A Phase 1 Study of LY3127804 as Monotherapy and in Combination With Ramucirumab in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: Eli Lilly and Company

Protocol I7W-MC-JQBA(d) 
 
 
A Phase 1 Study of LY3127804 as Monotherapy and in Combination with Ramucirumab in Patients 
with Advanced Solid Tumors 
 
 
NCT02597036 
 
 
Approval Date: 11-Sep-2017 
 
 

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1.
Protocol I7W-MC-JQBA(d)
A Phase 1 Study of LY3127804 as Monotherapy and in 
Combination with Ramucirumab in Patients with 
Advanced Solid Tumors
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 
LY3127804, 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 Exemption 4.
LY3127804
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study,
potentially followed by dose expansion of intravenous LY3127804 administered as 
monotherapy and in combination with ramucirumab (dependent on the safety and 
tolerability data under monotherapy) in patients with advanced solid tumors who have failed 
standard therapy or for whom no standard therapy is available.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 29 July 2015
Amendment (a) Electronically Signed and Approved by Lilly:  06 September 2015 
Amendment (b) Electronically Signed and Approved by Lilly: 14 December 2015
Amendment (c) Electronically Signed and Approved by Lilly: 29 July 2016                                 
Amendment (d) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 11-Sep-2017 GMT

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2.
Synopsis
This Phase 1 first-in-human study is a multicenter, nonrandomized, open-label, dose-escalation 
study of intravenous LY3127804 in patients with advanced or metastatic solid tumors who have 
failed standard of care or for whom no standard of care is available. Study I7W-MC-JQBA 
(JQBA) will determine a recommended dose range and schedule for LY3127804 that may be 
safely administered as monotherapy and in combination with ramucirumab. The study will 
consist of a dose escalation for LY3127804 monotherapy (Part A) and combinations with 
ramucirumab (Parts B and C).

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3.
Table of Contents
A Phase 1 Study of LY3127804 as Monotherapy and in 
Combination with Ramucirumab in Patients with Advanced 
Solid Tumors
Section
Page
1.
Protocol I7W-MC-JQBA(d)  A Phase 1 Study of LY3127804 as 
Monotherapy and in Combination with Ramucirumab in Patients 
with Advanced Solid Tumors..............................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................3
4.
Abbreviations and Definitions...........................................................................................10
5.
Introduction ......................................................................................................................15
5.1.
Rationale and Justification for the Study ......................................................................15
5.1.1.
Rationale for Protocol Amendment (a).................................................................18
5.1.2.
Rationale for Protocol Amendment (b).................................................................18
5.1.3.
Rationale for Protocol Amendment (c).................................................................18
5.1.4.
Rationale for Protocol Amendment (d).................................................................19
5.2.
Objectives ....................................................................................................................19
5.2.1.
Primary Objective ................................................................................................19
5.2.2.
Secondary Objectives...........................................................................................19
5.2.3.
Exploratory Objectives.........................................................................................20
5.3.
General Introduction to LY3127804.............................................................................20
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................20
5.3.2.
Nonclinical Toxicokinetics...................................................................................21
5.3.3.
Nonclinical Toxicology........................................................................................21
5.4.
Ramucirumab...............................................................................................................23
5.5.
Rationale for Selection of Dose....................................................................................24
5.5.1.
LY3127804 Dose.................................................................................................24
5.5.2.
Ramucirumab Dose..............................................................................................26
6.
Investigational Plan...........................................................................................................28
6.1.
Study Population..........................................................................................................28
6.1.1.
Inclusion Criteria .................................................................................................28
6.1.2.
Exclusion Criteria ................................................................................................30

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6.2.
Summary of Study Design............................................................................................33
6.2.1.
Sample Size .........................................................................................................35
6.2.2.
Study Completion and End of Trial......................................................................36
6.2.3.
Continued Access Period......................................................................................36
6.3.
Discontinuations ..........................................................................................................37
6.3.1.
Discontinuation of Patients...................................................................................37
6.3.2.
Discontinuation of Study Sites .............................................................................38
6.3.3.
Discontinuation of the Study................................................................................38
7.
Treatment..........................................................................................................................39
7.1.
Materials and Supplies .................................................................................................39
7.1.1.
LY3127804..........................................................................................................39
7.1.2.
Ramucirumab.......................................................................................................39
7.2.
Study Drug Administration ..........................................................................................39
7.2.1.
Dosing Schedule ..................................................................................................40
7.2.1.1.
LY3127804 Dosing ........................................................................................40
7.2.1.2.
Ramucirumab Dosing .....................................................................................41
7.2.2.
Dose Escalation....................................................................................................42
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................44
7.2.2.2.
Dose-Escalation Method for LY3127804 monotherapy in 
Part A.............................................................................................................45
7.2.2.3.
Dose-Exploration Method for LY3227804 + 
ramucirumab in Parts B and C ........................................................................46
7.2.2.4.
Biologically Effective Dose Range .................................................................46
7.2.2.5.
Dose Adjustments and Delays ........................................................................46
7.2.2.6.
Dose Modifications—LY3127804 ..................................................................47
7.2.2.7.
Dose Modifications—Ramucirumab...............................................................48
7.2.2.8.
Infusion-Related Reactions.............................................................................51
7.2.2.9.
Hypertension ..................................................................................................54
7.3.
Method of Assignment to Treatment ............................................................................54
7.4.
Blinding .......................................................................................................................55
7.5.
Concomitant Therapy...................................................................................................55
7.6.
Treatment Compliance .................................................................................................56
7.6.1.
Evaluable Patients................................................................................................56
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................58
8.1.
Safety Evaluations........................................................................................................58
8.1.1.
Safety Data Collection and Review ......................................................................58
8.1.2.
Adverse Events ....................................................................................................58

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8.1.2.1.
Serious Adverse Events ..................................................................................60
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................61
8.1.2.2.1.
Prior to Administration of Study Drug(s) ..................................................61
8.1.2.2.2.
On Therapy...............................................................................................61
8.1.2.2.3.
Follow-Up Visit........................................................................................61
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................62
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................62
8.1.3.
Other Safety Measures .........................................................................................63
8.1.3.1.
Electrocardiograms.........................................................................................63
8.1.3.2.
Thyroid Function............................................................................................64
8.1.4.
Safety Monitoring ................................................................................................64
8.1.5.
Complaint Handling.............................................................................................65
8.2.
Sample Collection and Testing.....................................................................................65
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................65
8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics..................................................................66
8.2.2.1.
Pharmacokinetic Samples...............................................................................66
8.2.2.2.
Pharmacodynamic Samples ............................................................................66
8.2.3.
Samples for Biomarker Research..........................................................................67
8.2.4.
Samples for Immunogenicity Research.................................................................68
8.3.
Efficacy Evaluations ....................................................................................................68
8.4.
Procedure/Sampling Compliance..................................................................................69
9.
Data Management Methods...............................................................................................70
9.1.
Data Quality Assurance................................................................................................70
9.2.
Data Capture Systems ..................................................................................................70
9.2.1.
Case Report Form ................................................................................................70
10.
Data Analyses...................................................................................................................71
10.1. General Considerations ................................................................................................71
10.2. Patient Disposition .......................................................................................................71
10.3. Patient Characteristics ..................................................................................................71
10.4. Safety Analyses............................................................................................................72
10.5. Pharmacokinetic Analyses............................................................................................72
10.6. Pharmacodynamic Analyses.........................................................................................73
10.7. Pharmacokinetic/Pharmacodynamic Analyses..............................................................73
10.8. Immunogenicity...........................................................................................................73
10.9. Efficacy........................................................................................................................73
10.10. Safety Reviews and Interim Analyses...........................................................................73
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................75

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11.1. Informed Consent.........................................................................................................75
11.2. Ethical Review.............................................................................................................75
11.3. Regulatory Considerations ...........................................................................................75
11.3.1.
Investigator Information.......................................................................................76
11.3.2.
Protocol Signatures ..............................................................................................76
11.3.3.
Final Report Signature .........................................................................................76
12.
References ........................................................................................................................77

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List of Figures
Figure
Page
Figure JQBA.5.1.Ang2 promotes sprouting angiogenesis induced by angiogenic growth 
factors (eg, VEGF). .......................................................................................16
Figure JQBA.5.2.Allometric scaling..........................................................................................24
Figure JQBA.6.1.Study design..................................................................................................33
Figure JQBA.6.2.Study JQBA Parts A to C design:  dose-escalation monotherapy and 
exploratory combination cohorts with ramucirumab.......................................35

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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JQBA Study Schedule .....................................................................80
Attachment 2.
Protocol JQBA Clinical Laboratory Tests ......................................................86
Attachment 3.
Protocol JQBA Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................88
Attachment 4.
Protocol JQBA Pharmacokinetic and Pharmacodynamic Sampling 
Schedule........................................................................................................89
Attachment 5.
Protocol JQBA Recommendations for Reporting 
Serious Adverse Events .................................................................................91
Attachment 6.
Protocol JQBA ECOG Performance Status....................................................92
Attachment 7.
Protocol JQBA Creatinine Clearance Formula ...............................................93
Attachment 8.
Protocol JQBA Sampling Summary...............................................................94
Attachment 9.
Protocol JQBA RECIST Criteria 1.1..............................................................95
Attachment 10.
Protocol JQBA Child-Pugh Score................................................................102
Attachment 11.
Protocol JQBA Protocol Amendment I7W-MC-JQBA(d) Summary
A Phase 1 Study of LY3127804 as Monotherapy and in Combination 
with Ramucirumab in Patients with Advanced Solid Tumors.......................103

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4.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
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.
AFP
alpha-fetoprotein
ALT
alanine aminotransferase
ANC
absolute neutrophil count
Ang1/Ang2
angiopoietin 1/2
assent
agreement from a minor or other individual who is not legally capable of 
providing consent, but who can understand the circumstances and potential risks 
involved in participating in a study (required by some Institutional Review 
Boards [IRBs]/ethical review boards [ERBs]).  
AST
aspartate aminotransferase
AUC(-ss)
area under the concentration versus time curve during a dosing interval at steady 
state
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to last 
measurable plasma concentration
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)
BIW
twice a week 
BP
blood pressure
CI
confidence interval
Cmax
maximum observed drug concentration
Cmin
minimal concentration over the dosing interval

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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
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
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCE-MRI
dynamic contrast-enhanced magnetic resonance imaging
DCSI
Development Core Safety Information
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of trial
End of trial is the date of the last visit/study contact or last scheduled procedure 
for the last patient last visit.
enroll
patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least 1 dose of study treatment
enter
patients who are entered in the trial are those who have signed the informed 
consent form directly or through their legally acceptable representatives

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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
FFPE
formalin-fixed paraffin-embedded
GCP
good clinical practice
GEJ
gastro-esophageal junction
GnRH
gonadotropin-releasing hormone
HCC
hepatocellular carcinoma
HED
human equivalent dose
HIV
human immunodeficiency virus
IB
investigator’s brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
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.
INR
international normalized ratio
interim analysis
an analysis of clinical study data that is conducted before the final reporting 
database is authorized for data lock
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 
Lilly Safety System
global safety database that tracks and reports serious adverse and spontaneous 
events occurring while using a drug/drug delivery system
mAb
monoclonal antibody

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monitor
a person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local standard operating procedures (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
N
number of patients
NCI
National Cancer Institute
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect level
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
objective response rate
OS
overall survival
patient
a subject with a defined disease
PD
pharmacodynamic
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
Q2W
every 2 weeks
QTcF
corrected QT interval using Fridericia’s correction
QW
weekly
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
a point-in-time copy of the collection database.  The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data.
rescreen
to screen a patient who was previously declared a screen failure for the same 
study

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RP2D
recommended Phase 2 dose
RR
respiratory 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
screen failure
a patient who does not meet one or more criteria required for participation in a 
trial
SOC
standard of care
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 after all parts (Parts A, B, and C) are 
complete. The dose-escalation and exploration phases of the study (Parts A, B, 
and C) will be considered complete after all patients required to determine the 
RP2D for LY3127804 have completed DLT treatment-observation period and 
the patients in Part C have completed 4 cycles of study therapy or discontinued 
from the treatment (last patient).
SUSAR
suspected unexpected serious adverse reaction
% ΔT/ΔC 
% of treated tumor volume difference from baseline/control tumor volume 
difference from baseline
t1/2
half-life
T4
thyroxine
Tie2
tunica interna endothelial tyrosine kinase 2
TPO
third-party organization
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
VEGF/VEGFR
vascular endothelial growth factor/vascular endothelial growth factor receptor

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A Phase 1 Study of LY3127804 as Monotherapy and in 
Combination with Ramucirumab in Patients with Advanced 
Solid Tumors
5.
Introduction
5.1.
Rationale and Justification for the Study
Angiogenesis, the growth of new blood vessels, has been widely accepted to play a pivotal role 
in tumor growth, propagation, and metastasis.  Anti-angiogenic therapy has become the focus of 
therapeutic interventions, which led to the approval of several therapies targeting vascular 
endothelial growth factor (VEGF)/vascular endothelial growth factor-receptor 2 (VEGFR2)
pathways. Anti-VEGF pathway therapies primarily target immature blood vessels in tumors. 
However, emerging approaches to combine anti–VEGF/VEGFR2 therapies with therapies
impacting the different stages of remodeling and vessel maturation are expected to improve 
clinical efficacy by expanding the target vessel population (Gerald et al. 2013). The ligands of 
vascular receptor tunica interna endothelial tyrosine kinase 2 (Tie2), angiopoietin1 (Ang1), and 
angiopoietin 2 (Ang2), play an important role in remodeling of tumor vasculature. Ang1 is 
produced by periendothelial cells including pericytes, to act in a paracrine manner; whereas 
Ang2 is produced by vascular endothelial cells and acts on endothelial cells in an autocrine 
manner (Scharpfenecker et al. 2005).  Ang1- and Tie2-deficient mice die in mid gestation 
because of perturbed vessel remodeling and maturation. The phenotypic similarity between 
Ang1 ligand and Tie2 receptor-deficient mice suggests Ang1 to be an agonistic ligand for Tie2 
(Dumont et al. 1994; Suri et al. 1996). Ang2 overexpressing transgenic mice phenocopy the 
mid-gestational embryonic lethal phenotype of Ang1-deficient mice inferring the antagonistic 
mode of action of Ang2 (Gerald et al. 2013). Ang2 promotes tumor angiogenesis and growth by 
destabilizing the Tie2-expressing vasculature enhancing the endothelial cells response to 
angiogenic stimuli such as VEGF (Figure JQBA.5.1) and by induction of Tie2-independent 
integrin-mediated sprouting tip cell migration (Scharpfenecker et al. 2005; Felcht et al. 2012).

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Abbreviations:  Ang2 = angiopoietin 2; VEGF = vascular endothelial growth factor.
Figure JQBA.5.1.
Ang2 promotes sprouting angiogenesis induced by angiogenic 
growth factors (eg, VEGF).  
Ang1 and Ang2 have been identified to exert opposing functions during vessel development, but 
recently Daly et al (Daly et al. 2013) also proposed the model wherein Ang2 functions to activate 
Tie2 signaling, particularly in endothelial cells that are not exposed to significant levels of 
pericyte-derived Ang1 (likely the majority of tumor endothelial cells). Thus, Ang2 can act on 
Tie2 at disparate ends of the angiogenesis process, both to initiate sprouting in a quiescent 
pericyte-covered vessel and to provide a weak survival activity in phases of angiogenesis prior to 
pericyte recruitment. As a hallmark of activated endothelium engaged in ongoing angiogenesis, 
Ang2 is a poor prognostic factor and is upregulated in several tumor types including colon, 
gastric, lung, and breast carcinoma correlating with disease progression and metastasis (Etoh et 
al. 2001; Sfiligoi et al. 2003; Ochiumi et al. 2004; Andersen et al. 2011). Ang2 has also been 
shown to promote pulmonary metastasis (in mice [Mazzieri et al. 2011]), and an increased 
expression of Ang2 has been observed in metastatic tumors as compared to primary tumors 
(Rigamonti and De Palma 2013).  Several Ang2 pathway inhibitors, both small and large 
molecules, have significantly inhibited tumor growth in several preclinical tumor models. 
Combined inhibition of Ang2 and VEGF pathways has greater efficacy than monotherapy in 
preclinical models (Brown et al. 2010; Hashizume et al. 2010; Koh et al. 2010). In addition to 
the anti-angiogenic effect, Ang2 inhibitors also limit metastatic growth (Mazzieri et al. 2011; 
Srivastava et al. 2014).  
Currently, there are several molecules targeting the Ang2 pathway in early to advanced clinical 
trials (Gerald et al. 2013). Amgen’s Ang1/2 blocker, trebananib (formerly known as AMG 386), 
is a peptide-Fc fusion protein that blocks Ang1 and Ang2 binding to Tie2. Previous experience 
with AMG 386 indicated that combination therapies in advanced solid tumors were tolerated and 
that there were no interactions affecting the pharmacokinetic (PK) profiles of either AMG 386 or 
the other drugs (Hong et al. 2008).  The most common adverse effects associated with AMG 386 
plus bevacizumab (N=25), AMG 386 plus motesanib (AMG 706, an antagonist of VEGF 
receptors; [N=11]), and AMG 386 plus sorafenib (N=10) were diarrhea, hypertension, weight 

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5.1.4. Rationale for Protocol Amendment (d)
The Sponsor implemented amendment (d) in order to eliminate Parts D and E from the current
study protocol and to clarify that LY3127804 at a dose of 27 mg/kg was tested as monotherapy 
(Part A) and as combination therapy with ramucirumab (Part B).
The rationale for the elimination of Parts D and E was based on the following: (i) based on 
Lilly’s current oncology portfolio strategies, it was concluded that combining paclitaxel with 
LY3127804 for treating second-line gastric cancer was no longer desired to be investigated in 
this particular study. Other regimens will be used to treat second-line gastric cancer in the 
foreseeable future, ii) the primary and secondary end points of this study were reached, and (iii) 
information collected from Parts A, B, and C (fully enrolled and ongoing as of August 21, 2017) 
was considered sufficient to conclude the primary objective of the study and to answer all 
scientific questions. Therefore, further accrual of patients was not required.
5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to determine a recommended Phase 2 dose (RP2D) range 
and schedule of LY3127804, as monotherapy and in combination with ramucirumab that may be 
safely administered to patients with advanced solid tumors.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3127804 as monotherapy
and in combination with ramucirumab.

to assess the maximum tolerated dose (MTD) of LY3127804 monotherapy
and in combination with ramucirumab based on the dose-limiting toxicity
(DLT), if applicable.

to assess the PK parameters of LY3127804 monotherapy and when
administered in combination with ramucirumab.

to assess limited PK (peak and trough concentration) of ramucirumab when
given in combination with LY3127804.

to evaluate the incidence and level of antibodies against LY3127804
(anti-drug antibodies [ADAs]) and ramucirumab.

to document any antitumor activity of LY3127804 as monotherapy and in
combination with ramucirumab.

to estimate PFS of LY3127804 monotherapy and when given in combination
with ramucirumab.

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5.2.3. Exploratory Objectives

to evaluate tumor tissue, blood, and DNA for biomarkers related to the gene
and gene products associated with mechanism of action of LY3127804,
Tie2-Ang2-Ang1, and VEGF-signaling pathway and the tumor biology of the
respective tumor types enrolled in the study, which may include but are not
necessarily limited to tumor expression (eg, Ang-2, Tie-2, Tie-1,VEGFR-2)
and circulating biomarker (eg, Ang-2, Ang-1, s-Tie-2, VEGF-A) and their
potential association with the objectives of the study (including PK/PD
biomarker relationship)

to explore biological activity of LY3127804 as monotherapy and when given
in combination with ramucirumab based on dynamic contrast-enhanced
magnetic resonance imaging (DCE-MRI)
5.3.
General Introduction to LY3127804
Detailed information about the characteristics of LY3127804 and the known and expected 
benefits and risks of LY3127804 may be found in the most recent version of the investigator’s 
brochure (IB).
5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
LY3127804 is a humanized IgG4 mAb that targets Ang2 ligand. LY3127804 was selected for 
having high-affinity binding to Ang2 and for blocking the binding of human Ang2 to human 
Tie2-Fc in a dose-dependent manner with a half-maximal inhibitory concentration (IC50) of 
0.0268 nM (95% confidence interval [CI]: 0.00089-0.8029). LY3127804 neutralizes the 
Ang2-induced phospho-Tie2 in CHO-Tie2 cells dose dependently with an IC50 of 0.773 nM 
(95% CI: 0.412-1.450).
The in vivo inhibition of blood vessel development in the mouse retina was used to study the 
evidence for repression of developmental angiogenesis by LY3127804. The results showed that 
LY3127804 similarly repressed vascular progression, reduced the number of endothelial tip cells
and the vascular density while increasing the pericyte coverage, at 3 mg/kg, 10 mg/kg, and 
30 mg/kg.
The antiangiogenic effect of DC101 (anti-mouse VEGFR-2, murine surrogate of ramucirumab), 
LY3127804, and the combination was assessed in mice bearing PC3 (prostate) xenograft tumors.  
Animals bearing PC3 xenograft tumors at approximately 250 mm3 volume were either dosed 
with control immunoglobulin G 1 (IgG1), DC101, LY3127804, DC101+ LY3127804, or 
LSN3150895 (DC101-Ang2 bispecific antibody) for 6 days twice a week (BIW); and the tumors 
were collected, fixed, sectioned, and stained for CD105/endoglin (upregulated in actively 
proliferating endothelial cells; Nassiri et al. 2011) to determine the total vessel area.  Overall 
total vessel area was reduced by 65% with DC101 (p<.0001), 69% with LY3127804 (p<.0001), 
84% with the DC101 + LY3127804 combination (p<.0001), and 84% with LSN3150895 
(p<.0001).

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LY3127804
The antitumor efficacy of DC101, LY3127804, and its combination was further assessed in 
multiple in vivo xenograft models, including the triple-negative orthotopic breast cancer model 
(MDA-MB-231-MET2), subcutaneous triple-negative patient-derived breast cancer model
(TNBC PDX), and subcutaneous ovarian xenograft model (SKOV3x.1).  Antibodies were 
administered BIW for 4 consecutive weeks by intraperitoneal injection, and SOC was 
administered weekly (QW) for 4 consecutive weeks by either intraperitoneal or intravenous (IV) 
injection after tumors reached 250 to 400 mm3 in volume.  The impact on tumor growth was 
determined by 3-dimensional caliper measurements of the tumor volumes BIW during the course 
of treatment.  The results from these assessments are summarized below.  
Immuno-deficient mice bearing MDA-MB-231-MET2 breast xenografts orthotopically in 
mammary fat pad were treated with either vehicle control, DC101, LSN3052473 (unoptimized 
earlier version of LY3127804, specific and cross-reactive to human/mouse/rat Ang2), or the 
combination of DC101 + LSN3052473 antibody.  The combination of DC101 with LSN3052473 
and DC101 alone resulted in tumor regression by 61% and 63%, respectively.  LSN3052473 
alone resulted in a % ΔT/ΔC (% of treated tumor volume difference from baseline/control tumor 
volume difference from baseline) of 24%.  The OS of vehicle treatment and DC101 alone were 
similar.  Anti-Ang2 Ab (LSN3052473) and the combination with DC101 improved the OS
compared to vehicle or DC101 alone.
Immuno-deficient mice bearing EL1997 triple-negative breast patient–derived xenografts 
(TNBC PDX) were treated with either vehicle control; DC101; LY3127804; cyclophosphamide 
+ doxorubicin; the combination of DC101 and LY3127804; or the combination of 
cyclophosphamide + doxorubicin, DC101, and LY3127804 BIW for 4 consecutive weeks.  The 
combination of DC101 and LY3127804 resulted in ΔT/ΔC of 19.9% compared to ΔT/ΔC of 
35.2% for DC101 and 56.7% for LY3127804 alone.  The combination of cyclophosphamide, 
doxorubicin, DC101, and LY3127804 resulted in ΔT/ΔC of 0.4% compared to ΔT/ΔC of 32% 
for the combination of cyclophosphamide and doxorubicin.  
5.3.2. Nonclinical Toxicokinetics
LY3127804 toxicokinetics were evaluated in rats and monkeys following 5-weekly IV 
administrations of LY3127804.  In both studies, increases in dose demonstrated roughly 
proportional increases in exposure, and there were no exposure differences between males and 
females.  Elimination half-lives in monkeys were 281 and 248 hours for males and females, 
respectively.
5.3.3. Nonclinical Toxicology
The nonclinical safety assessment of LY3127804 has been adequately assessed in a 5-week QW
IV bolus dosing (5, 20, or 100 mg/kg) with an 8-week reversibility study in monkeys and in a 
5-week rat study (10, 30, or 100 mg/kg).  
In cynomolgus monkeys, LY3127804 was well tolerated at doses up to 100 mg/kg.  No 
compound-related changes in electrocardiogram (ECG) parameters (PR interval, QRS duration, 
QT interval, or QTc interval), clinical pathology parameters (including urine biomarker 

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LY3127804
assessment), organ weights, or macroscopic or microscopic findings were present.  Therefore, 
the no-observed-effect level (NOEL) is 100 mg/kg.  After 5 weeks of dosing, a dose of 
100 mg/kg corresponded to LY3127804 maximum observed drug concentration (Cmax) and area 
under the plasma concentration-time curve from time zero to 168 hours (AUC0-168hr) values of 
4720 g/mL and 518,000 g·hr/mL, respectively, in males and 5210 g/mL and 
515,000 g·hr/mL, respectively, in females as determined by antigen (Ang2) capture.
In a rat study, LY3127804 was well tolerated.  No toxicologically important changes in clinical 
pathology parameters (including urine biomarker assessment) or macroscopic findings were 
present at the end of dosing phase.  Increased thyroid/parathyroid weight parameters were 
present in males given ≥10 mg/kg and correlated with nonadverse microscopic findings of 
increased colloid in the thyroid.  Effects on the thyroid organ are an expected potential 
pharmacologic effect based on antiangiogenic mechanism (Kamba and McDonald 2007); in 
clinical trials, patients will be monitored for thyroid function.  Therefore, the no-observed-
adverse-effect level (NOAEL) is 100 mg/kg.  After 5 weeks of dosing (Day 29), a dose of 
100 mg/kg corresponded to LY3127804 Cmax and AUC0-168hr values of 4160 g/mL and 
374000 g·hr/mL, respectively, in males and 3450 g/mL and 316000 g·hr/mL, respectively, in 
females as determined by antigen (Ang2) capture.
The NOEL in monkeys treated for 5 weeks is 100 mg/kg which corresponds to a human 
equivalent dose (HED) of 32 mg/kg, and the proposed starting human dose based on monkey 
NOEL is 5.3 mg/kg (1/6th HED).  The NOAEL in rats is 100 mg/kg, which corresponds to a 
HED of 16 mg/kg, and the proposed starting human dose based on rat NOAEL is approximately 
1.6 mg/kg (1/10th HED).  Therefore, based on monkey NOEL and rat NOAEL, the proposed 
starting dose is 4 mg/kg (1.6 – 5.3 mg/kg) and is approximately 8-fold lower than monkey NOEL 
and 4-fold lower than rat NOAEL.  In addition, it should be noted that LY3127804 was 
administered QW in animal studies but will be administered once every 2 weeks (Q2W) in 
clinical studies.  Thus, based on total dose received in a 2-week period, the dose multiples would 
be expected to be higher than expressed in Table JQBA.5.3.1.  Please see Section 5.5.1 for a 
detailed rationale for selection of the starting dose.

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Table JQBA.5.3.1.
Margins of Safety for Intravenous Administration of LY3127804 
Based on Administered Dose and Predicted Exposure
Dose (mg/kg) 
HEDa
Dose
Multipleb
AUC(g h/mL)
Predicted 
Exposure 
Multiplec
Humana,d
  Starting dose (HSD) Q2W
  Highest dose (HHD) Q2W
4
20
13800c
117000c
Rat NOAELe 100 mg/kg QW
16
117000e
  Multiple relative to HSD  
4
8
  Multiple relative to HHD 
<1
1
Monkey NOELf 100 mg/kg QW
32
191000f
  Multiple relative to HSD
8
14
  Multiple relative to HHD
1.6
1.6
Abbreviations:  AUC = area under the plasma concentration versus time curve; AUCss = area under the 
concentration versus time curve during one dosing interval at steady state; AUC(0-∞) = area under the 
concentration versus time curve from zero to infinity; HED = human equivalent dose; HHD = human highest 
dose; HSD = human starting dose; NOAEL = no-observed-adverse-effect level; NOEL = no-observed-effect 
level; Q2W = every 2 weeks; QW = weekly.
a
Assuming a 70-kg person.  
b
Dose multiples is the dose in animals (as HED) / dose in humans based on mg/kg basis.
c
Exposure multiple is the calculated AUC in animals / median predicted AUC in humans.  
d
Proposed starting and highest clinical dose, with the median and 5th to 95th percentile prediction for AUC(0-∞)
following a single dose (ie, equivalent to AUCss assuming time-independent PK, is 2-week period). The 
predictions for human AUC(0-∞) are based on allometric scaling from preclinical species.
e
NOAEL determined in a multiple-dose (QW) rat toxicity study (Study 8307246).  The exposure reported is mean 
value following a single dose (ie, equivalent to AUCss assuming time-independent PK, is a week period).
f
NOEL determined in a multiple-dose (QW) monkey toxicity study (Study 8307247) n=X recovery animals only.  
The exposure reported is mean value following a single dose (ie, equivalent to AUCss assuming 
time-independent PK, is a week period).  
5.4.
Ramucirumab
Ramucirumab (Cyramza®) 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.
Lilly obtained marketing authorization for ramucirumab in the European Union and in the United 
States for the treatment of adult patients with advanced gastric cancer or GEJ adenocarcinoma 
with disease progression after prior platinum and/or fluoropyrimidine chemotherapy, as a single 
agent (REGARD) (Fuchs et al. 2014) and in combination with paclitaxel (RAINBOW) (Wilke et 
al. 2014).
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 

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LY3127804
To predict LY3127804 dose range in humans that may lead to inhibitory effect on the Ang2 
pathway and subsequently to antitumor activity, the assumption was made that LY3127804 
exposure similar to “efficacious” exposure observed in mice should lead also to antitumor 
activity in humans. The preclinical mouse data indicate that the 3-mg/kg and 10- to 20-mg/kg 
dose can be considered, respectively, as minimal and optimal efficacious dose levels when given 
BIW to mice. Steady-state exposures for 2 weeks’ treatment in mice following 3 mg/kg and 
10 mg/kg (administered BIW) are 14800 g.h/mL (4400 to 25200 g.h/mL) (predicted mean 
[range] values based on 1 and 10 mg/kg data) and 84000 g.h/mL (observed mean), respectively.  
In humans, the planned dosing frequency of LY3127804 is Q2W based on the predicted t1/2 of 
6.6 days (90% CI:  5 to 9 days) in order to prevent significant drug accumulation (predicted 
accumulation ratio: approximately 1.2 and <1.5 following Q2W dosing).  
Based on the predicted mean clearance in humans, 11.6 mL/h (5 to 18 mL/h, 95% prediction 
interval), the predicted human LY3127804 exposures at different human doses were derived and 
are presented in Table JQBA.5.5.1.
Table JQBA.5.5.1.
Predicted Human Exposure
Dose (mg/kg)
Every 2 Weeks
Steady-State AUC (g h/mL)
over the Dose Interval 2 Weeks
Median (5th - 95th Percentile)
1
1661 
(1015 - 4483)
2
5135
(3182 – 12566)
4
13828
(8501 – 34739)
8
32941
(20190 – 78235)
12
70000
(46667 – 168000)
16
93333
(62222 – 224000)
20
116667
(77778 – 280000)
Abbreviation:  AUC = area under the concentration versus time curve.
Table JQBA.5.5.1 indicates that a LY3127804 dose of 4 mg/kg and 16 mg/kg are predicted to 
deliver a human steady-state mean exposure (exposure over 2 weeks’ treatment) of 
approximately 14000 and 93000 g.h/mL (assuming human body weight of 70 kg and 
time-independent PK), respectively. These exposure values are similar to the predicted minimal 
and optimal efficacious exposures (over 2 weeks of treatment), 14800 and 84000 g.h/mL, 
respectively, based on preclinical mouse data. The anticipated efficacious LY3127804 dose of 
12 and 16 mg/kg are predicted to lead to a minimal concentration over the dosing interval (Cmin) 
mean value of approximately 70 and 90 g/mL, respectively, following Q2W dosing. These 

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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LY3127804
of 8 mg/kg (ie, at a 1:1 ratio).  Based on pharmacological consideration, administering 
LY3127804 at least at the same dose as ramucirumab (ie, 1:1 ratio) is expected to be the minimal 
ratio leading to additional biological activity of LY3127804 when given in combination with 
ramucirumab. Therefore, Part B is designed to not study any dose lower than 8 mg/kg of 
LY3127804 in combination with the approved ramucirumab 8-mg/kg dose.  This approach is 
fostered by the absence of any foreseeable toxic effects in vital organs based on nonclinical 
studies for the combination treatment at this ratio and the ethical consideration to minimize the 
number of patients exposed to combination therapy at ratios likely to be sub-therapeutic.
The dosage rationale for eventually using 12 mg/kg Q2W is based on the exposure-efficacy 
analyses from REGARD and RAINBOW, which indicated an association between efficacy and 
ramucirumab exposure. Additionally, the overall favorable safety profile of ramucirumab and 
the exposure-efficacy relationship observed in REGARD and RAINBOW suggested that there 
may be an opportunity to further improve efficacy while maintaining an acceptable safety profile 
in this combination therapy setting.
Hence, Study JQBA will be performed initially with a ramucirumab dosage of 8 mg/kg Q2W,
and, if considered appropriate and safe, a ramucirumab dose of 12 mg/kg will be explored with a 
well-defined Ang2 combination dose.  

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[19] have a known sensitivity to mAbs or other therapeutic proteins, to agents of 
similar biologic composition as LY3127804 and ramucirumab, or to any 
products used in the formulation of LY3127804/ramucirumab (refer to the IB 
for LY3127804 and ramucirumab for details) or are incompatible with the 
treatment of LY3127804/ramucirumab. 
[20]  are patients receiving any of the following:

full-dose (therapeutic) anticoagulation with warfarin and/or other
anticoagulants like low-molecular weight heparin, thrombin inhibitors
(dabigatran), and Factor Xa inhibitors (rivaroxaban)
Patients receiving prophylactic, low-dose anticoagulation therapy are
eligible provided that they are on low-molecular-weight heparin or
oral Factor Xa inhibitors or it is medically appropriate at the
investigator’s judgment that patients switch to low-molecular-weight
heparin or oral Factor Xa inhibitors before initiation of study therapy.

chronic daily treatment with aspirin at a daily dosage >325 mg/day or
nonsteroidal anti-inflammatory medications known to inhibit platelet
function (eg, indomethacin, ibuprofen, naproxen, or similar agents) or
other antiplatelet agents (eg, clopidogrel, ticlopidine, dipyridamole,
anagrelide) within 7 days prior to the first dose of study treatment.
Patients receiving cyclooxygenase 2 (COX-2) inhibitors are eligible.

low-dose methotrexate maintenance therapy
[21] have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding 
episode within 12 weeks prior to receiving treatment
[22] have experienced any arterial thromboembolic event, including myocardial 
infarction, unstable angina, cerebrovascular accident, or transient ischemic 
attack, within 6 months prior to receiving treatment
[23] have experienced any Grade 3 or 4 venous thromboembolic event that is 
considered by the investigator to be life-threatening or that is symptomatic 
and not adequately treated by anticoagulation therapy within 6 months prior to 
receiving treatment. Patients with chronic portal vein thrombosis who are 
asymptomatic and not considered to need anticoagulation therapy are eligible.
[24] have symptomatic congestive heart failure (New York Heart Association class 
≥3) or symptomatic or poorly controlled cardiac arrhythmia
[25] have a serious nonhealing: (a) wound, (b) peptic ulcer, or (c) bone fracture, 
within 28 days prior to receiving treatment
[26] have undergone major surgery within 28 days prior to randomization or 
central venous access device placement within 7 days prior to receiving 
treatment
[27] plans to undergo elective major surgery during the course of the trial

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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LY3127804
[28] have a history of gastrointestinal perforation or fistula within 6 months prior 
to receiving treatment
[29] have a history of inflammatory bowel disease or Crohn’s disease requiring 
medical intervention (immunomodulatory or immunosuppressive medications 
or surgery) ≤12 months prior to receiving treatment
[30] have an acute or subacute bowel obstruction or history of chronic diarrhea that 
is considered clinically significant in the opinion of the investigator
[31] have liver cirrhosis with a Child-Pugh class B or worse or cirrhosis (any 
degree) and a history of hepatic encephalopathy or clinically meaningful 
ascites resulting from cirrhosis. Clinically meaningful ascites is defined as 
ascites resulting from cirrhosis and requiring ongoing treatment with diuretics
and/or paracentesis.
[32] have a history of hypertensive crisis or hypertensive encephalopathy or 
current poorly controlled hypertension (systolic BP ≥150 mm Hg and/or 
diastolic BP ≥95 mm Hg) despite standard medical management.
[33] have received treatment within 28 days of the initial dose of study drug with 
any investigational product or nonapproved use of a drug or device (other than 
the study drug/device used in this study) for noncancer indications or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study
[34] for patients with non–small cell lung cancer only:

The patient has radiographic evidence of intratumor cavitation
regardless of tumor histology.
For squamous cell histology or for centrally located mediastinal masses
(<30 mm from the carina) identified by computed tomography (CT) scan or
chest x-ray, the patient must undergo a magnetic resonance imaging (MRI) of
the chest or IV contrast CT scan prior to study treatment to exclude major
airway or blood vessel invasion by cancer.

The patient has a history of gross hemoptysis (defined as bright red
blood or ≥1/2 teaspoon) within 2 months prior to study treatment.

The patient has radiologically documented evidence of major blood
vessel invasion or encasement by cancer

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LY3127804
and an 8-week period will be used for efficacy assessments.  LY3127804 will be investigated as 
a monotherapy and in combination with ramucirumab.  
In Part A, the LY3127804 single-agent, dose-escalation part of the study, LY3127804 will be 
investigated as a monotherapy at a dose ranging from 4 mg/kg up to 27 mg/kg, given Q2W.  
Cohorts of 3 patients will be enrolled at each of the planned monotherapy dose levels. PK 
samplings and ECGs are being performed at expected time of maximal plasma concentration of 
LY3127804 to rule out the potential for LY3127804 to affect the QTc interval. The sponsor and 
the investigators will review and discuss all available patient safety data prior to dose escalation. 
In addition, available PK results from the previous cohort will be reviewed prior to dose 
escalation. The decision will be documented in writing.
Part B (LY3127804 dose exploration with ramucirumab 8mg/kg) will be opened after 
patients in Cohort A2 (ie, LY3127804 monotherapy at 8 mg/kg, Q2W) have completed the DLT 
period and the dose was assessed to be safe.  An analysis of the data will be conducted, and 
feasibility to combine LY3127804 with ramucirumab dose of 8 mg/kg will be evaluated.  Based 
on the results from this analysis, the dose exploration of B cohorts will be initiated (LY3127804 
dose [ranging from 8 mg/kg up to 27 mg/kg] + ramucirumab at a fixed dose of 8 mg/kg) at the 
same time as LY3127804 monotherapy will be dose escalated at higher doses. Dose escalation 
for LY3127804 will occur up to 27 mg/kg Q2W or until the MTD has been reached; while for all 
dose levels starting from 8 mg/kg onwards, the feasibility of combining LY3127804 with 
ramucirumab will be explored. Cohorts of 6 patients will be scheduled at each of the planned 
combination dose levels.  Safety data over the first 28 days of treatment with any LY3127804 
dose and the available PK/PD data at that time will be reviewed prior to dose-escalation decision 
to the next dose level. More detailed information about the dose-escalation method and dosing 
decision in the course of Parts A to C of the study are available in Section 7.2.2.2 and Section 
7.2.2.3.
Part C (LY3127804 with ramucirumab 12 mg/kg) will be opened once all the combination B 
cohorts (B2, B3, B4, B5 and B6) have been completed (unless prohibited by DLTs). After 
completion of Part B, an analysis will be triggered, and based on safety and tolerability data 
observed in Part B cohorts, it will be determined if and at which dose it is appropriate to combine 
LY3127804 with ramucirumab at a dose of 12 mg/kg.  Based on the result from this analysis, a 
combination C cohort may be initiated (LY3127804 + ramucirumab dose of 12 mg/kg, 
6 patients).  
Figure JQBA.6.2 illustrates the planned dose-escalation scheme in Parts A through C of the 
study.  

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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LY3127804
well as an evaluation of the relationship between exposure and pharmacologic effects using 
descriptive statistics and appropriate modeling techniques, if data warrant. The overall sample 
size for this study is estimated to be a total of approximately up to 72 patients.  
In Part A, approximately 15 to 30 patients (3 per cohort/dose level with 6 per cohort/dose level at 
which a DLT has been observed) are planned to be enrolled following a 3+3 dose-escalation 
scheme in this dose-escalation portion for LY3127804 monotherapy. The actual sample size will 
depend on the incidence of DLTs.
In Part B, approximately 24 patients (6 per cohort/dose level) are planned to be enrolled. The 
choice of having 6 patients per combination cohort is based on the assumption that this 
combination treatment can be beneficial for the patients (therapeutic dose of ramucirumab) and 
the intention to have a broad (safety) base before escalating to a higher dose of LY3127804 in 
the combination setting. In line, 6 patients will be enrolled in combination dose-exploration 
Cohort in Part C.
6.2.2. Study Completion and End of Trial
This study will be considered complete after all parts (Parts A, B, and C) are complete. The 
dose-escalation and exploration phases of the study (Parts A, B, and C) will be considered 
complete after all patients required to determine the RP2D for LY3127804 have completed the 
DLT treatment-observation period and the patients in Part C have completed 4 cycles of study 
therapy or discontinued from the treatment (last patient). The unconfirmed objective responses 
of the patients in Part C need to be confirmed before the completion of the trial.
“End of trial” refers to the date of the last visit/study contact or last scheduled procedure for the 
last patient last visit.
6.2.3. Continued Access Period
All patients remaining on study treatment without evidence of disease progression or 
unacceptable toxicity, following the final analysis for safety or disease status, will be able to 
enter the continued access period of the study.  The continued access period begins after study 
completion and ends at the end of trial.  During the continued access period, patients on study 
treatment who continue to experience clinical benefit may continue to receive study treatment 
until disease progression, death, unacceptable toxicity, or start of new anticancer treatment.  The 
continued access period includes a 30-day follow-up visit after last drug exposure. The 
follow-up visit begins on Day 1 after the cycle at which the patient and the investigator agree 
that the patient will no longer continue treatment in the continued access period and lasts 
approximately 30 days.  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.
A new patient ICF for the continued access period will need to be signed only if required by 
local law and regulations. Lilly will notify investigators when the continued access period 
begins.  

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During the continued access period, all AEs, SAEs, study drug dosing, and dose reduction and/or 
infusion duration continued access (due to infusion-related events) of treatment will be collected 
on the case report form (CRF).
SAEs will also be reported to Lilly Global Patient Safety and collected in the pharmacovigilance 
system. In the event that an SAE occurs, additional information (such as local laboratory results, 
concomitant medications, and hospitalizations) may be requested by Lilly to evaluate the 
reported SAE.
Investigators will perform any standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the Investigator’s discretion; Lilly 
will not routinely collect the results of these assessments unless required for the safety follow-up 
of the patients.
6.3.
Discontinuations
6.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly. If the investigator site or the monitor at 
any time 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 clinical research physician (CRP) and the 
investigator to determine whether the patient may continue in the study, with or without 
investigational product, and this must be done prior to any further drug administration.  
Inadvertently enrolled patients may be maintained in the study and on investigational product 
when the Lilly CRP agrees with the investigator that it is medically appropriate and in the best 
interest for that patient. The patient may not continue in the study (with or without 
investigational product) if the Lilly CRP does not agree with the investigator’s determination that 
it is medically appropriate and indicated for the patient to continue.  The investigator must obtain 
documented approval from the Lilly CRP to allow the inadvertently enrolled patient to continue 
in the study with or without investigational product.
In addition, patients will be discontinued from the study drug and/or from the study (when 
specified) 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 the treatment of cancer,

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7.
Treatment
7.1.
Materials and Supplies
7.1.1. LY3127804
LY3127804 for Injection is a lyophilized product supplied in a 75-mg vial (3 mL prior to 
lyophilization not including excess volume to enable withdrawal and delivery of the dose).  This 
product is reconstituted with 3.2 mL of Sterile Water for Injection, resulting in 25 mg/mL of 
LY3127804.  LY3127804 will be administered as an IV infusion by injection of the reconstituted 
drug product into sterile IV bags containing 250 to 500 mL normal saline. Lilly instructions 
regarding dilution requirements, infusion times, and appropriate use of filters during 
administration of LY3127804 should be followed.
Clinical study materials will be labeled according to the country’s regulatory requirements.  
7.1.2. 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 to slightly 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.
Ramucirumab should be prepared according to the manufacturer’s instructions at dosages as 
specified in Table JQBA.7.2.2 and Section 7.2.1.2.
7.2.
Study Drug Administration
The investigator or designee will be responsible for:

the correct use of the investigational agent(s) and planned duration of each individual’s
treatment to the site personnel;

verifying that instructions for preparation and administration are followed properly; and

maintaining accurate records of study drug dispensation, destruction, and collection, and
destroying or returning 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 drug so that the situation can be assessed.
The date and time (start and end of infusion) of LY3127804 and ramucirumab administration 
will be recorded into the electronic CRF (eCRF).

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LY3127804
infusion container (see IB for details). A sufficient quantity of sterile normal saline (0.9% 
weight/volume) solution will be added to (or removed in the case of a prefilled bag such as 
AVIVA) the container so that the total/final volume of administration is 250 mL/500 mL. If the 
dose requires a volume 250 mL/500 mL, the addition of sterile normal saline is not required. 
The container must be gently inverted to ensure adequate mixing. Different LY3127804 drug 
product lots must not be mixed in a single infusion.  
LY3127804 will be administered as an IV infusion using either a central or a peripheral venous 
line. A 0.22-micron in-line, sterile, non-pyrogenic filter should be used. Using 0.9% normal 
saline to flush the line at the end of the infusion or ensure overfill to ensure delivery of the 
calculated dose is recommended (but not mandatory). For more details regarding the 
administration of LY3127804, please refer to the pharmacy manual.
Premedication may be provided prior to LY3127804 infusion at the investigator’s discretion.  In 
case of infusion-related reaction suspected to be related to LY3127804, treatment (and further 
prophylaxis) is recommended and can be based on the ramucirumab recommendations for 
premedications.  Recommended premedication agents include histamine H1 antagonists (IV or 
orally) such as diphenhydramine hydrochloride 50 mg (or equivalent).  Additional premedication 
may be provided at investigator discretion. Premedication must be provided in the setting of a 
prior Grade 1 to 2 infusion-related reaction, as detailed in Section 7.2.2.8.
Patients will be observed closely for infusion-related or other AEs every 15 minutes during and 
following each administration of LY3127804 until 1 hour after the end of infusion. For patients 
receiving LY3127804 and ramucirumab, patients will be observed every 30 minutes during the 
ramucirumab infusion until 1 hour following the infusion. Afterwards, the patients should 
contact their treating physician as soon as possible in case of a late-occurring clinical event 
possibly related to the administration of LY3127804 or ramucirumab.
Observations should occur in an area containing resuscitation equipment and medications 
necessary for advanced life support and cardiopulmonary resuscitation, such as bronchodilators, 
vasopressor agents (eg, epinephrine), oxygen, glucocorticosteroids, antihistamine, and IV fluids. 
Vital signs will be collected as outlined in Attachment 1.
A written approval of the sponsor will be required in case the body weight of the patient 
indicates to administer a dose of LY3127804 exceeding 3000 mg on the day of treatment.  
7.2.1.2.
Ramucirumab Dosing
Patients will receive ramucirumab by IV infusion over approximately 60 minutes (±10 min) at 8 
mg/kg (or 12 mg/kg, according to cohort attributed to the patient) Q2W in the absence of disease 
progression or other withdrawal criteria.  
On treatment days, ramucirumab will be administered after the LY3127804 infusion. The 
ramucirumab infusion should be started after a minimum of a 60-minute observation period 
(minimum of 30-minute observation period in Cycle 2 and beyond) after the end of the 
LY3127804 administration as specified in Section 7.2.1.1. Every attempt should be made in 

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order to start the ramucirumab infusion NO later than 60 minutes after the end of the LY3127804 
infusion.
The administered dose of ramucirumab will be dependent on the patient’s baseline body weight 
in kilograms.  This dose will be recalculated if there is a ≥10% change (increase or decrease) in 
body weight from baseline; subsequent doses will have to be calculated with this new body
weight reference unless there is another ≥10% change (increase or decrease) in body weight from 
“new baseline” dose calculation.  Ramucirumab will be administered Q2W.
For patients undergoing repeated palliative drainage procedures to remove pleural or peritoneal 
fluid, the dry weight will be defined as weight obtained after the drainage procedure and before 
fluid reaccumulation.  In such circumstances, dry weight will be used for dose calculation, if 
obtained within 30 days prior to dose.  If no recent dry weight is available, actual weight will be 
used.
Ramucirumab administration guidelines can be found in the most recent pharmacy manual for 
ramucirumab.  Aseptic technique is to be used when preparing and handling ramucirumab.  
Different drug product lots must not be mixed in a single infusion.  DO NOT dilute with other 
solutions or co-infuse with other electrolytes or medications.
It is recommended that ramucirumab be diluted into normal saline in an IV infusion container to 
a final volume of 250 mL.  Add to an empty IV container (or remove from AVIVA IV bag,
which comes prefilled with 0.9% normal saline) a sufficient quantity of sterile normal saline 
(0.9% weight/volume) to the container to make the total volume 250 mL. Aseptically transfer 
the calculated dose of ramucirumab drug product at 10 mg/mL to the container. The container 
should be gently inverted to ensure adequate mixing.  The use of a low protein-binding 
0.22-micron in–line filter is required.  
Prior to each ramucirumab infusion, all patients should be premedicated. Recommended 
premedication agents include histamine H1 antagonists such as diphenhydramine hydrochloride 
(or equivalent).  Additional premedication may be provided at the investigator’s discretion.  For 
patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with 
dexamethasone (or equivalent) and acetaminophen before each ramucirumab infusion.  All 
premedication administered must be adequately documented in the eCRF.
7.2.2. Dose Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
MTD is reached or the RP2D is determined, whichever occurs first. RP2D can be concluded on 
appropriate biomarker or clinical evidence obtained during the period the patient is in the trial.
Safety data, in particular AEs, will be the primary criteria for dose escalation. The DLT period is 
defined as a 28-day period. Dose-escalation decision will be made based on safety data from 
Cycle 1 (observations of the first 28-day period). In addition, if available at the time of 
dose-escalation decision, PK (Cmax, AUC, and systemic clearance) results will be used as 
secondary/supporting data for dose escalation.  No dose escalation/opening of new cohort can 

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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
CTCAE Grade 4 thrombocytopenia (unless recovered in 24 hours and in the
absence of bleeding) or Grade 3 thrombocytopenia complicated with ≥ Grade 2
bleeding

evidence of newly developed edema characterized by a body weight increase
>10% as compared to the onset of therapy

nephrotic syndrome or proteinuria exceeding 3.5 g/24 hours

any other significant toxicity deemed by the primary investigator and Lilly
clinical research personnel to be dose limiting (for example, 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 DLTs unless the investigator or Lilly medical monitor provides compelling rationale 
to support their inclusion as a DLT.  
At the time of DLT reporting, special attention will be given to determine whether the DLT
observed is primarily related to LY3127804, ramucirumab, or the combination of study drugs.. 
For the purpose of this study, the MTD is defined as the highest tested dose in a single-agent 
setting that has <33% probability of causing a DLT.  MTD in the combination setting will be 
determined based on the nature and timing of the DLTs in the combination setting.
Patients in Parts A through C (Cycle 2 or greater) 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). The investigators and Lilly CRP/CRS will have to 
agree as to whether such AEs are considered as DLT-equivalent.
7.2.2.2.
Dose-Escalation Method for LY3127804 monotherapy in Part A
In this part of the study, a 3+3 dose-escalation paradigm will be used. If 1 of 3 patients at any 
dose level experiences a DLT in Cycle 1, then up to 3 additional patients will be enrolled at that 
dose level.  If 2 (or more) out of a maximum of 3 patients at any dose level experience a DLT, 
dose escalation will cease and either the previous dose level will be declared the MTD or, 
following discussions between the investigators and the sponsor, additional patients may be 
treated at the previous or intermediate dose levels.
If a DLT is observed in 2 out of a maximum of 6 patients at any given dose, the sponsor, together 
with the investigators, will examine the safety.  Following consultation, the sponsor and the 
investigators will decide if the dose level is intolerable or, in the case of confounding events (eg, 
ambiguity whether any toxicity with a potential DLT characteristic is possibly related to study 
treatment, the underlying tumor disease, or concomitant medication), additional patients may be 
enrolled at the current dose level or an intermediate dose level to further investigate the 
tolerability. If >2 patients experience a DLT at any time, dose escalation will cease, and the 
MTD will be defined at 1 dose level down.  Following discussions between the investigators and 

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Dose adjustments of LY3127804 should be discussed and agreed on between the CRP and the 
investigator.
7.2.2.7.
Dose Modifications—Ramucirumab
Toxicities assumed to be related to ramucirumab and potentially requiring dose delays or 
adjustments will have to be dose handled according to the guidelines in the most recent
ramucirumab IB and pharmacy manual.
The ramucirumab dose may be delayed and/or reduced if the patient experiences an AE.  Doses 
may be delayed to allow time for the patient to recover from the event. If a patient receiving 
8 mg/kg experiences toxicity requiring ramucirumab dose modification, the dosage will be 
reduced to 6 mg/kg Q2W.  If a second dose reduction becomes necessary, the dosage will be 
reduced to 5 mg/kg Q2W.  Table JQBA.7.2.3 presents the dose reductions applicable to 
ramucirumab.
Table JQBA.7.2.3.
Ramucirumab Dose Reductions
Starting Dose
First Dose Reduction
Second Dose Reduction
8 mg/kg
6 mg/kg
5 mg/kg
Any patient who requires a ramucirumab dose reduction will continue to receive a reduced dose 
until discontinuation from ramucirumab or discontinuation from the study. Any patient who has 
had 2 ramucirumab dose reductions and who experiences an event that would cause a third dose 
reduction must be discontinued from ramucirumab.
For patients eventually entered at ramucirumab 12 mg/kg Q2W, the same toxicity criteria as used 
for 8 mg/kg will be used.  If a patient at 12 mg/kg experiences toxicity requiring ramucirumab 
dose modification, the dose will be reduced to 10 mg/kg Q2W.  If a second dose reduction 
becomes necessary, the dose will be reduced to 8 mg/kg Q2W.  
Table JQBA.7.2.4 provides an overview of the criteria for ramucirumab dose modifications 
applicable if the patient experiences an AE.  

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Table JQBA.7.2.4.
Dose-Modification Guidelines for Ramucirumab for Adverse Events 
at Least Possibly Related to Ramucirumab, including Adverse 
Events of Special Interest (see also Ramucirumab IB) 
Adverse Event
CTCAE 
Grade
Dose-Modification Guidelines
1.
Infusion-related reaction
1.a.
Infusion-related reaction 
2
Interrupt and reduce the infusion rate by 50% for the 
duration of the infusion and for all future infusions.
Prior to all future infusions of ramucirumab, 
premedicate with:

a histamine H1 antagonist, such as
diphenhydramine hydrochloride

dexamethasone or equivalent

acetaminophen/paracetamol
1.b.
Infusion-related reaction
3-4
Immediately and permanently discontinue 
ramucirumab
2.
Hypertension
2.a.
Hypertension (non–life-
threatening and associated with 
symptoms)
3

Delay ramucirumab until the hypertension is
controlled with medication and is resolved to
Grade 0-2.
o
If controlled with medication and resolved to
Grade 0-2, then may resume ramucirumab at
current dose.
o
If NOT controlled with medication and not
resolved to Grade 0-2 within a reasonable
timeframe, discontinue ramucirumab at
investigator’s discretion.
2.b.
Uncontrolled hypertension, 
hypertensive crisis, or 
hypertensive encephalopathy 
4
Immediately and permanently discontinue 
ramucirumab.
3.
Proteinuria
3.a.
Proteinuria = 2+ (dipstick or 
routine urinalysis)a

Administer ramucirumab at the current dose if
clinically indicated.

Obtain 24-hour urine protein results within 3 days
prior to the next ramucirumab dose.
o
If urine protein is <2 g/24 h, administer
ramucirumab at the patient's current dose.
o
If urine protein is 2 g/24 h, modify the
ramucirumab dose based on 24-hour
collection.  See Proteinuria 2 g/24 h
(24-hour urine collection), Line 3.c. in this
table.

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Dose-Modification Guidelines for Ramucirumab for Adverse Events at Least Possibly Related to 
Ramucirumab, including Adverse Events of Special Interest (see also Ramucirumab IB)
Adverse Event
CTCAE 
Grade
Dose-Modification Guidelines
3.b.
Proteinuria >2+ (dipstick or 
routine urinalysis)a

Delay ramucirumab until urine protein returns to
<2 g/24 h.

Obtain 24-hour urine protein results within 3 days
prior to the next ramucirumab dose.
o
If urine protein is <2 g/24 h, no further dose
delay or dose reduction is required.
o
If urine protein remains 2 g/24 h and is not
resolved within a reasonable timeframe,
discontinue ramucirumab at investigator’s
discretion.
3.c.
Proteinuria 2 g/24 h (24-hour 
urine collection)a

First or second occurrence:  delay ramucirumab
until urine protein returns to <2 g/24 h.
o
If urine protein returns to <2 g/24 h, reduce
ramucirumab dose.
o
If urine protein remains 2 g/24 h and is not
resolved within a reasonable timeframe,
discontinue ramucirumab at investigator’s
discretion.

Third occurrence:  discontinue ramucirumab.
3.d.
Proteinuria >3 g/24 h or in the 
setting of nephrotic syndromea
Immediately and permanently discontinue 
ramucirumab.
4.
Arterial thromboembolic events, 
venous thromboembolic events
3 or 4
Immediately and permanently discontinue 
ramucirumab.
5.
Bleeding/hemorrhage
3 or 4
Immediately and permanently discontinue 
ramucirumab.
6.
Gastrointestinal perforation
Immediately and permanently discontinue 
ramucirumab.
7.
Reversible posterior 
leukoencephalopathy syndrome
Immediately and permanently discontinue 
ramucirumab.
8.
Congestive heart failure
3-4
Immediately and permanently discontinue 
ramucirumab.
9.
Fistula formation
Immediately and permanently discontinue 
ramucirumab.
10.
Impaired wound healing
10.a.
Prior to planned surgery
Withhold ramucirumab.
10.b
After surgery
Resume ramucirumab based on clinical judgment.
10.c.
Wound-healing complications 
developed during study 
treatment
Delay ramucirumab dosing until the wound is fully 
healed.
11.
Liver injury/liver failure
11.a.
Hepatic encephalopathy and/or 
hepatorenal syndrome resulting 
from liver cirrhosis
Immediately and permanently discontinue 
ramucirumab.

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Dose-Modification Guidelines for Ramucirumab for Adverse Events at Least Possibly Related to 
Ramucirumab, including Adverse Events of Special Interest (see also Ramucirumab IB)
Adverse Event
CTCAE 
Grade
Dose-Modification Guidelines
12.
Hypothyroidism
2-4
Therapy with ramucirumab can be continued while 
treatment for the thyroid disorder is instituted.
13.
Other adverse events considered 
at least possibly related to 
ramucirumabb
13.a.
Non–life-threatening and 
reversible adverse event
3
May delay ramucirumab until resolved to Grade 0-1.

If resolved to Grade 0-1, may reduce
ramucirumab dose.

If NOT resolved to Grade 0-1 within a
reasonable timeframe, discontinue ramucirumab
at investigator’s discretion.
13.b.
4
Permanently discontinue treatment immediately, with 
the exception of Grade 4 fever or Grade 4 laboratory 
abnormality, in which case:

First occurrence:  Delay ramucirumab until
resolved to Grade 0-1.
o
If resolved to Grade 0-1, may resume
ramucirumab original dose at the
discretion of the investigator.
o
If NOT resolved to Grade 0-1 within a
reasonable timeframe, discontinue
ramucirumab at investigator’s discretion.

Second occurrence:  Delay ramucirumab until
resolved to Grade 0-1.
o
If resolved to Grade 0-1, reduce
ramucirumab dose.
o
If NOT resolved to Grade 0-1 within a
reasonable timeframe, discontinue
ramucirumab at investigator’s discretion.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events (version 4.0; NCI 2009); h = hour(s); 
IB = investigator’s brochure.
a
If 24-hour urine collection is also performed the results of 24-hour urine collection should be used for clinical 
decision making.
b
Patients who enter the study with symptoms or laboratory values equivalent to CTCAE Grade 1 or 2 adverse 
events should not necessarily have dose delays or reductions related to the persistence or mild worsening of those
symptoms or laboratory values.  If the patient experiences Grade 2 toxicities that represent clinically significant 
worsening of symptoms from baseline, the ramucirumab dose may be delayed at the discretion of the 
investigator.  
7.2.2.8.
Infusion-Related Reactions
As with other mAbs, infusion-related reactions may occur during or following LY3127804
monotherapy and in combination with ramucirumab administration.  Infusion-related reactions 
will be defined according to the NCI-CTCAE 4.0 definition of infusion-related reactions (refer to 
“General disorders and administration site conditions” in NCI-CTCAE 4.0), as detailed below.

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For a second Grade 1 or 2 infusion-related reaction, administer dexamethasone 8 to 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 to 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 to 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 treatment
with LY3127804 but will continue to be followed per protocol.
Grade 4

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone
8 to 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.

Patients who have a Grade 4 infusion-related reaction will not receive further treatment
with LY3127804 but will continue to be followed in the study.
If a patient should have an infusion-related reaction to study drugs, all attempts should be made 
to obtain an anti-LY3127804 and anti-ramucirumab antibody blood sample as close to the onset 
of the event as possible, at the resolution of the event, and 30 days after the onset of the event.  
The procedure for sample collection and handling is described in a separate procedural manual.
The investigator will have to ensure that all therapy given for the infusion-related events are 
reported accordingly.
7.2.2.9.
Hypertension
Monitoring of BP is required during LY3127804 and ramucirumab therapy as outlined in
Attachment 1. Every attempt should be made to control systolic BP to <140 mm Hg and 
diastolic BP to <90 mm Hg before starting treatment with LY3127804 and ramucirumab. 
Routine clinical and laboratory monitoring is required in patients who again develop 
hypertension or experience a deterioration in previous hypertension. Patients are allowed to 
continue either investigational drug as long as they experience ≤ CTCAE Grade 2 hypertension 
(ie, systolic BP <160 mm Hg and/or diastolic BP <100 mm Hg) or obtain such BP within 7 days 
following initiation of intensified antihypertensive therapy.
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment in this trial will be assigned to receive LY3127804
as monotherapy or in combination with ramucirumab as presented in Table JQBA.7.2.2 in this 
study.  Before each patient’s enrollment into the study, an eligibility check must be conducted 

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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 cohort and identification number assignment for each patient.  
If investigators have eligible patients who have consented concurrently, more patients may be 
entered at a particular monotherapy dose level or combination 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 needs to be approved by the sponsor following discussions with the 
investigators.
7.4.
Blinding
This is an open-label study with data evaluation at the end of each cohort.
7.5.
Concomitant Therapy
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study. An exception will be 
made for:

prostate cancer patients continuing GnRH agonist therapy or breast cancer patients
continuing anti-estrogen therapy (for example, an aromatase inhibitor) as long as those
therapies have been installed for at least 3 months and are known to have been well
tolerated

palliative radiotherapy of ≤14 calendar days in Cycles 2 and beyond following
discussions between the investigators and the sponsor (eg, for pain control of a solitary
[non-skull] skeletal metastasis) and written approval by the sponsor, as long as the patient
has not developed another reason for study discontinuation
The need for any other form of radiotherapy will be the cause for early discontinuation from the 
study unless an agreement existed prior to enrollment for a painful bone lesion (to be irradiated 
in the first 2 weeks of the study). In addition, any disease progression requiring other forms of 
specific antitumor therapy will also necessitate discontinuation from the study.  Appropriate 
documentation for all forms of premedications, supportive care, and concomitant medications 
(with special attention for antihypertensive and therapy for infusion related events) must be 
captured on the CRF.  
Patients should receive full supportive care with the exception that the routine use of granulocyte 
colony–stimulating factors is not permitted during Parts A, B, and C of this study.  The use of 
colony-stimulating factors may be given as needed for patients in Part E and follow local 
guidelines. 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, 

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anagrelide, triflusal, or similar agents) and NSAIDs with a high risk of bleeding (for example, 
indomethacin, ibuprofen, naproxen, or similar agents) is strongly discouraged but is 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 low-molecular-weight heparin 
therapy may be instituted during the course of treatment on study (eg, 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.
Males and females with reproductive potential must agree to use medically approved highly 
effective contraceptive precautions during the trial and for 3 months following the last dose of 
study drug. Female patients who are of child-bearing potential will be required to use 1 of the 
following highly effective contraceptive methods: combined oral contraceptive pill and 
mini-pill, NuvaRing®, implantable contraceptives, injectable contraceptives, intrauterine device,
or contraceptive patch (only women <198 lb or 90 kg).  Both males and females receiving 
LY3127804 may use total abstinence.  Males receiving LY3127804 or males who have had a 
vasectomy who are the partners of females receiving LY3127804 do not need further 
contraception.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.6.
Treatment Compliance
LY3127804 and ramucirumab will be administered intravenously at the investigational site, 
under the direction of the investigator.  As a result, a patient’s compliance with study drug 
administration should be 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 CRF.  
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have been exposed to 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 DLT cycle period will be 
deemed nonevaluable for assessment of a dose level, unless they experience a DLT prior to 
withdrawal.

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If the patient is noncompliant, missed a dose, or had a dose administered outside of the 3-day 
time window 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 (single-agent cohorts) or 
6 (combination cohorts) patients complete 1 cycle of therapy at each dose level, unless accrual to 
that cohort has stopped due to DLTs.
Patients who are not evaluable for PK but who complete 1 cycle of therapy may be replaced 
upon consultation with the investigator(s), the Lilly CRP or CRS, and the PK/PD scientist to 
ensure adequate PK data, unless accrual to that cohort has stopped due to a DLT.

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laboratory findings, vital sign measurements, and so on, that occur should also be reported to 
Lilly or its designee as 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 CTCAE v4.0, and the investigator should make an effort to try to 
allocate the observed AEs to the underlying disease, LY3127804, ramucirumab, or the 
combination of treatments.
The NCI-CTCAE v4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms. All AEs observed 
will be graded using CTCAE v4.0.  Any minor version of CTCAE v4.0 (for example, version 
4.0X) may be used for this study.  Minor CTCAE v4.0 updates from the NCI will not necessitate 
a protocol amendment. For AEs without matching terminology within the NCI-CTCAE v4.0 
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 CRF. 
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 drug 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 female patient must be removed from the study, and 
treatment with study drug(s) must be stopped immediately. The patient (mother and fetus) will 
be followed throughout gestation, birth, and for a short time postnatally for safety assessment.
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 must be reported to Lilly or its 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 designated data transmission methods
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 or study drug via designated data transmission 
methods.

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The investigator will decide whether he or she interprets the observed AEs as either related to 
disease, the study medications (if possible), 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 primary cause-and-effect relationship between at least one of
the study treatments and the AE is likely.

Possibly related:  a primary cause-and-effect relationship between at least one of
the study treatments 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 any of the
study treatments.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1.
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 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
or underlying preexisting conditions that didn’t change during therapy)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered 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.  
SAEs due to disease progression, including death, should not be reported unless the investigator
deems them to be possibly related to the study drug.

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Once the new anticancer therapy is initiated, any subsequent AEs or SAEs should no longer be 
assigned to the study drug(s) in this protocol.
After the 30-day follow-up visit (Visit 801), AEs are not required to be reported unless the 
investigator feels that the AEs were related to either study drug, drug delivery system, or 
protocol procedure. If an investigator becomes aware of an SAE believed to be related to 
protocol procedures or study drug, the investigator should report the SAE to the sponsor, and the 
SAE will be entered in the Lilly Safety System.
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the
DCSI in the IB and that the investigator identifies as related to study drug or procedure.  The 
United States 21 CFR 312.32, the European Union Clinical Trial Directive 2001/20/EC, and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulatory regulations and the 
associated detailed guidances.
8.1.2.4.
Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JQBA.8.1.1.  Refer to 
Attachment 5 for SAE reporting recommendations.

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Decisions for additional assessments (eg, endoscopy), as well as the requirement for transfusion,
will be left to the investigator but should preferably be discussed with the CRP.
A 24-hour urine collection will be required at screening for any patients with a urine dipstick (or 
equivalent) of ≥2+ to document the proteinuria to be <2 g/24 hours (as a proteinuria of 
>2 g/24 hours will exclude the patient from study participation). During trial treatment, 
worsening in the proteinuria (urine dipstick result: ≥2+) will trigger an additional 24-hour urine 
collection to exclude a (treatment-related) proteinuria >3.5 g/24 hours (which will require the 
study treatment to be stopped).
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies 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 will be responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated
AEs 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.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.  
Attachment 8 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood (serum/plasma) and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health throughout the study.
Tumor samples will be labeled with patient number and tissue of origin 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 an FFPE tissue block will be 
sectioned and returned to the sites by the end of study or upon request. Slides will not be 
returned.  Personal identifiers, including the patient’s name and initials, must be removed from 
the institutional pathology report prior to submission.

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
tumor measurement by RECIST 1.1 (Eisenhauer et al. 2009)

evaluation of tumor markers, if indicated.
Radiological images may be collected centrally and overread.
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 6 to 
8 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 and documented 
accordingly. Patients should be followed for survival (investigator contacting patients after 
evidence of disease progression) for the length of the study duration.
Optional DCE-MRI may be performed but will be subject to agreement between sponsor and 
investigator. For those patients, a DCE-MRI should be performed prior to study entry, after
approximately 2 weeks of therapy, and eventually after approximately 4 weeks of therapy. The 
timing of the on-treatment DCE-MRI might be adjusted based on emerging information and 
following discussion between the sponsor and the investigators. Centralized independent 
reviewers will be involved in reviewing the imaging (DCE-MRI) data to minimize any bias in 
radiological assessment.
8.4.
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 (including ECGs), PK samples, 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 on the eCRF or laboratory requisition form.  
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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9.
Data Management Methods
9.1.
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.
9.2.
Data Capture Systems
9.2.1. 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.
CRF data will be encoded and stored in a clinical trial database.  Data managed by a central 
vendor, such as laboratory test data or ECG data, will be stored electronically in the central 
vendor’s database system.  Data will subsequently be transferred from the central vendor to the 
Lilly generic labs system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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10. Data Analyses
10.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
The interpretation of the study results will be the responsibility of the investigator with the Lilly
CRP or CRS, pharmacokineticist, and statistician.  The CRP 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, minimum, and maximum. Categorical endpoints 
will be summarized using N, frequency, and percentages.  Missing data will not be imputed. 
Exploratory analyses of the data that are not described in the protocol will be conducted as 
deemed appropriate. A detailed description of data analyses will be provided in a separate 
statistical analysis plan document for this study.
This is a Phase 1 study with an open-label, dose-escalation design. Patients will be enrolled into
cohorts sequentially without randomization to dose level. During dose escalation, the total
sample size per cohort will be guided by the standard oncology 3+3 method and determined by 
the occurrences of DLTs for the monotherapy-treated patients. The LY3127804 plus 
ramucirumab combination cohorts will enroll 6 patients per dose level. The size of 6 patients per 
combination cohort will ensure a broad (safety) base before exploring a higher dose of 
LY3127804 in the combination setting and is assumed to be beneficial for the patients 
(therapeutic dose of ramucirumab). The total sample size is estimated to be approximately up to 
72 patients.
10.2. 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.
Additional summary of patient participation flow will be performed for the purpose of fulfilling 
the Clinical Trial Registry requirements.  A participant flow will describe how many enrolled 
patients completed the study, and for those who did not, the frequency of each reason for not 
completing.  
10.3. Patient Characteristics
Patient characteristics will include a summary/listing of the following:

patient demographics, including age, sex, screening height and weight, and screening
body mass index

baseline disease characteristics

prior disease-related therapies

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
concomitant medications
Other patient characteristics will be summarized as deemed appropriate.
10.4. Safety Analyses
All patients who receive at least 1 dose of LY3127804 and/or ramucirumab will be evaluated for 
safety and toxicity.  AE terms and severity grades will be assigned by the investigator using 
CTCAE, version 4.0.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

dose adjustments

laboratory values

vital signs

DLTs at each dose level

ECGs readings

concomitant medications
10.5. Pharmacokinetic Analyses
PK analyses will be conducted on patients who have received at least 1 dose of the study drug(s)
and have had samples collected.  
PK parameter estimates for LY3127804 will be calculated by standard noncompartmental 
methods of analysis.
The primary parameters for analysis will be maximum observed drug concentration (Cmax) and 
area under the concentration-time curve (from time zero to time t, for which t is the last time 
point with a measurable concentration [AUC0-tlast], from time zero to infinity [AUC0-∞]) of 
LY3127804.  Other noncompartmental parameters, such as t1/2, systemic clearance, and volume 
of distribution may be reported.  
PK parameter estimates AUC0-∞, area under the concentration versus time curve during a dosing 
interval at steady state (AUC-ss), and Cmax will be evaluated to delineate effects of dose 
proportionality and temporal linearity.  Log-transformed Cmax and AUC estimates will be 
assessed to estimate ratios of geometric means and the corresponding 90% CIs. Summary 
descriptive statistics of the PK parameters will be carried out by dose group and also per 
monotherapy/combination therapy.
The limited ramucirumab PK information collected following administration of ramucirumab in 
combination with LY3127804 will be summarized by time point (Cmin and Cmax) and compared 
with historical data following ramucirumab monotherapy.
Additional exploratory analyses will be performed if warranted by data, and other validated PK 
software programs (for example, NONMEM) may be used if appropriate and approved by 
Global Pharmacokinetic management.  The version of any software used for the analysis will be 
documented, and the program will meet the Lilly requirements of software validation.

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10.6. Pharmacodynamic Analyses
All patients enrolled in this trial will undergo blood sampling during the extent of their treatment. 
PD samples will be taken at the same time as PK samples are scheduled.
PD data from all patients undergoing PD assessments will be analyzed.
10.7. Pharmacokinetic/Pharmacodynamic Analyses 
Relationship will be explored between LY3127804 concentration and biomarkers/PD response 
such as, but not limited to, Ang2/Ang1 ratio and other biomarkers (eg, markers of either 
Tie2-Ang2-Ang1 and VEGF pathways activity or tumor activity) . Nonlinear mixed-effect 
modelling using software such as NONMEM may be used if appropriate to derive those 
relationships.
The PD endpoints versus time information will be analyzed (summary statistic performed by 
time point), and the change relative to pretreatment-baseline value will also be considered in the 
analysis.
In addition, if deemed appropriate based on the ECG read out, the central ECG database may be 
built using the stored digital central 12-lead ECGs. From those data, the relationship between 
LY3127804 concentration and ECG numerical results (QTcF and change in QTcF relative to 
baseline) may be explored to identify whether LY3127804 may lead to QTcF prolongation and
to support/supplement the analysis of the cardiac safety monitoring.  
10.8. Immunogenicity
Immunogenicity data will be summarized, and any relationship of immunogenicity to study drug 
level, activity, and safety will be explored as appropriate.
10.9. Efficacy
The study was not designed to make an efficacy assessment. However, any tumor response data
and PFS data will be summarized if appropriate and will be listed.  
Reported lesion data (target/nontarget or measurable/nonmeasurable) will be listed for all 
enrolled patients.  
10.10.
Safety Reviews and Interim Analyses
Since this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
study until the RP2D range or MTDs are determined for monotherapy and combination dose 
level.  The purpose of these cohort-by-cohort reviews (Safety Reviews) is to evaluate the safety 
data at each dose level/combination and determine if a DLT has been observed that would 
suggest MTD has been met or exceeded.  The investigators and the Lilly study team will make 
the determination regarding dose escalation based on their review of the safety and tolerability 
data as described in this protocol for the dose escalation of LY3127804 as well as the feasibility 
of the different combination settings.  

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Safety and/or PK data (when available) will be reviewed during the study if needed for dose 
escalation, modifications to the dose-escalation strategy, or other design elements.
After all patients who are deemed evaluable for the assessment of dose levels complete the DLT 
evaluation period or MTD is determined in Parts A and B, an interim safety and available PK 
data review will be conducted. A further safety review is planned after completion of Part C.
If it is deemed that enough data is obtained to assess the primary objective and the secondary 
objectives, a clinical study report might be created before the last patient visit.  In this case, all 
data until the data-cutoff date will be used for the analysis of safety, efficacy, PK, and PD 
biomarkers.  All data defined in the protocol will continue to be collected from patients on 
treatment after the data-cutoff date.  These data may be reported separately, and the analyses on 
all patients including these data may not be performed.

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11. Informed Consent, Ethical Review, and
Regulatory Considerations
11.1. Informed Consent
The investigator will be 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.  
In this protocol, the term "informed consent" includes all consent and assent given by patients.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
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 site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
11.3. 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
(CIOMS) 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 ERB(s).

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Some of the obligations of the sponsor will be assigned to a third-party organization (TPO).
An identification code assigned 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.
11.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
11.3.2. 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.
11.3.3. 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 enrolled 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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12. References
Amgen news release 2014.  Amgen web site.  Available at:
http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1985448.  Accessed April 23, 
2015.
Andersen S, Donnem T, Al-Shibli K, Al-Saad S, Stenvold H, Busund LT, Bremnes RM. 
Prognostic impacts of angiopoietins in NSCLC tumor cells and stroma: VEGF-A impact is 
strongly associated with Ang-2. PLoS ONE. 2011;6(5):e19773.
Appleman LJ, Gordon MS, Samlowski W, Rasmussen E, Sun Y, Zhong D, Friberg G, Hong D. 
Open-label phase Ib study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in 
combination with sorafenib or sunitinib in advanced renal cell carcinoma (RCC): interim 
results. Ann Oncol. 2010;21(suppl 8):viii165. Abstract 505P.
Brown JL, Cao ZA, Pinzon-Ortiz M, Kendrew J, Reimer C, Wen S, Zhou JQ, Tabrizi M, Emery 
S, McDermott B, Pablo L, McCoon P, Bedian V, Blakey DC. A human monoclonal 
anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors 
and chemotherapy agents in preclinical models. Mol Cancer Ther. 2010;9(1):145-156.
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.
Daly C, Eichten A, Castanaro C, Pasnikowski E, Adler A, Lalani AS, Papadopoulos N, Kyle 
AH, Minchinton AI, Yancopoulos GD, Thurston G. Angiopoietin-2 functions as a Tie2 agonist 
in tumor models, where it limits the effects of VEGF inhibition. Cancer Res. 
2013;73(1):108-118.
Dumont DJ, Gradwohl G, Fong GH, Puri MC, Gertsenstein M, Auerbach A, Breitman ML. 
Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, 
reveal a critical role in vasculogenesis of the embryo. Genes Dev. 1994;8(16):1897-1909.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M. Angiopoietin-2 is related to tumor 
angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. 
Cancer Res. 2001;61(5):2145-2153.
Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, Bartol A, Kienast Y, Vettel C, Loos 
EK, Kutschera S, Bartels S, Appak S, Besemfelder E, Terhardt D, Chavakis E, Wieland T, 
Klein C, Thomas M, Uemura A, Goerdt S, Augustin HG. Angiopoietin-2 differentially 
regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest.
2012;122(6):1991-2005.
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; 
REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced 

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
Page 78
LY3127804
gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, 
randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9.
Gerald D, Chintharlapalli S, Augustin HG, Benjamin LE. Angiopoietin-2: an attractive target for 
improved antiangiogenic tumor therapy. Cancer Res. 2013;73(6):1649-1657.
Hashizume H, Falcón BL, Kuroda T, Baluk P, Coxon A, Yu D, Bready JV, Oliner JD, 
McDonald DM. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor 
angiogenesis and growth. Cancer Res. 2010;70(6):2213-2223.
Hong D, Gordon M, Appleman L, Kuzrock R, Sun Y, Rasmussen E, Zhong D, Le N, Rosen L. 
Interim results from a Phase Ib study of safety, pharmacokinetics (PK) and tumor response of 
the angiopoietin1/2-neutralizing peptibody AMG 386 in combination with AMG 706, 
bevacizumab (B) or sorafenib (S) in advanced solid tumors. Ann Oncol. 2008;19(suppl 
8):viii154. Abstract 462PD.
Hyman DM, Rizvi NA, Natale RB, Armstrong DK, Birrer MJ, Recht LD, Dotan E, Gribbin MJ, 
McDevitt JT, Tavakkoli F, McCaffrey J, Sikorski R, Lai DW.  A phase 1 study of MEDI3617, 
a selective angiopoietin-2 inhibitor, alone and in combination with carboplatin/paclitaxel, 
paclitaxel, or bevacizumab in patients with advanced solid tumors. J Clin Oncol. 
2014;32(suppl 15). Abstract 3012.
Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J 
Cancer. 2007;96(12):1788-1795.
Kelley RK, Siu LL, Van Loon K, Tolcher AW, Razak ARA, Ziyeh S, Beeram M, Bedard PL, 
Arcos R, Gao B, Trail P, Adriaens L, Brownstein CM, Lowy I, Papadopoulos KP. Phase 1 
first-in-human (FIH) study of nesvacumab (REGN910) a fully human and selective 
angiopoietin-2 (Ang2) monoclonal antibody (MAb): results from hepatocellular carcinoma 
(HCC) cohort. J Clin Oncol. 2014;32(suppl 5). Abstract 2540.
Koh YJ, Kim HZ, Hwang SI, Lee JE, Oh N, Jung K, Kim M, Kim KE, Kim H, Lim NK, Jeon 
CJ, Lee GM, Jeon BH, Nam DH, Sung HK, Nagy A, Yoo OJ, Koh GY. Double antiangiogenic 
protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and 
vascular leakage. Cancer Cell. 2010;18(2):171-184.
Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown JL, 
Naldini L, De Palma M. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis 
by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer 
Cell. 2011;19(4):512-526.
Nassiri F, Cusimano MD, Scheithauer BW, Rotondo F, Fazio A, Yousef GM, Syro LV, Kovacs 
K, Lloyd RV. Endoglin (CD105): a review of its role in angiogenesis and tumor diagnosis, 
progression and therapy. Anticancer Res. 2011;31(6):2283-2290.
[NCI] National Cancer Institute. Common terminology criteria for adverse events, version 4.0. 
28 May 2009.  
Ochiumi T, Tanaka S, Oka S, Hiyama T, Ito M, Kitadai Y, Haruma K, Chayama K. Clinical 
significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced 
colorectal carcinoma. Int J Oncol. 2004;24(3):539-547.

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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 
1982;5(6):649-655.
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-649.
Rigamonti N, De Palma M. A role for angiopoietin-2 in organ-specific metastasis. Cell Rep.
2013;4(4):621-623.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
Society of Clinical Oncology; American Society of Hematology. Use of epoetin and 
darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American 
Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-149. 
Erratum in: J Clin Oncol. 2008;26(7):1192.
Scharpfenecker M, Fiedler U, Reiss Y, Augustin HG. The Tie-2 ligand angiopoietin-2 
destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci. 
2005;118(Pt 4):771-780.
Sfiligoi C, de Luca A, Cascone I, Sorbello V, Fuso L, Ponzone R, Biglia N, Audero E, Arisio R, 
Bussolino F, Sismondi P, De Bortoli M. Angiopoietin-2 expression in breast cancer correlates 
with lymph node invasion and short survival. Int J Cancer. 2003;103(4):466-474.
Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow 
LQ, Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, Rowinsky EK, 
Eckhardt SG. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully 
human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth 
factor receptor-2. J Clin Oncol. 2010;28(5):780-787.
Srivastava K, Hu J, Korn C, Savant S, Teichert M, Kapel SS, Jugold M, Besemfelder E, Thomas 
M, Pasparakis M, Augustin HG. Postsurgical adjuvant tumor therapy by combining anti-
angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell. 
2014;26(6):880-895.
Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. 
Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic 
angiogenesis. Cell. 1996;87(7):1171-1180.
.

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During and Poststudy Assessments
Cycle 1
Cycle 2
Cycle 
3-n
Follow-
Up
Comments
30-day 
(V801)
Relative Day 
Within a Cycle
1
2
4 or 
5
8
15
16
22
1
8
15
22
1
8
15
In Cycle 2 and beyond, visits may be performed ±3 days 
around scheduled visits. No shortening of the treatment 
cycles is allowed
LY3127804
X
X
X
X
X
X
Ramucirumab
X
X
X
X
X
X
Only patients in Parts B and C
Physical 
examination
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
Temperature, pulse rate, RR, and BP. On study drug infusion 
days, measure pulse rate and BP within 15 min prior to 
infusion(s), after completion of each infusion(s), and 1h after 
completion of the last antibody infusion. Additional 
measurements as clinically indicated.  Day 2 Cycle 1 only for 
patients in Parts A, B, and C
Central ECG 
(12 lead)
X
X
X
X
X
Only for patients in Parts A, B, and C during Cycle 1 and 2;
see Attachment 4 for exact timing; triplicate ECGs to be 
conducted
Hematology
X
X
X
X
X
X
X
X
X
X
See Attachment 2; may be done within 3 days prior to 
administration of study drugs (except Cycle 1, Day 1 [within 
3 days]); Only patients in Part A-C:  Day 8 only in Cycle 1 
and Day 15 in Cycle 3 and beyond only if abnormal (different 
from previous assessment) on Day 1

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Cycle 1
Cycle 2
Cycle 
3-n
Follow-
Up
Comments
30-day 
(V801)
Relative Day 
Within a Cycle
1
2
4 or 
5
8
15
16
22
1
8
15
22
1
8
15
In Cycle 2 and beyond, visits may be performed ±3 days 
around scheduled visits. No shortening of the treatment 
cycles is allowed
Fresh tumor biopsy 
(optional)
X
Throughout the study, see Section 8.2.3; 
Radiological tumor 
assessment
X
X
Assessment performed at the end of every even cycle until 
discontinuation, preferentially between Days 22 and 29. After 
Cycle 8, every 2 to 4 cycles as clinically indicated
Functional tumor 
imaging 
(DCE-MRI)
X
DCE-MRI can be scheduled pending agreement between 
sponsor and investigator
Tumor markers
X
X
If applicable to tumor type and patient; Cycle 3, Cycle 5, 
Cycle 7, and every 4 cycles thereafter
Immunogenicity
X
X
X
X
X
Sampling for ADAs against LY3127804 (all patients) and 
ramucirumab (only patients receiving LY3127804 + 
ramucirumab); after Cycle 4, every 2 cycles.  If a patient 
experiences an infusion-related reaction, immunogenicity 
samples 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
Pregnancy test 
(WOCBP)
X
X
X
See Attachment 2
Abbreviations:  ADA = anti-drug antibody; aPTT = activated partial thromboplastin time; BP = blood pressure; CTCAE = Common Terminology Criteria for 
Adverse Events; DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; exam = examination; fT4 = free thyroxine; h = hour(s); HCC = hepatocellular carcinoma; INR = international normalized ratio; PD = 
pharmacodynamic; PK = pharmacokinetic; RR= respiration rate; SAEs = serious adverse events; TSH = thyroid stimulating hormone; WOCBP = women of 
child-bearing potential.

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Attachment 2.
Protocol JQBA Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical chemistrya
Hemoglobin
Serum concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Magnesium
Neutrophils
Total bilirubin
Lymphocytes
Direct bilirubin
Monocytes
Alkaline phosphatase
Eosinophils
Alanine aminotransferase
Basophils
Aspartate aminotransferase
Platelets
Gamma-glutamyl transpeptidaseb
Lactate dehydrogenase
Coagulationa
Blood urea nitrogen/blood urea
activated partial thromboplastin time
Creatininee
Prothrombin time/INR
C-reactive protein
Uric acidb
Urinalysisa
Calcium
Specific gravity
Chloride
pH
Total protein
Proteind
Albumin
Glucose
Ketones
HbA1c (at baseline only)
Blood
Urine leukocyte esterase
Hormone panela
Thyroid stimulating hormone
Hepatitis testsa
Free thyroxine
Hepatitis B surface antigen
Hepatitis C
Pregnancy test (females only)a,c
Tumor markera
As applicable to tumor type and patient 

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Abbreviations:  HbA1c = glycosylated hemoglobin; HCC = hepatocellular carcinoma; INR = international 
normalized ratio; pts = patients; RBC = red blood cells; WBC = white blood cells.
a
Assayed by local laboratory.
b
Gamma glutamyl transferase and uric acid will be optional.  To be measured if part of the routine panel.  
c
For women of childbearing potential only (as judged by the investigator). Serum pregnancy test result will be 
required within 7 days prior to enrollment. Values above the reference range can be accepted if explained by 
disease history (and/or confirmed absence of pregnancy with echographic examination of the pelvis). Urine or 
serum test may be performed prior to treatment at all other time points.
d If urine dipstick or routine urinalysis indicates proteinuria ≥2+ at screening and/or worsening relative to baseline 
while receiving study drugs, a 24-hour urine collection must be obtained to locally assess urine protein 
concentrations.
e   For patients in Part E, creatinine clearance will be calculated according the formula by Cockcroft and Gault  
   (1976) (see Attachment 7). 

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Attachment 3.
Protocol JQBA Hepatic Monitoring Tests 
for Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment emergent hepatic abnormality 
(clinically relevant ALT/AST increase and/or bilirubin >ULN range) and may be required in 
follow up with patients in consultation with the Lilly CRP.
Hepatic Monitoring Tests
Hepatic hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic coagulationa
RBC
Prothrombin time
WBC
Partial prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic serologiesa
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 aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; ULN = upper limit of normal; WBC = white blood cells.
a
Assayed by local laboratory.

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Attachment 5.
Protocol JQBA Recommendations for 
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report a SAE, please have the following information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, 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 and 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 JQBA ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all predisease 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 self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair
5
Dead
Abbreviation:  ECOG = Eastern Cooperative Oncology Group.
Source:  Oken et al. 1982.

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Attachment 7.
Protocol JQBA Creatinine Clearance 
Formula
  
For serum creatinine 
concentration in mg/dL:
CrCl =
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
(mL/min)
0.81 serum creatinine 
(mol/L)
Abbreviations:  CrCl = creatinine clearance; wt = weight.
a age in years, weight in kilograms.
Reference:  Cockcroft and Gault 1976.

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Attachment 8.
Protocol JQBA Sampling Summary
This table summarizes the maximum number of samples, volumes for all sampling, and tests
during the study.  The summary below provides estimates for patient completing 6 cycles of 
treatment. More samples could be required in the 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 (for example, patients who discontinue from the 
study).
Protocol I7W-MC-JQBA Sampling Summary
Purpose
Sample Type
Maximum 
Amount per 
Sample
Maximum 
Number 
Samples
Maximum Total 
Amount
Study qualificationa
Blood
5 mL
6
30 mL
Health monitoring (may 
be more than 1 tube)b
Blood
5 mL
52
260 mL
PD/tailoring biomarkers
Tissue biopsy
5 mm, 0.5 oz, 
1 cc
2
10 mm
1 oz
2 cc
Drug concentration
Blood
3.5 mL
28
98 mL
PD biomarkers
Plasma
10 mL
19
190 mL
Pharmacogenetics
Blood
10 mL
1
10 mL
Immunogenicity
Blood
8.5 mL
14
119 mL
Hepatic monitoringb
Blood
3 - 30 mL
—
—
Total
Blood: 517 mL
Tissue biopsy: 10 mm,
1 oz, 2 cc
Plasma: 190 mL
Abbreviation:  PD = pharmacodynamic.
a
Additional samples may be drawn if needed for safety purposes.
b
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with the designated medical monitor

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Attachment 9.
Protocol JQBA 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 CT or MRI scan (slice thickness 5 mm) 

10-mm caliper measurement by clinical examination (nonmeasurable 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 
nonmeasurable include leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, or abdominal masses/abdominal organomegaly identified by physical examination that is 
not measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions

Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are nonmeasurable.

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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 nonmeasurable unless there has been 
demonstrated progression in the lesion.  
Baseline Documentation of Target and Nontarget Lesions
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. Nonnodal 
target lesions should be selected on the basis of their size (lesions with the longest diameter), 
should 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 [cm]).
Nontarget Lesions
All other lesions (or sites of disease) should be 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 (for example, multiple liver metastases recorded as 1 liver 
lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 

I7W-MC-JQBA(d) 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 examination.  
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to the best effect and a consistent method is used on subsequent examinations for 
any given patient.  If, prior to enrollment, it is known that a patient is not able to undergo CT 
scans with IV contrast due to allergy or renal insufficiency, the decision as to whether a 
noncontrast CT or MRI (with or without IV contrast) should be used to evaluate the patient at 
baseline and follow-up should be guided by the tumor type under investigation and the anatomic 
location of the disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10-mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  When lesions can be evaluated by both clinical examination 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 in which recurrence following CR or 
surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the ULN, they must normalize for a patient to be considered in CR.  Specific 
guidelines for both prostate-specific antigen response (in recurrent prostate cancer) and CA-125 
response (in recurrent ovarian cancer) have been published.  
Cytology, Histology:  These techniques can be used to differentiate between PRs and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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tumors, in which 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 cytologic 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 to differentiate between response (or stable disease) and progressive disease.
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan.
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a CR or PR in target disease or when progression in bone is 
suspected.
Response Criteria
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or nontarget) 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:  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of 1 or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease, 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 nonpathological or normal in size (<10-mm short axis).
Non-CR/nonprogressive Disease:  Persistence of 1 or more nontarget lesions and/or maintenance 
of tumor marker level above the normal limits.

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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; NE = inevaluable; PD = progressive disease; PR = partial response;
SD = stable disease.
Table 2 is to be used when patients have nonmeasurable disease only.
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; NE = inevaluable; PD = progressive disease.
a
Non-CR/non-PD is preferred over SD for nontarget disease.

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Frequency of Tumor Reevaluation
A baseline tumor evaluation must be performed within 4 weeks before the patient begins study 
treatment. Frequency of tumor reevaluation while on and adapting 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 to 8 weeks is 
reasonable.  Normally, all target and nontarget sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.  
Confirmatory Measurement/Duration of Response
Confirmation
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. The confirmation of response is particularly important in 
nonrandomized trials where response (PR/CR) is the primary endpoint.  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 a randomized trial (Phase 2 or 3) or studies in which SD or progression is the 
primary endpoint, 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 that 
are not blinded.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 8 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 progressive disease the smallest measurements 
recorded on study).
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 
progressive disease).  

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Independent Review of Response and Progression
When objective response (CR + PR) is the primary endpoint 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 10.
Protocol JQBA Child-Pugh Score
Child-Pugh Score
Clinical and 
Biochemical 
Parameters
Points
1
2
3
Bilirubin (mg/dL)
<2
2-3
>3
Albumin (g/dL
>3.5
2.8-3.5
<2.8
Ascites
Absent
Moderate
Tense
Encephalopathy
Absent
Moderate (Stage I-II)
Severe (Stage III-IV)
Prothrombin time
    Seconds prolonged
    %
    INRa
<4
>60
<1.7
4-6
40-60
1.7-2.3
>6
<40
>2.3
In case of primary biliary cirrhosis
1
2
3
Bilirubin (mg/dL)
<4
4-10
>10
Total points:

5 to 6:  Child-Pugh class A

7 to 9:  Child-Pugh class B

10 to 15:  Child-Pugh class C
a
INR (International Normalized Ratio) is an expression of prothrombin time, corrected by the sensitivity of the 
reactive to anticoagulants and should be validated as an alternative to prothrombin time in liver insufficiency.
Source: Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg. 1973;60:646-649.

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Attachment 11.
Protocol JQBA Protocol Amendment 
I7W-MC-JQBA(d) Summary
A Phase 1 Study of LY3127804 as Monotherapy and in 
Combination with Ramucirumab in Patients with Advanced 
Solid Tumors
Overview
Protocol I7W-MC-JQBA, A Phase 1 Study of LY3127804 as Monotherapy and in Combination 
with Ramucirumab in Patients with Advanced Solid Tumors, has been amended.  The new 
protocol is indicated by Amendment (d) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall major changes and rationale for the changes made to this protocol are as follows:

Part D was removed from the study since the primary and secondary end points were met
and data collected from Parts A-C were adequate to fulfil primary objective of this study.
Additional patient enrollment was not required.

Part E was removed from the study since it was concluded based on Lilly’s current 
oncology portfolio strategies that combining paclitaxel with LY3127804 for treating 
second-line gastric cancer was no longer desired to be investigated in this particular 
study.

The necessary corrections were made in all sections and subsections of this protocol to 
align with the deletion of Parts D and E from the current study design.

Clarified the testing of the higher dose 27 mg/kg through the addition of new cohorts of 
LY3127804 to Parts A and B to confirm MTD from expected DLTs at that particular 
dose.

In Attachment 8, Protocol JQBA Sampling Summary was corrected to be inline with the 
rest of the protocol.

Other minor corrections and editorial changes were made throughout the protocol to 
improve clarity and to secure alignment with the intended study design. These changes 
are not documented below.

Corresponding changes (eg. study arms, sample size, etc.) were made in the standalone 
Protocol synopsis of Study JQBA to ensure consistency with the current amendment in 
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.
2.
Synopsis
This Phase 1 first-in-human study is a multicenter, nonrandomized, open-label, dose-escalation 
study of intravenous LY3127804 in patients with advanced or metastatic solid tumors who have 
failed standard of care or for whom no standard of care is available.  Study I7W-MC-JQBA 
(JQBA) will determine a recommended dose range and schedule for LY3127804 that may be 
safely administered as monotherapy and in combination with ramucirumab.  The study will 
consist of a dose escalation for LY3127804 monotherapy (Part A) and combinations with 
ramucirumab (Parts B and C). followed by a safety confirmation of the RP2D for LY3127804 in 
combination with ramucirumab (Part D) and a safety exploration for the combination of 
LY3127804 plus ramucirumab and paclitaxel (Part E).
4.
Abbreviations and Definitions
RR
Study Completion
respiratory rate
This study will be considered complete after all parts (Parts A, B and C) are 
complete. The dose-escalation and exploration phase of the study (Parts A, B, 
and C) will be considered complete after all patients, required to determine the 
RP2D for LY3127804 have completed DLT treatment-observation period and 
the patients in Part C have completed four cycles of study therapy or 
discontinued from the treatment (last patient)
all parts (Parts A, B, C, D, and E) are complete.  The dose escalation and 
exploration phase of the study (Parts A, B, and C) will be considered complete 
after all patients, required to determine the RP2D for LY3127804 have 
completed DLT treatment observation period.  The safety confirmation phase of 
the study (Part D) and combination with ramucirumab and paclitaxel (Part E) 
will be considered complete if the study objectives have been reached or 
patients have discontinued from the treatment (last patient)
5.1.
Rationale and Justification for the Study
Study I7W-MC-JQBA (JQBA) is the first-in-human Phase 1 dose-escalation study of 
LY3127804 designed to evaluate the safety and tolerability and the PK properties, as well as to 
gather evidence of pharmacodynamic (PD) effects and antitumor activity, of LY3127804 in 
patients with advanced solid tumors who have failed SOC or for whom no SOC is available and .  
Tthe feasibility to combine LY3127804 with the approved VEGFR2-blocking antibody 
ramucirumab (see Section 6.2) with and without paclitaxel will also be investigated in this study
5.1.4. Rationale for Protocol Amendment (d)
The Sponsor implemented amendment (d) in order to eliminate Parts D and E from the current 
study protocol and to clarify that LY3127804 at a dose of 27 mg/kg was tested as monotherapy 
(Part A) and as combination therapy with ramucirumab (Part B).

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The rationale for the elimination of Parts D and E was based on the following:  (i) based on 
Lilly’s current oncology portfolio strategies, it was concluded that combining paclitaxel with 
LY3127804 for treating second-line gastric cancer was no longer desired to be investigated in 
this particular study. Other regimens will be used to treat second-line gastric cancer in the 
foreseeable future, ii) the primary and secondary end points of this study were reached, and (iii) 
information collected from Parts A, B, and C (fully enrolled and ongoing as of August 21, 2017) 
was considered sufficient to conclude the primary objective of the study and to answer all 
scientific questions.  Therefore, further accrual of patients was not required.
5.2.1.Primary Objective
The primary objective of this study is to determine a recommended Phase 2 dose (RP2D) range 
and schedule of LY3127804, as monotherapy and in combination with ramucirumab +/-
paclitaxel that may be safely administered to patients with advanced solid tumors
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3127804 as monotherapy 
and in combination with ramucirumab +/ paclitaxel

to assess the maximum tolerated dose (MTD) of LY3127804 monotherapy 
and in combination with ramucirumab +/- paclitaxel based on the 
dose-limiting toxicity (DLT), if applicable

to assess the PK parameters of LY3127804 monotherapy and when 
administered in combination with ramucirumab +/- paclitaxel

to assess limited PK (peak and trough concentration) of ramucirumab when 
given in combination with LY3127804 +/- paclitaxel

to evaluate the incidence and level of antibodies against LY3127804 
(anti-drug antibodies [ADAs]) and ramucirumab when given in combination 
+/ paclitaxel

to document any antitumor activity of LY3127804 as monotherapy and in 
combination with ramucirumab +/ paclitaxel

to estimate PFS of LY3127804 monotherapy and when given in combination 
with ramucirumab +/ paclitaxel
5.2.3. Exploratory Objectives

to explore biological activity of LY3127804 as monotherapy and when given 
in combination with ramucirumab +/ paclitaxel based on dynamic contrast-
enhanced magnetic resonance imaging (DCE-MRI)
5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
Immuno-deficient mice bearing SKOV3x.1 ovarian xenografts were treated with either different 
doses of LY3127804, vehicle control, paclitaxel, or the combination of paclitaxel + LY3127804 

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Currently, Study I4T MC JVCZ is being performed in patients with metastatic or locally 
advanced gastric or gastroesophageal junction adenocarcinoma to compare the standard 
ramucirumab dose (8 mg/kg) and a new, higher ramucirumab dose (12 mg/kg), both 
administered on Days 1 and 15, in combination with paclitaxel (80 mg/m2) administered on 
Days 1, 8, and 15 of a 28 day cycle in order to examine the potential improvement in efficacy as 
measured by PFS.  The new ramucirumab dosing regimen (12 mg/kg) is predicted to produce 
approximately 50% higher exposure relative to the 8 mg/kg standard dose based on linear PK 
assumption and, therefore, is expected to improve PFS.  However, it is unknown whether the 
dosage of 12 mg/kg Q2W will result in an acceptable toxicity profile.  
5.5.3. Paclitaxel Dose
Ramucirumab in combination with paclitaxel (80 mg/m² intravenously on days 1, 8 and 15 of a 
28 day cycle) is approved by FDA and EMA.  Paclitaxel at this dose and schedule is an accepted 
standard of care in advanced cancer patients in several tumor types and patients with no other 
treatment options. 
In the randomized phase 3 study “RAINBOW” the combination of ramucirumab and paclitaxel 
demonstrated an overall favourable safety profile and significantly increased overall survival in 
2nd line gastric cancer patients (Wilke et al. 2014).  The same dose and schedule of paclitaxel 
will be used in JQBA Part E (ie, 80 mg/m² intravenously on days 1, 8, and 15 of a 28 day cycle) 
to explore the safety and tolerability when given in combination with ramucirumab and 
LY3127804.  As outlined in Section 5.5.2 the dose of ramucirumab and LY3127804 to be given 
in combination with paclitaxel in Part E will depend on the safety and tolerability observed in 
Part B and C and the ongoing study JVCZ. 
6.1.2. Exclusion Criteria
[35] for patients in Part E (LY3127804 +ramucirumab/paclitaxel) only: 

The patient received previous systemic chemotherapy with a cumulative dose 
of >900 mg/m2 of epirubicin or >400 mg/m2 of doxorubicin

The patient has sensory peripheral neuropathy ≥Grade 2 

have a known allergy or hypersensitivity to paclitaxel or to any products used 
in the formulation of paclitaxel or are incompatible with the treatment of 
paclitaxel
6.2.
Summary of Study Design

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Study JQBA is a multicenter, nonrandomized, open-label, dose-escalation Phase 1 study that will 
consist of 4 3 parts:  
Old Figure Deleted

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New Figure Inserted
Abbreviations:  GEJ = gastroesophageal junction; HCC = hepatocellular carcinoma; 
PD = pharmacodynamics; PK = pharmacokinetics; pts = patients; Q2W = every 
2 weeks; Ram = ramucirumab.

Part D:  safety confirmation cohort for LY3127804 at RP2D in combination with 
ramucirumab 8mg/kg Q2W 

Part E:  dose exploration of LY3127804 in combination with ramucirumab and 
paclitaxel to determine a RP2D range and schedule for LY3127804 that may be safely 
administered in combination with ramucirumab Q2W (dose tbd) and paclitaxel (80 
mg/m2 day 1, 8, and 15)  
In Part A, the LY3127804 single-agent, dose-escalation part of the study, LY3127804 will be 
investigated as a monotherapy at a dose ranging from 4 mg/kg up to 20 27 mg/kg, given Q2W.  
Cohorts of 3 patients will be enrolled at each of the planned monotherapy dose levels
Part B (LY3127804 dose exploration with ramucirumab 8mg/kg) will be opened after 
patients in Cohort A2 (ie, LY3127804 monotherapy at 8 mg/kg, Q2W) have completed the DLT 
period and the dose was assessed to be safe.  An analysis of the data will be conducted, and 
feasibility to combine LY3127804 with ramucirumab dose of 8 mg/kg will be evaluated.  Based 
on the results from this analysis, the dose exploration of B cohorts will be initiated (LY3127804 
dose [ranging from 8 mg/kg up to 20 27 mg/kg] + ramucirumab at a fixed dose of 8 mg/kg) at the 

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Part E (LY3127804 dose exploration with ramucirumab/paclitaxel) will be opened once 
Parts B and Part C have been completed.  In this part, approximately 9 12 patients will receive 
ramucirumab and paclitaxel at a fixed dose in combination with LY3127804. The first cohort of 
3 patients will receive paclitaxel and ramucirumab in combination with LY3127804 starting at 
least 1 dose level below the RP2D of LY3127804 with ramucirumab for Part D.  If tolerated, the 
LY3127804 dose will be increased to the RP2D for Part D and administered in combination with 
ramucirumab plus paclitaxel.  
The dose levels of ramucirumab and LY3127804 to be explored in Part E will be defined based 
on safety data observed in Parts A through C as well as in Study JVCZ (see Section 5.5.2).  The 
sponsor, in collaboration with the investigators, will review all the data prior to determining the 
recommended schedule and dose of LY3127804 and ramucirumab to be explored in Part E.  The 
decision will be documented in writing, and a written notification will be sent to the IRB prior to 
enrollment of patients into Part E.  No amendment will be required.  Paclitaxel will be 
administered according to its label (80mg/m2 day 1, 8, and 15).  More detailed information is 
available in Section7.2.2.6.
The protocol for Study JQBA may be amended prior to commencement of Part D and Part E, 
depending on the safety, tolerability, and preliminary clinical activity observed in Parts A 
through C.  In addition, further expansion cohorts for other tumor types and combination 
treatments may be added by a protocol amendment if indicated by emerging scientific data from 
preclinical and ongoing clinical studies
6.2.1. Sample Size
To determine the RP2D of LY3127804, an adequate 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 pharmacologic effects using 
descriptive statistics and appropriate modeling techniques, if data warrant.  The overall sample 
size for this study is estimated to be a total of approximately up to 8472 patients.  
In Part D, a total of approximately 6 12 patients will be enrolled to confirm safety and 
tolerability of the RP2D of study drugs.
In Part E, a total of approximately 9 12 patients will be enrolled to explore the safety and 
tolerability of LY3127804 when given in combination with ramucirumab and paclitaxel (3 per 
cohort/dose level and a total of approximately 6 per cohort/dose level at the MTD level).
6.2.2. Study Completion and End of Trial
This study will be considered complete after all parts (Parts A, B, and C) are complete. The 
dose-escalation and exploration phases of the study (Parts A, B, and C) will be considered 
complete after all patients required to determine the RP2D for LY3127804 have completed the 
DLT treatment-observation period and the patients in Part C have completed 4 cycles of study 
therapy or discontinued from the treatment (last patient).  The unconfirmed objective responses 
of the patients in Part C need to be confirmed before the completion of the trial. (that is, the 

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scientific evaluation will be complete [study completion]) all parts (Parts A, B, C, D and E) are 
complete.  The dose escalation and exploration phase of the study (Parts A, B, and C) will be 
considered complete after all patients, required to determine the RP2D for LY3127804 (in a 
single agent setting and in a combination setting with ramucirumab) have completed a DLT 
treatment observation period.  The safety confirmation (Part D) and combination with 
ramucirumab and paclitaxel (Part E) phase of the study will be considered complete if the study 
objectives have been reached or the last patient has discontinued from treatment. 
6.2.3. Continued Access Period
Investigators will perform any standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the Investigator’s discretion.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments unless required 
for the safety follow-up of the patients.
7.1.3. Paclitaxel
Paclitaxel will be provided by Lilly and will be labeled according to the country's regulatory 
requirements.  Refer to the manufacturer’s instructions on preparation, handling, and storage of 
paclitaxel. 
7.2.1. Dosing Schedule
A treatment cycle is defined as an interval of 28 days.  Treatment should continue on schedule if 
possible, but a variance of up to +3 days in Cycle 2 and beyond, may be allowed to 
accommodate holidays and clinic scheduling conflicts.  No shortening of the treatment cycle will 
be allowed.
7.2.1.1.
LY3127804 Dosing
LY3127804 infusion time is to be determined based on an infusion rate not to exceed 25 mg/min
and on the LY3127804 dose level administered.  Table JQBA.7.2.1 provides an overview of the 
planned LY3127804 infusion duration.  Patients receiving 4-mg/kg, 8-mg/kg, or 12-mg/kg doses 
should have infusion times not less than 60 minutes.  Patients receiving 16-mg/kg, 20-mg/kg or 
27-mg/kg doses should have drug infused in not less than 90 minutes.
Table JQBA. 7.2.1.
LY3127804 Infusion Duration
Dose Level
Total Dose
LY3127804 Infusion Duration
4, 8, and 12 mg/kg
≤1500 mg
60 (±10) min
>1500 - 2250 mg
90 (±15) min
>2250 mg-3000 mg
120 (±20) min
16,and 20 and 27 mg/kg
≤2250 mg
90 (±15) min
>2250 mg-3000 mg
120 (±20) min
Abbreviation:  min = minutes.

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7.2.1.2.
Ramucirumab Dosing
On treatment days, ramucirumab will be administered after the LY3127804 infusion.  The 
ramucirumab infusion should be started after a minimum of a 60-minute observation period 
(minimum of 30-minute observation period in Cycle 2 and beyond) after the end of the 
LY3127804 administration as specified in Section 7.2.1.2.7.2.1.1.  Should it be 7.2.1.1Every 
attempt should be made in order to start the ramucirumab infusion NO later than 60 minutes after 
the end of the LY3127804 infusion.
7.2.1.3.
Paclitaxel Dosing
Patients will receive paclitaxel by IV infusion over approximately 60 minutes at 80 mg/m2 on 
Days 1, 8, and 15, every 28 days. 
On treatment days the paclitaxel will be administered after the ramucirumab infusion.  Refer to 
the manufacturer’s instructions for complete prescribing information and follow institutional 
procedures for administration of paclitaxel. 
The patient’s first dose of paclitaxel is dependent upon the patient’s baseline body surface area 
(BSA).  Subsequent doses of paclitaxel must be recalculated if the patient’s BSA changes by 
10% from his or her baseline BSA.
On Day 1 of each cycle, the patient must meet the criteria shown in Table 7.2.2prior to 
administration of paclitaxel.  On Day 8 and Day 15, the patient must meet the criteria shown 
inTable 7.2.3. 
Table 7.2.2.
Criteria to Be Met Prior to Paclitaxel Administration
On Day 1 of Each Cycle
Laboratory Test
Required Value
Neutrophils
1.5 × 109/L
Platelets
100 × 109/L
Hemoglobin
8.0 g/dL
Serum creatinine or CrCl
1.5 × ULN or CrCl 50 mL/min
Bilirubin
1.5 × ULN
AST/ALT

if the patient has liver metastases
5 × ULN

if the patient does not have liver metastases
3 × ULN
Paclitaxel related toxicities/AEs (except for clinically 
insignificant events, as determined by the investigator)
CTCAE Grade <2 or the patient's baseline level
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CrCl = creatinine clearance; CTCAE = Common Toxicity Criteria for Adverse Events; ULN = upper limit of 
normal.

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Table7.2.3.
Criteria to Be Met Prior to Paclitaxel Administration
On Day 8 and Day 15 of Each Cycle
Laboratory Test
Required Value
Neutrophils
1.0 × 109/L
Platelets
75 × 109/L
Hemoglobin
8.0 g/dL
Bilirubin
1.5 × ULN
AST/ALT

if the patient has liver metastases
5 × ULN

if the patient does not have liver metastases
3 × ULN
Paclitaxel related toxicities/AEs (except for clinically 
insignificant events, as determined by the investigator)
CTCAE Grade <2 or the patient's baseline level
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = Common Toxicity Criteria for Adverse Events; ULN = upper limit of normal.
Premedication is required prior to infusion of paclitaxel according to the manufacturer’s 
instructions and local standards.  Recommended premedication include:

dexamethasone 8 to 20 mg (or equivalent) administered:
o
orally 12 hours and 6 hours prior to paclitaxel, or
o
intravenously 30 to 60 minutes prior to paclitaxel

an antihistamine (H1 antagonist) such as diphenhydramine hydrochloride (or equivalent) 
50 mg 

cimetidine (H2 antagonist) (or equivalent) 300 mg 
Additional premedication may be provided at the investigator’s discretion. On treatment days 
with paclitaxel, premedication administered for ramucirumab need not be repeated for 
premedication for paclitaxel.  An antiemetic, such as ondansetron 8 mg administered orally or 
intravenously (or equivalent) 30 to 120 minutes before paclitaxel, is recommended.
7.2.2. Dose Escalation
Table JQBA.7.2.2.
Planned Dose Levels and Treatment Schedule by Cohorts

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Patients in Parts A through C (Cycle 2 or greater) and Part D through E will be evaluated on an 
ongoing basis for AEs.  .
7.2.2.5.
Dose Confirmation for LY3127804 + ramucirumab in Part D
The dose and schedule of LY3127804 in combination with ramucirumab 8mg/kg  for 
combination treatment in Part D will be defined based on safety, PK/PD, and antitumor activity 
observed in Parts A and B.  The sponsor, in collaboration with the investigators, will review 
Parts A and B results prior to determining the recommended schedule and dose of LY3127804 to 
be studied in Part D.  The decision will be documented in writing and a written notification will 
be sent to the IRB prior to enrollment of patients into Part D.  No amendment will be required.  If 
indicated by safety, PK/PD, and/or emerging clinical data, the recommended schedule and dose 
of LY3127804 and ramucirumab in Part D might be adjusted following written notification by 
the sponsor.  Patients in Part D will be treated at a dose and schedule of LY3127804 in 
combination with ramucirumab no greater than the dose and schedule explored in Part B.
7.2.2.6.
Dose Exploration for LY3127804 + ramucirumab/Paclitaxel in Part E
This part of the study will consist of evaluating 2 different doses of LY3127804 in combination 
with a “fixed” dose of ramucirumab (either 8 mg/kg or 12 mg/kg) and paclitaxel (80mg/m2).
The sponsor, in collaboration with the investigators, will review the results of Parts A through C 
prior to determine the recommended dose for LY3127804 and for ramucirumab (ramucirumab 8 
or 12mg/kg; Q2W) to be evaluated in combination with paclitaxel 80mg/m2 (day 1, 8, and 15).  
Available safety data from Study JVCZ combining ramucirumab 12 mg/kg Q2W and paclitaxel 
80mg/m2 day 1, 8, and 15 will be reviewed as well (see also Section 5.5.2).  The decision for 
dose levels of ramucirumab and LY3127804 to be explored in Part E will be documented in 
writing, and a written notification will be sent to the IRB prior to enrollment of patients into Part 
E.  No amendment will be required.  Based on the results from this review, patients in Part E will 
receive ramucirumab and paclitaxel at a fixed dose in combination with LY3127804 starting at 
least 1 dose level below the RP2D for LY3127804 in combination with ramucirumab in Part D.  
If tolerated in the initial cohort of 3 patients, the LY3127804 dose will be increased to the RP2D 
for LY3127804 in combination with ramucirumab and a total of 6 patients will be enrolled at this 
dose level.  
The cohorts of LY3127804 in combination with ramucirumab and paclitaxel will be determined 
to be safe if the incidence of DLTs (Section7.2.2.1) is <33%. If a DLT is observed in 1 out of 3 
patients in the initial cohort, the sponsor, together with the investigators, will examine the safety.  
Following consultation, the sponsor and the investigators will decide if the dose level is 
intolerable or, in case of confounding events (e.g., ambiguity whether any toxicity with a 
potential DLT characteristic is possibly related to study treatment, the underlying tumor disease, 
or concomitant medication), additional patients may be enrolled at the this dose level to further 
investigate the tolerability.  If >2 patients experience a DLT at either cohort, further dose 
exploration of this combination treatment will cease, and lower dose levels of LY3127804 and/or 
ramucirumab may be explored in combination with paclitaxel. No amendment will be required in 
this case.

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7.2.2.7.7.2.2.5.
Dose Adjustments and Delays
In Cycle 1, no dose adjustments or delays of LY3127804 or the combination of LY3127804 and 
ramucirumab +/ paclitaxel will be allowed (ie, DLT assessment period), except in case of any 
DLT or safety concerns following discussion and written approval by the study CRP.
In Parts B through and DC, 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 Part E, initiation of a new treatment cycle will be defined by administration of paclitaxel.  If 
paclitaxel cannot be administered on the planned Day 1 of the next cycle, LY3127804 + 
ramucirumab will be administered within the current cycle.  Once paclitaxel can be administered, 
the new treatment cycle will start, and LY3127804, ramucirumab and paclitaxel administration 
should be synchronized.  If a patient cannot be treated with 1 component of the study therapy 
(LY3127804, ramucirumab, or paclitaxel) for more than 28 days from the last administered dose, 
that component will be permanently discontinued.  The other component should be continued, 
with the patient remaining on study, if clinically indicated.
7.2.2.8.7.2.2.6.
Dose Modifications—LY3127804
7.2.2.9.7.2.2.7.
Dose Modifications—Ramucirumab
7.2.2.10.7.2.2.8.
Infusion-Related Reactions
7.2.2.11.7.2.2.9.
Hypertension
7.2.2.12.
Dose Modifications Paclitaxel
This section provides instructions for paclitaxel dose modifications applicable if the patient 
experiences AEs or laboratory toxicities possibly related to paclitaxel.
On Days 8 and 15 of each cycle, the patient must meet the criteria shown inTable 7.2.3.  If the 
patient does not meet these criteria, omit the paclitaxel dose.  
If the patient experiences any of the following CTCAE toxicities, reduce the paclitaxel dose by 
10 mg/m2 beginning at the next cycle:

Grade 4 hematological toxicity

Grade 3 paclitaxel related nonhematological toxicity that is clinically significant (as 
determined by the investigator)
Discontinue paclitaxel if the patient experiences Grade 4 nonhematological toxicity that is 
related to paclitaxel.
No reductions of the paclitaxel dose are allowed within a given cycle.  Any patient who requires 
a paclitaxel dose reduction will continue to receive a reduced dose.
Any patient who has had 2 paclitaxel dose reductions and who experiences a toxicity that would 
cause a third dose reduction must be discontinued from paclitaxel.
7.5.
Concomitant Therapy

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LY3127804
Patients should receive full supportive care with the exception that the routine use of granulocyte 
colony–stimulating factors is not permitted during Parts parts A, B, and C, and D of this study.  
The use of colony-stimulating factors may be given as needed for patients in Part E and follow 
local guidelines.
7.6.
Treatment Compliance
LY3127804, and ramucirumab, and paclitaxel will be administered intravenously at the 
investigational site, under the direction of the investigator.  
8.1.2. Adverse Events
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 CTCAE v4.0, and the investigator should make an effort to try to 
allocate the observed AEs to the underlying disease, LY3127804, ramucirumab, paclitaxel, or the 
combination of treatments.
In addition addition, all AEs related to protocol procedures must be reported to Lilly or its 
designee
The investigator will decide whether he or she interprets the observed AEs as either related to 
disease, to which one of the study medications (if possible), to study procedure, or to other 
concomitant treatment or pathologies.  
8.1.4. Safety Monitoring
A 24-hour urine collection will be required at screening for any patients with a urine dipstick (or 
equivalent) of ≥2+ to document the proteinuria to be <2 g/24 hours (as a proteinuria of 
>2 g/24 hours will exclude the patient from study participation).  ).  During trial treatment, 
worsening in the proteinuria assessments (urine dipstick) result: s ≥2+) will trigger an additional 
24-hour urine collection to exclude a (treatment-related) proteinuria >3.5 g/24 hours (which will 
require the study treatment to be stopped)
8.3.
Efficacy Evaluations
Each patient will be assessed by 1 or more of the following radiologic tests for tumor 
measurement:

CT scan

MRI
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
Radiological images may be collected centrally and overread.

I7W-MC-JQBA(d) Phase 1 Oncology Protocol 
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LY3127804 
Optional DCE-MRI may be performed but will be subject to agreement between sponsor and 
investigator.  For those patients, a DCE-MRI should be performed prior to study entry, after 
approximately 2 weeks of therapy, and eventually after approximately 4 weeks of therapy.  The 
timing of the on-treatment DCE-MRI might be adjusted based on emerging information and 
following discussion between the sponsor and the investigators. Centralized independent 
reviewers will be involved in reviewing the imaging (DCE-MRI) data to minimize any bias in 
radiological assessment. 
10.1. General Considerations 
This is a Phase 1 study with an open-label, dose-escalation design.  Patients will be enrolled into 
cohorts sequentially without randomization to dose level.  During dose escalation, the total 
sample size per cohort will be guided by the standard oncology 3+3 method and determined by 
the occurrences of DLTs for the monotherapy-treated patients.  The LY3127804 plus 
ramucirumab combination cohorts will enroll 6 patients per dose level.  The size of 6 patients per 
combination cohort will ensure a broad (safety) base before exploring a higher dose of 
LY3127804 in the combination setting and is assumed to be beneficial for the patients 
(therapeutic dose of ramucirumab).  The total sample size is estimated to be approximately up to 
84 72 patients.  In Parts A through C, the sample size is estimated to be approximately 45 to 60 
patients.  In Part D, a total of approximately 6 12 patients has been selected to confirm safety of 
selected RP2D.  In Part E, a total of approximately 9 12 patients has been estimated to explore 
and confirm RP2D range and schedule of LY3127804 in combination with ramucirumab and 
paclitaxel.  
10.10. Safety Reviews and Interim Analyses 
After all patients who are deemed evaluable for the assessment of dose levels complete the DLT 
evaluation period or MTD is determined in Parts A and B, an interim safety and available PK 
data review will be conducted. for planning Part D.  A further safety review is planned after 
completion of Part C to inform dosing in Part E or next studies.  The decision to proceed to Part 
D and E will be made following discussions between the investigators and Lilly clinical research 
personnel.   
During Part D and E, interim analyses may be conducted to review available safety, PK, and PD.  
The goal of the interim analyses is to aid in the planning of future trials.  Further interim analysis 
may be considered if deemed appropriate by the sponsor. 
 
12. 
References 
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, 
Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, 
Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab 
plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced 
gastric or gastro oesophageal junction adenocarcinoma (RAINBOW): a double blind, 
randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224 35. 

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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LY3127804
therapy with sorafenib (REACH): a randomised, double blind, multicentre, phase 3 trial. 
Lancet Oncol. 2015 Jul;16(7):859 70.

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LY3127804
Attachment 1.Protocol JQBA Study Schedule
During and Poststudy Assessments
Cycle 1
Cycle 2
Cycle 
3-n
Follow-
Up
Comments
30-day 
(V801)
Relative Day 
Within a Cycle
1
2
4 or 
5
8
15
16
22
1
8
15
22
1
8
15
In Cycle 2 and beyond, visits may be performed ±3 days 
around scheduled visits.  No shortening of the treatment 
cycles is allowed
LY3127804
X
X
X
X
X
X
Ramucirumab
X
X
X
X
X
X
Only patients in Parts B and C, D, and E
Paclitaxel
X
X
X
X
X
X
X
X
X
Only patients in Part E
Physical 
examination
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
Temperature, pulse rate, RR, and BP. On study drug infusion 
days, measure pulse rate and BP within 15 min prior to 
infusion(s), after completion of each infusion(s), and 1h after 
completion of the last antibody infusion. Additional 
measurements as clinically indicated.  Day 2 Cycle 1 only for 
patients in Parts A, B, and C
Central ECG 
(12 lead)
X
X
X
X
X
Only for patients in Parts A, B, and C during Cycle 1 and 2; 
see Attachment 4 for exact timing; triplicate ECGs to be 
conducted
Local ECG 
(12 lead)
X
X
X
X
X
X
Single ECGs to be conducted predose; if a central ECG is 
performed at the same time point for patients in Parts A, B, 
and C during Cycle 1 and 2, no additional local ECG needs to 
be performed

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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LY3127804
Cycle 1
Cycle 2
Cycle 
3-n
Follow-
Up
Comments
30-day 
(V801)
Relative Day 
Within a Cycle
1
2
4 or 
5
8
15
16
22
1
8
15
22
1
8
15
In Cycle 2 and beyond, visits may be performed ±3 days 
around scheduled visits.  No shortening of the treatment 
cycles is allowed
Hematology
X
X
X
X
X
X
X
X
X
X
See Attachment 2; may be done within 3 days prior to 
administration of study drugs (except Cycle 1, Day 1 [within 
3 days]); Only patients in Part A-DC:  Day 8 only in Cycle 
1 and Day 15 in Cycle 3 and beyond only if abnormal 
(different from previous assessment) on Day 1 
Coagulation 
X
X
X
X
X
X
X
X
See Attachment 2; may be done within 3 days prior to 
administration of study drugs (except Cycle 1, Day 1 [within 
3 days]); in Cycle 3 and beyond, Day 15 only if abnormal 
(different from previous assessment) on Day 1
Serum chemistry
X
X
X
X
X
X
X
X
X
X
See Attachment 2; may be done within 3 days prior to 
administration of study drugs (except Cycle 1, Day 1 [within 
3 days]); Only patients in Part A-DC: Day 8 only in Cycle 
1, and Day 15 in Cycle 3 and beyond only if abnormal 
(different from previous assessment) on Day 1
Urinalysis
X
X
X
X
X
X
X
X
See Attachment 2; 24-hour collection if dipstick worsened 
after initiation of study treatment; in Cycle 3 and beyond, Day 
15 only if abnormal (different from previous assessment) on 
Day 1
TSH +fT4
X
X
See Attachment 2; Cycle 3, Cycle 5, Cycle 7, and every 
4 cycles thereafter
Adverse event 
reporting 
X
X
X
X
Throughout study as needed (according CTCAE v4.0 
grading).  Refer to Section 8.1.2.2 for reporting guidelines
Concomitant 
medications
X
X
X
X
Throughout study as needed.

I7W-MC-JQBA(d) Phase 1 Oncology Protocol
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LY3127804
Cycle 4
Day 1
0
16 
Predose LY
X
X
Visit 
801 
follow 
up
720
17 
30 day post last dose
X
X
Note:  PK/PD samples and ECGs up to 4 hours after the end of LY3127804 should be obtained within ±10 minutes of the scheduled sampling time.  It is 
essential that the actual date and times of ALL LY3127804 and ramucirumab doses are recorded accurately in the eCRF and date and times of collection of 
PK samples are recorded accurately on the appropriate forms.
Abbreviations:  EOI = end of LY infusion; h = hour; IV = intravenous; LY = LY3127804; PK = pharmacokinetic; PD = pharmacodynamic; 
a Cycle length = 28 days.
b Approximate time relative to start of last LY3127804 dose given (except for predose).
c
Up to 5 additional PK samples can be drawn from each patient during the study, at the discretion of the sponsor after communication with the investigator.  
The number of sampling time points might be reduced if PK/PD has been sufficiently characterized and if approved in writing by the sponsor.
d
This sample should be taken immediately after the end of ramucirumab infusion.

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LY3127804
Attachment 8.
Protocol JQBA Sampling Summary
Purpose
Sample Type
Maximum 
Amount per 
Sample
Maximum 
Number 
Samples
Maximum Total 
Amount
Study qualificationa
Blood
105 mL
46
40 30 mL
Health monitoring (may 
be more than 1 tube)b
Blood
10 5 mL
2452
240 260 mL
PD/tailoring biomarkers 
Tissue biopsy
5 mm, 0.5 oz, 
1 cc
2
10 mm
1 oz
2 cc
Drug concentration
Blood
4 3.5 mL
28
112 98 mL
PD biomarkers
Serum/pPlasm
a
10 mL
1219
120 190 mL
Tailoring 
biomarkersPharmacogenet
ics
Blood
3 10 mL
31
9 10 mL
Immunogenicity
Blood
10 8.5 mL
4 14
40 119 mL
Hepatic monitoringb
Blood
3 - 30 mL
—
—
Total
Blood: 441517 mL
Tissue biopsy:  10 mm,
1 oz, 2 cc
Serum/pPlasma: 120 190
mL

Leo Document ID = 696ee745-9b5a-4b24-a3ee-6d1689c87454
Approver: 
Approval Date & Time: 08-Sep-2017 18:46:07 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Sep-2017 09:19:12 GMT
Signature meaning: Approved
PPD
PPD