
which the investigator 
becomes aware
x
Abbreviations:  AE = adverse event; SAE = serious adverse event.
10.1.3. Other Safety Measures
10.1.3.1. Electrocardiograms
For each patient, single 12-lead ECGs will be obtained according to the Study Schedule
(Attachment 1). The patient must be supine for approximately 5 to 10 minutes before ECG

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collection and remain supine during ECG collection. Electrocardiograms must be recorded 
before collecting any blood for safety or PK tests. Electrocardiograms may be obtained at 
additional times, when deemed necessary (eg, for safety reasons). All recorded ECGs should be 
stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant finding is identified (including but not limited to
changes in QT/QTc interval from baseline), the investigator will determine if the patient can
continue in the study. The investigator or qualified designee is responsible for determining if 
any change in patient management is needed and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE.
10.1.4. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study. 
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or CRS, and periodically review:

trends in safety data

laboratory analytes

AEs

If a study patient experiences elevated ALT >5 X ULN and elevated total bilirubin >2 X
ULN, clinical and laboratory monitoring should be initiated by the investigator.  For 
patients entering the study with ALT >3 X ULN, monitoring should be triggered at ALT 
>2 X baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 3).
10.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

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
recording a complete description of the complaint reported and any associated 
adverse events using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.2. Sample Collection and Testing
Attachment 1 lists the schedule of study evaluations in this study.
Attachment 2 lists the specific laboratory tests that will be performed for this study.  
Attachment 4 lists the schedule for PK and PD sample collections in this study.
Attachment 7 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
10.2.1. Samples for Study Qualification and Health Monitoring
Tumor tissue, blood, and urine samples will be collected at the times specified in the Study 
Schedule (Attachment 1). Attachment 7 summarizes volumes for all invasive sampling 
(screening, safety evaluations, and bioanalytical markers).
Investigators must document their review of each laboratory safety report.
To meet study eligibility criteria, patients must have available a FFPE tumor specimen taken by 
core needle biopsy or surgical biopsy prior to study treatment but after progression (or 
discontinuation) to the most recent line of systemic tumor therapy (“post-progression tumor 
sample”) or be willing to undergo a tumor biopsy of a pre-study treatment by core needle biopsy 
or surgical biopsy. Tumor specimen samples may be of any type of tissue, with the exception of 
bone or CNS metastases.  Cytological samples and fine-needle aspiration specimens are not 
acceptable. Tumor tissue specimens must have adequate evaluable tumor cells. Due diligence 
should be used to make sure that tumor specimens (not a normal adjacent or a tumor margin 
sample) are provided.  An associated pathology report may also be requested to be sent with the 
samples. Tumor samples will be labeled with patient number and tissue of origin.
For the “post-progression tumor sample”, submission of a tissue block is preferred.  
Alternatively, approximately 15 serially cut unstained sections from the FFPE block can be 
submitted. If the requested amount of tumor samples from the “post-progression tumor sample”
are not available, the patient may still be eligible, upon discussion with the Lilly study team, with 
the assumption that the patient can provide sufficient tumor tissue specimen for assessment of at 
least MET expression and VEGFR-2 status.
Blood and urine samples collected for specified laboratory tests will be destroyed within 60 days 
of receipt of confirmed test results.  Tests are run and confirmed promptly whenever 
scientifically appropriate.  When scientific circumstances warrant, however, it is acceptable to 
retain samples to batch the tests run, or to retain the samples until the end of the study to confirm 

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that the results are valid.  Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards.
The tumor tissue samples will be coded with the patient number and stored for up to a maximum
15 years after the last patient visit for the study at a facility selected by the sponsor. The samples
and any data generated from them can only be linked back to the patient by investigator site
personnel. The duration allows the sponsor to respond to regulatory requests related to the study
drugs. Tumor specimens submitted as a FFPE tissue block will be returned to the sites by end of
study or upon request.
10.2.2. Samples for Biomarker Research 
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.  
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to ramucirumab and LY2875358.  These investigations may be limited 
to a focused candidate gene study or, if appropriate, genome-wide analysis may be performed to 
identify regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
Collection of samples for biomarker research and PK/PD analyses is an integral part of this 
study.  Assessments may include analysis of tumor tissue and blood for exploratory biomarkers 
related to the VEGFR-2 and HGF/MET signaling pathways as well as to biology of the 
respective tumor types in this study and potential resistance mechanisms.  The association of 
biomarkers with the objectives of the study (including PK/PD biomarker relationship) may be 
assessed.  The exploratory biomarker sampling times are listed in Attachment 1.  The exploratory 
biomarker analysis may be performed by the sponsor or at a laboratory selected by the sponsor.  
Samples for exploratory biomarker research to be collected from patients in this study are the 
following:

Tumor tissue samples: Mandatory “post-progression tumor samples” and optional tumor 
samples from any time since diagnosis of the tumor disease (ie, archival tumor samples)
may be analyzed for, including but not necessarily limited to, VEGFR-2, MET 
expression, MET and EGFR amplification, and HGF expression. 
Optional tissue samples for biomarker research from patients willing to consent to 
additional on study biopsies should be collected at any time during the study if safe and 
feasible and upon notification of the sponsor (preferably core tumor biopsies; 
alternatively, cytology or fine-needle aspiration).  In particular, biopsies from patients 

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progressing on study therapy are encouraged to be performed, provided no other cancer 
treatment has been started and the procedure does not impede or delay planned cancer 
treatment.

Blood samples: Blood samples may be analyzed for, including but not necessarily 
limited to, circulating levels of VEGF-A, soluble VEGFR-2, PlGF, HGF, and MET-ECD.  
Blood biomarker levels from the study treatment period may be compared with baseline 
(screening).  In addition, the time course of blood biomarker levels during the study and 
PK/PD biomarker relationship may be evaluated.
Details for the handling and shipping of tumor biopsy samples will be provided in a separate 
document.  Instructions and supplies required for the collection, processing, and shipment of the 
patients’ tissue and blood samples will be provided by the sponsor. 
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
10.2.3. Samples for Drug Concentration Measurements 
Pharmacokinetics
Pharmacokinetic samples will be collected as specified in the Pharmacokinetic and 
Pharmacodynamic Sampling Schedule (Attachment 4). 
10.2.3.1. Pharmacokinetic Samples
Blood samples will be collected for the analysis of ramucirumab and LY2875358 levels to 
estimate the PK parameters of both compounds when administered in combination.  
Furthermore, PK parameters will be assessed for evaluation of PK/PD relationship, and to inform 
dose escalation.
The PK sampling times are listed in Attachment 4.  Up to 5 additional PK samples may be drawn 
during the study if warranted and agreed upon by both the investigator and sponsor.
Instructions for the collection and handling of blood samples will be provided by the sponsor or 
central lab.  The actual date and time (24-hour clock time) of each sampling will be recorded.
These samples will be analyzed at a laboratory designated by the sponsor.  Serum concentrations 
of LY2875358 and ramucirumab will be assayed using validated enzyme-linked immunosorbent 
assay methods.
The PK samples will be stored at a facility designated by the sponsor.
The remaining serum from the samples collected for PK may be pooled and used for exploratory
biomarker work as deemed appropriate.

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Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
10.2.4. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine antibody production 
against study drugs (ramucirumab and LY2875358).  Immunogenicity will be assessed by a 
validated assay designed to detect anti-drug antibodies in the presence of study drugs.  
Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
activity of study drugs.
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to study drugs.  
The duration allows the sponsor to respond to regulatory requests related to study drugs.
10.3. Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1
for details regarding the timing of specific efficacy measures. Efficacy measures include:  

ORR:  The proportion of patients who exhibit a confirmed complete response (CR) or PR 
relative to baseline as defined by RECIST 1.1 (Eisenhauer et al. 2009)

DCR:  The proportion of patients in the analysis population who exhibit a SD or 
confirmed CR or PR relative to baseline during the study  

PFS:  The time from the date of study enrollment to the date of first observation of 
objective progression or death from any cause

Change in tumor size:  The change in tumor size from baseline measurement to the 
measurement with the smallest tumor size during the study.
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement:

CT scan

MRI

Chest x-ray.
Each patient’s full extent of disease will also be assessed with: 

Tumor measurement by RECIST 1.1 (Eisenhauer et al. 2009)

Evaluation of tumor markers, if indicated

Evaluation of ECOG performance status (refer to Attachment 6).
Consistent with RECIST, all patients may undergo alternative imaging studies consistent with 
institutional guidelines to assess tumor response.  This may include, but is not limited to, FDG-
PET, dynamic contrasted-enhanced MRI, or other modalities.

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To confirm objective responses, all lesions should be radiologically assessed, and the same 
radiologic method used for the initial response determination should be repeated at least 4 weeks
following the initial observation of an objective response, using the sample method that was used 
at baseline.  If a patient is discontinued from the study, repeat radiology assessments may be 
omitted if clear clinical signs of progressive disease are present.
10.4. Procedure/Sampling Compliance
Every attempt will be made to enroll patients who have the ability to understand and comply 
with instructions.  Noncompliant patients may be discontinued from the study.
The collection times of safety assessments, PK and PD samples, and efficacy measurements are 
given as targets, to be achieved within reasonable limits.  The scheduled time points may be 
subject to minor alterations; however, the actual collection time must be correctly recorded.
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.

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11. Data Management Methods
11.1. 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/or 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.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable IRB/ERBs 
with direct access to the original source documents.
11.2. Data Capture Systems
11.2.1. Case Report Form
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 the sponsor-provided electronic data capture system.
Any data for which 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 measures (eg, a rating scale), a daily dosing schedule, or an event diary. 
For data handled by a data management third-party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to the Lilly data 
warehouse, using standard Lilly file transfer processes.
For data handled by the sponsor internally, CRF data and some or all data that are related will be 
managed by the sponsor and stored electronically in the sponsor’s system.

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11.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system and/or TPO’s system.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system and/or TPO’s system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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12. Data Analyses
12.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
The interpretation of the study results will be the responsibility of the investigator with the Lilly
CRP and/or CRS, pharmacokineticist, and statistician.  The CRP and/or CRS and statistician will 
also be responsible for the appropriate conduct of an internal review for both the final study 
report and any study-related material to be authorized by Lilly for publication.
The analyses for this study will be descriptive, except for possible exploratory analyses as 
deemed appropriate. Data analyses will be provided by dose levels and for all patients combined 
wherever appropriate. For continuous variables, summary statistics will include number of 
patients (N), mean, median, standard deviation, standard error (SE), minimum, and maximum.  
Categorical endpoints will be summarized using N, frequency, percentages, and associated SE.  
Missing data will not be imputed. Exploratory analyses of the data that are not described in the 
protocol will be conducted as deemed appropriate.
Up to approximately 70 patients may be enrolled in this multicenter Phase 1b/2 study with an 
open-label, dose escalation design. Patients will be enrolled into cohorts sequentially without 
randomization to dose level. During dose escalation (Part A), the total samples size per cohort 
will be determined by DLTs (up to 6 patients per cohort before establishing the MTD). For the 
tumor-specific expansion cohorts (Part B), additional patients will be enrolled within 3 cohorts 
for specified tumor types (approximately 15 patients per group). The sample size of 
approximately 15 patients for the tumor-specific expansion cohorts was selected to allow 
adequate assessment of safety at the recommended dose and to identify evidence of activity 
worthy of further investigation in Phase 2.
12.2. Patient Disposition
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
12.3. Patient Characteristics
Patient characteristics will include a summary of the following:

Patient demographics including age, sex, screening height and weight, and screening 
body mass index

Baseline disease characteristics

Prior disease-related therapies 

Concomitant medications.
Other patient characteristics will be summarized as deemed appropriate.

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12.4. Safety Analyses
All patients who receive at least 1 dose of ramucirumab and/or LY2875358 will be evaluated for 
safety and toxicity.  Adverse event terms and severity grades will be assigned by the investigator 
using NCI CTCAE Version 4.03.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drugs

Dose adjustments

Laboratory values 

Vital signs 

DLTs at each dose level 

ECG readings.
12.5. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of 
study drug(s) and have had samples collected.  
Population PK models for LY2875358 and ramucirumab may be developed using nonlinear 
mixed effect modeling.  The LY2875358 PK data from this study may be added to data available 
from other studies, such as the Phase 1 Study JTBA, and the base model for LY2875358 will be 
the previously developed TMDD model.  Noncompartmental methods may also be used if 
warranted by the data.
The parameters for ramucirumab will include steady-state maximum (Css,max) and steady-state 
minimum (Css,min) and area under the concentration-time curve during the dosing interval at 
steady state (AUCτ,ss).
The parameters for LY2875358 may include systemic clearance (CL), volume of distribution 
(V), Css,min, or TMDD model parameters, such as receptor-mediated clearance, non–receptor-
mediated clearance, volume of the central compartment, and volume of the peripheral 
compartment.
Additional exploratory analyses will be performed if warranted by data.  These exploratory 
analyse may include:

Evaluating the relationship between PK and antitherapeutic antibodies 

Evaluating the relationship between PK and biomarkers, such as MET ECD

Evaluating the relationship between exposure and response in terms of safety and 
efficacy (eg, incidence of adverse reactions, PFS, OS, change in tumor size).
The version of any software used for the analysis will be documented, and the program will meet 
the Lilly requirements of software validation.  It is possible that other validated equivalent PK 
software programs may be used if appropriate, warranted, and approved by Global 
Pharmacokinetic Management.

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12.6. Efficacy
The study was not designed to make a comparative efficacy assessment.  However, as a co-
primary objective for Part B, this study will evaluate preliminary antitumor activity observed 
with ramucirumab in combination with LY2875358 in the tumor-specific expansion cohorts in 
terms of ORR. Any tumor response data will be tabulated for Part A and Part B.
12.7. Biomarker Analyses 
Section 10.2.2 provides a description of the biomarker samples that may be used to carry out 
biomarker-specific exploratory analyses as mentioned in Section 6.3. Planned exploratory 
analyses will include, but are not limited to, known or hypothesized biomarkers that are related 
to VEGF and MET signaling pathways, or tumor biology of the respective tumor types enrolled 
or associated with sensitivity/resistance to the study drugs. 
Across all parts of the study, blood and tissue samples specified (including post-progression-
and/or archived tumor samples) may be analyzed to explore potential biomarker(s) associated 
with response to treatment. Somatic mutation status and/or copy number variations of genes that 
are targets of the study drug(s), known to be risk factors for cancer, or associated with resistance 
to anticancer therapies will be analyzed at a laboratory designated by the sponsor. This analysis 
may employ targeted or whole-exome sequencing approaches. 
In Parts B1-4 of the study, tumor-specific biomarker results based on immunohistochemical
(IHC), fluorescence in-situ hybridization (FISH), polymerase chain reaction (PCR), or other 
means for detection and quantitation of cancer-associated protein or nucleic acid changes may be 
investigated with the aim of identifying genetic variation(s) and/or variations in protein 
expression that are associated with favorable clinical response within each tumor type or more 
broadly across multiple tumor types. 
All biomarkers will be specifically investigated with the aim of developing a patient stratification 
strategy that will enable defining a target patient population that is more likely to respond to the 
treatment regimen being investigated and/or less likely to suffer from TEAEs.
Where applicable, the above associative/correlative assessments involving clinical response and 
biomarker data may be extended or adjusted to include relevant safety, toxicity, and PK/PD 
endpoints.
12.8. Interim Analyses
An interim analysis will be performed after completion of Part A.
Since this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
study until the MTD is determined.  The purpose of these cohort-by-cohort reviews is to evaluate 
the safety data at each dose level and to determine if a DLT has been observed that would 
suggest MTD has been met or exceeded.  Based on these interim results, modifications to the 
dose escalation strategy or other design elements may be made via protocol amendment to ensure 
patient safety. The investigators and the Lilly study team will make the determination regarding 

I4C-MC-JTBF(b) Phase 1 Oncology Protocol
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dose escalation based upon their review of the safety and tolerability data as described in this 
protocol.  
For Part B, interim analyses will be conducted approximately 3 months after the 15th patient in
Parts B1, B2, and B4 (that is gastric, hepatocellular, and non-small cell lung cancers) and 
approximately 6 months after the 15th patient in Part B3 (renal cell cancer) starts study therapy. 
Further interim analysis may be considered if deemed appropriate by the sponsor.

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13. Informed Consent, Ethical Review, and 
Regulatory Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including 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 study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient before the study is started.  This includes obtaining the appropriate signatures and dates 
on the ICF prior to the performance of any protocol procedures and prior to the administration of 
study drug. 
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the ICH guideline on GCP.  
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites.  The ERBs will review the protocol as required.
The study site’s ERBs should be provided with the following:

the current IB, Patient Information Leaflet, or Package Insert, and updates during the 
course of the study

ICF

relevant curricula vitae.
13.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
International Ethical Guidelines 
2) the ICH GCP Guideline [E6]
3) applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERBs.

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Some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data.
13.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
13.3.2. Protocol Signatures
The sponsor’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.
13.3.3. Final Report Signature
The final report coordinating investigator or designee will sign the 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 qualified and evaluable patients will serve as the final report 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s 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.

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14. References
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Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic 
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Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated 
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Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
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Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev 
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Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438(7070):967-974.
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos 
LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, 
Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; 
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PJ. Cottingham S, Watson MA, Ellis MJ, Sigler, RE, Furge KA, Vande Woude GF. Met 
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Ghoussoub RA, Dillon DA, D’Aquila T, Rimm EB, Fearon ER, Rimm DL. Expression of c-met 
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Kong DS, Song SY, Kim DH, Joo KM, Yoo JS, Dong SM, Suh YL, Lee JI, Park K, Kim JH, 
Nam DH. Prognostic significance of c-Met expression in glioblastomas. Cancer. 
2009;115(1):140-148.
Lai AZ, Abella JV, Park M. Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 
2009;19(10):542-551.
Lee VH, Wijdicks EFM, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior 
leukoencephalopathy syndrome. Arch Neurol. 2008;65:205–210.
Lengyel E, Prechtel D, Resau JH, Gauger K, Welk A, Lindemann K, Salanti G, Richter T, 
Knudsen B, Vande Woude GF, Harbeck N. C-Met overexpression in node-positive breast 
cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer. 
2005;113(4):678-682.
Marinella MA, Markert RJ. Reversible posterior leucoencephalopathy syndrome associated with 
anticancer drugs. Intern Med J. 2009;39(12):826-834.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program Common Terminology 
Criteria for Adverse Events, version 4.0. Available at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
Published May 28, 2009. Updated June 14, 2010. Accessed October 22, 2013.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
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Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, 
Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to 
increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220-231.
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Perol M, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Göksel T, Park K, Kowalyszyn RD,
Pikiel J, Czyzewicz G, Orlov S, Lewanski CR, Alexandris E, Zimmerman A, Chouaki N, John
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(DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-
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Tajima Y, Isonishi K, Kashiwaba T, Tashiro K. Two similar cases of encephalopathy, possibly a 
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Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in 
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Wistuba II, Heymach JV. Epidermal growth factor receptor regulates MET levels and 
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Zhu AX, Finn RS, Mulcahy M, Gurtler J, Sun W, Schwartz JD, Dalal RP, Joshi A, Hozak RR, 
Xu Y, Ancukiewicz M, Jain RK, Nugent F, Duda DG, Stuart K. A phase II and biomarker 
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Attachment 1.
Protocol JTBF Study Schedule

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Screening/Baseline Assessments
Relative Day Prior to Day 1 of 
Cycle 1
28
14
7
Comments
Informed Consent 
X
Informed consent MUST be signed before performing 
any protocol procedure
Radiological Tumor Assessment
(including head-contrasted CT or 
brain MRI)
X
These scans can be performed locally and may be from 
prior to consent if taken within 28 days of Day 1, Cycle 1.  
PET/CT allowed if CT portion is of diagnostic quality
Chest X-Ray
X
May be omitted in patients having a chest CT for their 
radiological tumor assessment
Functional Tumor Imaging
X
FDG-PET mandatory in Part B1 (gastric).  Further 
functional tumor imaging (including but not limited to 
DCE-MRI, FLT-PET) is permitted in all patients if 
appropriate for the respective tumor type at the discretion 
of the investigator and considered institutional standard of 
care or is part of an appropriate imaging study open at the 
site. 
Hepatitis B and C Screening
X
Screening is required (see Attachment 2); may be from 
prior to consent if done within 6 months of Day1, Cycle 
1; Hepatitis B surface antigen and hepatitis C (antibodies 
or RNA according to local standard)
“Post-Progression Tumor Sample”
(baseline)
X
Mandatory (see Section 10.2.1); may be from prior to 
consent if taken within 8 weeks of Day 1, Cycle 1.  If this 
is not available, patient must undergo a tumor biopsy pre-
study treatment
Archival Tumor Sample
X
Optional (see Section 10.2.2)
Medical History
X
Including alcohol/tobacco use/other relevant habits
Physical Examination
X
Including height and body weight
Vital Signs 
X
Temperature, blood pressure (seated), heart rate, and 
respiration rate
Performance Status
X
Per ECOG scale (see Attachment 6)
CTCAE Version 4.03 Grading 
(Preexisting Conditions)
X
To be reported only after study eligibility is confirmed.  
Refer to Section 10.1.2 for reporting expectations.
Concomitant Medications
X
See Section 9.5
Local 12-Lead Electrocardiogram 
X
Single ECG
Hematology 
X
See Attachment 2
Serum Chemistry including 
calculated creatinine clearance
X
See Attachment 2
Coagulation
X
See Attachment 2
Urinalysis 
X
See Attachment 2
Immunogenicity
X
Sampling for Exploratory Blood
Biomarkers
X
See Section 10.2.2
Serum Pregnancy Test 
X
Negative serum pregnancy test result required prior to 
dosing for women of child-bearing potential

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Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; DCE-
MRI = dynamic contrasted-enhanced magnetic resonance imaging; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; FDG-PET = 2-deoxy-2[F-18]fluoro-D-glucose positron emission tomography; 
FLT-PET = 3-deoxy-3[F-18]fluorothymidine positron emission tomography; PET = positron emission 
tomography; RNA = ribonucleic acid.

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During- and Post-study Assessments  
 
Cycle 1 
Cycle 2 
Cycle 
3–n 
Short Term 
Follow-Up
Visit 801a 
Comments 
Relative Day Within a 
Cycle  
1 
2 
8 
(±1 
day)
15 
(±1 
day)
22 
(±1 
day)
1 
(±2 
days)
8 
(±2 
days)
15 
(±2 
days)
1 
(±3 
days)
15 
(±3 
days)
 
 
Ramucirumab 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
LY2875358 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Physical 
Examination 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
All physical examinations should 
include palpation of the thyroid 
Weight 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Vital Signs  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Temperature, blood pressure (seated), 
heart rate, and respiration rate 
ECOG Performance 
Status 
X 
 
 
 
 
X 
 
 
X 
 
X 
See Attachment 6 
Local 12-Lead ECGb  X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Single ECG at each time point
Hematology c 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Predose (see Attachment 2) 
Serum Chemistryc 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Predose (see Attachment 2) 
Coagulationc 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Predose (see Attachment 2) 
Urinalysisc,d 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Predose (see Attachment 2) 
Pregnancy Test 
 
 
 
 
 
X 
 
 
X 
 
 
Serum or urine.  Females of 
childbearing potential only (see 
Attachment 2) 
Tumor Marker 
X 
 
 
 
 
X 
 
 
X 
 
X 
Depending on the respective tumor type 
(see Attachment 2) 
Hormonal Panel 
(TSH and fT4) 
X 
 
 
 
 
X 
 
 
Xe 
 
X 
See Attachment 2 
CTCAE 
Version 4.03 
Grading 
X 
X 
X 
X 
Collected throughout the study as 
needed.  Refer to Section 10.1.2 for 
reporting expectations  
Concomitant 
Medications 
X 
X 
X 
X 
Throughout study as needed.  See 
Section 9.5 

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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Cycle 1
Cycle 2
Cycle
3–n
Short Term 
Follow-Up
Visit 801a
Comments
Relative Day Within a 
Cycle
1
2
8
(±1
day)
15
(±1
day)
22
(±1
day)
1
(±2
days)
8
(±2
days)
15
(±2
days)
1
(±3
days)
15
(±3
days)
PK and PD 
Samplingf
Refer to Attachment 4 and Attachment 7
Refer to Attachment 4 and Attachment 
7 for details.  No further sampling 
after Cycle 9 but a sample is required 
at short term follow up visit (V801)
Immunogenicityf
X
X
X
X
X
X
See Section 9.2.3.1
Exploratory Blood
Biomarker Sampling
X
X
X
X
X
X
Xe
X
Pharmacogenetic 
Sampling 
X
This is a one-time sample which may 
be taken during Cycles 1 or 2
Optional Tumor 
Biopsy 
X
Throughout study (see Section 10.2.1)
Radiological Tumor 
Assessmentg
X
Every 6 weeks after initiation of study 
treatment; after Cycle 9 every 2-4 
cycles as clinically indicated
Functional Tumor 
Imaging
Xh
FDG-PET mandatory in Part B1 
(gastric) 6 weeks after initiation of 
study therapy
Abbreviations:  CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; DCE-MRI = 
dynamic contrasted-enhanced magnetic resonance imaging; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FDG-PET = 2-deoxy-
2[F-18]fluoro-D-glucose positron emission tomography; FLT-PET = 3-deoxy-3[F-18]fluorothymidine positron emission tomography; fT4 = free thyroxine; 
PD = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; TSH = thyroid-stimulating hormone; V = visit.
a  Short-term follow-up begins on the day after the patient’s last dose of study drug and ends approximately 30 days later.  This visit should be scheduled 30 ± 3 
days after last dose of study drug.  
b
Electrocardiograms must be recorded before any study drug is administered. In Cycle 1, Day 1 and 15 only, additional ECGs must be recorded pre- and post-
LY2875358 infusion, immediately before collecting the corresponding PK samples.  

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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c
Local hematology, coagulation tests, and urinalysis may be done within 2 days prior to administration of study drugs (except Cycle 1, Day 1 [within 3 days]). 
An additional local chemistry panel according to local standard of care may be done and used for on-study dosing decisions; if done so, chemistry testing 
must also still be performed by the central laboratory at the regularly scheduled time points.  The central chemistry laboratory results will be used for patient 
eligibility and subsequent safety analyses. In exceptional cases, patient may be enrolled based on local chemistry results after discussion with the sponsor if 
central laboratory samples results required for eligibility are not available in a timely manner (e.g., due to inclement weather conditions).  
d  If, while receiving the investigational product(s), a patient has proteinuria ≥2+ per a dipstick or routine urinalysis test, a 24-hour urine collection will be 
conducted prior to the subsequent scheduled treatment (see Section 9.2.3.2.2).
e
Samples will be collected at Cycle 3, Cycle 5, Cycle 7, Cycle 9, and every 4 cycles thereafter while patient is on study treatment.  
f
If a patient experiences an infusion-related reaction (see Section 9.2.3.1), immunogenicity samples for anti-ramucirumab and anti-LY2875358 antibodies and 
PK samples will be taken as close to the onset of the event as possible, at the resolution of the event, and approximately 30 days following the event.
g
The method of assessment used at baseline must be used consistently for tumor assessment and will be repeated approximately every 6 weeks (±7 days)
during the study treatment period for lesions outside the CNS.  For those patients with known CNS metastases, ongoing CNS surveillance using the same 
modality is required approximately every 12 weeks (±7 days). Positron emission tomography /CT is allowed if CT portion is of diagnostic quality.
h
For patients in Part B1 (gastric), the mandatory FDG-PET approximately 6 weeks (±7 days) after initiation of study treatment should be performed only if the 
baseline FDG-PET demonstrated PET avid lesion(s).  Further functional tumor imaging (including but not limited to DCE-MRI, FLT-PET) is permitted 
throughout the study in all patients if appropriate for the respective tumor type at the discretion of the investigator and considered as institutional standard of 
care or is part of an appropriate imaging study open at the site.

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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Attachment 2.
Protocol JTBF Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistryd:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Chloride
Neutrophils 
Magnesium
Lymphocytes
Total bilirubin
Monocytes
Alkaline phosphatase
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Aspartate aminotransferase (AST) 
Platelets
Lactate Dehydrogenase (LDH)
Total protein
Coagulation Testsa:
Albumin
Prothrombin time (PT/INR)
Blood urea nitrogen (BUN)
Partial thromboplastin time (PTT)
Creatinine
Uric acid
Urinalysisa:
Calcium
Specific gravity
Glucose, random
pH
C-reactive protein
Proteinb
Cholinesterase (CHE)
Glucose
Ketones
Calculated creatinine clearanced, e
Blood
Urine leukocyte esterase
Hormone paneld
Thyroid stimulating hormone (TSH)
Hepatitis Testsa
Free thyroxine (fT4)
Hepatitis B surface antigen (HBSAg)
Hepatitis C
Tumor markerd
Carcinoembryonic antigen (CEA; all pts)
Pregnancy Test (female patients only)a,c
Alpha Fetoprotein (AFP; HCC pts only)
CA19.9 (gastric cancer pts only)
Abbreviations:  HCC = hepatocellular carcinoma; INR = International Normalized Ratio; pts = patients; RBC = red 
blood cells; WBC = white blood cells; 
a
Local or investigator-designated laboratory.
b   If urine dipstick or routine urinalysis indicates proteinuria ≥2+ at screening and/or while receiving study drugs,
a 24-hour urine collection must be obtained to locally assess urine protein concentrations.
c
For women of child-bearing potential only. Serum test required at screening and within 7 days prior to initiation 
of study treatment. Urine or serum test may be performed prior to treatment at all other time points.
d
Assayed by Lilly-designated laboratory.
e
For screening/baseline assessment only.

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Attachment 3.
Protocol JTBF 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/clinical research scientist.
Hepatic Monitoring Testsa
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
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
ALT
Anti-nuclear antibodya
AST
GGT
Anti-smooth muscle antibodya
CPK 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferease; CPK = creatine
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = International Normalized 
Ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 4.
Protocol JTBF Pharmacokinetic and 
Pharmacodynamic Sampling Schedule
Pharmacokinetic and Pharmacodynamic Sampling Schedule
Study Period
Approximate 
Running 
Time (h)a
Unique 
Sample 
ID
Sample Description
LY2875358
Ram
MET 
ECD
Cycle 1
Day1
0
1
Pre-Ramucirumab Infusion
X
X
X
1
2
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 60 minutes between infusions
2
3
Pre-LY2875358 Infusionb
X
X
3.5
4
End of LY2875358 Infusion (EOI)
X
X
X
6.5
5
3 h Post-LY2875358 EOI
X
X
8.5
6
5 h Post-LY2875358 EOI
X
X
11.5
7
8 h Post-LY2875358 EOI
X
X
Day 2
24
8
21 h Post-LY2875358 EOI
X
X
X
Day 8
168
9
Anytime on Day 8
X
X
X
Day 15
0
10
Pre-Ramucirumab Infusion
X
X
X
1
11
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 60 minutes between infusions
2
12
Pre-LY2875358 Infusionb
X
X
3.5
13
End of LY2875358 Infusion (EOI)
X
X
X
6.5
14
3 h Post-LY2875358 EOI
X
X
8.5
15
5 h Post-LY2875358 EOI
X
X
Day 22
168
16
Anytime on Day 22
X
X
X
Cycle 2
Day 1
0
17
Pre-Ramucirumab Infusion
X
X
X
1
18
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
19
Pre-LY2875358 Infusionb
X
X
3
20
End of LY2875358 Infusion
X
X
X
Day 8
168
21
Anytime on Day 8
X
X
X
Day 15
0
22
Pre-Ramucirumab Infusion
X
X
X
1
23
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
24
Pre-LY2875358 Infusionb
X
X
3
25
End of LY2875358 Infusion
X
X
X

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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Study Period
Approximate 
Running 
Time (h)*
Unique 
Sample 
ID
Sample Description
LY2875358
Ram
MET 
ECD
Cycle 3
Day1
0
26
Pre-Ramucirumab Infusion
X
X
X
1
27
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
28
Pre-LY2875358 Infusionb
X
X
3
29
End of LY2875358 Infusion (EOI)
X
X
X
Day 15
0
30
Pre-Ramucirumab Infusion
X
X
X
1
31
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
32
Pre-LY2875358 Infusionb
X
X
3
33
End of LY2875358 Infusion (EOI)
X
X
X
Cycle 5
Day1
 0
34
Pre-Ramucirumab Infusion
X
X
X
1
35
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
36
Pre-LY2875358 Infusionb
X
X
3
37
End of LY2875358 Infusion (EOI)
X
X
X
Day 15
0
38
Pre-Ramucirumab Infusion
X
X
X
1
39
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
40
Pre-LY2875358 Infusionb
X
X
3
41
End of LY2875358 Infusion (EOI)
X
X
X

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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LY2875358
Study Period
Approximate 
Running
Time (h)*
Unique 
Sample 
ID
Sample Description
LY2875358
Ram
MET 
ECD
Cycle 7
Day1
0
42
Pre-Ramucirumab Infusion
X
X
X
1
43
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
44
Pre-LY2875358 Infusionb
X
X
3
45
End of LY2875358 Infusion (EOI)
X
X
X
Day 15
0
46
Pre-Ramucirumab Infusion
X
X
X
1
47
End of Ramucirumab Infusion
X
X
X
Minimum of approximately 30 minutes between infusions
1.5
48
Pre-LY2875358 Infusionb
X
X
3
49
End of LY2875358 Infusion (EOI)
X
X
X
Cycle 9
Day1
0
50
Pre-Ramucirumab Infusion
X
X
X
1
51
End of Ramucirumab Infusion
X
X
X
Approximately 30 minutes between infusions
1.5
52
Pre-LY2875358 Infusionb
X
X
3
53
End of LY2875358 Infusion (EOI)
X
X
X
Day 15
0
54
Pre-Ramucirumab Infusion
X
X
X
1
55
End of Ramucirumab Infusion
X
X
X
Approximately 30 minutes between infusions
1.5
56
Pre-LY2875358 Infusionb
X
X
3
57
End of LY2875358 Infusion (EOI)
X
X
X
Follow-up Visit 
(Visit 801)
58
Anytime During Follow-up Visit
X
X
X
Abbreviations:  EOI = end of infusion; MET ECD = mesenchymal epithelial transition factor – extracellular cleaved 
domain; Ram= ramucirumab.
a
Approximate running time relative to start of each ramucirumab infusion.
b
Sample should be obtained immediately prior to LY2875358 infusion.
Note: Samples are requested to be taken immediately before and immediately after the end of the study drug
infusions.  Aberrations to specified sampling times will not be considered protocol deviations as long as the 
samples are taken and the actual sampling time is recorded. It is essential that the actual times of ramucirumab 
and LY2875358 doses and samples are recorded accurately on the appropriate forms.

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Attachment 5.
Protocol JTBF Recommendations for 
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events (SAEs)
When contacting Lilly to report a SAE, please have the following information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, and weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalization), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug & Protocol Procedures
Concomitant Drug Therapy

indication, total daily dose, duration of treatment, start date, action taken
In Case of Death

cause, autopsy finding (if available), date, relationship to study drug and protocol 
procedures.

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Attachment 6.
Protocol JTBF 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 performance of a light or sedentary nature, for example,
light housework, 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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Attachment 7.
Protocol JTBF Sampling Summary
This table summarizes the maximum number of samples, average volume amount per sample, 
and laboratory tests to be obtained during the study.  The summary below provides estimates 
only.  More samples could be required in case of retests, additional health monitoring (if 
needed), or for patients continuing treatment beyond the protocol-specified number of cycles in 
the study.  Fewer samples may actually be taken (eg, patients who discontinue from the study).
Protocol I4C-MC-JTBF Sampling Summarya
Purpose
Sample 
Type
Average Amount 
per Sample
Maximum 
Number of 
Samples
Maximum 
Total Amount
Screening Testsb
Blood
6 mL
9
52 mL
Cycle 1 Health Monitoring 
Testsa
Blood
4.5 mL
12
54 mL
Cycle 2 Health Monitoring 
Testsa
Blood
4.5 mL
9
41 mL
Cycle 3-5 Health Monitoring 
Testsa  
Blood
5.0 mL 
9
87 mL 
Visit 801 Health Monitoring 
Testsa
Blood
5.0 mL 
3
16 mL 
Exploratory Biomarkersc
Blood
5.5 mL 
36
203 mL 
Drug Concentration for 
Ramucirumabc
Blood
2 mL
42
84 mL
Drug Concentration for 
LY2875358c
Blood
2 mL
42
84 mL 
Pharmacogenetic Sample
Blood
10
1
10 mL
Immunogenicity (for 
Ramucirumab and 
LY2875358)c
Blood
8.5 mL 
8
68 mL 
MET-ECD 
Blood 
3mL 
29
87 mL 
Hepatic Monitoringc
Blood
3 - 30 mL
-
-
Tumor Biopsy Tissued
Tumor tissue 
FFPE block 
or unstained 
tumor tissue 
slides
N/A
1 FFPE block 
OR 
approximately 
15, 4 micron 
unstained slides
Total 
Blood
788 mL 
Total 
Tissue
1 FFPE block 
OR 
approximately 
15, 4 micron 
unstained slides

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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Abbreviations:  FFPE = formalin-fixed paraffin-embedded; MET-ECD = mesenchymal epithelial transition factor –
extracelluar cleaved domain; N/A = not applicable.
a
Additional samples may be drawn, if needed, for safety purposes.
b
Covers all tests collected at screening.
c   Covers Cycles 1 through 5 and Visit 801.
d   This references only the required mandatory “post-progression tumor sample” collected at baseline.  An optional 
archival biopsy tissue sample and/or optional tumor biopsy sample performed on study and/or at Visit 801 may 
also be collected.

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Attachment 8.
Protocol JTBF RECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST):  Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).  
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis,  inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:  

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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Cystic lesions:  

Simple cysts should not be considered as malignant lesions (neither measurable 
nor nonmeasurable) 

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability.  If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated at a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion.  
Baseline Documentation of Target and Non-Target Lesion
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. Non-nodal Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements..  
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of 15 mm by 
CT scan.  All measurements are to be recorded in the CRF in millimeters (or decimal fractions of 
centimeters ).
Nontarget Lesions
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline.  Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’  In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (eg, multiple liver metastases recorded as one liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.  
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient.  If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and follow-
up should be guided by the tumour type under investigation and the anatomic location of the 
disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion is recommended.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may be reviewed at the 
end of the study.
Chest X-ray:  Chest CT is preferred over chest X-ray when progression is an important endpoint.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
CT and MRI:  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm.  When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (for example, for body scans).  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.  
Ultrasound:  Ultrasound should not be used to measure lesion size.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  Specific guidelines for both prostate-specific antigen (PSA) response 
(in recurrent prostate cancer) and CA-125 response (in recurrent ovarian cancer) have been 
published.  

14C-MC-JTBF(b) Phase 1 Oncology Protocol
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Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete response (CR) in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease (PD). 
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment.  If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan. 
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected. 
Response Criteria
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of one or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response.
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).

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Non-CR/ non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable:  When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.  
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline.
Table 1.
Time Point Response: Patients with Target (Nontarget) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease.; PD = progressive disease; NE 
= inevaluable. 
Table 2 is to be used when patients have nonmeasurable disease only.

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

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

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Attachment 9.
Protocol Amendment I4C-MC-JTBF(b) 
Summary:  A Phase 1b/2 Study of Ramucirumab in 
Combination with LY2875358 in Patients with Advanced 
Cancer
Overview
The overall changes and rationale for the changes made to this protocol are as follows:

The primary rationale for amendment (b) is to is to modify Exclusion Criterion [28] 
and allow patients that have been previously treated with ramucirumab may be 
included in Part B1.

Updated Sections 5.2.1 and 5.2.1.2 (ramucirumab clinical information)

Updated Section 5.2.2 (LY2875358 clinical information)

Modified Section 9.2.3 (dosage adjustments and delays) to align with discontinuation 
criteria

Clarified Section 9.5 (use of granulocyte colony stimulating factor)

Corrected Section 12.1 (approximately 70 patients may be enrolled in this multicenter 
Phase 1b/2 study)

Minor editorial changes have been made throughout the protocol to improve clarity 
and practicability of the protocol.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
5.2.1.  Ramucirumab
Ramucirumab has been studied and/or continues to be investigated in ongoing clinical studies for 
multiple tumor indications.  As of 31 December 2012, safety information was available for 1199 
patients receiving ramucirumab in 7 Phase 1/1b studies, 16 open-label Phase 2 studies, and 1 
Phase 3 study, including monotherapy and combination therapy with cytotoxic chemotherapy 
agents.  In these studies, ramucirumab has demonstrated a favorable safety and clinical activity 
profile.  The most frequently observed possibly related treatment-emergent adverse events 
(TEAEs) of special interest include adverse events (AEs) which have been associated with anti-
angiogenic agents and therapeutic mAbs, and include the following categories:  infusion-related 
reaction, hypertension, proteinuria, arterial thromboembolic events (ATEs), venous 
thromboembolic events (VTEs), bleeding/hemorrhagic events, gastrointestinal (GI) perforation, 
impaired wound healing, reversible posterior leukoencephalopathy syndrome (RPLS), and 
congestive heart failure (CHF) in patients who received ramucirumab following prior 
anthracycline therapy.  
Data from Phase 1, 2, and 3 studies provide supporting evidence for ramucirumab activity in 
advanced solid tumors, including gastric or GEJ adenocarcinoma, hepatocellular carcinoma, 
renal cell cancer, and NSCLC.
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 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, and in 
combination with docetaxel as a treatment for people with metastatic NSCLC whose cancer has 
progressed on or after platinum-based chemotherapy.  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.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of ramucirumab may be found in the IB.  Information on AEs expected to 
be related to ramucirumab may be found in Section 7 (Development Core Safety Information 
[DCSI]) of the IB.  Information on serious adverse events (SAEs) expected in the study 

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population independent of drug exposure and that will be assessed by the sponsor in aggregate, 
periodically during the course of the study, may be found in Section 6 (Effects in Humans) of the 
IB.
5.2.1.2  Ramucirumab and Hepatocellular Cancer
A randomized, controlled Phase 3 trial of ramucirumab monotherapy versus placebo in a second-
line setting (post-sorafenib) for advanced hepatocellular carcinoma is currently ongoing 
(NCT01140347).
A randomized, controlled Phase 3 trial (Study I4T-IE-JVBF; Study JVBF, also known as 
REACH) of ramucirumab monotherapy versus placebo in a second-line setting (post-sorafenib) 
for advanced HCC is currently ongoing (NCT01140347).  Study JVBF is a global, randomized, 
double-blind Phase 3 study of ramucirumab plus BSC compared to placebo and BSC as a 
second-line treatment in patients with HCC who have been previously treated with sorafenib in 
the first-line setting.  The study did not meet its primary endpoint of OS; although the OS results 
favored the ramucirumab arm, they were not statistically significant.  Encouraging single-agent 
ramucirumab activity was observed, with meaningful improvements in key secondary endpoints 
of PFS, objective response rate (ORR), and time to progression (TTP).
5.2.2.  LY2875358
As of 1918 March 20132014, cumulatively 83184 subjects have received LY2875358 in the 26
ongoing clinical trials, Studies JTBA and JTBDincluding 123 patients receiving LY2875358 
monotherapy.  No dose-limiting toxicities (DLTs) have been reported for either LY2875358 
monotherapy or for combination therapy with erlotinib in these studies.in the dose escalation 
Studies JTBA and JTBD.  The most frequently reported treatment-emergent adverse events 
(TEAEs) possibly related to LY2875358 monotherapy in Study JTBA (N=60 patients) 
includedacross all studies within the LY2875358 clinical program include fatigue (1316.3%),
nausea (9.8.3%), diarrhea (5.0%), and vomiting (5.0%) (all Grade 1 7%), and 2).  In this study, 3 
Grade 3 AEs were consideredperipheral edema (5.7%).  A total of 7 possibly related toTEAEs 
(≥Grade 3) for LY2875358:  edema, monotherapy were reported:  2 events of fatigue, and 1 
event each of peripheral edema, pancreatitis.  In Study JTBD (N=9 patients), the only AE that 
study investigators have considered possibly related to LY2875358 monotherapy in >1 patient 
was hypoalbuminemia (n=2; 1 Grade 1 and 1 Grade 2).  In this study, 1 Grade 3 AE was 
considered possibly related to LY2875358: , anemia., nausea, and hyponatremia.  A total of 45 
serious adverse events (87 SAEs) have been reported in the Lilly Safety System (LSS) database 
in Studies JTBA and JTBD as of 1918 March 20132014.  Of these SAEs, 5 were considered 
possibly related to LY2875358 by either the investigator or the sponsor, including 1 event each 
of thrombocytopenia, pancreatitis, dyspnea, pyrexia, and pleural effusion in a patient with non-
small cell lung cancer (NSCLC) and 2 events of peripheral edema in patientsa patient with pre-
existing edema. 
Study JTBA has been amended and is currently enrolling patients in 5 different tumor-specific 
expansion cohorts for dose confirmation of LY2875358 monotherapy at 2000 mg Q2W, 
including cohorts for renal cancer and hepatocellular carcinomaHCC patients (approximately 15 

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patients each).  In the renal cell cancer cohort, 3 out of 15 evaluable patients demonstrated SD as 
their best response, including a papillary renal cancer patient who has been on study for 12 
months as of October 2013 (data on file).  A furtherFurther durable, confirmed PRPRs for 
LY2875358 monotherapy hashave been observed in a patient enrolled in the HCC cohort and for 
a patient in the uveal melanoma with liver metastases cohort.  No data are so far available for 
LY2875358 monotherapy in hepatocellular carcinoma and gastric cancer patients, as the 
respective expansion cohort for hepatocellular carcinoma in JTBA and an Asian gastric cancer 
patient study for LY2875358 monotherapy (Study I4C-JE-JTBE) have been opened only 
recentlyis pending analysis.  
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) for ramucirumab and LY2875358 may be found in the respective molecule 
IBs.  Information on AEs expected to be related to the investigational products may be found in 
Section 7 (Development Core Safety Information [DCSI]) of the respective IBs.  Information on 
SAEs expected in the study population independent of drug exposure and that will be assessed 
by the sponsor in aggregate, periodically during the course of the study, may be found in Section 
6 (Effects in Humans) of the respective IBs. 
5.3.2.  Rationale for Amendment (b)
The rationale for amendment (b) is to modify Exclusion Criterion [28] and allow patients 
previously treated with ramucirumab to enroll in Part B1 (Gastric or GEJ adenocarcinoma) and 
Part B4 (NSCLC) cohorts reflecting the approval of ramucirumab for those tumors since 
initiation of the study.  
Minor editorial changes have been made throughout the protocol to improve clarity and 
practicability of the protocol, secure alignment with the intended study design, and update 
information available for study drugs.
7.2.  Exclusion Criteria
[28]    Have received previous treatment with ramucirumab or LY2875358, except 
for patients enrolled in Cohort B1 (Gastric or GEJ adenocarcinoma) and B4 
(NSCLC) who may have received previous ramucirumab treatment.  
9.2.3.  Dose Adjustments and Delays
In case the toxicity is specifically attributable to 1 of the 2 experimental study drugs in the 
opinion of the investigator (eg, ramucirumab-related hypertension), the patient may continue to 
receive the other study drug following the regularly scheduled Q2W treatment time points (eg,
LY2875358). In this setting, treatment of the withheld study drug (eg, ramucirumab) should be 
resumed at the next regularly scheduled Q2W treatment time point of the continued study drug 
(eg, LY2875358) following the resolution of the event causing the hold.  Make-up doses of the 
withheld study drug occurring between regularly scheduled Q2W treatment time points are not 
permitted in order to keep the administration of both study drugs synchronized to the same study 
days (ie, Day 1 or 15 of a cycle). In situations where >2 consecutive doses have been missed, 
events related to the missed doses have resolved, and there is evidence of ongoing disease 

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control, continuation of ramucirumab and/or LY2875358 may be considered and must be 
discussed with the Lilly clinical team.
9.5.  Concomitant Therapy
Patients should receive full supportive care, with the exception that the.  The routine use of 
granulocyte colony stimulating factors (G-CSF) is not permitted during this study. Patients 
should not receive G-CSF prophylactically in any cycle.  Granulocyte colony stimulating factors 
may only be used for patients who have absolute neutrophil count <0.5 109, neutropenic fever, 
or documented infections while neutropenic.  Granulocyte colony stimulating factors or 
pegylated G-CSF must be discontinued at least 24 hours or 1 week before the start of the next 
cycle of treatment, respectively.  If clinically indicated, the use of G-CSF is permitted during 
investigational therapy at the discretion of the investigator.  G-CSF or similar agents are 
recommended following Grade 3 or 4 neutropenia of duration >5 days or following any 
incidence of febrile neutropenia (ANC <1.0 × 109/L with temperature ≥38.5°C).
12.1.  General Considerations
Up to approximately 5570 patients may be enrolled in this multicenter Phase 1b/2 study with an 
open-label, dose escalation design. Patients will be enrolled into cohorts sequentially without 
randomization to dose level. During dose escalation (Part A), the total samples size per cohort 
will be determined by DLTs (up to 6 patients per cohort before establishing the MTD). For the 
tumor-specific expansion cohorts (Part B), additional patients will be enrolled within 3 cohorts 
for specified tumor types (approximately 15 patients per group). The sample size of 
approximately 15 patients for the tumor-specific expansion cohorts was selected to allow 
adequate assessment of safety at the recommended dose and to identify evidence of activity 
worthy of further investigation in Phase 2.

Leo Document ID = bb87f68c-a79e-4ea1-9ced-9d0e3d706a73
Approver: 
Approval Date & Time: 12-Mar-2015 16:06:58 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-Mar-2015 10:35:44 GMT
Signature meaning: Approved
PPD
PPD