Conditions: Neoplasms Neoplasm Metastasis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the safety of a study drug known as LY3164530 in participants with cancer that is advanced and/or has spread to another part(s) of the body.

Detailed description:

Arms:
arm 1: LY3164530 in escalating dose cohorts given intravenously (IV) once on Days 1 and 15 or on Days 1, 8, 15, and 22 of a 28-day cycle. Participants may continue to receive study drug until discontinuation criteria are met.

Interventions: intervention 1: LY3164530
Intervention descriptions: intervention 1: Administered IV.

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol I7H-MC-JNBA(b) 
 
 
A Phase 1 Study of LY3164530, a Bispecific Antibody Targeting MET and EGFR, in Patients 
with Advanced or Metastatic Cancer 
 
 
NCT02221882 
 
 
Approval Date: 28-Sep-2015 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530
1. Protocol I7H-MC-JNBA(b)
A Phase 1 Study of LY3164530, a Bispecific Antibody 
Targeting MET and EGFR, in Patients with Advanced or 
Metastatic Cancer
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3164530, a bispecific antibody targeting MET and EGFR, 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 UnitedStates Freedom of 
Information Act (FOIA) Exemption4.
Anti-MET/EGFRB
ispecific Antibody(LY3164530)
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study of 
intravenous LY3164530in patients with advanced or metastatic cancer.
Approval Date: 28-Sep-2015 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol ElectronicallyS
igned and Approved by Lilly02 April 2014
Amendment (a) Electronically Signed and Approved by Lilly 11 August 2014
Amendment (b) Electronically Signed and Approved by Lilly on date provided below


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LY3164530
2.
Synopsis
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study of 
intravenous LY3164530 in patients with advanced or metastatic cancer.


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3. Table of Contents
A Phase 1 Study of LY3164530, a Bispecific Antibody 
Targeting MET and EGFR, in Patients with Advanced or 
Metastatic Cancer 
Section
Page
CCI
1.
Protocol I7H-MC-JNBA(b)   A Phase 1 Study of LY3164530, a 
Bispecific Antibody Targeting MET and EGFR, in Patients with 
Advanced or Metastatic Cancer...........................................................................................1
2.
Synopsis.............................................................................................................................2
3.
Table of Contents................................................................................................................3
4.
Abbreviations and Definitions.............................................................................................9
5.
Introduction......................................................................................................................14
5.1. Rationale and Justification for the Study......................................................................14
5.2. Objectives....................................................................................................................15
5.2.1.
Primary Objective................................................................................................15
5.2.2.
Secondary Objectives...........................................................................................15
5.2.3.
Exploratory Objectives.........................................................................................15
5.3. General Introduction to LY3164530.............................................................................15
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................16
5.3.4.
Biomarkers...........................................................................................................18
5.4. Rationale for Selection of Dose....................................................................................19
5.5. Rationale for Amendment (b).......................................................................................19
6.
Investigational Plan...........................................................................................................21
6.1. Study Population..........................................................................................................21
6.1.1.
Inclusion Criteria.................................................................................................21
6.1.2.
Exclusion Criteria................................................................................................22
6.2. Summary of Study Design............................................................................................23
6.2.1.
Primary Endpoint Analysis, Study Completion, and End of 
Trial.....................................................................................................................24
6.3. Discontinuations..........................................................................................................24
6.3.1.
Discontinuation of Patients...................................................................................24
6.3.2.
Discontinuation of Study Sites.............................................................................25
6.3.3.
Discontinuation of the Study................................................................................25
7.
Treatment..........................................................................................................................26


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7.1.
Materials and Supplies .................................................................................................26
7.2.
Study Drug Administration ..........................................................................................26
7.2.1.
Dosing Schedule ..................................................................................................26
7.2.2.
Dose Escalation....................................................................................................26
7.2.2.1.
Dose-Limiting Toxicity Determination ...........................................................26
7.2.2.2.
DLT-Equivalent Toxicities .............................................................................27
7.2.2.3.
Dose Escalation Method.................................................................................27
7.2.3.
Recommended Phase 2 Dose Determination.........................................................30
7.2.4.
Monitoring and Treatment Guidance for the Investigator......................................30
7.2.4.1.
Infusion-Related Reactions.............................................................................30
7.2.4.2.
Skin Reactions................................................................................................31
7.2.5.
Dose Delays and Adjustments..............................................................................31
7.2.5.1.
Dose Delays and Omissions............................................................................31
7.2.5.2.
Dose Adjustments...........................................................................................32
7.3.
Method of Assignment to Treatment ............................................................................34
7.4.
Blinding .......................................................................................................................34
7.5.
Concomitant Therapy...................................................................................................34
7.6.
Treatment Compliance .................................................................................................35
7.6.1.
Evaluable Patients................................................................................................35
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................36
8.1.
Safety Evaluations........................................................................................................36
8.1.1.
Safety Data Collection and Review ......................................................................36
8.1.2.
Adverse Events ....................................................................................................36
8.1.2.1.
Serious Adverse Events ..................................................................................37
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................38
8.1.2.2.1.
Prior to Administration of Study Drug ......................................................38
8.1.2.2.2.
On Therapy...............................................................................................39
8.1.2.2.3.
Follow-Up Visit........................................................................................39
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................39
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................40
8.1.3.
Other Safety Measures .........................................................................................40
8.1.3.1.
Electrocardiograms.........................................................................................40
8.1.4.
Safety Monitoring ................................................................................................41
8.1.5.
Complaint Handling.............................................................................................41
8.2.
Sample Collection and Testing.....................................................................................42
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................42


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8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics..................................................................42
8.2.2.1.
Pharmacokinetic Samples...............................................................................42
8.2.2.2.
Pharmacodynamic Samples ............................................................................42
8.2.3.
Samples for Tailoring Biomarkers........................................................................43
8.2.3.1.
Tumor Tissue .................................................................................................43
8.2.3.2.
Blood Samples for Pharmacogenetic Evaluations............................................44
8.2.3.3.
Exploratory Biomarker Blood Samples...........................................................45
8.2.4.
Samples for Immunogenicity Research.................................................................45
8.3.
Efficacy Evaluations ....................................................................................................45
8.4.
Procedure/Sampling Compliance..................................................................................46
9.
Data Management Methods...............................................................................................47
9.1.
Data Quality Assurance................................................................................................47
9.2.
Data Capture Systems ..................................................................................................47
9.2.1.
Case Report Form ................................................................................................47
9.2.2.
Ancillary Data......................................................................................................47
10.
Data Analyses ...................................................................................................................49
10.1. General Considerations ................................................................................................49
10.2. Patient Disposition .......................................................................................................49
10.3. Patient Characteristics ..................................................................................................49
10.4. Safety Analyses............................................................................................................49
10.5. Pharmacokinetic Analyses............................................................................................50
10.6. Pharmacodynamic Analyses.........................................................................................50
10.7. Pharmacokinetic/Pharmacodynamic Analyses..............................................................50
10.8. Efficacy........................................................................................................................51
10.9. Biomarker Analyses.....................................................................................................51
10.10. Interim Analyses ..........................................................................................................51
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................52
11.1. Informed Consent.........................................................................................................52
11.2. Ethical Review.............................................................................................................52
11.3. Regulatory Considerations ...........................................................................................52
11.3.1.
Investigator Information.......................................................................................53
11.3.2.
Protocol Signatures ..............................................................................................53
11.3.3.
Final Report Signature .........................................................................................53
12.
References ........................................................................................................................54


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List of Tables
Table
Page
CCI
Table JNBA.3. Sample Dose Escalation Schema...................................................................30
Table JNBA.4. Dose Modifications and Treatment Alterations in Patients Treated with 
LY3164530...................................................................................................33
Table JNBA.5. Adverse Event and Serious Adverse Event Reporting Guidelines for 
Study JNBA..................................................................................................40


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List of Figures
Figure
Page
Figure JNBA.1. Dose-finding spreadsheet of the modified toxicity probability interval 
method showing number of patients treated at a given dose vs. number 
of DLTs observed at that dose .......................................................................29


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List of Attachments
List of Protocol Attachments
Attachment
Page
Protocol JNBA Study Schedule .....................................................................56
Attachment 1.
Protocol JNBA Clinical Laboratory Tests ......................................................65
Attachment 2.
Protocol JNBA Pharmacokinetic and Pharmacodynamic Sampling 
Attachment 3.
Schedule........................................................................................................66
Protocol JNBA ECG, Chemistry, and Hematology Collection Schedule ........68
Attachment 4.
Protocol JNBA Hepatic Monitoring Tests for Treatment-Emergent 
Attachment 5.
Abnormality ..................................................................................................70
Protocol JNBA Recommendations for Reporting 
Attachment 6.
Serious Adverse Events .................................................................................71
Protocol JNBA mTPI and Simulation ............................................................72
Attachment 7.
Protocol JNBA Protocol I7-MC-JNBA(b) Amendment Summary A 
Attachment 8.
Phase 1 Study of LY3164530, a Bispecific Antibody Targeting MET 
and EGFR, in Patients with Advanced or Metastatic Cancer ..........................74


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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.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the serum concentration-time curve
AUC(0-tlast)
area under the serum concentration-time curve from time zero to last measurable 
serum concentration
AUC(0-∞)
area under the serum concentration-time curve from time zero to infinity
AUC0-τ
area under the serum versus time concentration-time curve over the dosing interval
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).
Cav,τ
average serum concentration over the dosing interval
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
systemic clearance
Cmax
maximum serum concentration
Cmin,τ
minimum serum concentration over the dosing interval
CNS
central nervous system


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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.
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
CSF
colony-stimulating factor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
D
deescalate the dose
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DU
deescalate the dose due to unacceptable toxicity
E
escalate the dose
EC50
the half maximal effective serum concentration
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
EGFR/ECD
epidermal growth factor receptor extracellular domain
EI
equivalence interval
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a treatment 
and have received at least one dose of study treatment.  
enter
Patients who are entered in the trial are those who have signed the informed consent 
form directly 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.
FISH
fluorescence in situ hybridization
GCP
good clinical practice
HGF
hepatocyte growth factor
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IgG
immunoglobulin G
IHC
immunohistochemistry
IV
intravenous
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.
interim 
analysis
An analysis of clinical study data that is conducted before the final 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.
Lilly Safety 
System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
MedDRA
Medical Dictionary for Regulatory Activities
MET
mesenchymal-epithelial transition factor
MET/ECD
mesenchymal-epithelial transition factor extracellular domain
monitor
A person responsible for ensuring the investigator site complies with the monitoring 
plan, applicable local SOPs (if any), and global Medical SOPs.  Monitors are trained
on the investigational product(s), the protocol, informed consent document, any other 
written information provided to subjects, relevant SOPs, International Conference on 
Harmonisation Good Clinical Practice guidelines (ICH-GCP), and all applicable laws 
(for example, privacy and data protection) and regulations.  


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MRI
magnetic resonance imaging
mRNA
microribonucleic acid
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
NCI
National Cancer Institute
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.
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
QTc
corrected QT interval
Q2W
once every 2 weeks
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase 2 dose
S
stay at the same dose
SAE
serious adverse event
SCCHN
squamous cell cancer of the head and neck
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
SE
standard error
Sponsor
The party who takes responsibility for the initiation, management, and/or financing 
of a clinical study.
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TGF
transforming growth factor
TPO
third-party organization
ULN
upper limit of normal


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V
volume of distribution


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A Phase 1 Study of LY3164530, a Bispecific Antibody 
Targeting MET and EGFR, in Patients with Advanced or 
Metastatic Cancer
5.
Introduction
5.1.
Rationale and Justification for the Study
The epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition factor 
(MET) are receptor tyrosine kinases that each play a key role in cancer signaling.  They are co-
expressed in many tumors, and crosstalk between the signaling pathways controlled by these 
receptors has emerged as a major mechanism for cancer progression and resistance to therapy.  
Mesenchymal-epithelial transition factor, also known as the hepatocyte growth factor (HGF) 
receptor, and its ligand HGF, have a significant role in tumor growth and metastasis.  Aberrant 
MET signaling has been implicated in the development of many human cancers, including 
breast, cholangiocarcinoma, colorectal, endometrial, esophageal, head and neck, gastric, renal, 
pancreatic, bladder, liver, lung, prostate, melanoma, thyroid, and ovarian cancers (Gherardi et al.
2012).  Mesenchymal-epithelial transition factor signaling alterations can result from the 
overexpression of HGF or MET, activating mutations in MET, transactivation, autocrine or 
paracrine signaling, or MET gene amplification (Graveel et al. 2013).  In addition, MET/HGF is
a critical player in developed resistance to targeted therapies, including therapies directed at 
EGFR (Remon et al. 2014).  
Epidermal growth factor receptor signaling has a crucial role in tumor biology by modulating 
cellular proliferation, angiogenesis, metastasis, and survival of cancer cells.  Therapies targeting 
EGFR signaling are used to treat non-small cell lung, colorectal, pancreatic, and head and neck 
cancers.  Multiple mechanisms of resistance to EGFR-targeted therapies have been identified,
and include mutations in EGFR and downstream proteins such as KRAS, histologic 
transformation, and the activation of alternative pathways, including the MET signaling pathway 
(Chong and Janne 2013).  
Co-expression and activation of MET and EGFR are found in a number of tumor types,
including non-small cell lung, colorectal, gastric, and head and neck cancers (Scheving et al.
2002; Bonine-Summers et al. 2007; Nanjo et al. 2013).  Blocking one receptor tends to up-
regulate the other, leading to resistance to single-agent treatment (Engelman et al. 2007).  
Amplification of MET and/or high levels of HGF expression has been observed in non-small cell 
lung cancer patients with intrinsic or acquired resistance to tyrosine kinase inhibitors of EGFR, 
including erlotinib and gefitinib (Engelman et al. 2007; Yano et al. 2011).  Conversely, MET-
amplified lung cancer cells exposed to MET-inhibiting agents for a prolonged period develop 
resistance via the EGFR pathway (McDermott et al. 2010).  
The crosstalk between the MET and EGFR pathways suggests that dual inhibition of these 
targets may lead to improved outcomes for patients with an MET- and EGFR-positive cancer,


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LY3164530
and that simultaneous inhibition may overcome or delay resistance compared to blockade of just 
1 pathway.
Unlike early versions of bispecific antibodies, which simply aimed at crosslinking receptors on 
the surface of immune cells, LY3164530 is an engineered bispecific antibody designed to 
neutralize, internalize, and disrupt signaling via both the MET and EGFR receptors.  It consists 
of an immunoglobulin G (IgG)4 antibody to MET and a single-chain variable fragment (scFv) to 
EGFR fused to the N-terminus of each heavy chain.  LY3164530 consists of 2 identical heavy 
chains and 2 identical light chains.  
This bispecific antibody may offer an advantage over combining 2 different antibodies since, as 
described below (Section 5.3) and in the Investigator’s Brochure, the dual inhibition may lead to 
more efficient internalization and subsequent degradation of both the MET and EGFR receptors.  
The initial Phase 1 study with LY3164530, Study I7H-MC-JNBA (JNBA), will characterize the 
safety and determine the recommended Phase 2 dose (RP2D) of LY3164530 in patients with 
advanced or metastatic cancer.
The Sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.
5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to determine an RP2D and schedule of LY3164530 that 
may be safely administered to patients with advanced or metastatic cancer.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3164530

to estimate the pharmacokinetic (PK) parameters of LY3164530

to document any antitumor activity observed with LY3164530.
5.2.3. Exploratory Objectives
The exploratory objectives of this study are:

to explore the effect of LY3164530 on pharmacodynamic (PD) markers 

to identify exploratory biomarkers associated with tumor response and/or 
safety.  
5.3.
General Introduction to LY3164530
LY3164530 is an engineered bispecific antibody targeting MET and EGFR, derived from a MET 
antibody (LY2875358) and humanized cetuximab, an EGFR antibody.  During Phase 1 dose 


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escalation,LY2875358 has been well tolerated.  No dose-limiting toxicities (DLTs), serious 
adverse events (SAEs), or ≥Grade 3 adverse events (AEs)possibly related to LY2875358 were 
reported at doses up to 2000 mg administered every 2 weeks. The most frequent AEs possibly 
related to LY2875358 were nausea (8.7%), vomiting (8.7%), and diarrhea (8.7%) (Goldman et al.
2013).  The toxicities of cetuximab have been well characterized, and include cutaneous AEs 
(rash, pruritus, and nail changes), diarrhea,and infusion-relatedreactions.  It is expected that 
LY3164530 will have a toxicity profile consistent with these agents.  
More information about the known and expected benefits, risks,and reasonably anticipated AEs 
may be found in the Investigator’s Brochure.  Information on AEs expected to be related to the 
investigational productmay be found in Section 7 (Development Core Safety Information) of the 
Investigator’s Brochure.  Information on SAEs expected in the study population independent of 
drug exposure and that will be assessed by the Sponsorin aggregate, periodically during the 
course of the study, may be found in Section 6 (Effects in Humans) of the Investigator’s 
Brochure.
5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
CCI
LY3164530 has high affinity for both MET and EGFR and binds both receptors simultaneously
in tumor cells.  As described in the Investigator’sBrochure(Section 5.2.2), binding of 
LY3164530 to MET and EGFR blocks activation of both receptors by their respective ligands.  
In addition to its ligand-blocking activity, LY3164530 also leads to internalization and 
degradation of both receptors in tumor cells.  The ability of LY3164530 to internalize both 
receptors is superior to the combination of individual monoclonalantibodies.  The internalization 
of both receptors is most commonlyobserved in cells expressing high levels of MET.  In 
addition, LY3164530 also increases the avidity binding to MET in cells expressing both MET 
and EGFR, leading to better neutralizationof HGF compared to the parental MET antibody 
alone or in combination with cetuximab.  The ability of LY3164530 to block ligand-receptor 
interactionsandefficiently internalize MET and EGFR,and its increased avidity for MET,is 
believed to be responsible for the in vitro antiproliferative activity observed against a panel of 
tumor cell lines.  In vivo, administration of LY3164530 results in dose-dependent antitumor 
activity in cell line-derived non-small cell lung cancer,gastriccancer,and squamous cell cancer 
of the head and neck (SCCHN)xenografts,as well as in colorectal cancer and SCCHN patient-
derived xenografts.  


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CCI


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5.3.4. Biomarkers
CCI
In order to assess the capacity of LY3164530 to inhibit the MET and EGFR pathways, pre-and 
post-treatment assessments of circulating biomarkers including, but not limited to,the MET 
ligand (HGF), EGFR ligands (eg,EGF, transforming growth factor [TGF]-alpha), MET 
extracellular domain (MET/ECD), and EGFR extracellular domain (EGFR/ECD)may be 
analyzed.  
Mesenchymal-epithelial transition factorprotein expression in tumors has been linked to clinical 
outcomes to MET therapy (Martens et al. 2006; Jin et al. 2008, Spigel et al. 2013).  Therefore,
pre-treatment tumor biopsy tissue should be obtainedand prior archived tissue will be requested
in order to retrospectively assess potential markers associated with response.  However, for 
patients who have disease recurrence/metastasis in technically challenging sites to obtain 
biopsies or who have tissue available from a prior post-treatment biopsy and have not received 
intervening therapy, the investigator and Sponsor may agree to omit the pretreatment biopsy.  In
archived and pre-treatment tissue samples, analytes related to the MET and EGFR pathways and 
cancer pathobiology including, but not limited to,METandEGFR protein expression may be 
evaluated.  In tumor tissue and circulating deoxyribonucleic acid (DNA),somatic mutation status 
and/or copy number variations of MET and EGFR pathway-related genes (eg,KRAS, BRAF) or 
genes related to cancer pathobiology may be assessed.  In addition, tumor samples may be 
evaluated for potential tumor gene signature(s), potentially employing targeted or high-
throughput sequencing approaches.  
A blood sample will be stored to study genetic variants in drug metabolism and transport, to 
measure levels of target pathway proteins, or for genetic analysis of pathway-related markersof 
either response or toxicity, if deemed necessary by the Sponsor.


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5.4. Rationale for Selection of Dose
A fixed starting dose of 300 mg LY3164530 administeredIV once every 2 weeks was selected 
based on data from nonclinical toxicology studies and modeling ofPK/PD data from nonclinical 
studies of LY3164530.  
 
Thestarting dose is significantly lower than the 
corresponding weekly dose of cetuximabbased on body surface area.  
 
 
 
 
 
See Section 5of the 
LY3164530 Investigator’s Brochurefor additional details.
In addition, astarting dose of 300mgispredicted to be in a range to achieve biological effects in 
humans.  
 
The PK/PD 
relationship (eg, the model structureand maximal effect) observed in MKN45 xenograft models 
was assumed to translate directly to patients with cancer.As a result, whenadministered IV
every2weeks, LY3164530 doses greater than 100 mg are predicted to achieve biological effects 
in humans.Since weight-based dosing of monoclonal antibodies has not been correlated with a 
reduction in PK or PD variability, a fixed-dose strategy was chosen because it minimizes the 
potential for dosing errors in the clinic, eliminates the need for complex dosing algorithms based 
on body size, and is considered to be safe (Wang et al. 2009).  
Based on the data from nonclinical toxicology studies and modeling of PK/PD data,the starting 
dose of LY3164530 in Study JNBA will be 300 mg administered IV once every2 weeks.
5.5. Rationale for Amendment (b)
CCI
As of 27July2015, 15 patients have been treatedin Study JNBA at doses of 300, 600, 1000, and 
1250 mg on Days 1 and 15 of a 28 day cycle.  One DLT (Cycle 1) has been reported in a patient 
at the 1000 mg dose level who experienced intolerable,Grade 2 rash.  Two of the 3patients 
treated at the 1250 mg dose level experienced AEs in Cycle 2 that would have met the criteria for 
a DLT had they occurred in Cycle 1 (DLT-equivalent toxicity).  These events included Grade 3 
pustular rash in one patient and Grade 3 dermatitis acneiform and Grade 4 hypomagnesaemia in 
another patient.  As a result, a dose of 1250 mg was deemed to exceed themaximum tolerated 
dose.  As of 27 July 2015, 6 patients have been treated at the 1000mg dose level and enrollment 
will continue until 10-20 patients have been treatedat the recommended Phase 2dose. 
The drug-related, treatment emergent adverse events reported for LY3164530 are consistent with 
inhibition of EGFR and include skin reactions[maculo-papular rash, dermatitis acneiform, skin 
fissures, rash, skin exfoliation,and/or pustular rash] (n=14, 93.3%), hypomagnesaemia (n=7, 
CCI
CCI


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530
46.7%), and paronychia (n=4, 26.7%).  The following drug-related events occurred in 2 patients 
each (13.3%):  decreased appetite, dysgeuesia, fatigue, and hypokalaemia.  One SAE 
(hypomagnesaemia) was considered to be related to LY3164530 by the investigator and the 
Sponsor.  The event occurred in a metastatic cutaneous squamous cell carcinoma patient who 
had Grade 1 hypomagnesaemia at baseline that worsened and resulted in study drug 
discontinuation.
An interim analysis of the LY3164530 PK data was conducted from all of the 15 patients who 
received at least 1 dose of LY3164530 administered as a 1 or 2-hour infusion once every 2
weeks (Q2W) across the dose range of 300-1250 mg. Dose-dependent increases in the systemic 
exposure (AUC, Cmax) of LY3164530 following single and multiple doses were observed. A 
minor amount of accumulation in serum was observed within Cycle 1 and between Cycles 1 and 
2 of treatment after 1000 mg Q2W (mean accumulation ratio of 1.1 within and between cycles). 
The LY3164530 systemic clearance (CL) decreased by approximately 2-fold on average when 
the dose was escalated from 600 mg to 1000 mg, indicating the saturation of cell-surface 
receptors by LY3164530 and a slower non-receptor-mediated clearance predominating at doses 
>600 mg.  While a more rapid receptor-mediated clearance (ie, target mediated drug disposition
[TMDD]) predominates at low doses (ie, ≤600 mg).  In addition, the LY3164530 exposure 
following 1000 mg Q2W appears to be in an exposure range expected to achieve biological 
effects based on the nonclinical MKN45 xenograft PK/PD model estimates for the MET and 
EGFR half maximal effective serum concentrations (EC50) values.  The LY3164530 maximum 
serum concentration (Cmax) after 1000 mg in Cycles 1 and 2 is greater (mean Cmax range: 295-394 
µg/mL) than both the MET EC50 (79.5 µg/mL; 0.4 µM) and EGFR EC50 (7.95 µg/mL; 0.04 µM) 
concentrations. The average LY3164530 serum concentration over the dosing interval (Cav,τ)
during Cycles 1 and 2 is also greater (mean Cav,τ range: 102-132 µg/mL) than the MET EC50 and 
EGFR EC50.  However, the minimum serum concentration over the dosing interval (Cmin,τ) of 
LY3164530 following 1000 mg in Cycles 1 and 2 (mean Cmin,τ range: 19-49 µg/mL) is lower
than the MET EC50 (79.5 ug/mL), which is the desired concentration to maintain throughout the 
dosing interval in order to maximize the biological activity of LY3164530.
At a dose of 1000 mg, the mean terminal elimination-life (t1/2) is approximately 100 hours 
(approximately 4 days).  As a result, the administration of LY3164530 every 2 weeks may not be 
the optimal schedule of administration in order to achieve a LY3164530 Cmin,τ near the MET 
EC50.  Therefore, it is hypothesized that weekly dosing of LY3164530 (ie, Days 1, 8, 15, and 22 
of a 28 day cycle) will minimize the fluctuation between the peak (Cmax) and trough (Cmin,τ)
serum concentrations of LY3164530 leading to a more consistent inhibition of both MET and 
EGFR over the dosing interval (with minimal impact on the accumulation of LY3164530) and 
potentially greater pharmacologic activity (PD response).  The MTD of LY3164530 when 
administered on Days 1 and 15 of a 28 day cycle is 1000 mg.  As a result, the starting dose for 
the weekly schedule will be 500 mg.  The safety, toxicity, PK, and PD associated with a weekly 
schedule will be assessed.  


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LY3164530
6.
Investigational Plan
6.1.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be re-
screened.  Each time re-screening is performed, the individual must sign a new informed consent 
form (ICF) and will be assigned a new identification number.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
[1]
Have histological or cytological evidence of a diagnosis of cancer that is 
advanced and/or metastatic.  The patient must be, in the judgment of the 
investigator, an appropriate candidate for experimental therapy (eg, available 
standard therapies have been used, the patient is not eligible for standard 
curative therapy, or the patient has refused standard therapies).  
[2]
Have the presence of measurable and/or nonmeasurable disease as defined by 
the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
(Eisenhauer et al. 2009).
[3]
Are 18 years of age.
[4]
Have given written informed consent prior to any study-specific procedures.
[5]
Have adequate organ function, including:

Hematologic:  Absolute neutrophil count (ANC) 1.5 x 109 cells /L, 
platelets 100 x 109/L, and hemoglobin 8 g/dL.  Transfusions to meet 
enrollment criteria are not allowed in the 14 days preceding the first dose 
of study drug.  

Hepatic:  Bilirubin 1.5 times upper limits of normal (ULN), alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST) 3 times 
ULN.  If the liver has tumor involvement, AST and ALT equaling 
5 times ULN are acceptable.

Renal:  Serum creatinine 1.5 times ULN.
[6]
Have a performance status of 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale.
[7]
Prior Treatments

Systemic treatments:  Have discontinued previous systemic treatments 
for cancer and recovered from the acute effects of therapy.  Prior to first 
dose of study treatment, patients must have discontinued:


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530

Cytotoxic therapies or targeted agents that are small molecule
inhibitors for 5 half-lives or at least 28 days (whichever is shorter).  

Mitomycin-C or nitrosourea therapy for at least 42 days.

Biologic agents (eg, antibodies) for at least 28 days.

At the discretion of the investigator, hormone-sensitive prostate 
cancer patients receiving gonadotropin releasing hormone agonist 
therapy and breast cancer patients on antiestrogen therapy (eg, an 
aromatase inhibitor) may have that treatment continued while they 
are enrolled in Study JNBA.  However, the treatment should have 
been started at least 3 months prior to first dose of study drug.

Radiation therapy:  Limited field therapy must be completed 2 weeks 
before the first dose of study drug.  All other radiation therapy must be 
completed at least 4 weeks before the first dose of study treatment.  
Patients must have recovered from the acute toxic effects of the treatment 
prior to first dose of study treatment.

Major surgery (excluding biopsy):  Must be completed at least 4 weeks 
prior to first dose of study treatment and patient must have recovered from 
the acute effects of the surgery.
[8]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[9]
Men and women with reproductive potential:  Must agree to use a reliable 
method of birth control during the study and for 3 months following the last 
dose of study drug or country requirements, whichever is longer.
[10] Females with childbearing potential:  Must have had a negative serum 
pregnancy test ≤7 days before the first dose of study drug and also must not be 
breastfeeding.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[11] Have received treatment within 28 days of the initial dose of study drug with 
an investigational product or non-approved use of a drug or device (other than 
the study drug/device used in this study) for non-cancer indications or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
[12] Have serious preexisting medical conditions or concomitant disorders that, in 
the opinion of the investigator, would exclude the patient as a candidate for 
this study.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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[13] Have active central nervous system (CNS) or leptomeningeal metastasis 
(brain metastasis) at the time of study entry.  Patients with a history of a CNS 
metastasis previously treated with curative intent (eg, stereotactic radiation or 
surgery) that have not progressed on follow-up imaging, have been 
asymptomatic for at least 28 days and are not receiving corticosteroids and 
or/anticonvulsants, are eligible.  Patients with signs or symptoms of 
neurological compromise should have appropriate radiographic imaging 
performed before study entry to rule out brain metastasis.  
[14] Have current acute or chronic leukemia.
[15] Have an active symptomatic fungal, bacterial, and/or known viral infection 
including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis 
(screening is not required).  
[16] Have a second primary malignancy that, in the judgment of the investigator or 
Sponsor, may affect the interpretation of results.
[17] Have Bazett’s corrected QT interval (QTc) of >470 msec on screening 
electrocardiogram (ECG) in repeated measurements.
Note:  Patients with permanent pacemakers may enter study if QTc is 
>470 msec if measured from a paced conduction and not an intrinsic (non-
paced beat) conduction.  
[18] Have a serious cardiac condition, such as congestive heart failure; New York 
Heart Association Class III/IV heart disease; unstable angina pectoris; 
myocardial infarction within the last 3 months; valvulopathy that is severe, 
moderate, or deemed clinically significant; or arrhythmias that are 
symptomatic or require treatment (not including patients with rate-controlled 
atrial fibrillation).
[19] Have a known allergy/history of hypersensitivity to any of the study drug 
components, or to monoclonal antibodies or other therapeutic proteins such as 
fresh frozen plasma, human serum albumin, cytokines, or interleukins.
6.2.
Summary of Study Design
Study JNBA is a multicenter, nonrandomized, open label, dose escalation Phase 1 study of IV 
LY3164530 in patients with advanced and/or metastatic cancer. Eligible patients will receive 
LY3164530 as an infusion on Days 1 and 15 (Schedule 1) or on Days 1, 8, 15, and 22 (Schedule 
2) of each cycle.  A cycle will consist of 28 days and the schedules will enroll in parallel. 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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Dose escalation will be driven by a modified toxicity probability interval (mTPI) method.  The 
RP2D and schedule will be determined once at least 10 patients, but no more than 20, are treated 
at a dose and schedule that is at or below the maximum tolerated dose (MTD).  The actual 
sample size for Study JNBA is anticipated to be approximately 50 patients depending on the 
incidence of DLTs.
The planned duration of treatment is 2 cycles. Patients who are receiving benefit from study 
drug may continue to be treated with LY3164530 until 1 or more of the criteria for 
discontinuation have been fulfilled (Section 6.3.1).  
6.2.1. Primary Endpoint Analysis, Study Completion, and End of Trial
The primary endpoint analysis will occur after the final patient enrolled has been evaluated for at 
least 1 cycle.  Any patient enrolled that has completed at least 1 cycle of treatment or 
discontinued due to an AE (during Cycle 1), and completed the required post-treatment safety 
assessment, will be considered to have completed the study.  However, additional cycles of 
therapy may continue as long as the patient is receiving benefit and no criteria for 
discontinuation have been met. All secondary/exploratory endpoint analyses will be updated at 
study completion.
Both the study completion and end of trial will be the date of the last visit or last scheduled 
procedure for the last patient.
6.3.
Discontinuations
6.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly. If a patient who did not meet enrollment 
criteria and was inadvertently enrolled is identified, either by the Sponsor or investigator, a 
discussion must occur between the clinical research physician (CRP)/clinical research scientist 
(CRS) and the investigator to determine if the patient may continue in the study.  The 
investigator must obtain documented approval from the Lilly CRP/CRS to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with study drug.
In addition, patients will be discontinued from the study drug and from the study in the following 
circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530

Investigator/Physician Decision
o
the investigator/physician decides that the patient should be discontinued from the 
study or study drug

Patient Decision
o
the patient requests to be discontinued from the study or study drug

Sponsor Decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP

The patient has radiographic progressive disease or significant symptomatic disease 
deterioration characterized as progression of disease, in the opinion of investigator, in the 
absence of radiographic evidence of progressive disease.

The patient experiences unacceptable toxicity.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

A dose cannot be administered within 28 days of the prior dose due to an AE (except as 
noted in Section 7.2.5.1).
6.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for any scientific, medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.
6.3.3. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges it necessary for any scientific, medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.


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LY3164530
7.
Treatment
7.1.
Materials and Supplies
LY3164530 is supplied for clinical trial use as a lyophilized powder in a glass vial.  The vial is 
manufactured to deliver 75 mg of LY3164530. LY3164530 will be supplied to the investigative 
sites by Lilly.  Detailed instructions for the reconstitution of the study drug and the preparation 
of the different dilutions will be provided separately by the Sponsor.
LY3164530 should be stored refrigerated at 2 to 8°C.
7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agent and planned duration of each 
individual’s treatment to the site personnel or patient

verifying that instructions are followed properly 

maintaining accurate records of study drug dispensation, destruction, and collection

returning or destroying all unused medication to Lilly or its designee at the end of the 
study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
7.2.1. Dosing Schedule
For doses ≤1000 mg, LY3164530 will be administered intravenously over approximately 
60 minutes. The Sponsor may instruct sites to extend the infusion time for up to 3 hours for 
doses >1000 mg. 
LY3164530 will be administered on Days 1 and 15 every 28 days (Schedule 1) or on Days 1, 8, 
15, and 22 every 28 days (Schedule 2).  The assigned dose, schedule, and duration of infusion of 
LY3164530 will be provided by the Sponsor on a patient registration form. A patient will be 
assigned to either Schedule 1 or Schedule 2 and will be maintained on that schedule for the 
duration of therapy.  Subsequent doses and/or infusion times should be adjusted as described in 
Section 7.2.5.
7.2.2. Dose Escalation 
7.2.2.1.
Dose-Limiting Toxicity Determination  
Dose-limiting toxicity is defined as an AE during Cycle 1 that is considered by the investigator 
to be at least possibly related to LY3164530 and fulfills any one of the following criterion using 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.03:

Grade 3 non-hematological toxicity.  Exceptions will be made for:


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530

nausea, vomiting, diarrhea, and constipation that can be controlled with 
treatment.  Grade 3 and Grade 4 nausea, vomiting, or diarrhea should be 
considered DLTs if persisting more than 48 hours despite supportive 
intervention.

Grade 3 rash that resolves with treatment to ≤Grade 1 within 14 days

Grade 3 or 4 asymptomatic electrolyte abnormalities that respond to 
standard treatment

Grade 3 elevations of ALT and/or AST lasting fewer than 8 days, without 
evidence of other hepatic injury, in the setting of preexisting hepatic 
metastasis and baseline elevation of these values, may not be considered a 
DLT if agreed by the study investigator and Lilly CRP/CRS.

Grade 4 neutropenia or leukopenia, of >7 days duration.

Grade 4 thrombocytopenia of any duration.

Grade 3 thrombocytopenia with bleeding.

Any febrile neutropenia.

Any other significant toxicity deemed by the primary investigator and Lilly
clinical research personnel to be dose limiting (eg, any toxicity that is possibly 
related to the study drug that requires the withdrawal of the patient from the study 
during Cycle 1).
7.2.2.2.
DLT-Equivalent Toxicities
A DLT-equivalent toxicity is defined as an AE occurring in Cycle 2 and beyond that would have 
met the criteria for a DLT if it had occurred during Cycle 1.  For individual patients experiencing 
a DLT-equivalent toxicity, dose adjustments will be made as outlined in Section 7.2.5.  
At each interim analysis (as defined in Section 10.10), the rate of DLT-equivalent toxicities will 
be assessed.  If the rate of DLT-equivalent toxicities is unacceptable (eg, a DLT-equivalent 
toxicity is observed in >33% patients at a given dose level), then a safety analysis will be 
triggered and the data will be reviewed by study investigators and the Lilly CRP/CRS.  If the 
findings indicate that a dose level does not have an acceptable safety profile for chronic (Cycle 2 
or later) administration, then a lower dose level will be chosen for further investigation.  This 
decision will be documented in writing.
7.2.2.3.
Dose Escalation Method
Dose escalation will be driven by a mTPI method (Ji and Wang 2013) (Attachment 7).  A 3+3 
design is commonly used in Phase 1 trials due to its simple, intuitive, and pre-specified 
escalation rules. However, the 3+3 method has been criticized for being conservative because 
the method is dictated by the observed DLT rate without acknowledging the variability arising 
from small cohort size.  
Like the 3+3 design, the mTPI method incorporates pre-specified escalation rules.  In contrast, 
the mTPI method is based on quantitative models that incorporate uncertainty into the decision 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530
rules, thereby allowing more aggressive dose escalation.  In the mTPI method, the number of 
patients in each cohort is not fixed, but a minimum of 3 patients are required for this study at 
each dose (unless the rule in the table indicates to deescalate the dose due to unacceptable 
toxicity [DU]). If 3 to 6 patients are enrolled in a cohort, the escalation rule parallels a 
traditional 3+3 design.  However, the stay/deescalation rule of the mTPI is more aggressive than 
the 3+3 design.  For instance, with 2 to 3 DLTs per 6 patients enrolled, the mTPI would 
recommend staying at the current dose, whereas the 3+3 design would recommend deescalation.
Figure JNBA.1 provides the mTPI escalation rules for any cohort size up to 20 patients.
In Figure JNBA.1, the number of patients dosed at a given dose level are shown in the columns 
(x-axis), while the number of DLTs experienced are shown in the rows (y-axis). The rules in this 
figure will be used for each dose level evaluated; the patient numbers and DLTs do not carry 
over from cohort to cohort.  By locating the intersection of the number of patients dosed and the 
number of DLTs, 1 of 4 pre-defined rules is used:  

E:  Escalate the dose

S:  Stay at the same dose

D:  Deescalate the dose

DU:  Deescalate the dose due to unacceptable toxicity.  The dose cannot be re-escalated
to this dose level at a future point in the escalation.
If agreed upon by the investigators and Sponsor (for instance, if PK/PD data suggest that 
increasing the dose further is not expected to yield additional benefit), a more conservative rule 
may be applied.  For instance, if the rule indicates “E” to escalate, the dose may remain at the 
current dose level or be deescalated to a lower level.
As shown in Figure JNBA.1, if 1 of 3 patients experiences a DLT, the decision (located in 
column 3 row 1) is ”S”, stay at the same dose.  Therefore, the next patient must be treated at the 
same dose level.  If 1 of 6 patients experience a DLT, the decision (located at column 6 row 1) is 
“E”, escalate the dose.  However, if 2 of 3 patients experience a DLT the decision is “D” and the 
dose must be deescalated.
In the mTPI, the cohort size is not fixed.  However, each cohort in this study will contain a 
minimum of 3 patients, unless the escalation rules dictate that the dose should be deescalated due 
to unacceptable toxicity (“DU”).  Doses can be escalated, deescalated, and re-escalated following 
the rules in Figure JNBA.1.  If the dose decision was “DU,” the dose cannot be re-escalated to 
that level.
This study is designed to identify a dose level with a dose-limiting target toxicity rate of 30%.  In 
reality, the exact target toxicity rate is almost never achieved for a dose.  To this end, instead of
using a single target rate, the mTPI method considers an equivalence interval (EI) around the 
target toxicity rate.  For this study, the EI is calibrated to be (28.7%, 30.1%), resulting in the 
rules in Figure JNBA.1.  If the observed toxicity rate exceeds 40% and the model is still 
recommending “S”, the Sponsor, in discussion with the investigators, may choose to deescalate. 
Deescalation may not be required for toxicities confounded by patient comorbidities or other 
clinical factors that make direct attribution to study drug difficult to determine, particularly if 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530
they are deemed non-serious (eg, fatigue, anorexia), reversible, or inconsistent with the known 
toxicities of MET or EGFR inhibitors by study investigators and the Lilly CRP/CRS.
Figure JNBA.1.
Dose-finding spreadsheet of the modified toxicity probability 
interval method showing number of patients treated at a given 
dose vs. number of DLTs observed at that dose .
The beginning dose level for Schedule 1 was 300 mg.  The starting dose level for Schedule 2 will 
be 500 mg.  The dose will be escalated by a maximum increment of 100%. If the beginning dose 
level is determined to be unacceptably toxic, a -1 dose level may be explored.  
The exact increment will be determined by the investigators and Lilly CRP/CRS, and may be 
less than the maximum increment allowed in the protocol.  Safety data will be the primary 
criteria for both the decision to dose-escalate and for selecting the dose to be administered in the 
next cohort.  In addition, if available at the time of the dose escalation decision, PK (maximum 
serum concentration [Cmax], area under the serum concentration-time curve [AUC], and CL)
and/or PD results will be used as secondary/supporting data for dose escalation.  No dose 
escalation can occur without prior discussion and agreement between the investigator and the
Lilly CRP or CRS; the decision will be documented in writing.  Intrapatient dose escalations are 
not permitted.
Although an example escalation table is shown in Table JNBA.3, alternate doses may be 
selected. 


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Table JNBA.3.
Sample Dose Escalation Schema
In Cohort 1 for Schedule 1 only, the first patient is required to complete a full cycle (28 days) 
before subsequent patients can be dosed.  Subsequent patients in Cohort 1 can be dosed 
concurrently. Beginning with Cohort 2 for Schedule 1 and for all cohorts with Schedule 2,
patients within a cohort can be dosed concurrently.  
The decision to stop dose escalation will be primarily driven by the appearance of DLTs and the 
rules in Figure JNBA.1.  However, if PK/PD data suggest that increasing the dose further is not 
expected to yield additional benefit, escalation may cease.  
7.2.3. Recommended Phase 2 Dose Determination
The RP2D will be a dose at which at least 10 patients, but no more than 20, have been enrolled.  
The RP2D will be agreed upon following discussion between the investigators and the Lilly CRP 
or CRS and will include an assessment of safety, PK, and PD data. At the RP2D, the intersection 
of the number of patients dosed and the number of DLTs at that dose level on the mTPI grid 
should indicate “S” or “E.”
7.2.4. Monitoring and Treatment Guidance for the Investigator
7.2.4.1.
Infusion-Related Reactions
Due to the risk of hypersensitivity reactions with any biological agents, all patients should 
continue to be closely monitored for signs and symptoms indicative of an infusion-related 
reaction both in the acute period (immediately or within 24 hours after dosing) and up to several 
days to a few weeks after dosing for delayed reactions.  In Cycles 1 and 2, acute assessments
should include an assessment of vital signs starting at the time of initiation of the infusion and 
continuing until at least 60 minutes after the end of the infusion.  At a minimum, vital signs 
should be obtained prior to infusion, during infusion, and at 1 hour post-infusion. The exact 
frequency of the monitoring is left to the discretion of the investigator.   Monitoring should be 
performed in an area where resuscitation equipment and other agents (eg, epinephrine, 
corticosteroids) are readily available.  
Per the CTCAE v 4.03 definition of infusion-related reactions, symptoms occurring during or 
following infusion of investigational therapy may be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome.  In the setting of symptoms 
occurring during or following infusion of investigational therapy, investigators are encouraged to 
Dose Level
(Cohort)
Schedule 1 Dose
Schedule 2 Dose
-1
100 mg
400 mg
1
300 mg
500 mg
2
600 mg
600 mg
3
1000 mg
700 mg
4
1250 mg


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use the AE term “Infusion-related Reaction” and any additional terms (including those not listed 
here) that best describe the event.  
Section 7.2.5 and Table JNBA.4 detail the treatment recommendations for LY3164530
infusion-related reactions.  If a patient should have an infusion-related reaction to LY3164530, 
all attempts should be made to obtain an anti-LY3164530 antibody blood sample 
(immunogenicity sample) as close to the onset of the event as possible, at the resolution of the 
event and 28 days following the event.  In addition, these same samples may be assessed for 
levels of LY3164530 and for PD markers to provide information on the nature of the 
infusion-related reaction.  Immunogenicity samples will be collected during the follow-up visit 
for all patients.  The procedure for sample collection and handling is described in a separate 
procedural manual.
If infusion-related reactions are observed, premedication with diphenhydramine hydrochloride
(or equivalent), dexamethasone (or equivalent), or other medications as medically indicated may 
be considered for future patients.  The decision to implement premedication for drug 
administration in subsequent patients will be made following a discussion between the 
investigators and Sponsor and will be documented in writing.
7.2.4.2.
Skin Reactions
Skin rash is a known toxicity of EGFR inhibitors, and skin effects were observed with 
LY3164530 in a 5-week repeat-dose toxicity study in monkeys.  In Study JNBA, skin reactions
were observed at all dose levels with Schedule 1 and were dose limiting at 1250 mg.  As a result, 
prophylaxis is permitted for the initial dose of LY3164530. Institutional-approved standard of 
care premedication for EGFR inhibitors, such as dexamethasone and/or topical and/or oral 
antibiotics, may be administered for the initial and subsequent doses.  .
Section 7.2.4.1 and Table JNBA.4 detail the treatment recommendations for LY3164530 skin
reactions.
7.2.5. Dose Delays and Adjustments
7.2.5.1.
Dose Delays and Omissions
The following rules should guide dosing:

Before each cycle of LY3164530 the following parameters are required:

Hematologic:  ANC 1.5 x 109/L, platelets 75 x 109/L, and hemoglobin 
8 g/dL.

Non-hematologic:  AEs must resolve to CTCAE v 4.03 Grade ≤1, or baseline.  
Exceptions will be made for:  alopecia, fatigue, skin reactions, or other 
toxicities that can be controlled with standard treatment; these toxicities must 
resolve to ≤Grade 2.

The start of a cycle is the date of the Day 1 dose.  
For Schedule 1: If the Day 15 dose cannot be administered within 21 days of the prior 
dose (by Day 22), it should be omitted. The interval between LY3164530 doses must not 


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be less than 14 days.  If a dose is delayed (for toxicity or other circumstances), the next 
dose should be adjusted so that there is at least a 14-day interval.

For Schedule 2:  If a dose cannot be administered within 10 days of the prior dose, it should be 
omitted.  The interval between LY3164530 doses must not be less than 7 days.  If a dose is 
delayed (for toxicity or other circumstances), the next dose should be adjusted so that there is at 
least a 7-day interval.If a dose cannot be administered within 28 days of the prior dose due to an 
AE, the patient should be removed from study drug treatment and should complete subsequent 
follow-up (Table JNBA.4).  

If the patient has completed the initial on-study radiographic assessment (eg, at the end of 
Cycle 2) and is continuing to receive benefit from therapy, delays of greater than 28 days  
may be acceptable if agreed upon by both the investigator and Sponsor.  For instance, if a 
patient has a non–drug-related AE such as prolonged flu, the patient may continue on therapy 
if, in the opinion of the investigator, he/she is showing benefit from therapy and has 
recovered sufficiently from the AE.  

A delay of no more than 7 days because of holidays, weekends, inclement weather, or other 
justifiable events will be permitted and will not be counted as a protocol deviation.  
7.2.5.2.
Dose Adjustments
Dose adjustments should follow the guidance in Table JNBA.4.
For patients requiring dose reductions, reescalation to the original assigned LY3164530 dose is 
not allowed.  The patient must be maintained at a reduced dose level for all remaining cycles.


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Table JNBA.4.
Dose Modifications and Treatment Alterations in Patients Treated 
with LY3164530
Toxicity
CTCAE Grade
Recommendations
Infusion-
related 
reaction 
Grade 1
First occurrence  
Decrease the LY3164530 infusion rate by 50% and monitor closely for any 
worsening.  For subsequent infusions, premedicate with diphenhydramine 
hydrochloride; additional premedication may be administered at the investigator’s 
discretion.  
Grade 2
First occurrence 
Stop LY3164530 infusion. Administer diphenhydramine hydrochloride and
acetaminophen for fever and oxygen.  Resume infusion at 50% of previous rate 
once infusion-related reaction has resolved or decreased to Grade 1 in severity, 
and monitor closely for any worsening.  
For subsequent infusions, premedicate with diphenhydramine hydrochloride; 
additional premedication may be administered at the investigator’s discretion.  
The reduced rate should be used for all subsequent infusions.
Grade 1 or 2
Second occurrence
Administer dexamethasone.
For subsequent infusions, premedicate with diphenhydramine hydrochloride, 
acetaminophen, and dexamethasone.  The reduced infusion rate should be used 
for all subsequent infusions.
≥Grade 3
Stop LY3164530 infusion immediately and disconnect infusion tubing from the 
patient.  
Administer diphenhydramine hydrochloride, dexamethasone, bronchodilators for 
bronchospasm, and other medications/treatment as medically indicated.
Patients must not receive any further LY3164530 treatment.
Skin 
reactions 
(eg, acne-
like rash)
Grade 3
First occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 following the rules in Section 
7.2.5.1. Treatment with topical and/or oral antibiotics should be considered.
Grade 3
Second occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 following the rules in Section 
7.2.5.1.  Dose reduce to the dose level used for the previous cohort for second 
occurrence.  Treatment with topical and/or oral antibiotics should be considered.  
Grade 3
Third occurrence
Or Grade 4
Patients must not receive any further LY3164530 treatment.
Other 
toxicities
≥Grade 3
First occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 or baseline following the 
rules in Section 7.2.5.1. Based on the investigator’s discretion, the full dose of 
LY3164530 may be administered or the dose may be reduced to the next lowest 
dose level. If event recurs at same grade, then dose reduce LY3164530 to the 
next lowest dose.  
≥Grade 3
Second occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 or baseline following the 
rules in Section 7.2.5.1. If event recurs at same grade, then dose reduce 
LY3164530 to the next lowest dose.  Exceptions may be made for transient 
changes in electrolytes that respond to treatment.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.
Note:  In addition, the dose may be reduced to the next lower level for any toxicity at the discretion of the 
investigator.


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7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3164530 in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted between 
the investigational site and the Lilly clinical research personnel to confirm that each patient 
meets all enrollment criteria.  Upon confirmation of eligibility, the Sponsor will confirm the 
dose, schedule, infusion duration, and identification number assignment for each patient.  
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
In the absence of clinical experience with LY3164530, patients should be closely evaluated to 
ensure identification of exacerbations of known side effects of concomitant medications.  These 
should be reported immediately to the Sponsor.  No other chemotherapy, radiotherapy, 
immunotherapy, herbal supplements intended to treat the cancer, 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 antiestrogen therapy (eg, an aromatase inhibitor). However, the 
treatment should have been started at least 3 months prior to first dose of study drug.  Patients on 
stable doses of bisphosphonates or denosumab are allowed to continue.  These agents should not 
be initiated within the 4 weeks prior to study enrollment or at any point while on the study.  
Palliative radiotherapy of no more than 14 calendar days to a solitary (non-skull) skeletal 
metastasis will be permitted following discussions between the investigators and the Sponsor, so 
long as the skeletal metastasis is not the primary measurable lesion and the patient has not 
developed another reason for study discontinuation.  
In addition, any disease progression requiring other forms of specific antitumor therapy will 
necessitate early discontinuation from the study.  Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the case 
report form (CRF).  Replacement hormonal therapy initiated before study entry will be allowed.
Patients should receive full supportive care during the trial.  Routine prophylactic use of 
granulocyte colony-stimulating factors (G-CSF) is not permitted during this study.  Should the 
use of hematopoietic colony-stimulating factors (CSFs) be necessary, follow the American 
Society of Clinical Oncology (ASCO) recommendations for the use of CSFs (Smith et al. 2015).  
Erythropoietin and packed red blood cell (RBC) transfusion may be used according to ASCO 
guidelines (Rizzo et al. 2008) if clinically indicated at any time during the study. Platelet 
transfusions may be used according to ASCO guidelines (Schiffer et al. 2001).
All concomitant medications, including premedication, should be recorded throughout the 
patient’s participation in the study on the electronic case report form (eCRF).


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7.6.
Treatment Compliance
LY3164530 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 is ensured.  
Patients should attend scheduled clinic visits and must comply with study criteria under their 
control.  Deviation(s) from the prescribed dosage regimen should be recorded on the eCRF.  
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug 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 1 cycle of LY3164530
treatment will be deemed non-evaluable for assessment of a dose level, unless they experience a 
DLT prior to withdrawal.  However, patients who receive all doses of LY3164530, but 
discontinue from study drug before the end of Cycle 1, will be considered evaluable for the 
assessment of a dose level, provided it can be documented whether the patient experienced a 
DLT during Cycle 1.  
If the patient is noncompliant during Cycle 1 due to reasons other than drug-related toxicity, he
or she will be considered non-evaluable and may be replaced.
Patients that require a dose reduction or omission during Cycle 1 or have a dosing delay of more 
than 3 days for reasons other than a study drug-related AE may be deemed non-evaluable for 
DLT assessment.  
Nonevaluable patients may be replaced to ensure that enough patients complete 1 cycle of 
therapy at each dose level, unless accrual to that cohort has stopped due to a DLT.
Patients who are not evaluable for PK, but who complete 1 cycle of therapy, may be replaced 
upon consultation with the investigator(s) and the Lilly CRP or CRS to ensure adequate PK data, 
unless accrual to that cohort has stopped due to a DLT.


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8. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
The safety and tolerability of LY3164530 have been assessed in nonclinical toxicology studies 
and this ongoing Phase 1 study.  The results from these studies are detailed in the Investigator’s 
Brochure.  This Phase 1 study contains safety monitoring that will permit initial characterization 
of the safety profile of LY3164530 in patients with advanced or metastatic cancer.  Study 
procedures and their timing, including collection of patient samples, are described in the Study 
Schedule (Attachment 1).
Standard laboratory tests will be performed as listed in Attachment 2.  A urine or serum 
pregnancy test will be administered to female participants, if applicable.  Other clinical 
laboratory tests will also be collected.  Attachment 2 lists the specific tests that will be performed 
for this study.
8.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator, but must meet the minimium requirements outlined in Table JNBA.5.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  Table 
JNBA.5 presents a summary of AE and SAE reporting guidelines.  Table JNBA.5 also shows 
which database or system is used to store AE and SAE data.
8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
vital sign measurements, and so on that occur should also be reported to Lilly or its designee as 


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an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect.
The investigator, monitor, and Sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE v 4.03.
The CTCAE v 4.03 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 v 4.03.  Any minor version of CTCAE v 4.0 (eg, v 4.03) may be used for this 
study.  Minor CTCAE v 4.0 updates from the NCI will not necessitate a protocol amendment.  
For AEs without matching terminology within the CTCAE v 4.03 criteria, the investigator will 
be responsible for selecting the appropriate system organ class and assessing severity grade 
based on the intensity of the event.  Note that both CTCAE term (actual or coded) and severity 
grade must be selected by study site personnel and collected on the eCRF.  This collection is in 
addition to verbatim text used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the Sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
Cases of pregnancy that occur during maternal or paternal exposures to study 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 patient must be 
removed from the study and treatment with study drug must be stopped immediately.
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition,
all AEs related to protocol procedures are reported to Lilly or designee.
If a patient's dosage is reduced, delayed, or omitted; or if 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 modification or 
discontinuation of treatment. 
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and/or study drug via eCRF/electronic data entry.
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 elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs.  Hospitalization or prolongation of hospitalization without a precipitating 


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clinical AE (eg, for the administration of study therapy or other protocol-required procedure) 
should not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the Sponsor, and the SAEs will be entered in the
Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the Sponsor in aggregate periodically during the course of the trial may be 
found in the Investigator’s Brochure.  
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drug
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the ICF.  For patients who do not enroll in the trial (eg, have 
not been exposed to LY3164530), only AEs and SAEs related to protocol procedures are 
required to be collected.  


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8.1.2.2.2. On Therapy
All AEs and SAEs, regardless of relatedness to study drug or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study drug 
to when he/she receives the last dose of study drug.
8.1.2.2.3. Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug or protocol procedures, occurring 
during the follow-up visit (Visit 801) must be reported to Lilly or its designee.  The follow-up 
visit starts following the last dose of study drug.  At the end of the follow-up visit, the patient 
will be required to have specific safety assessments (Attachment 1).  The timing of these 
assessments is 28 days ± 5 days after the last dose of study drug.  
If it is deemed to be in the best interest of the patient to start a new anti-cancer treatment prior to 
the scheduled end of the follow-up visit period, the follow-up visit duration may be shortened.  
In this case, follow up assessments, including AE and SAE reporting should be completed prior 
to the initiation of the new therapy.  
Following the safety assessments that mark the planned end of the follow-up visit (Visit 801), the 
patient will be discontinued from the study, unless there is an ongoing AE or SAE that is 
possibly related to study drug.  Particular focus should be placed on patients that have abnormal 
electrolytes, as electrolyte depletion is known to occur for >6 weeks after EGFR monoclonal 
antibody therapy.  
If a patient has an ongoing AE or SAE possibly related to LY3164530 (eg, abnormal 
electrolytes), the patient should be followed until the event is resolved, the event is no longer 
considered to be study drug-related, the event becomes stable or returns to baseline, a new 
treatment is initiated for the patient, or the patient dies or is lost to follow-up.  Any subsequent 
follow-up(s) for AEs will be no more than 28 days ± 5 days in duration.  
After the follow-up visit (Visit 801), AEs are not required to be reported unless the investigator 
feels the AEs were related to either study drug, drug delivery system, or a 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 (Attachment 6), 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
Development Core Safety Information in the Investigator’s Brochure and that the investigator 
identifies as related to study drug or procedure.  The US 21 CFR 312.32, the EU Clinical Trial 
Directive 2001/20/EC and the associated detailed guidances or national regulatory requirements 
in participating countries require the reporting of SUSARs.  Lilly has procedures that will be 
followed for the recording and expedited reporting of SUSARs that are consistent with global 
regulatory regulations and the associated detailed guidances.


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8.1.2.4.
Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JNBA.5.
Table JNBA.5.
Adverse Event and Serious Adverse Event Reporting Guidelines 
for Study JNBA 
Study Period
Timing
Types of AEs/SAEs 
Reported
Database used for 
Collection
Screening/Baseline
Starts at the signing of informed 
consent and ends just before the 
first dose of study drug
Preexisting conditions
All AEs and SAEs 
regardless of relatedness 
Clinical database 
and LSS
On therapy
Starts at first dose of study drug 
and ends at last dose of study 
drug
All AEs and SAEs 
regardless of relatedness
Clinical database 
and LSS
Follow-up Visit
(Visit 801)
Starts just after the last dose of 
study drug and ends when end of 
study safety assessments are 
completed 28 days (5 days)  
after last dose of study drug
All AEs and SAEs 
regardless of relatedness
Clinical database 
and LSS
Subsequent Follow-ups , 
if necessary for patient 
monitoring for ongoing 
related AEs (continuation 
of Visit 801)
Follow-ups no more than 28 day
intervals (5 days) and are 
continued until the criteria in 
Section 8.1.2.2.3 are met
Ongoing AEs possibly 
related to study drug, or 
protocol procedures.
All SAEs related to protocol 
procedures or study drug
Clinical database 
and LSS
Patient no longer on 
study
All SAEs related to protocol 
procedures or study drug 
that the investigator 
becomes aware of
LSS
Abbreviations:  AE = adverse event; LSS = Lilly Safety System; SAE = serious adverse event.
8.1.3. Other Safety Measures
8.1.3.1.
Electrocardiograms
For each patient, a 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1 and Attachment 4).  Patients must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection.  During Cycle 1, 
triplicate ECGs will be done as specified in the Study Schedule (Attachment 1).  Beginning with 
Cycle 2 and beyond, only a single ECG will be required (Attachment 4).
Electrocardiograms may be obtained at additional times, when clinically indicated.  Collection of 
more ECGs (more replicates) than expected at a particular time point is allowed to ensure high 
quality records.  
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible to determine whether 
the patient meets entry criteria and for immediate patient management, should any clinically 
relevant findings be identified.  


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If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (eg, palpitations, near syncope, 
syncope) to determine whether the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation from at least 1 of 
the replicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (eg, demographics and 
study details), and will then store the ECGs in a database.  At a future time, the stored ECG data 
may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements.  
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes, unless an overread of the ECGs is conducted prior to completion of the final study 
report (in which case the overread data would be used).
8.1.4. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study.  
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 5).

If a study patient experiences elevated ALT >5X ULN and elevated total bilirubin >2X 
ULN, clinical and laboratory monitoring should be initiated by the investigator.  

For patients entering the study with ALT >3X ULN, monitoring should be triggered at 
ALT >2X baseline.
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.  
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

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.


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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 3 lists the PK and PD sample collections.
Attachment 4 lists the ECG, chemistry, and hematology collection schedule.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health. Investigators must document their 
review of each laboratory safety report and include a determination of the clinical significance of 
abnormal labs.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics 
8.2.2.1.
Pharmacokinetic Samples
At the visits and times specified in Attachment 3, blood samples will be collected to determine 
the serum concentrations of LY3164530.  A maximum of 5 samples may be drawn at additional 
time points during the study if warranted and agreed upon between both the investigator and 
Lilly. Similarly, if sufficient data have been collected from other patients, a maximum of 5 
samples may be removed if agreed upon between both the investigator and Lilly.  Instructions for 
the collection and handling of blood samples will be provided by the Sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded.
These samples will be analyzed at a laboratory designated by the Sponsor.  Serum concentrations 
of LY3164530 will be assayed using a validated ELISA method.
The PK samples will be stored at a facility designated by the Sponsor.
Bioanalytical samples collected to measure LY3164530 will be retained for a maximum of 1 
year following last patient visit for the study.
8.2.2.2.
Pharmacodynamic Samples
At the visits and times specified in Attachment 3, serum and plasma samples will be collected. 
The effect of LY3164530 on MET and EGFR pathway-specific targets may be explored to 
determine changes in potential biomarkers such as circulating levels of the MET ligand HGF,  


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EGFR ligands (eg, EGF, TGFalpha), MET/ECD, and EGFR/ECD. These samples may be used 
for exploratory research on new biomarkers related to the MET/HGF and EGFR pathway.  In 
addition, exploratory samples to assess proteomic panel may be collected.  A maximum of 3 
timepoints may be removed per dosing schedule during the study if warranted and agreed upon 
between both the investigator and Lilly.
Bioanalytical samples collected to measure PD biomarkers will be identified by the patient 
number (coded) and retained for a maximum of 15 years following last patient visit for the study 
at a facility selected by the Sponsor. Supplies and detailed instructions required for the 
collection, handling, and shipment of the patients’ samples will be provided by the Sponsor.  The 
samples will be analyzed at a laboratory designated by the Sponsor.  
8.2.3. Samples for Tailoring Biomarkers
Collection of tumor samples for tailoring biomarker research is a component of this study.  
The following samples are required for biomarker research:

Pre-treatment tumor tissue 

Blood, plasma, and/or serum samples.
The following samples are optional samples and should be collected from patients in the study 
when possible:

If a patient has available archived tumor tissue previously taken to evaluate the patient’s 
disease, a small amount of this tissue will be requested for biomarker research

On treatment and/or post-treatment tumor tissue.
These samples are described in the following sections.
8.2.3.1.
Tumor Tissue
A pretreatment tumor biopsy should be obtained prior to the first dose of LY3164530. However, 
for patients who have disease recurrence/metastasis in technically challenging sites to obtain 
biopsies or who have tissue available from a prior post-treatment biopsy and have not received 
intervening therapy, the investigator and Sponsor may agree to omit the pretreatment biopsy.  
The decision must be documented in writing prior to the patient receiving the first dose of study 
drug and will not constitute a protocol violation.  Tissue will be taken by core biopsy prior to 
starting treatment.  Due diligence should be used to ensure that tumor specimen (not normal 
adjacent or tumor margins) is provided.  Pathology notes accompanying the tissue may also be 
requested.
In addition to the new biopsy tissue, prior archived tissue will be requested.  Pretreatment 
archived formalin-fixed paraffin-embedded tumor tissue should be in a whole block, partial 
block, or unstained slides. Bone samples should not be submitted.  Any blocks or slides 
submitted for analysis will either be returned to the site upon request or discarded within 15 
years after last patient visit for the trial.  


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Following treatment with LY3164530, optional on-treatment (eg, while still on study therapy) 
and/or post-progression biopsies (eg, following documentation of progressive disease on Study 
JNBA) for biomarker research from patients willing to consent may be collected if safe and 
feasible and upon notification and discussion with the Sponsor.  In particular, post-treatment 
biopsies from lesions in patients who have received clinical benefit and subsequently progress 
may help identify mechanisms of resistance to LY3164530.  Post-progression biopsies should be 
performed prior to the start of subsequent cancer treatment.  However, the procedure should not 
impede or delay the planned cancer treatment.
In archived and pre-treatment tissue samples, an evaluation of analytes related to the mechanism 
of action of MET-EGFR inhibition and cancer pathobiology may be performed to assess any 
potential correlation with response to LY3164530.  For example, the expression of MET protein, 
EGFR protein, HGF, and EGFR ligands may be assessed by immunohistochemistry (IHC) and/or 
fluorescence in situ hybridization (FISH).  In addition, mutation status, allelic imbalance, and/or 
copy number variations of cancer-related genes including, but not limited to, MET, HGF, EGFR, 
KRAS, HRAS, NRAS, BRAF, may be analyzed at a laboratory designated by the Sponsor.  Tumor 
samples may also be analyzed to explore potential tumor gene signature(s) associated with 
response to LY3164530 therapy.  
8.2.3.2.
Blood Samples for Pharmacogenetic Evaluations
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption,
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated. Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.  
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to LY3164530.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response. The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program. They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum of 15 years 
after the last patient visit for the study at a facility selected by the Sponsor. The samples and any 
data generated from them can only be linked back to the patient by investigator site 
personnel. The duration allows the Sponsor to respond to regulatory requests related to the study 
drug.
Samples will be destroyed according to a process consistent with local regulation.


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8.2.3.3.
Exploratory Biomarker Blood Samples 
In addition to blood samples, plasma samples to study circulating biomarkers associated with 
response to LY3164530 therapy, the underlying cancer, or cancer-related conditions will be 
collected.  This analysis may include, but is not limited to, circulating microribonucleic acids 
(microRNAs) and cell-free tumor DNA.  These analyses may employ targeted or high-
throughput sequencing approaches. For this purpose, the results of these analyses will be 
correlated with clinical efficacy data.  The samples will be coded with the patient number and 
stored for up to a maximum of 15 years.
8.2.4. Samples for Immunogenicity Research 
Blood samples for immunogenicity testing will be collected to determine antibody production 
against LY3164530.  Immunogenicity will be assessed by a validated assay designed to detect 
anti-drug antibodies (ADAs) in the presence of LY3164530 antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of LY3164530.  The 
presence of ADAs and neutralizing ADAs may be compared to any changes in expected PK/PD 
parameters.  In the event of any AE suspected of being related to immunogenicity, the presence 
of ADAs may also be evaluated.  A portion of the sample taken for immunogenicity testing may 
be used for PK analysis, in the setting of infusion-related reactions.
Samples may be stored for up to a maximum of 15 years following last patient visit for the trial 
at a facility selected by the Sponsor to enable further analysis of immune responses to
LY3164530.  The duration allows the Sponsor to respond to regulatory requests related to 
LY3164530.  
8.3.
Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1
for details regarding the timing of specific efficacy measures.  
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement:

Computed tomography (CT) scan

Magnetic resonance imaging (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

Evaluation of the ECOG performance status.
In rare circumstances, historical radiologic exams for RECIST criteria that are obtained greater 
than 28 days prior to the first dose may be used, but this decision must be discussed with the 
Sponsor and documented in writing.


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To confirm objective responses, all lesions should be radiologically assessed, and the same 
radiologic method used for the initial response determination should be repeated at least 4 weeks
following the initial observation of an objective response, using the sample method that was used 
at baseline.  If a patient is discontinued from the study, repeat radiology assessments may be 
omitted if clear clinical signs of progressive disease are present.
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, 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 and lab 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 eCRFs, 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 eCRF 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 ERB(s)
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.
For data handled by a data management third-party organization (TPO), eCRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to the Lilly data 
warehouse, using standard Lilly file transfer processes.
For data handled by the Sponsor internally, eCRF data and some or all data that are related will 
be managed by the Sponsor and stored electronically in the Sponsor’s system.
9.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system and the TPO’s system.


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Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system and the TPO’s system or directly to Lilly.  
Electrocardiogram data will be stored electronically in the central database system of Lilly’s 
central review organization.  Data may subsequently be transferred from the central review 
organization system to the TPO’s system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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10. Data Analyses
10.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
The interpretation of the study results will be the responsibility of the investigator with the Lilly
CRP/CRS, pharmacokineticist, and statistician.  The CRP/CRS and statistician will also be 
responsible for the appropriate conduct of an internal review for both the final study report and 
any study-related material to be authorized by Lilly for publication.
The analyses for this study will be descriptive, except for possible exploratory analyses as 
deemed appropriate.  Data analyses will be provided by dose levels and for all patients combined 
wherever appropriate.  For continuous variables, summary statistics will include number of 
patients (N), mean, median, standard deviation, standard error (SE), minimum, and maximum.  
Categorical endpoints will be summarized using N, frequency, percentages, and associated SE.  
Missing data will not be imputed.  Exploratory analyses of the data that are not described in the 
protocol will be conducted as deemed appropriate.
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 mTPI method and determined by the occurrences of 
DLTs (up to 20 patients per cohort before establishing the RP2D and schedule). The total 
sample size is anticipated to be approximately 50 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.  
Discontinuations due to AE or death will be listed and summarized with cause of death further 
partitioned into AE, study disease, or other cause and summarized.
10.3. Patient Characteristics
Patient characteristics will include a summary of the following:

Patient demographics including age, sex, and screening height and weight

Baseline disease characteristics

Prior disease-related therapies 

Concomitant medications.
Other patient characteristics will be summarized as deemed appropriate.
10.4. Safety Analyses
All patients who have been exposed to LY3164530 will be evaluated for safety and toxicity.  
Adverse event terms and severity grades will be assigned by the investigator using CTCAE v 
4.03.


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Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

dose adjustments (reductions, omissions, and delays)

laboratory values 

vital signs 

DLTs at each dose level

ECGs

Extent of concomitant medications.
10.5. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have been exposed to study drug 
and have had samples collected.  
Pharmacokinetic parameter estimates for LY3164530 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax, AUC0-tlast, AUC0-τ, and AUC0-∞of 
LY3164530.  Other noncompartmental parameters, such as t1/2, CL, volume of distribution (V),
and accumulation ratios may be reported.  Additional exploratory analyses will be performed if 
warranted by the data, and other validated PK software programs may be used if appropriate and 
approved by Lilly Global PK/PD management.  The version of any software used for the analysis 
will be documented and the program will meet the Lilly requirements of software validation.
Pharmacokinetic parameter estimates 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% confidence intervals 
(CIs).
10.6. Pharmacodynamic Analyses
Provided that the data allows, PD and immunogenicity data from all patients may be analyzed 
using linear and/or nonlinear fixed and mixed effects models as appropriate.  Pharmacodynamic 
and immunogenicity data will be summarized by dose, drug concentrations, and time from dose
for each schedule of administration.  Potential PD markers and immunogenicity versus time data 
will be presented graphically for each patient and summarized by dose and schedule of 
administration.  Absolute and/or percent change from baseline for the PD markers may also be 
evaluated. Data may be log-transformed prior to summarizing if necessary.  The interpatient and 
intrapatient variability of the PD markers and immunogenicity responses may also be assessed 
where appropriate.  Baseline measurements may be evaluated as potential covariates to assess 
their relationship to relevant PD responses.
10.7. Pharmacokinetic/Pharmacodynamic Analyses
In addition to a standard noncompartmental assessment, and provided that the data allows, the 
LY3164530 serum concentration-time data may be evaluated by model-based approaches as 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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warranted.  Additional analyses, such as exposure-response modeling using the efficacy 
endpoints, may also be explored.
Additional exploratory analyses may be performed if warranted by the data.
10.8. Efficacy
The study was not designed to make an efficacy assessment.  However, any tumor response data 
and duration of treatment will be tabulated.
10.9. Biomarker Analyses
Biomarker assessments in this study will focus on identifying markers and/or marker signatures 
that may indicate the patients most likely to respond or be resistant to LY3164530.  
In archived and pre-treatment tissue samples, biomarker data related to the MET and EGFR 
pathways and cancer pathobiology may be analyzed to assess any potential correlation with 
response to LY3164530.  These analyses may include, but are not limited to, MET and EGFR
protein expression, circulating DNA, somatic mutation status, and/or copy number variations of 
MET and EGFR pathway-related genes (eg, KRAS, BRAF) or genes related to cancer 
pathobiology.  In addition, tumor sample based gene signature(s) may be defined and evaluated 
to explore whether they are associated with response to LY3164530.  In all analyses, adjustments 
may be made to account for other baseline patient characteristics, safety, and PK/PD data.  
Unless otherwise stated, given the small sample sizes involved, statistical analyses results will be 
considered exploratory and will not consider multiple comparison adjustments.  
10.10.
Interim Analyses
Since this is a dose-escalation study, data will be reviewed on an ongoing basis during the study 
until the RP2D is determined.  The purpose of these ongoing reviews is to evaluate the safety 
data at each dose level.  A review of the data will be completed approximately after 6 patients 
have been treated for at least 1 cycle at a dose level without a cohort analysis.
An interim analysis will be triggered when at least 15 patients have been dosed at a given dose 
level for 1 cycle of treatment to evaluate the safety and tolerability of LY3164530.  The interim 
analysis may include, but are not limited to, an assessment of available safety, PK, and PD data.
Enrollment may continue during the interim analysis and the dose escalation rules as outlined in 
Figure JNBA.1 will continue to be followed.
Additional interim analyses may be triggered and may include, but are not limited to, assessment 
of available safety, PK, and PD data.
. 


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11. Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient before the study is started.  This includes obtaining the appropriate signatures and dates 
on the ICF prior to the performance of any protocol procedures and prior to the administration of 
study drug.  
In this protocol, the term "informed consent" includes all consent given by patients or their legal 
representatives.  
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 Investigator’s Brochure 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.


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The investigator or designee will promptly submit the protocol to applicable ERB(s).
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data.
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
Bonine-Summers AR, Aakre ME, Brown KA, Arteaga CL, Pietenpol JA, Moses HL, Cheng N.  
Epidermal growth factor receptor plays a significant role in hepathocyte growth factor 
mediated biological responses in mammary epithelial cells. Cancer Biol Ther. 2007;6(4):561-
570.
Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. 
Nat Med. 2013;19(11):1389-1400.
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.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, 
Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, 
Johnson BE, Cantley LC, Janne PA. MET amplification leads to gefitinib resistance in lung 
cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039-1043.
Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale 
and progress [published correction appears in Nat Rev Cancer. 2012;12(9):637]. Nat Rev 
Cancer. 2012;12(2):89-103.
Goldman JW, Rosen LS, Algazi AP, Turner PK, Wacheck V,  Tuttle J, Wooldridge JE, Banck 
MS. First-in-human dose escalation study of LY2875358 (LY), a bivalent MET antibody, as 
monotherapy and in combination with erlotinib (E) in patients with advanced cancer. J Clin 
Oncol. 2013;31(15 suppl). Abstract 8093.
Graveel CR, Tolbert D, Vande Woude GF. MET: a critical player in tumorigenesis and 
therapeutic target. Cold Spring Harb Perspect Biol. 2013;5(7):pii a009209.
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding 
trials. Clin Trials. 2010;7(6):653-663.
Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method 
than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785-1791. 
Jin H, Yang R, Zheng Z, Romero M, Ross J, Bou-Reslan H, Carano RA, Kasman I, Mai E, 
Young J, Zha J, Zhang Z, Ross S, Schwall R, Colbern G, Merchant M. MetMAb, the one-
armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves 
survival. Cancer Res. 2008;68(11):4360-4368.
Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, 
Lamszus K. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin
Cancer Res. 2006;12(20 Pt 1):6144-6152.
McDermott U, Pusapati RV, Christensen JG, Gray NS, Settleman J. Acquired resistance of non-
small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal 
growth factor receptor dependency. Cancer Res. 2010;70(4):1625-1634. 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 55
LY3164530
Nanjo S, Yamada T, Nishihara H, Takeuchi S, Sano T, Nakagawa T, Ishikawa D, Zhao L, Ebi H, 
Yasumoto K, Matsumoto K, Yano S. Ability of the Met kinase inhibitor crizotinib and new 
generation EGFR inhibitors to overcome resistance to EGFR inhibitors. PLOS One.
2013;8(12):e84700.
Remon J, Moran T, Majem M, Reguart N, Dalmau E, Marquez-Medina D, Lianes P. Acquired 
resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-
small cell lung cancer: a new era begins. Cancer Treat Rev. 2014;40(1):93-101.
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 [published correction appears in J 
Clin Oncol. 2008 Mar 1;26(7):1192]. J Clin Oncol. 2008;26(1):132-149.
Scheving LA, Stevenson MC, Taylormoore JM, Traxler P, Russell WE. Integral role of the EGF 
receptor in HGF-mediated hepatocyte proliferation. Biochem Biophys Res Comm. 2002; 
290(1):197-203.
Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, Goldstein M, 
Hume H, McCullough JJ, McIntyre RE, Powell BL, Rainey JM, Rowley SD, Rebulla P, 
Troner MB, Wagnon AH; American Society of Clinical Oncology. Platelet transfusion for 
patients with cancer: clinical practice guidelines of the American Society of Clinical 
Oncology. J Clin Oncol. 2001;19(5):1519-1538.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. 
2015 update of recommendations for the use of white blood cell growth factors: an evidence-
based clinical practice guideline. J Clin Oncol. 2015. doi: 10.1200/JCO.2015.62.3488.
Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, 
Krzakowski MJ, Robinet G, Godbert B, Barlesi F, Govindan R, Patel T, Orlov SV, Wertheim 
MS, Yu W, Zha J, Yauch RL, Patel PH, Phan SC, Peterson AC. Randomized phase II trial of 
Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung 
cancer. J Clin Oncol. 2013;31(32):4105-4114. 
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing 
of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-1024.
Yano S, Yamada T, Takeuchi S, Tachibana K, Minami Y, Yatabe Y, Mitsudomi T, Tanaka H, 
Kimura T, Kudoh S, Nokihara H, Ohe Y, Yokota J, Uramoto H, Yasumoto K, Kiura K, 
Higashiyama M, Oda M, Saito H, Yoshida J, Kondoh K, Noguchi M. Hepatocyte growth factor 
expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine 
kinase inhibitors in a Japanese cohort. J Thorac Oncol. 2011;6(12):2011-2017.


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Protocol JNBA Study Schedule
Attachment 1.


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 57
Baseline Schedule
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 28 days
Relative Day to C1D1
≤28
≤14
Procedure 
Category
Procedure
Comments
Study 
Entry/ 
Enrollment
Informed consent form signed (prior to conducting any 
protocol-specific tests/procedures)
X
Inclusion/Exclusion evaluation
X
Medical 
History
Initial history/preexisting conditions
X
Historical illnesses
X
Include HPV status if known in tumor as part of historical assessment and denote 
on eCRF.
Physical 
Examination
Physical examination (including height and weight)
X
ECOG performance status
X
Vital signs
X
Includes blood pressure, pulse, and temperature.
Tumor 
Assessment
Radiologic imaging according to RECIST 1.1
X
Radiologic assessments obtained previously as part of routine clinical care may be 
used as the baseline assessment.  This may be CT scan or MRI.
Tumor measurement (palpable or visible)
X
Adverse Events Collection/CTCAE Grading
X
Concomitant Medication Notation
X


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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Baseline Schedule
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 28 days
Relative Day to C1D1
≤28
≤14
≤7
Procedure 
Category
Procedure
Comments
Lab/
Diagnostic 
Tests
Local hematology
X
Local chemistry
X
Local coagulation
X
Local urinalysis
X
Local pregnancy test
X
Must be done 7 days prior to the first dose of study drug if patient is a woman of 
child-bearing potential.  May be urine or serum specimen.
Central  ECG
X
Triplicate ECG.  
Biopsy of pretreatment tumor tissue
X
Unless the Sponsor and investigator document that the biopsy may be omitted; 
sample should be taken only after study eligibility is confirmed  
Archived tumor tissue (only if available)
X
Only for those patients that meet inclusion/exclusion criteria
Tumor markers 
X
Only if appropriate for the tumor type of the patient.  
Exploratory biomarker blood sample 
X
If possible, this sample should be collected on the same day as the biopsy.
Immunogenicity sample
X


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During Treatment Study Schedule 
Study Period
Study Treatment Period
Cycle/Visit
1
2
3-Xa
Duration
28 days
28 days
28 days
Relative Day 
within Dosing 
Cycle
1
2
3
8 
15
22
1
8
15
22
1
8
15
22
Procedure 
Category
Procedure
Comments
Physical 
Examination
Physical exam (including 
weight and skin inspections)
X
X
X
May be completed up to 7 days prior to the treatment 
infusion. 
Vital signs
X
X
X
X
X
X
X
X
X
X*
X
X*
Includes blood pressure, pulse, and temperature. For 
Cycles 1-2, at a minimum, vital signs should be 
obtained prior to infusion, during infusion, and at 1 
hour EOI (Section 7.2.4.1). In Cycle 3-X, vitial signs 
should be taken predose and when clinically indicated.  
* Only need to be collected for patients on Schedule 2
ECOG performance status
X
X
X
May be completed up to 7 days prior to the treatment 
infusion
Lab/
Diagnostic 
Tests
Local hematology 
X
X
X
X
X
X
X
X
X
X
X
X
.  May be drawn up to 1 day prior to the planned 
assessment. On C1D1, post-dose samples should be 
drawn.  See Attachment 4
Schedule 2: In Cycle 3-X, if clinically significant 
changes are observed, hematology should be obtained 
at least weekly until no longer clinically significant.
Local chemistry
X
X
X
X
X
X
X
X
X
X
X
X
May be drawn up to 1 day prior to the planned 
assessment. On C1D1, post-dose samples should be 
drawn.  See Attachment 4.
Schedule 2: In Cycle 3-X, if clinically significant 
changes are observed, chemistry should be obtained at 
least weekly until no longer clinically significant.
Local Urinalysis
X
X
X
May be assessed up to 3 days prior to the planned 
assessment.
PK sampling 
X
X
X
See Attachment 3.
Immunogenicity Sample
X
X
X
In addition to the scheduled samples, if a patient 
should have an infusion-related reaction to 
LY3164530, all attempts should be made to obtain 
immunogenicity sample as close to the onset of the 
event as possible, at the resolution of the event and 28 
days following the event.  A portion of the sample 


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 60
taken for immunogenicity testing may be used for PK 
analysis.
MET and EGFR ECD
pharmacodynamic samples
X
X
X
X
X
X
See Attachment 3.  
MET and EGFR ligands 
pharmacodynamic samples
X
X
X
X
X
X
See Attachment 3.


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 61
During Treatment Study Schedule 
Study Period
Study Treatment Period
Cycle/Visit
1
2
3-X
Duration
28 days
28 days
28 days
Relative Day 
within Dosing 
Cycle
1
2
3
8 
15
22
1
8
15
22
1
8
15
22
Procedure 
Category
Procedure
Comments
Lab/
Diagnostic 
Tests 
(cnt’d)
Proteomic blood sample
X
X
X
X
X
X
See Attachment 3.  Sample is only collected through 
Cycle 6.
Stored sample for 
pharmacogenomics
X
Collect once.  Sample can be collected at any time if 
not collected on C1D1.
Exploratory biomarker blood 
sample 
X
X
Sample to be collected C7D1.
Central ECG
X
X
X
X
X
X
X
X
X
X
X
X*
X
X*
In Cycle 1, triplicate ECGs collected predose, at EOI, 
2 hours EOI, and 6 hours EOI on the day of dosing .  
If possible, obtain prior to any associated blood 
draws.  In Cycles 2-X, single ECGs should be 
obtained predose on the day of dosing. On non-dosing 
days,the ECG may be obtained at anytime, but if 
possible they should be obtained near to the same 
time of day as the C1D1 ECG. See Attachment 4.
*Schedule 2 only
Tumor markers
X
X
If applicable to tumor type of the patient; may be 
drawn up to 3 days prior to the planned assessment.
Optional tumor biopsy 
X
Tumor 
Assessment
Tumor measurement
(palpable or visible)
X
X
Perform at least every 8 weeks at the end of every 
even cycle.
Radiologic imaging according to 
RECIST
X
X
The same method of imaging used at baseline should 
be used for each subsequent assessment.  Perform at 
least every other cycle (approximately every 8 
weeks).  May be omitted if patient has clear signs of 
progressive disease.
Adverse Events Collection/CTCAE Grading
X
X
X
Concomitant Medication Notation
X
X
X
LY3164530 – Schedule 1
X
X
X
X
X
X


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 62
LY3164530 – Schedule 2
X
X
X
X
X
X
X
X
X
X
X
X
a Following discussion and agreement from the Sponsor, the frequency of some assessments may be reduced for patients that have been on treatment for more 
than 1 year and are continuing to derive benefit from treatment.  This decision will be documented in writing.


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 63
Post-Treatment Discontinuation Schedule
Study Period
Post-
discontinuation 
Follow-Up
Visit 801
Post-treatment discontinuation follow-up should begin after the last dose of 
study therapy or, if study therapy has been omitted for an extended period, the 
date it is decided that the patient will not restart study therapy.
Duration
28 5 days
Relative Day
28
Procedure 
Category
Procedure
Comments
Physical 
Examination 
Weight
X
Vital signs
X
Includes blood pressure, pulse, and temperature.
ECOG performance status
X
Tumor 
Assessment
Tumor measurement (palpable or visible)
X
Performed if lesion is assessed as target or non-target.  Not required if 
progressive disease is documented while on treatment.
Radiologic imaging according to RECIST
X
The same method of imaging used at baseline should be used for each 
subsequent assessment.  Not required if progressive disease is documented while 
on treatment or if there are clear signs of clinical progression.  
Adverse Events Collection/CTCAE Grading
X
After Visit 801, only study protocol- or drug-related events are reported.  If a 
patient has an ongoing AE or SAE possibly related to LY3164530 (eg, abnormal 
electrolytes), the patient should be followed until the event is resolved, the event 
is no longer considered to be drug-related, the event becomes stable or returns to 
baseline, a new treatment is initiated for the patient, or the patient dies or is lost 
to follow-up.  Any subsequent follow-up(s) for AEs will be no more than 28 
days ±5 days in duration.
Concomitant Medication Notation
X
Local hematology
X
Local chemistry
X
Particular focus should be placed on patients that have abnormal electrolytes, as 
electrolyte depletion is known to occur for >6 weeks after EGFR monoclonal 
antibody therapy.  
Central ECG
X
Single ECG.  
Tumor markers
X
If applicable to tumor type of the patient.


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 64
Lab/
Diagnostic 
Tests
Optional tumor biopsy
X
From patients willing to consent.  
Exploratory biomarker blood sample 
X
PK sample
X
Immunogenicity sample
X
In addition to the scheduled sample, if a patient should have an infusion reaction 
to LY3164530, all attempts should be made to obtain immunogenicity sample as 
close to the onset of the event as possible, at the resolution of the event, and 30 
days following the event.
If a patient requires subsequent follow-ups (eg, for an ongoing AE), an 
immunogenicity sample should be obtained, if possible.  A portion of the sample 
taken for immunogenicity testing may be used for PK analysis.
MET and EGFR ECD pharmacodynamic 
samples
X
MET and EGFR ligand pharmacodynamic 
samples
X
Proteomic blood sample
X
Only if patient discontinues prior to Cycle 6.
Abbreviations:  AE = adverse event; BL = baseline; C = cycle; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = 
day; ECD = extracellular domain; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EGFR = 
epidermal growth factor receptor; EOI = end of infusion; HPV = human papillomavirus; MET = mesenchymal-epithelial transition factor; MRI = magnetic 
resonance imaging; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 65
LY3164530
Protocol JNBA Clinical Laboratory Tests
Attachment 2.
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Basophils
Serum Concentrations of:
Eosinophils
Alanine aminotransferase
Erythrocyte count (RBC)
Albumin
Hematocrit
Alkaline phosphatase
Hemoglobin
Aspartate aminotransferase
Leukocytes (WBC)
Blood urea nitrogen 
Lymphocytes
Calcium and ionized calcium
Monocytes
Chloride
Neutrophils (segmented and bands) 
Cholinesterase
Platelets
Creatinine
Reticulocytes
Gamma-glutamyl transpeptidase
Glucose, random
Coagulation: a
LDH
aPTT
Magnesium
PT/INR
Potassium
Sodium
Urinalysisa
Total bilirubin; if total bilirubin is increased a direct 
bilirubin should be obtained.  
Blood
Total protein
Glucose
Uric acid
Ketones
pH
Tumor markers (if applicable)
Protein
Specific gravity
Serum or Urine Pregnancy Test (females only)a
Urine leukocyte esterase
Abbreviations:  aPTT = activated partial thromboplastin time; INR = International Normalised Ratio; LDH = lactate 
dehydrogenase; PT = prothrombin time; RBC = red blood cells; WBC = white blood cells.
a
Local or investigator-designated laboratory


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 66
LY3164530
Protocol JNBA Pharmacokinetic and 
Attachment 3.
Pharmacodynamic Sampling Schedule
Pharmacokinetic and Pharmacodynamic Sampling for Schedule 1
Cycle
Day
Collection Time
PK 
Sampling 
Time 
MET ECD 
and EGFR 
ECDa
MET and 
EGFR 
Ligandsa
Proteomic 
Blood Samplea
1 and 2
1
Predose
X
X
X
X
1
Mid-infusion
X
1
End of infusion
X
X
X
X
1
2 hours post end of infusion 
X
1
4 hours post end of infusion
X
1
6 hours post end of infusion 
(Cycle 1 only)
X
2
24 ±4 hours post-end of 
infusion (Cycle 1 only)
X
X
X
X
3
Anytime during day (Cycle 1 
only)
X
8±1
Anytime during day
X
15
Predose
X
X
X
X
15
End of infusion
X
X
X
X
15
2 hours post end of infusion 
(Cycle 1 only)
X
15
4 hours post end of infusion 
(Cycle 1 only)
X
15
6 hours post end of infusion 
(Cycle 1 only)
X
22±2
Anytime during day (Cycle 1 
only)
X
3-6
1
Predose
X
X
X
X
1
End of infusion
X
Follow-
ups
Occurs on the day the follow-
ups occur.
X
X
X
Abbreviations:  ECD = extracellular domain; EGFR = epidermal growth factor receptor; MET = mesenchymal-
epithelial transition factor; PK = pharmacokinetic; V = volume of distribution.
a
Samples are requested to be taken immediately before the dose and immediately after the end of the LY3164530 
infusion.  Aberrations to specified sampling times will not be considered protocol deviations as long as the 
samples are taken and the actual sampling time is recorded.  It is essential that the actual times of LY3164530 
dose and samples are recorded accurately on the appropriate forms.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 67
LY3164530
Pharmacokinetic 
and 
Pharmacodynamic 
Sampling for 
Schedule 2Cycle
Day
Collection Time
PK 
Sampling 
Time 
MET 
ECD and 
EGFR 
ECDa
MET and 
EGFR 
Ligandsa
Proteomic 
Blood 
Samplea
1 and 2
1
Predose
X
X
X
X
1
Mid-infusion
X
1
End of infusion
X
X
X
X
1
2 hours post end of 
infusion 
X
1
4 hours post end of 
infusion
X
1
6 hours post end of 
infusion 
X
2
24 ±4 hours post-end of 
infusion 
X
X
X
X
3
Anytime during day
X
8
Predose
X
8
End of infusion
X
22
Predose
X
X
X
X
22
End of infusion
X
X
X
X
22
2 hours post end of 
infusion (Cycle 1 only)
X
22
4 hours post end of 
infusion (Cycle 1 only)
X
22
6 hours post end of 
infusion (Cycle 1 only)
X
23
24 ±4 hours post-end of 
infusion (Cycle 1 only)
X
24
Anytime during day 
(Cycle 1 only)
X
3-6
1
Predose
X
X
X
X
1
End of infusion
X
Follow-up 
Occurs on the day the 
follow-ups occur.
X
X
X
Abbreviations:  ECD = extracellular domain; EGFR = epidermal growth factor receptor; MET = mesenchymal-
epithelial transition factor; PK = pharmacokinetic; V = volume of distribution.
a
Samples are requested to be taken immediately before the dose and immediately after the end of the LY3164530 
infusion.  Aberrations to specified sampling times will not be considered protocol deviations as long as the 
samples are taken and the actual sampling time is recorded.  It is essential that the actual times of LY3164530 
dose and samples are recorded accurately on the appropriate forms.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 68
LY3164530
Protocol JNBA ECG, Chemistry, and 
Attachment 4.
Hematology Collection Schedule
Schedule 1
Cycle
Day
Collection Time
Central 
Triplicate ECG
Central 
Single ECG
Local 
Hematology
Local 
Chemistry
Screening
X
X
X
1
1
Predose
X
X
X
1
EOI (+ 10 min)
X
Xa
Xa
1
2 ±0.25 hours EOI 
X
1
6 ±0.25 hours EOI
X
2
24 ±4 hours EOI 
X
Xa
Xa
3
48 ±4 hours EOI
X
Xa
Xa
8
X
X
X
15
Predose
X
X
X
15
EOI (+ 10 min)
X
15
2 ±0.25 hours EOI 
X
15
6 ±0.25 hours EOI
X
22
X
X
X
2
1
Predose
X
X
X
8
X
X
X
15
Predose
X
X
X
22
X
X
X
3-X
1
Predose
X
X
X
15
Predose
X
X
X
Follow up
28
X
X
X
Abbreviations:  ECG = electrocardiogram; EOI = end of infusion; min = minute.
a 
If an abnormality in hematology or chemistry is consistently observed in the 48 hours following the end of the 
first infusion, additional post-infusion laboratory samples (EOI, and 24 hours and 48 hours after EOI) must be 
repeated for subsequent infusions until they are normal or return to baseline levels.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 69
LY3164530
Schedule 2
Cycle
Day
Collection Time
Central 
Triplicate ECG
Central 
Single ECG
Local 
Hematology
Local 
Chemistry
Screening
X
X
X
1
1
Predose
X
X
X
1
EOI (+ 10 min)
X
Xa
Xa
1
2 ±0.25 hours EOI 
X
1
6 ±0.25 hours EOI
X
2
24 ±4 hours EOI 
X
Xa
Xa
3
48 ±4 hours EOI
X
Xa
Xa
8
Predose
X
X
X
8
EOI (+ 10 min)
X
8
2 ±0.25 hours EOI 
X
8
6 ±0.25 hours EOI
X
15
Predose
X
X
X
22
Predose
X
X
X
2-X
1
Predose
X
X
X
8
Predose
X
Xb
Xb
15
Predose
X
X
X
22
Predose
X
Xb
Xb
Follow up
28
X
X
X
Abbreviations:  ECG = electrocardiogram; EOI = end of infusion; min = minute.
a 
If an abnormality in hematology or chemistry is consistently observed in the 48 hours following the end of the 
first infusion, additional post-infusion laboratory samples (EOI, and 24 hours and 48 hours after EOI) must be 
repeated for subsequent infusions until they are normal or return to baseline levels.
b
In Cycle 2-X, if clinically significant changes are observed, hematology and/or chemistry should be obtained at 
least weekly until no longer clinically significant.  Otherwise these samples are not required.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 70
LY3164530
Protocol JNBA Hepatic Monitoring Tests for 
Attachment 5.
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented and bands
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Anti-smooth muscle antibodya
CPK 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = International Normalised Ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530
Protocol JNBA Recommendations for 
Attachment 6.
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report a serious adverse event (SAE), please have the following 
information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, and weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalization), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug & Protocol Procedures
Concomitant Drug Therapy

indication, total daily dose, duration of treatment, start date, action taken
In Case of Death

cause, autopsy finding (if available), date, relationship to study drug and protocol 
procedures.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 72
LY3164530
Protocol JNBA mTPI and Simulation
Attachment 7.
The modified toxicity probability interval (mTPI) method employs a simple beta-binomial 
hierarchical model.  Decision rules are based on calculating the unit probability mass (UPM) of 3 
intervals corresponding to underdosing, proper dosing, and overdosing in terms of toxicity.  
Specifically, the underdosing interval is defined as (0, pT-ε1), the overdosing interval as (pT+ε2, 
1), and the proper dosing interval as (pT-ε1, pT+ε2), where ε1 and ε2 are small fractions, such as 
0.05, to account for the uncertainty around the true target toxicity.  A sensitivity analysis 
reported by Ji et al. (2010) showed that the mTPI design is robust to the specification of ε values. 
In addition, ε1 and ε2 could take different values to reflect physician preference and the nature of 
the disease.  For advanced diseases with few treatment options, higher toxicity rates might be 
considered acceptable, implying a specification of ε2>ε1.  For less advanced diseases, the 2 ε
values could be identical or ε1 could be >ε2.  The 3 dosing intervals are associated with 3 
different dose-escalation decisions.  The under-dosing interval corresponds to a dose escalation 
(E), overdosing corresponds to a dose deescalation (D), and proper dosing corresponds to staying 
at the current dose (S). 
Given an interval and a probability distribution, the UPM of that interval is defined as the 
probability of the interval divided by the length of the interval.  The mTPI design calculates the 
UPMs for the three dosing intervals, and the one with the largest UPM implies the corresponding 
dose-finding decision.  That decision provides the dose level to be used for future patients.  For 
example, if the underdosing interval has the largest UPM, decision E, to escalate, will be 
executed, and the next cohort of patients will be treated at the next-higher dose level.  Ji et al.
(2010) show that the decision based on the UPM is optimal in that it minimizes a subsequent 
expected loss.  Under the mTPI design, a trial is terminated when either the lowest dose is above 
the maximum tolerated dose (MTD) or a pre-specified maximum sample size is reached.
Simulation
A small simulation study was conducted to compare the mTPI with 3+3 in identifying the right 
MTD.  Six scenarios were run, each with 1000 simulated trials.  As in Study JNBA, the MTD
has a target toxicity probability of  PT=0.3 and ε1 and ε2 are set at 0.013 and 0.001 respectively.  
The scenarios assumed the true probabilities of six doses as follows:  scenario 1= (0.1, 0.2, 0.3, 
0.4, 0.5, 0.6); scenario 2= (0.08, 0.16, 0.24, 0.3, 0.38, 0.46); scenario 3= (0.04, 0.08, 0.12, 0.16,
0.2, 0.24); scenario 4= (0.4, 0.5, 0.6, 0.7, 0.8, 0.9); scenario 5= (0.04, 0.08, 0.12, 0.16, 0.2, 0.58);
and scenario 6= (0.06, 0.46, 0.53, 0.6, 0.67, 0.74).  For all scenarios, the probability of selecting 
each dose was summarized, the average number of patients treated at each dose and average 
number of patients experience DLT at each dose.  The simulation demonstrates that, in general,
mTPI method correctly identifies the MTD more than 3+3 and appears to be as safe as 3+3 
method in that it puts a similar percentage of patients on toxic doses.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 73
LY3164530
Scenario
Dose
True
Selection Prob (%)
# of Subjects Treated
# of Toxicities
Level
Prob (tox)
mTPI
3+3
mTPI
3+3
mTPI
3+3
1
1
0.1
5.8
24.4
3.53
4.42
0.38
0.44
2
0.2
20.8
30.3
6.89
4.55
1.45
0.89
3
0.3
35.1
19.4
8.21
3.43
2.39
1
4
0.4
28.4
4.4
6.94
1.61
2.78
0.68
5
0.5
7.2
0.5
2.99
0.43
1.54
0.22
6
0.6
1.3
0
1.06
0.06
0.62
0.04
2
1
0.08
3.4
20.8
2.67
4.15
0.22
0.31
2
0.16
13.2
26.4
5.17
4.49
0.83
0.75
3
0.24
20.6
19.5
5.81
3.69
1.38
0.91
4
0.3
29.2
10.8
7.29
2.32
2.22
0.67
5
0.38
23.7
2.8
5.48
1.1
2.09
0.42
6
0.46
9.5
1.6
3.48
0.36
1.63
0.17
3
1
0.04
0.8
7.3
1.6
3.52
0.07
0.14
2
0.08
1.7
12.1
2.07
3.88
0.15
0.33
3
0.12
3.6
18.3
2.73
3.91
0.34
0.48
4
0.16
8.5
16.2
3.54
3.63
0.53
0.62
5
0.2
14.5
11.4
4.65
2.77
0.94
0.58
6
0.24
70.8
25.4
15.38
1.74
3.62
0.41
4
1
0.4
43.3
15.6
13.7
4.94
5.4
1.97
2
0.5
10.5
1.5
5.25
1.34
2.63
0.69
3
0.6
1.2
0
1.67
0.19
1
0.11
4
0.7
0
0.1
0.44
0.01
0.3
0
5
0.8
0
0
0.1
0.01
0.07
0.01
6
0.9
0
0
0.02
0
0.02
0
5
1
0.04
0.8
5.9
1.48
3.49
0.05
0.14
2
0.08
2.1
13.2
2.22
3.89
0.17
0.31
3
0.12
4
16.8
2.85
3.95
0.35
0.51
4
0.16
9.8
18.7
3.86
3.68
0.64
0.61
5
0.2
75.7
24.6
14.12
3.37
2.86
0.67
6
0.58
7.3
3.7
5.38
1.61
3.17
0.94
6
1
0.06
60.4
76.8
14.01
5.62
0.81
0.33
2
0.46
31.2
8.5
10.5
4.43
4.83
2.07
3
0.53
7.1
0.8
3.64
0.87
1.91
0.47
4
0.6
0.8
0
1.21
0.09
0.73
0.05
5
0.67
0
0.1
0.39
0.01
0.27
0
6
0.74
0
0.1
0.11
0.01
0.08
0
Abbreviation:  mTPI = modified toxicity probability interval.
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding 
trials. Clin Trials. 2010;7(6):653-663.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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Protocol JNBA Protocol I7-MC-JNBA(b) 
Attachment 8.
Amendment Summary A Phase 1 Study of LY3164530, a 
Bispecific Antibody Targeting MET and EGFR, in Patients 
with Advanced or Metastatic Cancer
Overview
Protocol I7-MC-JNBA, A Phase 1 Study of LY3164530, a Bispecific Antibody Targeting MET 
and EGFR, in Patients with Advanced or Metastatic Cancer has been amended.  The new 
protocol is indicated by Amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol.

Introduction of a new weekly schedule for dosing.

Minor changes were made to increase the clarity and consistency of the 
document and to correct typographical errors.


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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.
4.0 Abbreviations and Definitions
AUC
area under the serum plasma concentration-time curve
AUC(0-tlast)
area under the serum plasma concentration-time curve from time zero to last 
measurable plasma concentration
AUC(0-∞)
area under the serum plasma concentration-time curve from time zero to infinity
AUC0-τ
area under the serum versus time concentration-time curve over the dosing interval
Cav,τ
average serum concentration over the dosing interval
Cmax
maximum serum plasma concentration
Cmin,τ
minimum serum concentration over the dosing interval
EC50
the half maximal effective serum concentration
Q2W
once every 2 weeks
5.2.1
Primary Objective
The primary objective of this study is to determine an RP2D and schedule of LY3164530 that 
may be safely administered to patients with advanced or metastatic cancer.
5.3.1
Mechanism of Action and In Vitro/In Vivo Activity
LY3164530 has high affinity for both MET and EGFR and binds both receptors simultaneously 
in tumor cells.  As described in the Investigator’s Brochure (Section 5.2.2), binding of 
LY3164530 to MET and EGFR blocks activation of both receptors by their respective ligands.  
In addition to its ligand-blocking activity, LY3164530 also leads to internalization and 
degradation of both receptors in tumor cells.  The ability of LY3164530 to internalize both 
receptors is superior to the combination of the 2 componentindividual monoclonal antibodies.  
The internalization of both receptors is most commonly observed in cells expressing high levels 
of MET.  In addition, LY3164530 also increases the avidity binding to MET in cells expressing 
both MET and EGFR, leading to better neutralization of HGF compared to the parental MET 
antibody alone or in combination with cetuximab.  The ability of LY3164530 to block ligand-
receptor interactions and efficiently internalize MET and EGFR, and its increased avidity for 
MET, is believed to be responsible for the in vitro antiproliferative activity observed against a 
panel of tumor cell lines.  In vivo, administration of LY3164530 results in dose-dependent 
antitumor activity in cell line-derived non-small cell lung cancer, gastric cancer, and squamous 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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cell cancer of the head and neck (SCCHN) xenografts, as well as in colorectal cancer and 
SCCHN patient-derived xenografts.  
5.5
Rational for Amendment (b)
As of 27 July 2015, 15 patients have been treated in Study JNBA at doses of 300, 600, 1000, and 
1250 mg on Days 1 and 15 of a 28 day cycle.  One DLT (Cycle 1) has been reported in a patient 
at the 1000 mg dose level who experienced intolerable, Grade 2 rash.  Two of the 3 patients 
treated at the 1250 mg dose level experienced AEs in Cycle 2 that would have met the criteria for 
a DLT had they occurred in Cycle 1 (DLT-equivalent toxicity).  These events included Grade 3 
pustular rash in one patient and Grade 3 dermatitis acneiform and Grade 4 hypomagnesaemia in 
another patient.  As a result, a dose of 1250 mg was deemed to exceed the maximum tolerated 
dose.  As of 27 July 2015, 6 patients have been treated at the 1000 mg dose level and enrollment 
will continue until 10-20 patients have been treated at the recommended Phase 2 dose.
The drug-related, treatment emergent adverse events reported for LY3164530 are consistent with 
inhibition of EGFR and include skin reactions [maculo-papular rash, dermatitis acneiform, skin 
fissures, rash, skin exfoliation, and/or pustular rash] (n=14, 93.3%), hypomagnesaemia (n=7, 
46.7%), and paronychia (n=4, 26.7%).  The following drug-related events occurred in 2 patients 
each (13.3%):  decreased appetite, dysgeuesia, fatigue, and hypokalaemia.  One SAE 
(hypomagnesaemia) was considered to be related to LY3164530 by the investigator and the 
Sponsor.  The event occurred in a metastatic cutaneous squamous cell carcinoma patient who 
had Grade 1 hypomagnesaemia at baseline that worsened and resulted in study drug 
discontinuation.
An interim analysis of the LY3164530 PK data was conducted from all of the 15 patients who 
received at least 1 dose of LY3164530 administered as a 1 or 2-hour infusion once every 2 
weeks (Q2W) across the dose range of 300-1250 mg.  Dose-dependent increases in the systemic 
exposure (AUC, Cmax) of LY3164530 following single and multiple doses were observed.  A 
minor amount of accumulation in serum was observed within Cycle 1 and between Cycles 1 and 
2 of treatment after 1000 mg Q2W (mean accumulation ratio of 1.1 within and between cycles).  
The LY3164530 systemic clearance (CL) decreased by approximately 2-fold on average when 
the dose was escalated from 600 mg to 1000 mg, indicating the saturation of cell-surface 
receptors by LY3164530 and a slower non-receptor-mediated clearance predominating at doses 
>600 mg.  While a more rapid receptor-mediated clearance (ie, target mediated drug disposition 
[TMDD]) predominates at low doses (ie, ≤600 mg).  In addition, the LY3164530 exposure 
following 1000 mg Q2W appears to be in an exposure range expected to achieve biological 
effects based on the nonclinical MKN45 xenograft PK/PD model estimates for the MET and 
EGFR half maximal effective serum concentrations (EC50) values.  The LY3164530 maximum 
serum concentration (Cmax) after 1000 mg in Cycles 1 and 2 is greater (mean Cmax range: 295-394 
µg/mL) than both the MET EC50 (79.5 µg/mL; 0.4 µM) and EGFR EC50 (7.95 µg/mL; 0.04 µM) 
concentrations.  The average LY3164530 serum concentration over the dosing interval (Cav,τ) 
during Cycles 1 and 2 is also greater (mean Cav,τ range: 102-132 µg/mL) than the MET EC50 and 
EGFR EC50.  However, the minimum serum concentration over the dosing interval (Cmin,τ) of 
LY3164530 following 1000 mg in Cycles 1 and 2 (mean Cmin,τ range: 19-49 µg/mL) is lower 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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than the MET EC50 (79.5 ug/mL), which is the desired concentration to maintain throughout the 
dosing interval in order to maximize the biological activity of LY3164530.  
At a dose of 1000 mg, the mean terminal elimination-life (t1/2) is approximately 100 hours 
(approximately 4 days).  As a result, the administration of LY3164530 every 2 weeks may not be 
the optimal schedule of administration in order to achieve a LY3164530 Cmin,τ near the MET 
EC50.  Therefore, it is hypothesized that weekly dosing of LY3164530 (ie, Days 1, 8, 15, and 22 
of a 28 day cycle) will minimize the fluctuation between the peak (Cmax) and trough (Cmin,τ) 
serum concentrations of LY3164530 leading to a more consistent inhibition of both MET and 
EGFR over the dosing interval (with minimal impact on the accumulation of LY3164530) and 
potentially greater pharmacologic activity (PD response).  The MTD of LY3164530 when 
administered on Days 1 and 15 of a 28 day cycle is 1000 mg.  As a result, the starting dose for 
the weekly schedule will be 500 mg.  The safety, toxicity, PK, and PD associated with a weekly 
schedule will be assessed.  
6.2
Summary of Study Design
Study JNBA is a multicenter, nonrandomized, open label, dose escalation Phase 1 study of IV 
LY3164530 in patients with advanced and/or metastatic cancer.  Eligible patients will receive 
LY3164530 as an infusion on Days 1 and 15 (Schedule 1) or on Days 1, 8, 15, and 22 (Schedule 
2) of each cycle.  A cycle will consist of 28 days and the schedules will enroll in parallel.  
Dose escalation will be driven by a modified toxicity probability interval (mTPI) method.  The 
RP2D and schedule will be determined once at least 10 patients, but no more than 20, are treated 
at a dose and schedule that is at or below the maximum tolerated dose (MTD).  The actual 
sample size for Study JNBA is anticipated to be approximately 50 patients dependings on the 
incidence of DLTs and is anticipated to be approximately 50 patients.
…
7.2.1
Dosing Schedule
For doses less than <1000 mg, LY3164530 will be administered intravenously over 
approximately 60 minutes. on Days 1 and 15 of each 28-day cycle.  The Sponsor may instruct 
sites to extend the infusion time for up to 3 hours for doses > ≥1000 mg.  
LY3164530 will be administered on Days 1 and 15 every 28 days (Schedule 1) or on Days 1, 8, 
15, and 22 every 28 days (Schedule 2).  The assigned dose, schedule, and duration of infusion of 


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LY3164530
LY3164530 will be provided by the Sponsor on a patient registration form.  A patient will be 
assigned to either Schedule 1 or Schedule 2 and will be maintained on that schedule for the 
duration of therapy.  Subsequent doses and/or infusion times should be adjusted as described in 
Section 7.2.5.
7.2.2.3 Dose Escalation Method 
…
Figure JNBA.1.
Dose-finding spreadsheet of the modified toxicity probability 
interval method showing number of patients treated at a given 
dose vs. number of DLTs observed at that dose .
The beginning dose level for Schedule 1 was will be 300 mg.  The starting dose level for 
Schedule 2 will be 500 mg.  The dose will be escalated by a maximum increment of 100%.  If 
the beginning dose level is determined to be unacceptably toxic, a -1 dose level may be explored.  
The exact increment will be determined by the investigators and Lilly CRP/CRS, and may be 
less than the maximum increment allowed in the protocol.  Safety data will be the primary 
criteria for both the decision to dose-escalate and for selecting the dose to be administered in the 
next cohort.  In addition, if available at the time of the dose escalation decision, PK (maximum 
plasma serum concentration [Cmax], area under the plasma serum concentration-time curve 
[AUC], and CL) and/or PD results will be used as secondary/supporting data for dose escalation.  
No dose escalation can occur without prior discussion and agreement between the investigator 


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LY3164530
and the Lilly CRP or CRS; the decision will be documented in writing.  Intrapatient dose 
escalations are not permitted.
Although an example escalation table is shown in Table JNBA.3, alternate doses may be 
selected.
Table JNBA.3.
Sample Dose Escalation Schema
Dose Level
(Cohort)
Schedule 1 Dose
Schedule 2 Dose
-1
100 mg
400 mg
1
300 mg
500 mg
2
600 mg
600 mg
3
1000 mg
700 mg
4
1400 1250 mg
5
1700 mg
6
2000 mg
In Cohort 1 for Schedule 1 only, the first patient is required to complete a full cycle (28 days) 
before subsequent patients can be dosed.  Subsequent patients in Cohort 1 can be dosed 
concurrently.  Beginning with Cohort 2 for Schedule 1, and for all cohorts with Schedule 2,
patients within a cohort can be dosed concurrently.  
…
7.2.4.1 Infusion-Related Reactions
Due to the risk of hypersensitivity reactions with any biological agents, all patients should 
continue to be closely monitored for signs and symptoms indicative of an infusion-related 
reaction both in the acute period (immediately or within 24 hours after dosing) and up to several 
days to a few weeks after dosing for delayed reactions.  In Cycles 1 and 2, Aacute assessments 
should include an assessment of vital signs starting at the time of initiation of the infusion and 
continuing until at least 60 minutes after the end of the infusion.  At a minimum, vital signs 
should be obtained prior to infusion, during infusion, and at 1 hour post-infusion.  The exact 
frequency of the monitoring is left to the discretion of the investigator.   Monitoring should be 
performed in an area where resuscitation equipment and other agents (eg, epinephrine, 
corticosteroids) are readily available.  
…
7.2.4.2 Skin Rash Reactions
Skin rash is a known toxicity of EGFR inhibitors, and skin effects were observed with 
LY3164530 in a 5-week repeat-dose toxicity study in monkeys.  In Study JNBA, skin reactions 
were observed at all dose levels with Schedule 1 and were dose limiting at 1250 mg.  As a result, 
Pprophylaxis is not permitted for the initial dose of LY3164530. so that the toxicities of 
LY3164530 may be appropriately characterized.  However, iInstitutional-approved standard of 


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
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LY3164530
care premedication for EGFR inhibitors, such as dexamethasone and/or topical and/or oral 
antibiotics, may be administered for the initial and subsequent doses.  
If skin rash is identified as a DLT, prophylaxis may be permitted for the Cycle 1 Day 1 dose.  
Since LY3164530 is a bispecific antibody with a fixed stoichiometry for EGFR/MET, in the case 
of skin rash-only DLT, prophylaxis may be explored to maximize the chances of effective 
combined MET/EGFR.  This decision will be made following discussions with the investigators 
and the Lilly CRP/CRS and will be documented in writing.  The dose escalation rules in Figure 
JNBA.1 would be followed if this change is implemented.
…
7.2.5.1 Dose Delays and Omissions
The following rules should guide dosing:

Before each dose cycle of LY3164530 the following parameters are required:

Hematologic:  ANC >1.5 x 109/L, platelets >75 x 109/L, and hemoglobin >8 g/dL.

Non-hematologic:  AEs must resolve to CTCAE v 4.03 Grade <1, or baseline.  
Exceptions will be made for:  alopecia, fatigue, skin reactions, or other toxicities that 
can be controlled with standard treatment; these toxicities must resolve to <Grade 2.

The start of a cycle is the date of the Day 1 dose.  
For Schedule 1:  If the Day 15 dose cannot be administered within 21 days of the prior 
dose (by Day 22), it should be omitted.  The interval between LY3164530 doses must not 
be less than 14 days.  If a dose is delayed (for toxicity or other circumstances), the next 
dose should be adjusted so that there is at least a 14-day interval.
For Schedule 2:  If a dose cannot be administered within 10 days of the prior dose, it 
should be omitted.  The interval between LY3164530 doses must not be less than 7 days.  
If a dose is delayed (for toxicity or other circumstances), the next dose should be adjusted 
so that there is at least a 7-day interval.
The interval between LY3164530 doses must not be less than 14 days.  If a dose is 
delayed (for toxicity or other circumstances), the next dose should be adjusted so that 
there is at least a 14-day interval.
If a dose cannot be administered within 28 days of the prior dose due to an AE, the patient 
should be removed from study drug treatment and should complete subsequent follow-up (Table 
JNBA.4).  

If the patient has completed the initial on-study radiographic assessment (eg, at the end of 
Cycle 2) is in Cycle 3 or beyond and is continuing to receive benefit from therapy, delays of 
greater than 28 days may be acceptable if agreed upon by both the investigator and Sponsor.  
For instance, if a patient has a non–drug-related AE such as prolonged flu, the patient may 


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LY3164530
continue on therapy if, in the opinion of the investigator, he/she is showing benefit from 
therapy and has recovered sufficiently from the AE.  

A delay of no more than 7 days because of holidays, weekends, inclement weather, or other 
justifiable events will be permitted and will not be counted as a protocol deviation.  
7.2.5.2 Dose Adjustments 
Dose adjustments should follow the guidance in Table JNBA.4.
For patients requiring dose reductions, reescalation to the original assigned LY3164530 dose is 
not allowed.  The patient must be maintained at a reduced dose level for all remaining cycles.


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Table JNBA.4.
Dose Modifications and Treatment Alterations in Patients Treated with 
LY3164530
Toxicity
CTCAE Grade
Recommendations
Infusion-
related 
rReaction 
Grade 1
First occurrence  
Decrease the LY3164530 infusion rate by 50% and monitor closely for any 
worsening.  For subsequent infusions, premedicate with diphenhydramine 
hydrochloride; additional premedication may be administered at the investigator’s 
discretion.  
Grade 2
First occurrence 
Stop LY3164530 infusion.  Administer diphenhydramine hydrochloride and 
acetaminophen for fever and oxygen.  Resume infusion at 50% of previous rate 
once infusion-related reaction has resolved or decreased to Grade 1 in severity, 
and monitor closely for any worsening.  
For subsequent infusions, premedicate with diphenhydramine hydrochloride; 
additional premedication may be administered at the investigator’s discretion.  
The reduced rate should be used for all subsequent infusions.
Grade 1 or 2
Second occurrence
Administer dexamethasone. 
For subsequent infusions, premedicate with diphenhydramine hydrochloride, 
acetaminophen, and dexamethasone.  The reduced infusion rate should be used 
for all subsequent infusions.
≥Grade 3
Stop LY3164530 infusion immediately and disconnect infusion tubing from the 
patient.  
Administer diphenhydramine hydrochloride, dexamethasone, bronchodilators for 
bronchospasm, and other medications/treatment as medically indicated.
Patients must not receive any further LY3164530 treatment.
Skin 
reactions 
(eg, acne-
like rash)
Grade 3
First occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 following the rules in 
Section 7.2.5.1.  Treatment with topical and/or oral antibiotics may should be 
considered. 
Grade 3
Second occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 following the rules in Section
7.2.5.1.  Dose reduce by 20% from assigned dose to the dose level used for the 
previous cohort for second occurrence.  Treatment with topical and/or oral 
antibiotics may should be considered.  
Grade 3
Third occurrence 
Or Grade 4
Patients must not receive any further LY3164530 treatment.
Other 
toxicities
≥Grade 3
First occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 or baseline following the 
rules in Section 7.2.5.1.  Based on the investigator’s discretion, the full dose of 
LY3164530 may be administered or the dose may be reduced to the next lowest 
dose level.  If event recurs at same grade, then dose reduce LY3164530 to the 
next lowest dose.  
≥Grade 3
Second occurrence
Delay or omit LY3164530 treatment until ≤Grade 1 or baseline following the 
rules in Section 7.2.5.1.  If event recurs at same grade, then dose reduce 
LY3164530 to the next lowest dose.  Exceptions may be made for transient 
changes in electrolytes that respond to treatment. 
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.


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Note:  In addition, the dose may be reduced to the next lowest level for any toxicity at the discretion of the 
investigator.
7.3
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3164530 in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted between 
the investigational site and the Lilly clinical research personnel to confirm that each patient 
meets all enrollment criteria.  Upon confirmation of eligibility, the Sponsor will confirm the 
dose, schedule, infusion duration, and identification number assignment for each patient.  
7.5
Concomitant Therapy
…
Patients should receive full supportive care during the trial.  Routine prophylactic use of 
granulocyte colony-stimulating factors (G-CSF) is not permitted during this study.  Should the 
use of hematopoietic colony-stimulating factors (CSFs) be necessary, follow the American 
Society of Clinical Oncology (ASCO) recommendations for the use of CSFs (Smith et al. 2006
2015).  
…
8.1
Safety Evaluations
The safety and tolerability of LY3164530 have been assessed in nonclinical toxicology studies 
and this ongoing Phase 1 study.  and tThe results from these studies are detailed in the 
Investigator’s Brochure.  This Phase 1 study contains safety monitoring that will permit initial 
characterization of the safety profile of LY3164530 in patients with advanced or metastatic 
cancer.  Study procedures and their timing, including collection of patient samples, are described 
in the Study Schedule (Attachment 1).
…
8.2.2.2.
Pharmacodynamic Samples 
At the visits and times specified in Attachment 3, serum and plasma samples will be collected.  
The effect of LY3164530 on MET and EGFR pathway-specific targets may be explored to 
determine changes in potential biomarkers such as circulating levels of the MET ligand HGF,  
EGFR ligands (eg, EGF, TGFalpha), MET/ECD, and EGFR/ECD.  These samples may be used 
for exploratory research on new biomarkers related to the MET/HGF and EGFR pathway.  In 
addition, exploratory samples to assess proteomic panel may be collected.  A maximum of 3 
timepoints may be removed per dosing schedule during the study if warranted and agreed upon 
between both the investigator and Lilly.
…
8.2.3.3 Exploratory Biomarker Blood Samples 
…


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8.3
Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1 
for details regarding the timing of specific efficacy measures.  
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement:

Computed tomography (CT) scan

Magnetic resonance imaging (MRI)

Chest x-ray.
…
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 mTPI method and determined by the occurrences of 
DLTs (up to 20 patients per cohort before establishing the RP2D and schedule). The total 
sample size is anticipated to be approximately 50 patients.  
10.5
Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have been exposed to study drug 
and have had samples collected.  
Pharmacokinetic parameter estimates for LY3164530 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax, AUC0-tlast, AUC0-τ, and AUC0-∞of 
LY3164530.  Other noncompartmental parameters, such as t1/2, CL, volume of distribution (V), 
and accumulation ratios may be reported.  Additional exploratory analyses will be performed if 
warranted by the data, and other validated PK software programs may be used if appropriate and 
approved by Lilly Global PK/PD management.  The version of any software used for the analysis 
will be documented and the program will meet the Lilly requirements of software validation.
Pharmacokinetic parameter estimates 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% confidence intervals 
(CIs).
10.6
Pharmacodynamic Analyses
Provided that the data allows, PD and immunogenicity data from all patients may be analyzed 
using linear and/or nonlinear fixed and mixed effects models as appropriate.  Pharmacodynamic 
and immunogenicity data will be summarized by dose, drug concentrations, and time from dose 


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LY3164530
for each schedule of administration.  Potential PD markers and immunogenicity versus time data 
will be presented graphically for each patient and summarized by dose and schedule of 
administration.  Absolute and/or percent change from baseline for the PD markers may also be 
evaluated.  Data may be log-transformed prior to summarizing if necessary.  The interpatient and 
intrapatient variability of the PD markers and immunogenicity responses may also be assessed 
where appropriate.  Baseline measurements may be evaluated as potential covariates to assess 
their relationship to relevant PD responses.
10.7.
Pharmacokinetic/Pharmacodynamic Analyses
In addition to a standard noncompartmental assessment, and provided that the data allows, the 
LY3164530 serum concentration-time data may be evaluated by model-based approaches as 
warranted.  Additional analyses, such as exposure-response modeling using the efficacy 
endpoints, may also be explored.
Additional exploratory analyses may be performed if warranted by the data.
10.10 Interim Analyses
Since this is a dose-escalation study, data will be reviewed on an ongoing basis during the study 
until the RP2D is determined.  The purpose of these ongoing reviews is to evaluate the safety 
data at each dose level.  A review of the data will be completed approximately after 5 6 patients 
have been treated for at least 1 cycle at a dose level without a cohort analysis.
An interim analysis will be triggered when at least 10 15 patients have been dosed at a given 
dose level for 1 cycle of treatment to evaluate the safety and tolerability of LY3164530.  The 
interim analysis may include, but are not limited to, an assessment of available safety, PK, and 
PD data.
Enrollment may continue during the interim analysis and the dose escalation rules as outlined in 
Figure JNBA.1 will continue to be followed.
Additional interim analyses may be triggered and may include, but are not limited to, assessment 
of available safety, PK, and PD data.
12
References
…
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO. 2015 
update of recommendations for the use of white blood cell growth factors: an evidence-based 
clinical practice guideline. J Clin Oncol. 2015. doi: 10.1200/JCO.2015.62.3488.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor 
SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, 
Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. 2006 update 
of recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J Clin Oncol. 2006;24(19):3187-3205.


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LY3164530
Attachment 1
Protocol JNBA Study Schedule


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 87
Baseline Schedule
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 28 days
Relative Day to C1D1
≤28
≤14
≤7
Procedure 
Category
Procedure
Comments
Lab/
Diagnostic 
Tests
Local hematology
X
Local chemistry
X
Local coagulation
X
Local urinalysis
X
Local pregnancy test
X
X
Must be done 147 days prior to the first dose of study drug if patient is a woman 
of child-bearing potential.  May be urine or serum specimen.
Central  ECG
X
Triplicate ECG.  
Biopsy of pretreatment tumor tissue
X
Unless the Sponsor and investigator document that the biopsy may be omitted; 
sample should be taken only after study eligibility is confirmed  
Archived tumor tissue (only if available)
X
Only for those patients that meet inclusion/exclusion criteria
Tumor markers 
X
Only if appropriate for the tumor type of the patient.  
Exploratory biomarker blood sample for 
pharmacogenomics
X
If possible, this sample should be collected at the timeon the same day as ofthe 
biopsy.
Immunogenicity sample
X


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 88
During Treatment Study Schedule 
Study Period
Study Treatment Period
Cycle/Visit
1
2
3-Xa
Duration
28 days
28 days
28 days
Relative Day 
within Dosing 
Cycle
1
2
3
8 
15
22
1
8
15
22
1
8
15
22
Procedure 
Category
Procedure
Comments
Physical 
Examination
Physical exam (including 
weight and skin inspections)
X
X
X
May be completed up to 7 days prior to the treatment 
infusion. 
Vital signs
X
X
X
X
X
X
X
X
X
X*
X
X*
Includes blood pressure, pulse, and temperature.  For 
Cycles 1-2, Aat a minimum, vital signs should be 
obtained prior to infusion, during infusion, and at 1 
hour EOI (Section 7.2.4.1). In Cycle 3-X, vital signs 
should be taken predose and when clinically indicated.
* Only need to be collected for patients on Schedule 2
ECOG performance status
X
X
X
May be completed up to 7 days prior to the treatment 
infusion
Lab/
Diagnostic 
Tests
Local hematology 
X
X
X
X
X
X
X
X
X
X
X
X
On C1D1, both pre-dose and post-dose samples 
should be drawn.  See Attachment 4.  In Cycles 3-X
Mmay be drawn up to 1 day prior to the planned 
assessment.  On C1D1, post-dose samples should be 
drawn.  See Attachment 4
Schedule 2:  In Cycle 3-X, if clinically significant 
changes are observed, hematology should be obtained 
at least weekly until no longer clinically significant.
Local chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
On C1D1, both pre-dose and post-dose samples 
should be drawn.  See Attachment 4.  Beginning with 
Cycles 3-X, lab mMay be drawn up to 1 day prior to 
the planned assessment.  On C1D1, post-dose samples 
should be drawn.  See Attachment 4
Schedule 2:  In Cycle 3-X, if clinically significant 
changes are observed, chemistry should be obtained at 
least weekly until no longer clinically significant.
Local Urinalysis
X
X
X
May be assessed up to 3 days prior to the planned 
assessment.
PK sampling 
X
X
X
See Attachment 3.
Immunogenicity Sample
X
X
X
In addition to the scheduled samples, if a patient 
should have an infusion-related reaction to 
LY3164530, all attempts should be made to obtain 


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 89
immunogenicity sample as close to the onset of the 
event as possible, at the resolution of the event and 28 
days following the event.  A portion of the sample 
taken for immunogenicity testing may be used for PK 
analysis.
MET and EGFR ECD 
pharmacodynamic samples
X
X
X
X
X
X
See Attachment 3.  
MET and EGFR ligands 
pharmacodynamic samples,
X
X
X
X
X
X
See Attachment 3.


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 90
During Treatment Study Schedule 
Study Period
Study Treatment Period
Cycle/Visit
1
2
3-X
Duration
28 days
28 days
28 days
Relative Day 
within Dosing 
Cycle
1
2
3
8 
15
22
1
8
15
22
1
8
15
22
Procedure 
Category
Procedure
Comments
Lab/
Diagnostic 
Tests 
(cnt’d)
Proteomic blood sample
X
X
X
X
X
X
See Attachment 3.  Sample is only collected through 
Cycle 6.
Stored sample for 
pharmacogenomics
X
Collect once.  Sample can be collected at any time if 
not collected on C1D1.
Exploratory biomarker blood 
sample for pharmacogenomics
X
X
Sample to be collected C7D1.
Central ECG
X
X
X
X
X
X
X
X
X
X
X
X*
X
X*
In Cycle 1, triplicate ECGs collected predose, at EOI, 
2 hours EOI, and 6 hours EOI on the day of dosing .  
If possible, obtain prior to any associated blood 
draws.  In Cycles 2-X, single ECGs should be 
obtained predose on the day of dosing. On non-dosing 
days,the ECG may be obtained at anytime, but if 
possible they should be obtained near to the  same 
time of day as the C1D1 ECG. See Attachment 4.
*Schedule 2 only.  
Tumor markers
X
X
If applicable to tumor type of the patient; may be 
drawn up to 3 days prior to the planned assessment.
Optional tumor biopsy 
X
Tumor 
Assessment
Tumor measurement
(palpable or visible)
X
X
Perform at least every 8 weeks at the end of every 
even cycle.
Radiologic imaging according to 
RECIST
X
X
X
The same method of imaging used at baseline should 
be used for each subsequent assessment.  Perform at 
least every 8 weeks other cycle (approximately every 
8 weeks) between D22-28.  May be omitted if patient 
has clear signs of progressive disease.
Adverse Events Collection/CTCAE Grading
X
X
X
Concomitant Medication Notation
X
X
X
LY3164530 – Schedule 1
X
X
X
X
X
X


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 91
LY3164530 – Schedule 2
X
X
X
X
X
X
X
X
X
X
X
X
a Following discussion and agreement from the Sponsor, the frequency of some assessments may be reduced for patients that have been on treatment for more 
than 1 year and are continuing to derive benefit from treatment.  This decision will be documented in writing.


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 92
Post-Treatment Discontinuation Schedule
Study Period
Post-
discontinuation 
Follow-Up
Visit 801
Post-treatment discontinuation follow-up should begin after the last dose of 
study therapy or, if study therapy has been omitted for an extended period, the 
date it is decided that the patient will not restart study therapy.
Duration
28 5 days
Relative Day
28
Procedure 
Category
Procedure
Comments
Physical 
Examination 
Weight
X
Vital signs
X
Includes blood pressure, pulse, and temperature.
ECOG performance status
X
Tumor 
Assessment
Tumor measurement (palpable or visible)
X
Performed if lesion is assessed as target or non-target.  Not required if 
progressive disease is documented while on treatment.
Radiologic imaging according to RECIST
X
The same method of imaging used at baseline should be used for each 
subsequent assessment.  Not required if progressive disease is documented while 
on treatment or if there are clear signs of clinical progression.  
Adverse Events Collection/CTCAE Grading
X
After Visit 801, only study protocol- or drug-related events are reported.  If a 
patient has an ongoing AE or SAE possibly related to LY3164530 (eg, abnormal 
electrolytes), the patient should be followed until the event is resolved, the event 
is no longer considered to be drug-related, the event becomes stable or returns to 
baseline, a new treatment is initiated for the patient, or the patient dies or is lost 
to follow-up.  Any subsequent follow-up(s) for AEs will be no more than 28 
days ±5 days in duration.
Concomitant Medication Notation
X
Local hematology
X
Local chemistry
X
Particular focus should be placed on patients that have abnormal electrolytes, as 
electrolyte depletion is known to occur for >6 weeks after EGFR monoclonal 
antibody therapy.  
Central ECG
X
Single ECG.  
Tumor markers
X
If applicable to tumor type of the patient.
Optional tumor biopsy
X
From patients willing to consent.  


LY3164530
I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 93
Lab/
Diagnostic 
Tests
Exploratory biomarker blood sample
X
PK sample
X
Immunogenicity sample
X
In addition to the scheduled sample, if a patient should have an infusion reaction 
to LY3164530, all attempts should be made to obtain immunogenicity sample as 
close to the onset of the event as possible, at the resolution of the event, and 30 
days following the event.
If a patient requires subsequent follow-ups (eg, for an ongoing AE), an 
immunogenicity sample should be obtained, if possible.  A portion of the sample 
taken for immunogenicity testing may be used for PK analysis.
MET and EGFR ECD pharmacodynamic 
samples
X
MET and EGFR ligand pharmacodynamic 
samples
X
Proteomic blood sample
X
Only if patient discontinues prior to Cycle 6.
Abbreviations:  AE = adverse event; BL = baseline; C = cycle; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = 
day; ECD = extracellular domain; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EGFR = 
epidermal growth factor receptor; EOI = end of infusion; HPV = human papillomavirus; MET = mesenchymal-epithelial transition factor; MRI = magnetic 
resonance imaging; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 94
LY3164530
Attachment 3
Protocol JNBA Pharmacokinetic and Pharmacodynamic 
Sampling Schedule  
Pharmacokinetic and Pharmacodynamic Sampling for Schedule 1
Cycle
Day
Collection Time
PK 
Sampling 
Time 
MET ECD 
and EGFR 
ECDa
MET and 
EGFR 
Ligandsa
Proteomic 
Blood Sample a
1 and 2
1
Predose
X
X
X
X
1
Mid-infusion
X
1
End of infusion
X
X
X
X
1
2 hours post end of infusion 
X
1
4 hours post end of infusion
X
1
6 hours post end of infusion 
(Cycle 1 Oonly)
X
2
24 ±4 hours post-end of 
infusion (Cycle 1 only)
X
X
X
X
3
Anytime during day (Cycle 1 
only)
X
8±1
Anytime during day
X
15
Predose
X
X
X
X
15
End of infusion
X
X
X
X
15
2 hours post end of infusion 
(Cycle 1 only)
X
15
4 hours post end of infusion 
(Cycle 1 only)
X
15
6 hours post end of infusion 
(Cycle 1 Oonly)
X
22±2
Anytime during day (Cycle 1 
only)
X
3-6
1
Predose
X
X
X
X
1
End of infusion
X
Follow-
ups 
Occurs on the day the follow-
ups occur.
X
X
X
Abbreviations:  ECD = extracellular domain; EGFR = epidermal growth factor receptor; MET = mesenchymal-
epithelial transition factor; PK = pharmacokinetic; V = volume of distribution.
a Samples are requested to be taken immediately before the dose and immediately after the end of the LY3164530 
infusion.  Aberrations to specified sampling times will not be considered protocol deviations as long as the 
samples are taken and the actual sampling time is recorded.  It is essential that the actual times of LY3164530 
dose and samples are recorded accurately on the appropriate forms.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 95
LY3164530
Pharmacokinetic and Pharmacodynamic Sampling for Schedule 2
Cycle
Day
Collection Time
PK 
Sampling 
Time 
MET ECD 
and EGFR 
ECDa
MET and 
EGFR 
Ligandsa
Proteomic 
Blood Samplea
1 and 2
1
Predose
X
X
X
X
1
Mid-infusion
X
1
End of infusion
X
X
X
X
1
2 hours post end of infusion 
X
1
4 hours post end of infusion
X
1
6 hours post end of infusion 
X
2
24 ±4 hours post-end of 
infusion 
X
X
X
X
3
Anytime during day
X
8
Predose
X
X
8
End of infusion (Cycle 1 only)
X
X
15
Predose (Cycle 1 only)
X
X
X
15
End of infusion (Cycle 1 only)
X
X
22
Predose(Cycle 1 only)
X
X
X
X
22
End of infusion (Cycle 1 only)
X
X
X
X
22
2 hours post end of infusion 
(Cycle 1 only)
X
22
4 hours post end of infusion 
(Cycle 1 only)
X
22
6 hours post end of infusion 
(Cycle 1 only)
X
23
24 ±4 hours post-end of 
infusion (Cycle 1 only)
X
24
Anytime during day (Cycle 1 
only)
X
3-6
1
Predose
X
X
X
X
1
End of infusion
X
Follow-
ups 
Occurs on the day the follow-
ups occur.
X
X
X
Abbreviations:  ECD = extracellular domain; EGFR = epidermal growth factor receptor; MET = mesenchymal-
epithelial transition factor; PK = pharmacokinetic; V = volume of distribution.
a
Samples are requested to be taken immediately before the dose and immediately after the end of the LY3164530 
infusion.  Aberrations to specified sampling times will not be considered protocol deviations as long as the 
samples are taken and the actual sampling time is recorded.  It is essential that the actual times of LY3164530 
dose and samples are recorded accurately on the appropriate forms.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 96
LY3164530
Attachment 4
Protocol JNBA ECG, Chemistry, and Hematology Collection 
Schedule
Schedule 1
Cycle
Day
Collection Time
Central 
Triplicate ECG
Central 
Single ECG
Local 
Hematology
Local 
Chemistry
Screening
X
X
X
1
1
Predose
X
X
X
1
EOI (+ 10 min)
X
Xa
Xa
1
2 ±0.25 hours EOI 
X
1
6 ±0.25 hours EOI
X
2
24 ±4 hours EOI 
X
Xa
Xa
3
48 ±4 hours EOI
X
Xa
Xa
8
X
X
X
15
Predose
X
X
X
15
EOI (+ 10 min)
X
15
2 ±0.25 hours EOI 
X
15
6 ±0.25 hours EOI
X
22
X
X
X
2
1
Predose
X
X
X
8
X
X
X
15
Predose
X
X
X
22
X
X
X
3-X
1
Predose
X
X
X
15
Predose
X
X
X
Follow up
28
X
X
X
Abbreviations:  ECG = electrocardiogram; EOI = end of infusion; min = minute.
a 
If an abnormality in hematology or chemistry is consistently observed in the 48 hours following the end of the 
first infusion, additional post-infusion laboratory samples (EOI, and 24 hours and 48 hours after EOI) must be 
repeated for subsequent infusions until they are normal or return to baseline levels.


I7H-MC-JNBA(b) Phase 1 Oncology Protocol
Page 97
LY3164530
Schedule 2
Cycle
Day
Collection Time
Central 
Triplicate ECG
Central 
Single ECG
Local 
Hematology
Local 
Chemistry
Screening
X
X
X
1
1
Predose
X
X
X
1
EOI (+ 10 min)
X
Xa
Xa
1
2 ±0.25 hours EOI 
X
1
6 ±0.25 hours EOI
X
2
24 ±4 hours EOI 
X
Xa
Xa
3
48 ±4 hours EOI
X
Xa
Xa
8
Predose
X
X
X
8
EOI (+ 10 min)
X
8
2 ±0.25 hours EOI 
X
8
6 ±0.25 hours EOI
X
15
Predose
X
X
X
22
Predose
X
X
X
2-X
1
Predose
X
X
X
8
Predose
X
Xb
Xb
15
Predose
X
X
X
22
Predose
X
Xb
Xb
Follow up
28
X
X
X
Abbreviations:  ECG = electrocardiogram; EOI = end of infusion; min = minute.
a 
If an abnormality in hematology or chemistry is consistently observed in the 48 hours following the end of the 
first infusion, additional post-infusion laboratory samples (EOI, and 24 hours and 48 hours after EOI) must be 
repeated for subsequent infusions until they are normal or return to baseline levels.
b
In Cycle 2-X, if clinically significant changes are observed, hematology and/or chemistry should be obtained at 
least weekly until no longer clinically significant.  Otherwise these samples are not required.


PPD
Leo Document ID = 5b2565df-ce44-4304-ba4b-959e67a3df66
Approver:
Approval Date & Time: 28-Sep-2015 17:31:23 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 28-Sep-2015 21:59:40 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan I7H-MC-JNBA 
A Phase 1 Study of LY3164530, a Bispecific Antibody Targeting MET and EGFR, in Patients 
with Advanced or Metastatic Cancer 
NCT02221882 
Approval Date: 16-Jun-2014 


I7H-MC-JNBA Statistical Analysis Plan Version 1
Page 1
LY3164530
1.
Statistical Analysis Plan: 
I7H-MC-JNBA:  A Phase 1 Study of LY3164530, a 
Bispecific Antibody Targeting MET and EGFR, in Patients 
with Advanced or Metastatic Cancer
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
Anti-MET/EGFR Bispecific Antibody (LY3164530)
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study of 
intravenous LY3164530 in patients with advanced or metastatic cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I7H-MC-JNBA
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 16-Jun-2014 GMT


I7H-MC-JNBA Statistical Analysis Plan Version 1
Page 2
LY3164530
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  I7H-MC-JNBA:  A Phase 1 Study of 
LY3164530, a Bispecific Antibody Targeting MET and EGFR, in 
Patients with Advanced or Metastatic Cancer......................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objective ..........................................................................................................8
4.2.
Secondary Objectives.....................................................................................................8
4.3.
Exploratory Objectives...................................................................................................8
5.
Study Design.......................................................................................................................9
5.1.
Summary of Study Design..............................................................................................9
5.2.
Determination of Sample Size ........................................................................................9
5.3.
Method of Assignment to Treatment ..............................................................................9
6.
A Priori Statistical Methods ..............................................................................................10
6.1.
General Considerations ................................................................................................10
6.2.
Adjustments for Covariates ..........................................................................................11
6.3.
Handling of Dropouts or Missing Data.........................................................................11
6.4.
Multicenter Studies ......................................................................................................11
6.5.
Multiple Comparisons/Multiplicity...............................................................................11
6.6.
Population for Analysis ................................................................................................11
6.7.
Patient Disposition .......................................................................................................11
6.8.
Patient Characteristics ..................................................................................................12
6.9.
Treatment Compliance .................................................................................................12
6.10. Concomitant Therapy...................................................................................................12
6.11. Efficacy Analyses ........................................................................................................13
6.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................13
6.12.1.
Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses .......................................13
6.12.2.
Biomarker Analyses.............................................................................................13
6.13. Safety Analyses............................................................................................................14
6.13.1.
Recommended Phase 2 Dose Determination.........................................................18
6.13.2.
Extent of Exposure...............................................................................................18
6.13.3.
Adverse Events ....................................................................................................18
6.13.4.
Deaths, Serious Adverse Events, and Other Notable Adverse 
Events..................................................................................................................19
6.13.5.
Clinical Laboratory Evaluation.............................................................................19


I7H-MC-JNBA Statistical Analysis Plan Version 1
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LY3164530
6.13.6.
Vital Signs and Other Physical Findings...............................................................19
6.13.7.
Electrocardiograms ..............................................................................................19
6.14. Protocol Violations.......................................................................................................20
6.15. Interim Analyses and Data Monitoring.........................................................................20
6.16. Annual Report Analyses...............................................................................................20
6.17. Clinical Trial Registry Analyses...................................................................................21
7.
References ........................................................................................................................22
8.
Appendices .......................................................................................................................23


I7H-MC-JNBA Statistical Analysis Plan Version 1
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LY3164530
Table of Contents
Table
Page
Table JNBA.6.1. Data Handling Conventions and Rules...........................................................10


I7H-MC-JNBA Statistical Analysis Plan Version 1
Page 5
LY3164530
Table of Contents
Figure
Page
Figure JNBA.6.1.Dose-finding spreadsheet of the modified toxicity probability interval 
method...........................................................................................................17


I7H-MC-JNBA Statistical Analysis Plan Version 1
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LY3164530
Table of Contents
Appendix
Page
Appendix 1.
Protocol JNBA mTPI and Simulation ............................................................24


I7H-MC-JNBA Statistical Analysis Plan Version 1
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LY3164530
3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior the first visit when a subject 
receives study drug or any other protocol intervention.


I7H-MC-JNBA Statistical Analysis Plan Version 1
Page 8
LY3164530
4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to determine a recommended phase 2 dose (RP2D) of 
LY3164530 that may be safely administered to patients with advanced or metastatic cancer.
4.2.
Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3164530 

to estimate the pharmacokinetic (PK) parameters of LY3164530 

to document any antitumor activity observed with LY3164530.
4.3.
Exploratory Objectives
The exploratory objectives of this study are:

to explore the effect of LY3164530 on pharmacodynamic (PD) markers 

to identify exploratory biomarkers associated with tumor response and/or 
safety.  


I7H-MC-JNBA Statistical Analysis Plan Version 1
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LY3164530
5.
Study Design
5.1.
Summary of Study Design
Study I7H-MC-JNBA (JNBA) is a multicenter, nonrandomized, open label, dose escalation 
Phase 1 study of IV LY3164530 in patients with advanced and/or metastatic cancer.  Eligible 
patients will receive LY3164530 as an infusion on Days 1 and 15 of each cycle.  A cycle will 
consist of 28 days.  
The planned duration of treatment is 2 cycles.  Patients who are receiving benefit from study 
drug may continue to be treated with LY3164530 until 1 or more of the criteria for 
discontinuation have been fulfilled (Protocol Section 6.3.1).  
5.2.
Determination of Sample Size
To determine an RP2D of LY3164530 that may be safely administered to patients with advanced 
or metastatic cancer, an adequate patient sample size is required.  A sufficient sample size will 
allow for an accurate evaluation of the relationship between exposure and toxicity, as well as an 
evaluation of the relationship between exposure and pharmacological effects using descriptive 
statistics and appropriate modeling techniques, if data warrant.  
Dose escalation will be driven by a modified toxicity probability interval (mTPI) method.  The 
RP2D will be determined once at least 10 patients, but no more than 20, are treated at a dose 
level that is at or below the maximum tolerated dose (MTD).  The actual sample size for Study 
JNBA depends on the incidence of dose-limiting toxicities (DLTs) and is anticipated to be 
approximately 50 patients.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3164530 in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted between 
the investigational site and Eli Lilly and Company (Lilly) clinical research personnel to confirm 
that each patient meets all enrollment criteria.  Upon confirmation of eligibility, the Sponsor will 
confirm the dose, infusion duration, and identification number assignment for each patient.  


I7H-MC-JNBA Statistical Analysis Plan Version 1
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LY3164530
6.
A Priori Statistical Methods
6.1.
General Considerations
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 (SD), standard error (SE), minimum, and 
maximum. Categorical endpoints will be summarized using N, frequency, percentages, and 
associated SE.
Exploratory analyses of the data that are not described in the protocol will be conducted as 
deemed appropriate.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the clinical study report (CSR).
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
CRP and/or CRS, pharmacokineticist, and statistician. The CRP and/or CRS and statistician will 
also be responsible for the appropriate conduct of an internal review for both the final study 
report and any study-related material to be authorized by Lilly for publication.
The following data handling conventions will be used in the analysis:
Table JNBA.6.1.
Data Handling Conventions and Rules
Term
Definition or Rule
Study Day
If assessment is on or after date of first dose then 
(date of assessment) – (date of first study drug dose) +1
If assessment precedes first dose of drug then 
(date of assessment) – (date of first study drug dose)
There is no study day 0.  Study day 1 is the date of first dose and study day -1 is the day 
before the first dose.
Cycle Day 
If assessment is on or after date of first dose in the cycle then 
(date of assessment) – (date of first study drug dose in cycle) +1
If assessment precedes first dose of drug in a cycle then 
(date of assessment) – (date of first study drug dose in cycle)
There is no cycle day 0.  Cycle day 1 is the date of first dose in the cycle and cycle day -1 is 
the day before the first dose.
Baseline
For change from baseline analyses, baseline value is defined as the last reported measure on 
or before the first dose (prior to the dose administration).  For change from baseline within a 
cycle, the measure prior to the first dose of that cycle is baseline.  If more than one pre-dose 
measure is available, they may be averaged if appropriate.
Entered
Patients who sign the informed consent document (ICD).
Enrolled
Patients who have been assigned to a treatment (assigned means they received ≥1 dose for 
this study).


I7H-MC-JNBA Statistical Analysis Plan Version 1
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LY3164530
6.2.
Adjustments for Covariates
Adjustment for covariates is not applicable.
6.3.
Handling of Dropouts or Missing Data
Missing data will not be imputed.
Patients who withdraw from the study before receiving study drug will be replaced.
In the following situation, patients will be considered non-evaluable and may be replaced to 
ensure that enough patients complete 1 cycle of therapy at each dose level, unless accrual to that 
cohort has stopped due to a DLT:
1. Any patient who is discontinued from the study before completing 1 cycle of LY3164530 
treatment unless they experience a DLT prior to withdrawal
2. Patients who are not evaluable for PK
6.4.
Multicenter Studies
This is a multicenter, non-randomized, open-label study. Because of the limited sample size, 
endpoint analyses will not be conducted by enrollment center.
6.5.
Multiple Comparisons/Multiplicity
No adjustments will be made for multiple comparisons unless otherwise specified. 
6.6.
Population for Analysis
Safety analyses will be conducted on all patients who have received at least one dose of 
LY3164530.
Pharmacokinetic analyses will be conducted on patients who have received at least one dose of
LY3164530 and have sufficient samples collected to allow the estimation of LY3164530 PK 
parameters.  
Pharmacodynamic analyses will be conducted on patients who have received at least one dose of
LY3164530 and have sufficient samples collected to allow the assessment of 
pharmacodynamics.
6.7.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include summaries of the 
following:

The number and percentage of patients entered into the study, treated, as well as 
the number and percentage of patients discontinuing treatment and/or study. 

All patient discontinuations will be documented, and the extent of each patient’s 
participation in the study will be reported.  Data on patient discontinuation from study 


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drug and study (overall and by reason for discontinuation) will be collected. If known, 
reason(s) for discontinuation will be given. Discontinuations due to AE or death will be
summarized with cause of death further partitioned into AE, study disease, or other cause 
and summarized.

All clinically relevant and programmatically identifiable protocol deviations will be 
summarized by pre-determined categories (for example, inclusion/exclusion criteria, non-
compliance with protocol procedures, drug dosage/intervention, use of excluded 
treatments, informed consent/assent process, continuing after meeting withdrawal 
criteria, or other).
All patients entered into the study will be accounted for in the summary disposition tables. 
Patients entered into study are patients who signed main informed consent.  The number of 
patients who do not qualify for analysis, who die, or who discontinue before treatment begins 
will be specified. 
6.8.
Patient Characteristics
Patient characteristics for the treated population will include a summary of the following:

Patient demographics, including age, sex, screening height and weight, and 
screening body mass index, reported using descriptive statistics

Baseline disease characteristics, including initial diagnosis and Eastern 
Cooperative Oncology Group (ECOG) performance status, summarized by 
presenting frequency counts and percentages

Prior disease-related therapies if known, including dose, best response, duration 
of response, date of progression and etc. 

Concomitant medications.
6.9.
Treatment Compliance
LY3164530 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 is ensured.  
Potential discontinuation of a patient due to study noncompliance (not attending the scheduled
visits; see Protocol Attachment 1) will be presented overall as well as for each cycle.
6.10. Concomitant Therapy
Concomitant medications will be summarized for the safety population using the World Health 
Organization (WHO) preferred nomenclature.  The numbers and percentages of patients 
reporting concomitant therapies will be provided overall, by type of therapy (surgery, 
radiotherapy, or systemic therapy), and by drug name.  
Prior therapies, including systemic, radiotherapy, and cancer surgeries will be summarized by 
cohort and overall for all enrolled patients. The Lilly WHO Drug Version Dec 2012 B2 or 
higher will be used to code therapy.


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6.11. Efficacy Analyses
The study was not designed to make an efficacy assessment.  However, any tumor response data 
and duration of treatment will be tabulated.
6.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods 
6.12.1. Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses
Pharmacokinetic analyses will be conducted on patients who have been exposed to study drug 
and have had samples collected.  
Pharmacokinetic parameter estimates for LY3164530 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax, AUC0-tlast, and AUC0-∞of LY3164530.  Other 
noncompartmental parameters, such as t1/2, CL, and volume of distribution (V), may be reported.  
Additional exploratory analyses will be performed if warranted by the data, and other validated 
PK software programs may be used if appropriate and approved by Lilly Global PK/PD 
management.  The version of any software used for the analysis will be documented and the 
program will meet the Lilly requirements of software validation.
Pharmacokinetic parameter estimates 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% confidence intervals 
(CIs).
Provided that the data allows, PD and immunogenicity data from all patients may be analyzed 
using linear and/or nonlinear fixed and mixed effects models as appropriate.  Pharmacodynamic 
and immunogenicity data will be summarized by dose, drug concentrations, and time from dose.  
Potential PD markers and immunogenicity versus time data will be presented graphically for 
each patient and summarized by dose.  Absolute and/or percent change from baseline for the PD 
markers may also be evaluated.  Data may be log-transformed prior to summarizing if necessary.  
The interpatient and intrapatient variability of the PD markers and immunogenicity responses 
may also be assessed where appropriate.  Baseline measurements may be evaluated as potential 
covariates to assess their relationship to relevant PD responses.
In addition to a standard noncompartmental assessment, and provided that the data allows, the 
LY3164530 concentration-time data may be evaluated by model-based approaches as warranted.  
Additional analyses, such as exposure-response modeling using the efficacy endpoints, may also 
be explored.
Additional exploratory analyses may be performed if warranted by the data.
6.12.2. Biomarker Analyses
Protocol Sections 5.3.4 and 8.2.3 provide a description of the biomarker samples that may be 
collected and the rationale for their collection in the study. 


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Exploratory biomarker assessments in this study will focus on identifying markers and/or marker 
signatures that may indicate the patients most likely to respond or be resistant to LY3164530. In 
archived and/or pre-treatment tissue samples, biomarker data related to the MET and EGFR
pathways and cancer pathobiology may be analyzed to assess any potential associations with
response to LY3164530. These analyses may include, but are not limited to, MET and EGFR
protein expression, circulating biomarkers (for example, TGFa, HGF, extracellular cleaved 
domain of MET [MET ECD]), somatic mutation status, and/or copy number variations of MET 
and EGFR and pathway-related genes (for example, KRAS, BRAF) or genes related to cancer
pathobiology. In addition, tumor sample based gene signature(s) may be defined and evaluated
to explore whether they are associated with response to LY3164530. 
In all analyses, adjustments may be made to account for other baseline patient characteristics, 
safety, and PK/PD data. Unless otherwise stated, statistical analyses results will be considered 
exploratory and will not consider multiple comparison adjustments. In the event of emergence of 
important and relevant scientific findings, this SAP may be updated to allow further analyses on 
biomarkers and antitumor activities. 
6.13. Safety Analyses
All patients who receive at least 1 dose of LY3164530 will be evaluated for safety and toxicity.  
Adverse event (AE) terms and severity grades will be assigned by the investigator using National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03.
Safety analyses will include summaries of the following:

Adverse events, including severity and possible relationship to study drugs

Dose delays and dose adjustments

Laboratory values 

Vital signs 

Dose-limiting toxicities at each dose level 

Electrocardiogram readings

Deaths on treatment and within 28 +/- 5 days of treatment discontinuation
Hospitalizations and transfusions during the study treatment period or during the 28 +/- 5 days -
day postdiscontinuation follow-up period will be summarized.
Dose Limiting Toxicity 
Dose-limiting toxicity is defined as an AE during Cycle 1 that is considered by the investigator 
to be at least possibly related to LY3164530 and fulfills any one of the following criterion using 
the NCI CTCAE Version 4.03:

Grade 3 non-hematological toxicity.  Exceptions will be made for:


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
nausea, vomiting, diarrhea, and constipation that can be controlled with 
treatment.  Grade 3 and Grade 4 nausea, vomiting, or diarrhea should be 
considered DLTs if persisting more than 48 hours despite supportive 
intervention.

Grade 3 rash that resolves with treatment to ≤Grade 2 within 8 days

Grade 3 or 4 asymptomatic electrolyte abnormalities that respond to 
standard treatment 

Grade 3 elevations of ALT and/or AST lasting fewer than 8 days, without 
evidence of other hepatic injury, in the setting of preexisting hepatic 
metastasis.  Baseline elevation of these values may not be considered a 
DLT if agreed by the study investigator and Lilly CRP/CRS.

Grade 4 neutropenia or leukopenia, of >7 days duration.

Grade 4 thrombocytopenia of any duration.

Grade 3 thrombocytopenia with bleeding.

Any febrile neutropenia.

Any other significant toxicity deemed by the primary investigator and Lilly 
clinical research personnel to be dose limiting (eg, any toxicity that is possibly 
related to the study drug that requires the withdrawal of the patient from the study 
during Cycle 1).
DLT-Equivalent Toxicities
A DLT-equivalent toxicity is defined as an AE occurring in Cycle 2 and beyond that would have 
met the criteria for a DLT if it had occurred during Cycle 1.  
Dose Escalation Method 
Dose escalation will be driven by an mTPI method (Ji and Wang 2013) (Appendix 1).  A 3+3 
design is commonly used in Phase 1 trials due to its simple, intuitive, and pre-specified 
escalation rules.  However, the 3+3 method has been criticized for being conservative because 
the method is dictated by the observed DLT rate without acknowledging the variability arising 
from small cohort size.  
Like the 3+3 design, the mTPI method incorporates pre-specified escalation rules.  In contrast, 
the mTPI method is based on quantitative models that incorporate uncertainty into the decision 
rules, thereby allowing more aggressive dose escalation.  In the mTPI method, the number of 
patients in each cohort is not fixed, but a minimum of 3 patients are required for this study at 
each dose (unless the rule in the table indicates to deescalate the dose due to unacceptable 
toxicity [DU]).  If 3 to 6 patients are enrolled in a cohort, the escalation rule parallels a 
traditional 3+3 design.  However, the stay/de-escalation rule of the mTPI is more aggressive than 
the 3+3 design.  For instance, with 2 to 3 DLTs per 6 patients enrolled, the mTPI would 
recommend staying at the current dose, whereas the 3+3 design would recommend de-escalation.
Figure JNBA.6.1 provides the mTPI escalation rules for any cohort size up to 20 patients.


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In Figure JNBA.6.1, the number of patients dosed at a given dose level are shown in the columns 
(x-axis), while the number of DLTs experienced are shown in the rows (y-axis).  The rules in this 
figure will be used for each dose level evaluated; the patient numbers and DLTs do not carry 
over from cohort to cohort.  By locating the intersection of the number of patients dosed and the 
number of DLTs, 1 of 4 pre-defined rules is used:  

E:  Escalate the dose

S:  Stay at the same dose

D:  Deescalate the dose

DU:  Deescalate the dose due to unacceptable toxicity.  The dose cannot be re-escalated 
to this dose level at a future point in the escalation.
If agreed upon by the investigators and Sponsor (for instance, if PK/PD data suggest that 
increasing the dose further is not expected to yield additional benefit), a more conservative rule 
may be applied.  For instance, if the rule indicates “E” to escalate, the dose may remain at the 
current dose level or be deescalated to a lower level.
As shown in Figure JNBA.6.1, if 1 of 3 patients experiences a DLT, the decision (located in 
column 3 row 1) is ”S”, stay at the same dose.  Therefore, the next patient must be treated at the 
same dose level.  If 1 of 6 patients experience a DLT, the decision (located at column 6 row 1) is 
“E”, escalate the dose.  However, if 2 of 3 patients experience a DLT the decision is “D” and the 
dose must be deescalated.
In the mTPI, the cohort size is not fixed.  However, each cohort in this study will contain a 
minimum of 3 patients, unless the escalation rules dictate that the dose should be deescalated due 
to unacceptable toxicity (“DU”).  Doses can be escalated, deescalated, and re-escalated following 
the rules in Figure JNBA.6.1.  If the dose decision was “DU,” the dose cannot be re-escalated to 
that level.
This study is designed to identify a dose level with a dose-limiting target toxicity rate of 30%.  In 
reality, the exact target toxicity rate is almost never achieved for a dose.  To this end, instead of
using a single target rate, the mTPI method considers an equivalence interval (EI) around the 
target toxicity rate.  For this study, the EI is calibrated to be (28.7%, 30.1%), resulting in the 
rules in Figure JNBA.6.1.  If the observed toxicity rate exceeds 40% and the model is still 
recommending “S”, the Sponsor, in discussion with the investigators, may choose to deescalate.  


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Figure JNBA.6.1.
Dose-finding spreadsheet of the modified toxicity probability 
interval method.
The beginning dose level will be 300 mg.  The dose will be escalated by a maximum increment 
of 100%.  If the beginning dose level is determined to be unacceptably toxic, a -1 dose level may 
be explored.  
The exact increment will be determined by the investigators and Lilly CRP/CRS, and may be 
less than the maximum increment allowed in the protocol.  Safety data will be the primary 
criteria for both the decision to dose-escalate and for selecting the dose to be administered in the 
next cohort.  In addition, if available at the time of the dose escalation decision, PK (maximum 
plasma concentration [Cmax], area under the plasma concentration-time curve [AUC], and CL) 
and/or PD results will be used as secondary/supporting data for dose escalation.  No dose 
escalation can occur without prior discussion and agreement between the investigator and the
Lilly CRP or CRS; the decision will be documented in writing.  Intrapatient dose escalations are 
not permitted.
In Cohort 1 only, the first patient is required to complete a full cycle (28 days) before subsequent 
patients can be dosed.  Subsequent patients in Cohort 1 can be dosed concurrently. Beginning 
with Cohort 2, patients within a cohort can be dosed concurrently.  
The decision to stop dose escalation will be primarily driven by the appearance of DLTs and the 
rules in Figure JNBA.6.1.  However, if PK/PD data suggest that increasing the dose further is not 
expected to yield additional benefit, escalation may cease.  


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6.13.1. Recommended Phase 2 Dose Determination
The RP2D will be a dose at which at least 10 patients, but no more than 20, have been enrolled.  
The RP2D will be agreed upon following discussion between the investigators and the Lilly CRP 
or CRS and will include an assessment of safety, PK, and PD data.  At the RP2D, the intersection 
of the number of patients dosed and the number of DLTs at that dose level on the mTPI grid 
should indicate “S” or “E”.
6.13.2. Extent of Exposure
For doses less than 1000 mg, LY3164530 will be administered intravenously over approximately
60 minutes on Days 1 and 15 of each 28-day cycle. The Sponsor may instruct sites to extend the
infusion time for up to 3 hours for doses ≥1000 mg. The assigned dose and duration of infusion
of LY3164530 will be provided by the Sponsor on a patient registration form. Subsequent doses
and/or infusion times should be adjusted as described in Protocol Section 7.2.5.
A patient is said to have received a cycle if they received some of the scheduled/planned dose of 
study treatment in the cycle. A patient is said to have completed a cycle if they received all of 
study treatment planned for this cycle. The number of patients receiving/completing a given 
number of cycles will be presented by dose level and overall in a summary table, as well as by 
patient.
The number of dose reductions, dose delays, and number of cycles received will be summarized 
for all treated patients by cohorts. The number of patients with any dose reductions and delays
will be presented overall as well as for each cycle by cohorts.
6.13.3. Adverse Events
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 will be used to grade 
all AEs and other symptoms.  Minor updates to the CTCAE Version 4.03 from the NCI will not 
necessitate a protocol amendment, and the use of an updated CTCAE Version 4.03 will not be 
considered a protocol violation. For AEs without matching terminology within the NCI-CTCAE 
v 4.03 criteria, the investigator will be responsible for selecting the appropriate System Organ 
Class (SOC) and assessing severity grade based on the intensity of the event.  The verbatim text 
for these AEs will be coded according to the available version of the Medical Dictionary for 
Regulatory Activities (MedDRA).
A treatment-emergent adverse event (TEAE) is defined as (i) adverse event that occurred after 
the administration of at least one dose of study therapy, regardless of causality; or (ii) adverse 
events already present during screening that worsen following exposure to the treatment, 
regardless of causality. All analysis of AEs will be done according to the MedDRA hierarchy 
and the investigator assigned CTCAE term will be used as the assigned LLT, except where 
“other-specify” has been chosen, in which case the LLT  will come from the centrally mapped 
verbatim description of the event. Event worsen in severity is supported by higher CTCAE grade 
observed after first dose of study treatment for the corresponding MedDRA Lower Level Term 
(LLT). Treatment-emergent adverse events (AEs) will be aggregated and summarized by 
MedDRA System Organ Class (SOC) and Preferred Term (PT).


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The number of patients who experienced a TEAE, SAE, TEAE related to study drug, died, or 
discontinued from the study due to an AE will be summarized. Treatment-emergent adverse 
events will be summarized by SOC, by decreasing frequency within SOC, and by maximum 
CTCAE severity grade, including the total of patients with maximum severity grade 3.
6.13.4. Deaths, Serious Adverse Events, and Other Notable Adverse 
Events
Deaths and other SAEs will be listed and summarised. Summaries for patients on therapy will 
include:

Listing of Patients who Discontinued due to Adverse Events or Death

Listing of Deaths Reported

Listing of Serious Adverse Events
Reasons for death will be summarized separately for on-therapy and within 28 days of last dose 
of study drug/last visit.  All SAEs will be summarized by preferred term. 
6.13.5. Clinical Laboratory Evaluation
Laboratory data (including chemistry, hematology, and coagulation) will be summarized for all 
patients on therapy. Relevant hematology and chemistry laboratory values will be graded 
according to CTCAE Version 4.03. The grades will be summarized by the maximum grade over 
the entire study for all patients on therapy.
Abnormal laboratory results will be summarized for all patients on therapy by cycle. To the 
extent that they can be assessed according to CTCAE Version 4.03 specific grades, these 
abnormal lab results will be summarized by cohort and cycle independent of clinical findings 
determined by the investigator. International System of Units (SI units) will be presented in all 
outputs.
6.13.6. Vital Signs and Other Physical Findings
Vital sign data including blood pressure (BP), pulse rate (PR), temperature (T), height and 
weight will be summarized for all patients on therapy. Patients with abnormal vital signs will be
summarized.
6.13.7. Electrocardiograms
For each patient, 12-lead ECGs will be obtained according to the Study Schedule (Protocol 
Attachment 1). All ECGs will be analyzed for safety and categorical analysis will be provided 
including:
1. Number and percentage of individuals with abnormal ECG findings. 
2. Number and percentage of individuals with AEs that could be associated with 
prolongation of cardiac repolarization or proarrhythmia, for example, palpitations, 
dizziness, syncope, cardiac arrhythmias and sudden death.


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Categorical analysis of the following ECG parameter may be performed at day 1 and day 15 of 
each cycle and the short term follow up visit at the time points outlined in the protocol and 
changes will be compared to baseline (that is, Cycle 1, Day 1 pre-dose). Such analysis will be 
triggered only as needed. If triggered, the analysis will include the number and percentage of 
individuals with: 
1. Absolute QT/QTc values >450 ms, >480 ms, and >500 ms; as well as the number and 
percentage of individuals with change from baseline >30 ms and >60 ms. 
2. PR changes from baseline ≥50% if baseline value is <200 ms and ≥25% of baseline value 
is ≥200 ms. 
3. QRS changes from baseline ≥50% if baseline value is <110 ms and ≥25% of baseline 
value is ≥110 ms. 
6.14. Protocol Violations
All significant protocol deviations will be summarized by cohorts and by reasons (for example, 
inclusion/exclusion criteria, noncompliance with protocol procedures, informed consent/assent 
process etc.).
6.15. Interim Analyses and Data Monitoring
Since this is a dose-escalation study, data will be reviewed on an ongoing basis during the study 
until the RP2D is determined.  The purpose of these ongoing reviews is to evaluate the safety 
data at each dose level.  A review of the data will be completed approximately after 5 patients 
have been treated for at least 1 cycle at a dose level without a cohort analysis.
An interim analysis will be triggered when 10 patients have been dosed at a given dose level for 
1 cycle of treatment to evaluate the safety and tolerability of LY3164530.  The interim analysis 
may include, but are not limited to, an assessment of available safety, PK, and PD data.
Enrollment may continue during the interim analysis and the dose escalation rules as outlined in 
Figure JNBA.6.1 will continue to be followed.
Additional interim analyses may be triggered and may include, but are not limited to, assessment 
of available safety, PK, and PD data.
6.16. Annual Report Analyses
The following reports are needed as requested for annual reporting purposes
Clinical Investigator Brochure:
·
Summary of SAE (patients on therapy).
·
Summary of deaths reported (patients on therapy).
·
Summary of Patient disposition.
·
Summary of primary reason for treatment discontinuation.
·
Summary of treatment-emergent adverse events –by CTCAE category and term.


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Development Safety Update Report:
·
Cumulative Subject Exposure by Age Group and Sex
·
Cumulative Subject Exposure by Racial Group
·
Estimated Cumulative Subject Exposure
·
Subject Exposure by Gender
·
Listing of Patients Who Discontinued Due to Adverse Event
·
Listing of Deaths
6.17. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.
Both Serious Adverse Events (SAEs) and ‘Other’ Adverse Events are summarized: by 
treatment group, by MedDRA preferred term.

An adverse event flagged as an SAE by the investigator due to meeting one or more of 
the standard criteria (Protocol Section 8.1.2.1) is considered ‘Serious’ whether or not it is 
a treatment emergent adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of all treated patients/subjects may not be included if a 5% threshold is chosen 
(5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 
A participant flow summary will also be produced.  This participant flow will describe how 
many patients completed the study, and for those who did not, the frequency of each reason for 
not completing. At the time of database lock, any patient who completed one cycle of treatment 
or discontinued due to an adverse event and completed the required safety and full set of PK 
assessments during cycle 1 will be considered to have completed the study:


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7.
References
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding 
trials. Clin Trials. 2010;7(6):653-663.
Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method 
than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785-1791. 


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8.
Appendices


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Appendix 1.
Protocol JNBA mTPI and Simulation
The modified toxicity probability interval (mTPI) method employs a simple beta-binomial 
hierarchical model.  Decision rules are based on calculating the unit probability mass (UPM) of 3 
intervals corresponding to under dosing, proper dosing, and over dosing in terms of toxicity.  
Specifically, the under dosing interval is defined as (0, pT-ε1), the overdosing interval as (pT+ε2, 
1), and the proper dosing interval as (pT-ε1, pT+ε2), where ε1 and ε2 are small fractions, such as 
0.05, to account for the uncertainty around the true target toxicity.  A sensitivity analysis 
reported by Ji et al. (2010) showed that the mTPI design is robust to the specification of ε values. 
In addition, ε1 and ε2 could take different values to reflect physician preference and the nature of 
the disease.  For advanced diseases with few treatment options, higher toxicity rates might be 
considered acceptable, implying a specification of ε2>ε1.  For less advanced diseases, the 2 ε
values could be identical or ε1 could be >ε2.  The 3 dosing intervals are associated with 3 
different dose-escalation decisions.  The under-dosing interval corresponds to a dose escalation 
(E), overdosing corresponds to a dose de-escalation (D), and proper dosing corresponds to 
staying at the current dose (S). 
Given an interval and a probability distribution, the UPM of that interval is defined as the 
probability of the interval divided by the length of the interval.  The mTPI design calculates the 
UPMs for the three dosing intervals, and the one with the largest UPM implies the corresponding 
dose-finding decision.  That decision provides the dose level to be used for future patients.  For 
example, if the under dosing interval has the largest UPM, decision E, to escalate, will be 
executed, and the next cohort of patients will be treated at the next-higher dose level.  Ji et al. 
(2010) show that the decision based on the UPM is optimal in that it minimizes a subsequent 
expected loss.  Under the mTPI design, a trial is terminated when either the lowest dose is above 
the maximum tolerated dose (MTD) or a pre-specified maximum sample size is reached.
Simulation
A small simulation study was conducted to compare the mTPI with 3+3 in identifying the right 
MTD.  Six scenarios were run, each with 1000 simulated trials.  As in Study JNBA, the MTD 
has a target toxicity probability of PT=0.3 and ε1 and ε2 are set at 0.013 and 0.001 respectively.  
The scenarios assumed the true probabilities of six doses as follows:  scenario 1= (0.1, 0.2, 0.3, 
0.4, 0.5, 0.6); scenario 2= (0.08, 0.16, 0.24, 0.3, 0.38, 0.46); scenario 3= (0.04, 0.08, 0.12, 0.16,
0.2, 0.24); scenario 4= (0.4, 0.5, 0.6, 0.7, 0.8, 0.9); scenario 5= (0.04, 0.08, 0.12, 0.16, 0.2, 0.58); 
and scenario 6= (0.06, 0.46, 0.53, 0.6, 0.67, 0.74).  For all scenarios, the probability of selecting 
each dose was summarized, the average number of patients treated at each dose and average 
number of patients experience DLT at each dose.  The simulation demonstrates that, in general, 
mTPI method correctly identifies the MTD more than 3+3 and appears to be as safe as 3+3 
method in that it puts a similar percentage of patients on toxic doses.


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Scenario
Dose
True
Selection Prob (%)
# of Subjects Treated
# of Toxicities
Level
Prob (tox)
mTPI
3+3
mTPI
3+3
mTPI
3+3
1
1
0.1
4.3
31.5
5.583
4.473
0.534
0.42
2
0.2
29.5
33.2
10.02
4.617
1.985
0.979
3
0.3
42.7
19.5
9.306
3.15
2.811
0.983
4
0.4
18.4
5.7
4.023
1.371
1.624
0.57
5
0.5
4.5
0.7
0.9
0.381
0.442
0.194
6
0.6
0.4
0
0.114
0.048
0.07
0.029
2
1
0.08
1.1
21.1
4.5
4.083
0.339
0.295
2
0.16
15.7
30.6
8.082
4.494
1.237
0.735
3
0.24
33.1
23
8.832
3.642
2.125
0.902
4
0.3
31.3
14
5.601
2.28
1.659
0.692
5
0.38
14.2
4.3
2.325
1.083
0.886
0.409
6
0.46
4.6
0.1
0.66
0.297
0.305
0.141
3
1
0.04
0
7.1
3.561
3.51
0.146
0.139
2
0.08
1.7
10.9
4.626
3.81
0.375
0.315
3
0.12
8.1
16
5.811
3.918
0.743
0.45
4
0.16
19.1
20.8
6.045
3.723
0.953
0.578
5
0.2
24.4
14.5
4.776
3.132
0.934
0.654
6
0.24
46.7
1.2
5.181
1.908
1.251
0.451
4
1
0.4
46.5
22.2
18.318
4.914
7.374
1.931
2
0.5
5.4
3.1
3.276
1.434
1.64
0.721
3
0.6
0.5
0
0.408
0.228
0.253
0.139
4
0.7
0
0
0.021
0.018
0.014
0.012
5
0.8
0
0
0.003
0
0.003
0
6
0.9
0
0
0
0
0
0
5
1
0.04
0.4
6.8
3.648
3.51
0.155
0.146
2
0.08
1.3
11.6
4.398
3.834
0.354
0.314
3
0.12
6.3
16.7
5.613
3.909
0.657
0.448
4
0.16
21
20.7
6.171
3.669
0.998
0.604
5
0.2
55.8
37.6
6.813
3.594
1.32
0.729
6
0.58
15.2
0.8
3.357
1.788
1.936
1.038
6
1
0.06
59.3
80.9
13.71
5.556
0.809
0.314
2
0.46
36.7
13.5
13.98
4.461
6.513
2.038
3
0.53
3.7
1.5
2.067
0.858
1.098
0.481
4
0.6
0.1
0
0.195
0.102
0.114
0.064
5
0.67
0
0.1
0.009
0.006
0.004
0.002
6
0.74
0.1
0
0.015
0.006
0.008
0.004
Abbreviation:  mTPI = modified toxicity probability interval.


Leo Document ID = 15a182a5-6dd1-46c9-ad4d-674a3d806e6f
Approver:
Approval Date & Time: 16-Jun-2014 17:11:42 GMT
Signature meaning: Approved
PPD