A Phase 1 Study of LY3039478 in Patients With Advanced or Metastatic Cancer
Phase: PHASE1
Conditions: Neoplasms, Neoplasm Metastasis, Lymphoma
Sponsor: Eli Lilly and Company

 
Protocol I6F-MC-JJCA (e) 
 
A Phase 1 Study of LY3039478 in Patients with Advanced or Metastatic Cancer 
 
NCT01695005 
Approval Date: 08-Jul-2016 
 

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1.
Protocol I6F-MC-JJCA(e)
A Phase 1 Study of LY3039478 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 
LY3039478, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act (FOIA) Exemption 4.
LY3039478
This Phase 1 study is a multicenter, nonrandomized, open-label, 
dose-escalation/cohort-expansion study of oral LY3039478 in patients with advanced or 
metastatic cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  15 May 2012
Amendment (a) Electronically Signed and Approved by Lilly:  24 April 2013
Amendment (b) Electronically Signed and Approved by Lilly:  05 December 2013
Amendment (c) Electronically Signed and Approved by Lilly:  16 February 2015
Amendment (d) Electronically Signed and Approved by Lilly:  19 November 2015
Amendment (e) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 08-Jul-2016 GMT

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2.
Synopsis
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study followed 
by cohort expansion of oral LY3039478 in patients with advanced or metastatic cancer.

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Clinical Protocol Synopsis:  Study I6F-MC-JJCA
Name of Investigational Product:  LY3039478
Title of Study:  A Phase 1 Study of LY3039478 in Patients with Advanced or Metastatic Cancer
Number of Planned Patients:  Total study sample size will be approximately 
282 patients, with approximately 55 patients in Part A and approximately 
227 patients in Parts B, C, D, E, and F.
Phase of Development: 1
Length of Study:  
Planned first patient visit:  September 2012               Planned last patient visit:  December 2017
Objectives:  
Primary:  Part A: The primary objective of this study is to determine a recommended Phase 2 dose of 
LY3039478 that may be safely administered to patients with advanced or metastatic cancer.
Parts B, C, D, and E: The primary objectives are to confirm the recommended Phase 2 dose of LY3039478 that 
may be safely administered to patients with specific tumor types and to document antitumor activity.
Part F: The primary objective is to determine a recommended Phase 2 dose of LY3039478 that may be safely 
administered to patients according to 2 alternative dosing schedules with co-administration of prednisone and to 
document antitumor activity.
Secondary:  

To characterize the safety and toxicity profile of LY3039478 as assessed by National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0

To estimate the pharmacokinetic (PK) parameters of LY3039478

Part A:  To document any antitumor activity observed with LY3039478

Parts B, C, D, E, and F:  To assess duration of response, progression-free survival (PFS), and overall 
survival (OS)
Exploratory:  

To explore renal clearance of LY3039478 and PK of LY3039478 metabolites in plasma and urine

To explore predictive biomarkers related to LY3039478

To explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of Notch activity 
(Notch intracellular domain by immunohistochemistry or an alternative validated method) including 
cytokeratin 18 or Rules-Based Medicine

To explore the utility of positron emission tomography scan to assess treatment effect with LY3039478

To explore the utility of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to assess 
treatment effect with LY3039478
Study Design:  Phase 1, multicenter, nonrandomized, open-label, dose-escalation study followed by cohort 
expansion (Parts B, C, D, E, and F) of oral LY3039478 in outpatients with advanced or metastatic cancer.  
Diagnosis and Main Criteria for Inclusion and Exclusions:  Men and women, aged ≥18 years, having advanced 
or metastatic cancer (solid tumor or lymphoma including chronic lymphocytic leukemia [CLL]) for which 
available standard therapies have failed.  For Part B, patients must have prescreened alterations in the Notch
pathway such as mutations, amplification, or gene expressions related to Notch pathway.  Part C patients must 
have histological evidence of advanced or metastatic soft tissue sarcomas.  Part D patients must have advanced or 
metastatic cancer with specific tumor types harboring Notch molecular alterations including triple-negative breast 
cancer (ER-, PR-, HER2-), cholangiocarcinoma, hepatocellular carcinoma (HCC), CLL, and mature T cell, B cell,
or Natural Killer (NK) cell neoplasms.  Part E patients must have advanced or metastatic adenoid cystic carcinoma 
(ACC). Part F patients in the dose confirmation must have histological evidence of nonresectable or metastatic 
leiomyosarcoma with prescreened alterations in the Notch pathway such as mutations, amplification, or gene 
expressions related to Notch pathway.

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Test Product, Dosage, and Mode of Administration:  LY3039478, dose range 2.5 to 100 mg, given orally as 
capsules 3 times per week during a 28-day cycle. In Study Part F, dosing schedules will utilize a loading dose
(starting at 75 mg and escalating up to 150 mg) administered 3 times per week for 2 weeks during Cycle 1 
(schedule F1) or 2 times per week for 2 weeks during Cycle 1 (schedule F2), followed by 50 mg 3 times per week 
(TIW) from Week 3 onwards. In Study Parts F1 and F2, prednisone will be co-administered for 2 weeks in 
Cycle 1.
Planned Duration of Treatment:  Patients will receive 2 cycles (28 days each) of LY3039478 unless 1 or more of 
the criteria for discontinuation are fulfilled. In Study Parts F1 and F2, prednisone will be co-administered with 
LY3039478 for 2 weeks in Cycle 1. A patient may receive >2 cycles of treatment only if:  1) none of the criteria 
for discontinuation have been fulfilled and 2) the investigator determines that the patient is experiencing clinical 
benefit from treatment.  
Short-term follow-up period (postdiscontinuation):  30 days
Long-term follow-up period (postdiscontinuation):  after the short-term follow-up through death or study closure.
Continued-access period:  All patients remaining on study treatment without disease progression following the 
final analysis will be able to enter the continued-access period of the study, which begins approximately 12 months 
after the last patient was enrolled and ends after the last patient discontinues study treatment and performs safety 
follow-up visit.
Criteria for Evaluation:  
   Safety:  NCI CTCAE, version 4.0, dose-limiting toxicities (DLT)
   Bioanalytical:  Plasma concentrations of LY3039478
   Efficacy: Depending on the histology, efficacy will be assessed using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 for solid tumors (along with the Choi criteria for soft tissue sarcomas and HCC), the 
Revised Response Criteria for Malignant Lymphoma, the Guidelines from the National Cancer Institute Working 
Group for CLL, or the Response Assessment in Neuro-Oncology (RANO) criteria for glioblastoma.
Statistical Methods:  
   Safety: Dose escalation will be driven by safety using the 3+3 method.  Model-based analyses that incorporate 
prior expectations about the dose-toxicity curve will be fitted to the data at the end of each cohort, which will be 
used by the investigators and the Eli Lilly and Company (Lilly) clinical research physician to determine the next 
dose level.  The maximum tolerated dose is defined as the highest tested dose that has <33% probability of causing 
a DLT during Cycle 1.
   Efficacy:  Tumor response data will be tabulated and summarized by study part. For the purposes of statistical 
analysis, subjects will be grouped by mutation and/or amplification, and by tumor type. Change in tumor size 
(and/or change in tumor density) will be analyzed by analysis of covariance models with potential covariates 
including baseline measurements, mutations/amplification group, tumor type, Eastern Cooperative Oncology 
Group performance status, and other covariates as deemed appropriate.  Logistic regression analyses will also be 
utilized to estimate the overall response rate for each grouping of patients. Descriptive analyses of duration of 
response, PFS, and OS will be conducted using the Kaplan-Meier method.
   Pharmacokinetics: PK parameters for LY3039478 will be analyzed by standard non-compartmental methods of 
analysis.
   Pharmacodynamics: All PD data will be assessed.  Exploratory PK/PD analyses may be conducted to identify 
the exposure-biomarker response relationship.

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3.
Table of Contents
A Phase 1 Study of LY3039478 in Patients with Advanced or 
Metastatic Cancer
Section
Page
1.
Protocol I6F-MC-JJCA(e) A Phase 1 Study of LY3039478 in 
Patients with Advanced or Metastatic Cancer......................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................5
4.
Abbreviations and Definitions...........................................................................................11
5.
Introduction ......................................................................................................................16
5.1.
Rationale and Justification for the Study ......................................................................16
5.2.
Objectives ....................................................................................................................19
5.2.1.
Primary Objective ................................................................................................19
5.2.2.
Secondary Objectives...........................................................................................19
5.2.3.
Exploratory Objectives.........................................................................................19
5.3.
General Introduction to LY3039478.............................................................................20
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................20
5.3.2.
Nonclinical Pharmacokinetics/Pharmacodynamics...............................................20
5.3.3.
Nonclinical Toxicology........................................................................................21
5.3.4.
Biomarkers...........................................................................................................24
5.4.
Rationale for Selection of Dose....................................................................................25
5.4.1.
Rationale for Additional Dose-Expansion Cohorts 
(Amendment C) ...................................................................................................25
5.4.2.
Rationale for Additional Dose-Expansion Cohorts 
(Amendment D)...................................................................................................26
5.4.3.
Rationale for Amendment E.................................................................................26
6.
Investigational Plan...........................................................................................................28
6.1.
Study Population..........................................................................................................28
6.1.1.
Inclusion Criteria .................................................................................................28
6.1.2.
Exclusion Criteria ................................................................................................30
6.2.
Summary of Study Design............................................................................................31
6.2.1.
Continued-Access Period .....................................................................................34
6.3.
Discontinuations ..........................................................................................................35
6.3.1.
Discontinuation of Patients...................................................................................35
6.3.2.
Discontinuation of Study Sites .............................................................................36
6.3.3.
Discontinuation of the Study................................................................................36

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7.
Treatment..........................................................................................................................37
7.1.
Materials and Supplies .................................................................................................37
7.2.
Study Drug Administration ..........................................................................................37
7.2.1.
Dosing Schedule ..................................................................................................37
7.2.2.
Dose-Escalation Phase .........................................................................................38
7.2.2.1.
Dose-Escalation Method.................................................................................38
7.2.2.2.
Criteria for Dose Escalation............................................................................39
7.2.2.3.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................40
7.2.3.
Cohort-Expansion Phase ......................................................................................41
7.2.4.
Dose Adjustments and Delays..............................................................................42
7.2.4.1.
Part A.............................................................................................................42
7.2.4.1.1.
Dose Adjustments within a Cycle .............................................................42
7.2.4.1.2.
Dose Adjustments between Cycles............................................................42
7.2.4.2.
Parts B, C, D, and E........................................................................................43
7.2.4.2.1.
Dose Adjustments within a Cycle .............................................................43
7.2.4.2.2.
Dose Adjustments between Cycles............................................................43
7.2.4.3.
Part F..............................................................................................................43
7.2.4.3.1.
Dose Adjustments within a Cycle .............................................................43
7.2.4.3.2.
Dose Adjustments between Cycles............................................................44
7.3.
Method of Assignment to Treatment ............................................................................44
7.4.
Blinding .......................................................................................................................44
7.5.
Concomitant Therapy...................................................................................................44
7.6.
Treatment Compliance .................................................................................................45
7.6.1.
Evaluable Patients................................................................................................46
7.6.1.1.
Parts A, B, C, D, E, and F...............................................................................46
7.6.1.2.
Dose Escalation Only .....................................................................................46
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................47
8.1.
Safety Evaluations........................................................................................................47
8.1.1.
Safety Data Collection and Review ......................................................................47
8.1.2.
Adverse Events ....................................................................................................47
8.1.2.1.
Serious Adverse Events ..................................................................................49
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................49
8.1.2.2.1.
Prior to Administration of Study Drug ......................................................49
8.1.2.2.2.
On Study...................................................................................................50
8.1.2.2.3.
Follow-Up Visit........................................................................................50
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................50

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8.1.2.4.
Summary of Adverse Events and Serious Adverse Event 
Reporting Guidelines......................................................................................50
8.1.3.
Other Safety Measures .........................................................................................51
8.1.3.1.
Electrocardiograms.........................................................................................51
8.1.4.
Safety Monitoring ................................................................................................52
8.1.5.
Complaint Handling.............................................................................................52
8.2.
Sample Collection and Testing.....................................................................................52
8.2.1.
Samples for Standard Laboratory Testing.............................................................53
8.2.2.
Pharmacokinetic Samples.....................................................................................54
8.2.3.
Pharmacogenetic Samples....................................................................................54
8.2.4.
Exploratory Samples ............................................................................................55
8.2.4.1.
Blood Samples for Aβ Assays.........................................................................55
8.2.4.2.
Blood Samples................................................................................................55
8.2.4.3.
Tumor and Skin Biopsies................................................................................55
8.3.
Efficacy Evaluations ....................................................................................................56
8.4.
Procedure/Sampling Compliance..................................................................................58
9.
Data Management Methods...............................................................................................59
9.1.
Data Quality Assurance................................................................................................59
9.2.
Data Capture Systems ..................................................................................................59
9.2.1.
Case Report Form ................................................................................................59
9.2.2.
Ancillary Data......................................................................................................60
10.
Data Analyses...................................................................................................................61
10.1. General Considerations ................................................................................................61
10.1.1.
Patient Disposition...............................................................................................62
10.1.2.
Patient Characteristics..........................................................................................62
10.1.3.
Safety Analyses....................................................................................................63
10.1.4.
Pharmacokinetic Analyses....................................................................................63
10.1.5.
Exploratory Biomarker Analyses..........................................................................64
10.2. Efficacy........................................................................................................................64
10.3. Interim Analyses ..........................................................................................................65
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................66
11.1. Informed Consent.........................................................................................................66
11.2. Ethical Review.............................................................................................................66
11.3. Regulatory Considerations ...........................................................................................66
11.3.1.
Investigator Information.......................................................................................67
11.3.2.
Protocol Signatures ..............................................................................................67
11.3.3.
Final Report Signature .........................................................................................67
12.
References ........................................................................................................................68

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List of Tables
Table
Page
Table JJCA.5.1. Scientific Rationale for LY3039478 Clinical Development............................18
Table JJCA.5.2. Dose and Exposure Multiples to the Starting and Maximum Planned 
Clinical Dose of LY3039478 Based on Administered Dose and 
Predicted Exposure........................................................................................24
Table JJCA.7.1. Proposed LY3039478 Dose-Escalation Scheme for 
Study I6F-MC-JJCA and Predicted Human Exposure- Part A........................40
Table JJCA.7.2. Proposed LY3039478 Dose-Escalation Scheme for 
Study I6F-MC-JJCA and Predicted Human Exposure- Part F.........................40
Table JJCA.8.1. Adverse Event and Serious Adverse Reporting Guidelines for Study 
I6F-MC-JJCA................................................................................................51
Table JJCA.8.2. Tumor and Skin Biopsy Time Points .............................................................56
Table JJCA.8.3. Definition of Efficacy Endpoints ...................................................................57
Table JJCA.10.1. Estimated Exact 95% CI for Example Overall Response Rate for 
Proposed Sample Size....................................................................................62
Table JJCA.12.1. Tumor and Skin Biopsy Time Points ...........................................................113

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List of Figures
Figure
Page
Figure JJCA.6.1. Study design..................................................................................................34

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JJCA Study Schedule.......................................................................71
Attachment 2.
Protocol JJCA Clinical Laboratory Tests .......................................................80
Attachment 3.
Protocol JJCA Pharmacokinetic and Pharmacodynamic Sampling 
Schedule........................................................................................................82
Attachment 4.
Protocol JJCA Recommendations for Reporting 
Serious Adverse Events .................................................................................87
Attachment 5.
Protocol JJCA Eastern Cooperative Oncology Group Performance 
Status.............................................................................................................88
Attachment 6.
Protocol JJCA Creatinine Clearance Formula ................................................89
Attachment 7.
Protocol JJCA Sampling Summary................................................................90
Attachment 8.
Protocol JJCA Guidance on Alterations Related to Notch Pathway................91
Attachment 9.
Protocol JJCA Guidance for Diarrhea Management.......................................92
Attachment 10.
Protocol JJCA Child-Pugh Score ...................................................................95
Attachment 11.
Protocol JJCA Barcelona Clinic Liver Cancer Classification Table................96
Attachment 12.
Protocol JJCA Cancer of the Liver Italian Program Scoring System ..............97
Attachment 13.
Protocol JJCA Protocol Amendment 
I6F-MC-JJCA(e) Summary 
A Phase 1 Study of LY3039478 in Patients with Advanced or 
Metastatic Cancer ..........................................................................................98

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4.
Abbreviations and Definitions
Term
Definition
ACC
adenoid cystic carcinoma
adverse event (AE)
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 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
APP
amyloid precursor protein 
ASCO
American Society of Clinical Oncology 
AST
aspartate aminotransferase
AUC
area under the plasma drug concentration versus time curve 
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to last 
measurable plasma concentration
AUCτ,ss
area under the concentration-time curve over 1 dosing interval at steady state
audit
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s).
BID
twice daily
case report form 
(CRF) and 
electronic case 
report form (eCRF)
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.
CBF-1
C-promoter binding factor-1 
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL/F (or CL)
apparent systemic clearance

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CLL
chronic lymphocytic leukemia
Cmax
maximum plasma concentration
CNS
central nervous system
complaint
Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
consent
The act of obtaining informed consent for participation in a clinical study from 
patients deemed eligible or potentially eligible to participate in the clinical 
study.  Patients entered into a study are those who sign the informed consent 
document directly or through their legally acceptable representatives.
CRP
clinical research physician
CRS
clinical research scientist
CSF
colony-stimulating factor
CSL
C-promoter binding factor-1 (CBF-1) and Suppressor of Hairless (Su[H]), 
LAG-1
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCE-MRI
dynamic contrast-enhanced magnetic resonance imaging
DCSI
Development Core Safety Information 
DDI
drug-drug interaction 
DLL
Delta-like 
DLT
dose-limiting toxicity
DLET
dose-limiting equivalent toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group

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EGF
epidermal growth factor 
end of study 
End of study (trial) is defined as the date of the last visit or last scheduled 
procedure at the last site shown in the Study Schedule for the last active patient 
in the study.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least 1 dose of study treatment.
enter
Patients who are entered in the trial are those who have signed the informed 
consent document directly or through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board:  a board or committee 
(institutional, regional, or national) composed of medical and nonmedical 
members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical study are protected.
FFPE
formalin-fixed paraffin-embedded
FISH
fluorescence in situ hybridization
GALT
gut-associated lymphoid tissue 
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factors
GEP
gene expression profiling
GI
gastrointestinal 
GIST
gastrointestinal stromal tumors
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
hERG
human ether-a-go-go related gene 
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration 
ICF
informed consent form
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for datalock.

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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.
IVTI
in vivo Notch-1 cleavage 
LC-MS/MS
liquid chromatography-tandem mass spectrometry 
LDH
lactate dehydrogenase
LHRH
luteinizing hormone-releasing hormone
MedDRA
Medical Dictionary for Regulatory Activities 
monitor
A person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local SOPs (if any), and global Medical SOPs.  
Monitors are trained on the investigational product(s), the protocol, informed 
consent document, any other written information provided to subjects, relevant 
SOPs, International Conference on Harmonisation Good Clinical Practice 
guidelines (ICH-GCP), and all applicable laws (for example, privacy and data 
protection) and regulations. 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NICD
Notch intracellular domain 
NK cells
natural killer cells
NOAEL
no-observed-adverse-effect-level 
NOEL
no-observed-effect level 
ORR
overall response rate
patient
a subject with a defined disease
PD
pharmacodynamic 
PET
positron emission tomography
PK
pharmacokinetic
PSA
prostate-specific antigen
Q2D
every other day
QTc
corrected QT 
RANO
Response Assessment in Neuro-Oncology

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RBM
Rules-Based Medicine
RBP-J
recombination signal-binding protein-J
RECIST
Response Evaluation Criteria in Solid Tumors
S1/S2/S3
site 1/site 2/site 3 
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements for 
participation in a clinical study.  
sponsor
The party who takes responsibility for the initiation, management and/or 
financing of a clinical study.
Su[H]
Suppressor of Hairless 
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life
TACE
tumor necrosis factor-α converting enzyme 
TEC50
threshold plasma concentration of the compound required to inhibit cleavage by 
50%
TED50
threshold dose concentration of the compound required to inhibit cleavage by 
50%
TID
3 times per day
TIW
3 times per week 
tmax
time of maximal plasma concentration
TPO
third-party organization
ULN
upper limit of normal
V/F (or V)
apparent volume of distribution

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A Phase 1 Study of LY3039478 in Patients with Advanced or 
Metastatic Cancer
5.
Introduction
5.1.
Rationale and Justification for the Study
Notch signaling is an evolutionarily conserved pathway that plays an integral role in 
development and tissue homeostasis (Artavanis-Tsakonas et al. 1999).  There are 4 mammalian 
Notch receptors (Notch-1, -2, -3, and -4) and 5 ligands (Jagged-1 and Jagged-2 [homologs of 
Drosophila Serrate-like proteins] and Delta-like [DLL] 1, DLL3 and DLL4).  The Notch 
receptors and ligands contain single-pass transmembrane domains that are expressed on the cell 
surface, and, for that reason, Notch signaling is particularly important in mediating 
communication between adjacent cells expressing the receptors and ligands (Allenspach et al. 
2002).  The Notch receptors are heterodimeric proteins composed of extracellular and 
intracellular domains that are initially synthesized as a single polypeptide.  The precursor protein 
is cleaved at site 1 (S1) by a furin-like convertase in the Golgi before being transported to the 
cell surface and presented as a heterodimer to form a mature Notch transmembrane receptor.  
The extracellular domain of both the receptors and ligands consists of several epidermal growth 
factor (EGF)-like repeats, with the ligands also containing distinct Notch receptor binding 
domains at the N terminus.  The extracellular domain of the Notch receptor is glycosylated by 
the Fringe proteins which regulate the receptor–ligand interaction.  Receptor–ligand interaction 
triggers a series of proteolytic cleavage of Notch receptor.  First, it is processed by the 
metalloprotease tumor necrosis factor-α converting enzyme (TACE) at S2 cleavage site, which 
occurs in the ectodomain of the receptor immediately outside of the transmembrane domain,
thereby separating the intracellular and extracellular receptor domains and releasing the entire 
extracellular domain of the receptor.  This is followed by an S3 cleavage within the 
transmembrane domain by -secretase which releases the entire Notch intracellular domain 
(NICD).  -Secretase is a high molecular weight multiprotein complex possessing protease 
activity against a number of type I membrane proteins, including amyloid precursor protein 
(APP), ErbB4 receptor, and Notch receptors.  -Secretase cleavage of the Notch receptor results 
in the release of a peptide called the NICD and translocation to the nucleus.  The NICD is 
important in regulating transcriptional activity through interactions with the transcription 
repressor CSL (C-promoter binding factor-1 [CBF-1] and Suppressor of Hairless [Su[H]], 
LAG-1), also known as mammalian recombination signal-binding protein-J(RBP-J).  NICD 
binding to the CSL relieves suppressive function by displacing co-repressor and recruiting co-
activator to activate the transcription of downstream target genes responsible for various Notch 
functions including proliferation, differentiation, apoptosis, angiogenesis, migration and self-
renewal.  These diverse roles of Notch signaling during the development and maintenance of 
normal tissues are recapitulated in different forms of cancer.  The oncogenic functions of Notch 
signaling involve the inhibition of apoptosis and the promotion of cell proliferation (Radtke and 
Raj 2003).

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LY3039478
An oncogenic role for Notch was first reported as the result of a chromosomal translocation 
occurring in a patient with T-cell leukemia (Grabher et al. 2006).  Overexpression of NICD in 
hematopoietic progenitor cells of mice recapitulated this phenomenon, as they developed T-cell 
leukemia similar to humans.  Furthermore, treatment of these cells with the -secretase inhibitor 
prevented their cell growth.  Besides T-cell leukemia, there is increasing evidence that Notch 
signals are oncogenic in other cancers through multiple mechanisms including receptor 
amplification and overexpression of ligands and/or receptors.  Deregulated Notch signaling due 
to mutation or overexpression of ligands and/or receptors is implicated in a number of 
malignancies including lymphoid leukemias, melanoma, glioblastoma, and cancers of the breast, 
ovary, lung, pancreas, colon, head and neck, cervix, and kidney (Koch and Radtke 2007; 
CGARN 2011; Puente et al. 2011; Table JJCA.5.1).  In summary, inhibition of Notch signaling 
constitutes an attractive strategy to provide therapeutic benefits to cancer patients.

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LY3039478
Table JJCA.5.1.
Scientific Rationale for LY3039478 Clinical Development
Tumors
Frequency of Notch Mutations 
(% gene) 
Frequency of Amplifications (% gene) 
Ovarian 
N3a
11% N3b; 19.5% N3c; 6% N3d; 2% J1b;
2% J2b; 5% J1d; 2% J2d
Lung 
10% N1e; 6% N1f
3d
Colon 
17% N1f
<1% Nd; 5% J1d
Glioblastoma 
20% N1f
6% N1-4d
Triple Negative MBC 
(Breast) 
N3a
6% (MBC) N1-4d; 2% J1d; 2% J2d
Gastric 
13% N1f
9% N3d; 15% N4d; 6% J1d; 3% J2d
Pancreatic 
6.9% N2-4d
Melanoma 
35% N2g; 6% N2&4d
T-ALL 
58% N1h-j
CLL 
12.2% (N1p2515Rfs*4)k
MCL 
12% (N1p2515Rfs*4)l
Abbreviations:  CLL = chronic lymphocytic leukemia; J1 = Jagged-1, J2 = Jagged-2; MBC = metastatic breast 
cancer; MCL = mantle cell lymphoma; N1 = Notch-1; N2 = Notch-2; N3 = Notch-3; T-ALL = T-cell acute 
lymphoblastic leukemia.
a
Overexpression.
b
CGARN 2011.
c
Park et al. 2006.
d
Mining of public database.
e
Westhoff et al. 2009.
f
Eli Lilly and Company (Lilly), data on file.
g
Gast et al. 2010.
h
Grabher et al. 2006.
i
Weng et al. 2004.
j
Bhanushali et al. 2010.
k
Puente et al. 2011.
l
Kridel et al. 2012.
Eli Lilly and Company (Lilly) has developed a potent small-molecule inhibitor of Notch, 
LY3039478, for the treatment of cancer.  Study I6F-MC-JJCA (JJCA) is a Phase 1 clinical trial 
designed to evaluate the safety and tolerability of LY3039478 in humans.
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.

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LY3039478
5.2.
Objectives
5.2.1. Primary Objective
Part A: The primary objective of this study is to determine a recommended Phase 2 dose of 
LY3039478 that may be safely administered to patients with advanced or metastatic cancer.
Parts B, C, D, and E: The primary objectives are to confirm the recommended Phase 2 dose of 
LY3039478 that may be safely administered to patients with specific tumor types and to 
document antitumor activity.
Part F: The primary objective is to determine a recommended Phase 2 dose of LY3039478 that 
may be safely administered to patients according to 2 alternative dosing schedules with 
co-administration of prednisone and to document antitumor activity.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3039478 as assessed by National 
Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.0

to estimate the pharmacokinetic (PK) parameters of LY3039478

Part A:  to document any antitumor activity observed with LY3039478

Parts B, C, D, E, and F: to assess duration of response, progression-free survival 
(PFS) and overall survival (OS)
5.2.3. Exploratory Objectives
The exploratory objectives of this study are:

to explore renal clearance of LY3039478 and PK of LY3039478 metabolites in 
plasma and urine

to explore predictive biomarkers related to LY3039478

to explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of 
Notch activity (NICD by immunohistochemistry [IHC] or an alternative validated 
method) including cytokeratin 18 or Rules-Based Medicine (RBM)

to explore the utility of positron emission tomography (PET) scan to assess treatment 
effect with LY3039478

to explore the utility of dynamic contrast-enhanced magnetic resonance imaging 
(DCE-MRI) to assess treatment effect with LY3039478

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5.3.
General Introduction to LY3039478
Detailed information about LY3039478 is provided in the Investigator’s Brochure (IB).  This 
section provides a summary of the information most relevant for this initial Phase 1 study.  More 
information about the known and expected benefits, risks and reasonably anticipated adverse 
events (AEs) may be found in the IB.  Information on AEs expected to be related to the study 
drug may be found in Section 7 (Development Core Safety Information) of the IB.  Information 
on serious adverse events (SAEs) expected in the study population independent of drug exposure 
and that will be assessed by the sponsor in aggregate, periodically during the course of the study, 
may be found in Section 6 (Effects in Humans) of the IB.
5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
LY3039478 is a potent Notch inhibitor with a half-maximal inhibitory concentration (IC50) of 
≤1 nM in the majority of tumor cell lines tested for its ability to inhibit Notch-1 cleavage.
LY3039478 potently inhibits Notch cleavage and downstream Notch signaling in lung and skin 
of Balb/C mice in a dose-dependent manner with a threshold dose concentration of the 
compound required to inhibit cleavage by 50% (TED50) value for NICD inhibition of 0.8 and 0.9 
mg/kg, respectively, and threshold plasma concentration of the compound required to inhibit 
cleavage by 50% (TEC50) value of 6.2 and 6.6 ng/mL, respectively.
Doses of 7 to 10 mg/kg with an intermittent schedule of every other day (Q2D) produced optimal 
efficacy while balancing on-target gastrointestinal (GI) toxicity.  Furthermore, coadministration 
of dexamethasone with LY3039478 significantly decreased body-weight loss and GI toxicity 
without negatively impacting anti-tumor activity of LY3039478.  LY3039478 also inhibited 
Notch-1 cleavage and down-stream signaling as measured by analysis of Notch-regulated gene 
expression within the tumor microenvironment.
LY3039478 inhibited Notch signaling in the tumor and produced antitumor activity in patient 
derived human tumor models:  EL1989 adenocarcinoma of colon, EL1986 adenocarcinoma of 
colon, EL1997 triple-negative invasive ductal carcinoma of breast, and EL2056 glioblastoma; 
and cell line-derived xenograft tumors:  A2780 ovarian carcinoma, U-87 MG glioblastoma, 
HCT-116 colon carcinoma, SW480 colon carcinoma, and K562 chronic myelogenous leukemia.
5.3.2. Nonclinical Pharmacokinetics/Pharmacodynamics
Preliminary nonclinical PK of LY3039478 was characterized in mice, rats, and dogs.  Oral 
absorption was extensive and rapid (F = 65% to 67%; time of maximal plasma concentration
[tmax] = 0.25 to 0.4 hour). Elimination half-life (t1/2) of 2 to 6 hours was consistent with desired 
washout between 3 times per week (TIW) doses.  LY3039478 was well distributed into tissues 
(volume of distribution = 1.4 to 4.9 L/kg) with preferential tumor partitioning (tumor/plasma = 
3.4 to 33) and unbound brain concentrations 22- to 118-fold in excess of the Notch IC50.  In 
1-month rat and dog toxicokinetic studies (TIW dosing), LY3039478 exposure increased in 
proportion to dose, with no apparent sex differences or time-dependent changes in exposure 
(eg, accumulation).  LY3039478 was extensively cleared by urinary excretion of parent 
compound, and by hydrolysis of the amide bond connecting the azepine ring to the aliphatic side 

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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LY3039478
chain.  No drug-drug interaction (DDI) perpetrator potential was identified:  LY3039478 was not 
an inhibitor or inducer of key cytochrome P450s (CYPs) or transporters.  LY3039478 clearance 
mechanisms, urinary excretion of parent and amide hydrolysis, are consistent with low DDI 
potential.
A PK/PD model was developed to relate the LY3039478 plasma concentration to the level of 
in vivo Notch-1 cleavage (IVTI) in mouse lung, as a surrogate marker for tumor.  A 
precursor-dependent indirect-response model with a rebound was used to describe the 
relationship between plasma concentrations and Notch-1 cleavage.  The model identified a 
maximal inhibition of the Notch-1 signal of 98%, and the estimated IC50 was 1.8 ng/mL.  The 
model adequately characterized the observed rebound above baseline levels in Notch-1 that 
occurred between 12 and 24 hours with a recovery to baseline by 36 to 48 hours.  A tumor
growth kinetics model was also developed based on tumor sizes in mice bearing A2780 
xenografts.  This model supported an understanding of the relationship between LY3039478 
exposure and tumor growth delay.  
5.3.3. Nonclinical Toxicology
LY3039478 was evaluated in nonclinical toxicology studies up to 1-month in duration using 
TIW oral dosing in rats and dogs to characterize the toxicity.  Safety pharmacology parameters 
were evaluated in vitro and as part of the repeat-dose studies.  Based on results from nonclinical 
studies, the primary target organ is the GI tract.  The intestinal toxicity in rat and dog 1-month 
toxicology studies was characterized by fecal abnormalities and histologic changes described as 
a mucoid enteropathy (a known target mediated toxicity of Notch inhibitors) with increases in 
the size and/or number of goblet cells within the mucosal epithelial enterocytes.  All sections of 
the small and large intestine were affected.  Although the enteropathy contributed to the 
mortality in rats at the highest dose, the intestinal toxicity was almost completely reversed 
following a 3-week reversibility interval in the 1-month rat study.
In the 1-month rat toxicology study, LY3039478 hydrate was given by oral gavage TIW
(Monday, Wednesday, and Friday) to rats for up to 1 month and followed by a 3-week 
reversibility period at dose levels of 0 (vehicle), 1, 3, and 6 mg/kg/dose (equivalent to 0, 6, 18, 
and 36 mg/m2, respectively). Rats given 0 and 6 mg/kg/dose were also maintained for a 3-week 
recovery period.  
Mortality was observed on Days 20 to 22 in 2 male and 2 female main study rats and in 2 female 
toxicokinetic rats at 6 mg/kg/dose.  Prior to being euthanized or found dead, the early death rats 
exhibited significant decreases in body weight and food consumption from Days 17 to 21 and 
clinical observations consistent with poor clinical condition (including decreased activity, 
few/absent or watery feces, haircoat soiling and unkempt appearance).  The intestinal findings 
described below may have contributed to the declining clinical conditions of these rats found 
dead or euthanized early.  There were no test article-related effects on body weight or food 
consumption findings for surviving main study rats.  A mucoid enteropathy of the small and 
large intestine characterized by increases in the size and/or number of goblet cells within the 
mucosal epithelial enterocytes was observed at all doses.  This change was sometimes 

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LY3039478
accompanied by blunting of villi, subacute/chronic inflammation and increased mucus in the 
intestinal lumen.  The mucoid enteropathy was considered to be adverse at ≥3 mg/kg/dose in 
males and females due to the increased severity (mild to moderate) at these dose levels. 
Decreased number of ovarian follicles were observed in all female rats (≥1 mg/kg/dose) and 
were considered adverse to fertility, but not to the overall health of the female rat.  Notch 
inhibition has been previously reported to impact folliculogenesis in rodents.  Additional non-
adverse histology findings included bone growth plate thickening of the femur and sternum and 
single cell necrosis of epithelia in the pancreas, exorbital lacrimal glands, and mandibular 
salivary glands.  The mucoid enteropathy, decreased ovarian follicles, and all other toxicities 
were reversible or partially reversible following a 3-week recovery period in rats.  The 
no-observed-adverse-effect-level (NOAEL) was considered to be 1 mg/kg/dose in males and 
<1 mg/kg/dose in females based on adverse microscopic findings of mucoid enteropathy at 
≥3 mg/kg/dose and decreased ovarian follicles at ≥1 mg/kg/dose, respectively.  The MTD was 
considered to be 3 mg/kg/dose based on mortality observed at the high dose of 6 mg/kg/dose.  
Additional details and findings from this study are presented in the IB.
In the 1-month dog toxicity study, LY3039478 hydrate was administered to beagle dogs via oral 
gavage TIW (Monday, Wednesday, Friday) for 1 month at dose levels of 0 (vehicle), 0.1, 0.3,
and 1 mg/kg/dose (equivalent to 0, 2, 6, and 20 mg/m2, respectively).  No deaths occurred during 
the conduct of the dog study.  Substantial decreases in body weight and food consumption 
occurred early in the study at 0.3 and 1 mg/kg/dose and resulted in supplemental food being 
offered to all dogs at these dose levels. Clinical signs were limited to fecal changes including 
soft, watery, mucoid, and discolored feces in dogs administered 0.3 and 1 mg/kg/dose.  Fecal 
changes at 0.1 mg/kg/dose were less frequent and less severe than at higher doses.  These 
changes were consistent with the dose-dependent mucoid enteropathy that was evident 
histologically in the small and large intestines at all doses and was considered to be adverse at 
≥0.3 mg/kg/dose based on the presence of concurrent mucosal degeneration/necrosis at these mid 
and high doses.  Generalized lymphoid depletion occurred in multiple tissues including the 
thymus, spleen, mesenteric lymph nodes, and/or gut-associated lymphoid tissue (GALT) and was 
considered adverse at ≥0.3 mg/kg/dose.  Marginal zone lymphoid depletion is a known on-target 
effect of Notch inhibition.  Lymphoid depletion was not considered adverse at 0.1 mg/kg/dose 
based on occasional overlap with control animals, low magnitude of severity, and lack of impact 
on peripheral lymphocyte numbers.  Hypercellularity of the bone marrow (femur and sternum) at 
1 mg/kg/dose correlated with hematology findings including increased total leukocytes, likely 
associated with inflammation in the large and small intestines.  Increased thickness of the 
hypertrophy zone was also evident in cartilage of the rib and sternum at 1 mg/kg/dose, similar 
but more subtle than the finding in the rat.  The NOAEL was considered to be 0.1 mg/kg/dose 
based on the combination and severity of the GI changes observed clinically (soft, discolored, 
watery, mucoid feces) and histologically (mucoid enteropathy with concurrent mucosal 
degeneration/necrosis) at ≥0.3 mg/kg/dose.  The MTD in this dog study was 1 mg/kg/dose, the 
highest dose tested.  Additional details and findings from this study are presented in the IB.
In vitro evaluation of LY3039478 on the human ether-a-go-go related gene (hERG) channel
current estimates the IC50 to be >281.7 µM. Based on this result, there is no expected risk for 

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LY3039478
QT prolongation by hERG inhibition as the highest total human plasma concentration of 
LY3039478 is predicted to be <2.8 µM for the maximum planned clinical dose of 100 mg 
(maximum plasma concentration [Cmax] at the 90% prediction interval).  In vivo cardiovascular 
endpoints were evaluated in the 1-month repeat-dose dog toxicology study using a jacketed 
external telemetry system.  Dogs were continuously monitored for at least 22 hours for 
cardiovascular endpoints on Days 3 and 24.  No test article–related effects were observed in any 
of the electrocardiogram (ECG) parameters (heart rate, RR interval, PR interval, QRS duration, 
QT interval, and corrected QT [QTc]); therefore the no-observed-effect level (NOEL) for 
cardiovascular endpoints was 1 mg/kg/dose, the highest dose tested.
No evidence of mutagenicity was observed in a bacterial mutagenicity assay (Ames assay).  
LY3039478 was classified as a nonirritant based on the results of an in vitro assay that measured 
effects on corneal opacity and permeability.
In conclusion, nonclinical toxicology studies in rats and dogs dosed TIW for 1 month have 
characterized the target tissues for toxicity that may be clinically relevant.  Data indicate that the 
gastrointestinal tract is the primary target organ for LY3039478 toxicity. The mucoid 
enteropathy and all other toxicities were reversible or partially reversible following a 3-week 
recovery period in rats. The planned clinical starting human dose of 2.5 mg (equivalent to 
1.54 mg/m2) is 11.7-fold and 13.0-fold lower than the MTD dose level of 18 and 20 mg/m2 in 
rats and dogs, respectively. The predicted human area under the plasma drug concentration 
versus time curve (AUC) exposure at the starting dose of 2.5 mg (112 ng*hr/mL) is 7.0-fold and 
23.3-fold lower than AUC at the MTD in rats and dogs, respectively. Although exposure 
multiples will likely be <1 at higher clinical doses, the dose-limiting enteropathy in nonclinical 
studies was monitorable and/or reversible. Table JJCA.5.2 shows the dose and exposure 
multiples to the starting dose and highest anticipated clinical dose.

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LY3039478
Table JJCA.5.2.
Dose and Exposure Multiples to the Starting and Maximum 
Planned Clinical Dose of LY3039478 Based on Administered Dose 
and Predicted Exposure
Dose
(mg/kg)
Dose
(mg/m2)
Dose
Multiplea
AUC
(ng*hr/mL)
Exposure 
Multipleb
Humanc
Starting dose (2.5 mg)
0.04
1.54
–
112
–
Max. planned (100 mg)
1.67
61.7
–
4401
–
Rat MTDd
3.0
18
779
Starting
11.7x
7.0x
Max. planned 
0.29x
0.18x
Dog MTDe
1.0
20
2612
Starting
13.0x
23.3x
Max. planned 
0.32x
0.59x
Abbreviations:  AUC = area under the plasma concentration versus time curve; Max. = maximum; 
MTD = maximum tolerated dose. 
a
Dose multiple is the dose in animals/dose in humans based on mg/m2.  Doses were converted from mg/kg to 
mg/m2 using a km conversion factor of 6 for the rat, 20 for the dog, and 37 for a 60-kg human. 
b
Exposure multiple is the calculated AUC in animals/predicted AUC in humans (see Investigator’s Brochure for 
Predicted Human LY3039478 Steady-State Plasma Exposures).
c
Starting and highest proposed clinical dose, assuming a 60-kg human.  AUC values in humans are predicted 
values as presented in the Investigator’s Brochure. 
d
MTD determined in a 1-month repeat-dose rat toxicity study (Study 130-238).  AUC based on arithmetic mean of 
male and female exposure on Days 1, 15, and 29 combined. 
e
MTD determined in a 1-month repeat-dose dog toxicity study (Study 130-237).  AUC based on arithmetic mean 
of male and female exposure on Days 1, 15, and 29 combined. 
5.3.4. Biomarkers 
As part of an ongoing effort by Lilly to better understand how to predict which tumors are more 
likely to respond to LY3039478 treatment, the collection of samples to be stored for possible 
future biomarker research are a mandatory part of this study.
Biomarkers will be used to assess not only PD response to LY3039478 in plasma, surrogate 
tissues, and tumors, but also potential predictive markers of efficacy and/or patient tailoring.  
In Parts B, D, and the Part F dose confirmation, patients will be entered based on screened 
molecular alteration related to Notch pathway.
PD biomarkers will be measured before and after administration of study drug in plasma and 
skin throughout the study.  Whenever clinically feasible, biomarkers will be measured before and 
after administration of study drug in tumors during dose escalation and dose confirmation 
(Parts A, B, C, D, E, and F).  Potential predictive biomarkers will be measured (when the assays 
become available) throughout the study in archived tumor tissue (for example, from prior biopsy) 
as well as before and after administration of study drug in both tumors and blood during dose 
confirmation.  

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The following biomarkers will be studied:
•
Aβ in plasma (Parts A and B only)
•
gene expression profiling in tumors and skin biopsies (pre- and posttreatment)
•
NICD = Notch intracellular domain IHC in tumors
•
cytokeratin 18 in plasma
•
RBM in plasma
•
epigenomics in plasma 
Additional exploratory biomarkers potentially related to the mechanisms of action of 
LY3039478 may also be evaluated.
Additional details about sampling are summarized in Section 8.2.4, Attachment 1, and 
Attachment 3.
5.4.
Rationale for Selection of Dose
A dose range from 2.5 to 100 mg of LY3039478 administered orally TIW was selected based on 
nonclinical toxicology and PK/PD data modeling.  The dose of 2.5 mg is expected to be safe in 
patients based on nonclinical toxicology data.
The planned clinical starting human dose of 2.5 mg (equivalent to 1.54 mg/m2) is 11.7-fold and 
13.0-fold lower than the MTD dose level of 18 and 20 mg/m2 in rats and dogs, respectively. 
Table JJCA.5.2 shows dose multiples based on body surface area and exposure multiples based 
on predicted human AUC for the proposed clinical doses.
Based on the IVTI PK/PD model, simulations for humans suggest that oral doses of 20 to 50 mg 
LY3039478 TIW are expected to produce ≥85% target inhibition 4 hours after dosing, while 
doses of 20 to 150 mg LY3039478 TIW are expected to produce the required tumor growth 
delay.  Together, the human simulations with both the IVTI and xenograft efficacy models 
suggest that the biological efficacious dose is 50 mg (range 20 to 150 mg) LY3039478 TIW. 
5.4.1. Rationale for Additional Dose-Expansion Cohorts 
(Amendment C)
Part A was completed in November 2014, and the MTD has been determined to be 75 mg TIW. 
The dose-expansion phase of the study was opened at the MTD of 75 mg TIW.  
Dose-limiting toxicities (DLTs) observed at dose levels of 20 mg, 30 mg, and 60 mg LY3039478
were Grade 4 thrombocytopenia in 1 patient in each dose group.  DLTs at 100 mg included 
Grade 3 nausea (not manageable by medical treatment) and Grade 3 asthenia, and in addition, 
1 patient at 100 mg experienced Grade 3 colitis.
Signs of clinical activity have been observed in patients treated at doses of 75 and 100 mg.
Activity was observed in leiomyosarcoma, breast cancer, and adenoid cystic carcinoma.
The safety profile of LY3039478 may be impacted by the tumor type, tumor burden, and 
underlying conditions.

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In addition, in case of major response, patients might present with AEs related to tumor necrosis. 
Additional cohorts are being added to the dose-expansion part of this study to investigate the 
safety profile and the potential activity in patients with specific tumor types.  
Part C will investigate LY3039478 in sarcoma patients including leiomyosarcoma, 
rhabdomyosarcoma, angiosarcoma, liposarcoma, pleomorphic sarcoma, and gastrointestinal 
stromal tumors (GIST). This investigation is based on the reports of Notch pathway activation in 
these specific sarcoma subtypes and the early signs of activity in Study JJCA.
Part D will investigate LY3039478 in triple-negative breast cancer, chronic lymphocytic 
leukemia (CLL), hepatocellular carcinoma (HCC), and cholangiocarcinoma. It is important to 
have a minimum number of patients with specific tumors of interest to confirm the safety profile 
of LY3039478. An assessment of efficacy in these tumors will be performed to guide
LY3039478 clinical development.
Additional changes were made for dose adjustments and efficacy assessments as appropriate.
5.4.2. Rationale for Additional Dose-Expansion Cohorts 
(Amendment D)
Patients in the dose expansion cohorts were initially treated with a dose of 75 mg TIW.  There 
were a total of 41 patients treated at this dose level in the expansion cohorts.  After a review of 
safety data showed significant dose reductions or omissions related to adverse events, the 
recommended dose was adjusted to 50 mg TIW. 
In order to further explore the 50 mg dose TIW dose level and its potential effects, enrolment in 
the dose expansions cohorts is being increased and additional cohorts are being added to explore 
the activity of LY3039478 in patients with specific tumor types including adenoid cystic 
carcinoma and patients with T, B or natural killer (NK) cell neoplasms.
These tumor types were selected based on emerging published data (Stoeck et al. 2014 and Kluk 
et al. 2013) and internal data showing activation of Notch pathway in these tumor types. 
Given the initial observation of metabolic responses in patients receiving LY3039478, the use of 
PET scan or PET-CT scan is required to be used systematically for all new patients.  Tumor 
biopsies are required to characterize the changes in the tumor following treatment with 
LY3039478.
Additional editorial changes are being implemented in the protocol.
5.4.3. Rationale for Amendment E
As of November 2015, approximately 40 patients have been treated at 75 mg TIW and 62
patients have been treated at 50 mg TIW. Review of safety data (treatment emergent adverse 
events, dose-limiting equivalent toxicities, and dose reductions) confirmed the 50-mg TIW 
schedule to be adequately tolerated. Initial observations of metabolic responses were observed in 
patients treated at 100 mg, 75 mg, and 50 mg with exploratory analyses suggestive of a potential 
relationship to dose.

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Study Part F will be added in order to explore 2 alternative dosing schedules allowing a loading 
dose for 2 weeks in Cycle 1, followed by the current 50-mg TIW schedule. Prednisone will be 
co-administered with LY3039478 during the loading dose period in order to mitigate potential
GI toxicity. Study Part F dose confirmation will enroll patients with histologic evidence of 
advanced or metastatic leiomyosarcoma with Notch molecular alterations in order to allow a 
homogeneous population to further characterize the clinical activity of LY3039478.
In addition, a continued-access period was added to the protocol for patients who are benefitting 
from treatment after final database lock has occurred.  Minor editorial changes and clarifications 
have also been made.

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LY3039478
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 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]
For all parts:  The patient must be, in the judgment of the investigator, an 
appropriate candidate for experimental therapy after available standard 
therapies have failed to provide clinical benefit for their advanced or 
metastatic cancer.
For Dose Escalation (Part A):  The patient must have histological or 
cytological evidence of cancer, either a solid tumor or a lymphoma, which is 
advanced or metastatic.
For Part B:  All patients must have histological evidence of their advanced or 
metastatic cancer and prescreened alterations in the Notch pathway such as 
mutations, amplification, or gene expressions related to Notch pathway 
(Attachment 8).
For Part C: All patients must have histological evidence of advanced or 
metastatic soft tissue sarcoma. Eligible patients must have leiomyosarcoma, 
angiosarcoma, rhabdomyosarcoma, liposarcoma, pleomorphic sarcoma, or 
GIST.
For Part D: All patients must have histological evidence of advanced or 
metastatic cancer and prescreened alterations in the Notch pathway such as 
mutations, amplification, or gene expressions related to Notch (Attachment 8).

Cohort 1: Patients must have triple-negative breast cancer (ER-, 
PR-, HER2-).

Cohort 2: Patients must have HCC. These patients should have 
Child-Pugh stage A (Attachment 10).

Cohort 3: Patients must have cholangiocarcinoma.

Cohort 4: Patients must have CLL.

Cohort 5: Patients must have mature T cell, B cell, or Natural 
Killer (NK) cell neoplasms

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For Part E:  All patients must have histological evidence of advanced or 
metastatic adenoid cystic carcinoma (ACC).
For Part F: All patients must have: 
Dose Escalation: histological or cytological evidence of cancer, either a solid 
tumor or a lymphoma, which is advanced or metastatic.
Dose Confirmation: histological evidence of nonresectable or metastatic 
leiomyosarcoma and prescreened alterations in the Notch pathway such as 
mutations, amplification, or gene expressions related to Notch pathway 
(Attachment 8).
[2]
As defined by the Response Evaluation Criteria in Solid Tumors (RECIST 
1.1; Eisenhauer et al. 2009), the Revised Response Criteria for Malignant 
Lymphoma (Cheson et al. 2007), the Guidelines from the National Cancer 
Institute Working Group for CLL (Hallek et al. 2008), the Response 
Assessment in Neuro-Oncology (RANO) criteria for glioblastoma (Wen et al. 
2010).
For Dose Escalation (Part A):  Have measurable or nonmeasurable disease
For Parts B, C, D, E, and F:  Have measurable disease or reliable biomarker 
measure (for example, prostate-specific antigen [PSA], CA125)
[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/L (for CLL 
patients ANC ≥1.0 x 109/L), platelets ≥100 x 109/L (for patients with 
CLL and T cell, B cell, or NK cell neoplasms platelets ≥50 x 109/L), and 
hemoglobin ≥8 g/dL.  Patients may receive erythrocyte transfusions to 
achieve this hemoglobin level at the discretion of the investigator; 
however, initial study drug treatment must not begin earlier than the day 
after the erythrocyte transfusion.

Hepatic:  Bilirubin ≤1.5 times upper limits of normal (ULN) and alanine 
aminotransferase (ALT) ≤2.5 times ULN.  If the liver has tumor 
involvement, aspartate aminotransferase (AST) and ALT equaling 
5 times ULN are acceptable.

Renal:  calculated creatinine clearance >45 mL/min (Attachment 6)
[6]
Have a performance status ≤1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (refer to Attachment 5)

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[7]
Have discontinued all previous therapies for cancer (including chemotherapy, 
radiotherapy, immunotherapy, and investigational therapy) for at least 21 days 
for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior 
to receiving study drug, and recovered from the acute effects of therapy 
(treatment-related toxicity resolved to baseline) except for residual alopecia.  
At the discretion of the investigator, patients with breast or prostate cancers 
progressing on therapies may have that treatment continued while receiving 
study drug
[8]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[9]
Males and females with reproductive potential must agree to use medically 
approved contraceptive precautions during the trial and for 3 months 
following the last dose of study drug.
[10] Females with childbearing potential must have a negative serum pregnancy 
test within 7 days of the first dose of study drug
[11] Have an estimated life expectancy of ≥12 weeks
[12] Are able to swallow capsules
[21] For Parts B, C, D, E, and F:  Have available tumor tissue (archival or new 
biopsy)
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[13] Have received treatment with a drug that has not received regulatory approval 
for any indication within 14 or 21 days of the initial dose of study drug for a 
nonmyelosuppressive or myelosuppressive agent, respectively.
[14] Have serious preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study (for example, 
inflammatory bowel disease or history of major surgical resection involving 
the stomach or small bowel).
[15] Have central nervous system (CNS) malignancy, except:
a) Patients with treated CNS metastases are eligible for this study if they are 
not currently receiving corticosteroids and/or anticonvulsants, and their 
disease is asymptomatic and radiographically stable for at least 60 days 
(screening not required).
b) Patients with glioblastoma, World Health Organization (WHO) grade IV, 
or WHO grade II or III glioma are eligible.
[16] Have an acute leukemia.

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[17] Have received an autologous or allogeneic stem-cell transplant (for patients 
with CLL or T cell, B cell, or NK cell neoplasms, autologous stem cell 
transplant is allowed).
[18] Females who are pregnant or lactating.
[19] Have active bacterial, fungal, and/or known viral infection (for example, 
human immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen 
[HBsAg], or hepatitis C antibodies).  Screening is not required for enrollment.
[20] Have malabsorptive syndromes, enteropathies, gastroenteritis (acute or 
chronic), or diarrhea (acute or chronic).
[22] Patients with HCC that:

Have known HCC with fibro-lamellar or mixed histology

Have presence of clinically relevant ascites

Have had a liver transplant 

Have active or uncontrolled clinically serious hepatitis B virus or hepatitis 
C virus infection. Patients with stable and chronic viral hepatitis are 
eligible.

Have esophageal or gastric varices that require immediate intervention 
(eg, banding, sclerotherapy) or represent a high bleeding risk in the 
opinion of the investigator or consulting gastroenterologist or hepatologist 
or have experienced any CTCAE Grade 3 or 4 GI bleeding or any variceal 
bleeding episode in the 3 months prior to enrollment requiring transfusion 
or endoscopic or operative intervention
6.2.
Summary of Study Design
Study JJCA is a multicenter, nonrandomized, open-label, dose-escalation Phase 1 study of oral
LY3039478 in patients with advanced or metastatic cancer. In Study Parts A, B, C, D, and E,
eligible patients will receive LY3039478 administered orally TIW during a 28-day cycle.  In 
Study Part F, eligible patients will receive LY3039478 administered orally during a 28-day 
cycle, according to 2 alternative dosing schedules, with co-administration of prednisone for 
2 weeks in Cycle 1.
Patients will receive 2 cycles of LY3039478 unless 1 or more of the criteria for discontinuation 
(refer to Section 6.3.1) are fulfilled.  A patient may receive >2 cycles of treatment only if:  1) 
none of the criteria for discontinuation have been fulfilled and 2) the investigator determines that
the patient is experiencing clinical benefit from treatment.  The follow-up period for poststudy 
evaluation will be 30 days from the date of the last dose of study drug received.  
The study design consists of a dose-escalation phase (Part A), a cohort-expansion phase (Parts B, 
C, D, and E), and a dose-escalation phase with alternative dosing schedules followed by a 
cohort-expansion phase (Part F).

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The dose-escalation phase (Part A) (Figure JJCA.6.1), described in Section 7.2.2, will be guided 
primarily by safety assessments from Days 1 through 28 of Cycle 1 for patients in all cohorts.  
Dose escalation will occur until the maximum tolerated dose (MTD, defined in Section 7.2.2.3) 
is determined. Patients will be enrolled in cohorts starting with the first dose level at 2.5 mg; 
dose levels of LY3039478 ranging from 2.5 to 100 mg TIW may be evaluated. Table JJCA.7.1
outlines the proposed dose-escalation scheme. The maximum dose increase that will be allowed
is 100%.  Dose levels are determined based on the review of the safety, PK, and PD data from 
the previous doses.  Enrolment in Part A is complete with a total of 55 patients.
After the last patient on Part A has completed Cycle 1 and the recommended dose for the 
expansion phase is determined, the cohort expansion phase (Parts B, C, and D; Figure JJCA.6.1) 
will begin following an interim review of the data, as outlined in Section 10.3.  
In the cohort expansion phase (Parts B, C, D, and E), patients will be treated at a dose no greater 
than the MTD with LY3039478 administered orally TIW during a 28-day cycle.  
Part B focused on approximately 50 patients with tumors that have molecularly defined 
mutations, amplification, or gene expressions alterations related to Notch pathway or known
activated Notch pathways.  
Part C focused on approximately 65 patients with soft tissue sarcoma including patients with 
leiomyosarcoma (approximately 25), angiosarcoma (approximately 10), rhabdomyosarcoma 
(approximately 5), liposarcoma (approximately 10), pleomorphic sarcoma (approximately 5),
and GIST (approximately 10).
Part D focused on approximately 42 patients with specific tumor types harboring Notch 
molecular alterations, including patients with triple negative breast cancer (ER-, PR-, HER2-)
(approximately 8), cholangiocarcinoma (approximately 8), HCC (approximately 8), CLL 
(approximately 8), and mature T cell, B cell, or NK cell neoplasms (approximately 10).
Part E focused on approximately 15 patients with adenoid cystic carcinoma.  
Part F will focus on approximately 55 patients with histologic evidence of advanced or 
metastatic cancer with expansion cohorts in patients with leiomyosarcoma and prescreened 
alterations in the Notch pathway.  Approximately 10 to 15 patients will be treated in a 
dose-escalation phase and approximately 15 patients in a cohort-expansion phase at the 
recommended Phase 2 dose according to the following 2 dosing schedules, to be conducted 
concurrently.
F1: Dose escalation of a loading dose TIW for 2 weeks in Cycle 1 only followed by 50 mg TIW.
Prednisone will be co-administered with LY3039478 for the first 2 weeks in Cycle 1 only. 
F2: Dose escalation of a loading dose twice a week for 2 weeks in Cycle 1 only followed by 
50 mg TIW.  Prednisone will be co-administered with LY3039478 for the first 2 weeks in 
Cycle 1 only. 
The total sample size for Parts A, B, C, D, E, and F is estimated to be approximately 282
patients.  Further expansion is possible following the analysis of outcome.

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The planned duration of treatment is not fixed; patients will remain on study until they fulfill 1 of 
the criteria for study discontinuation.  The treatment period will be defined as the time from 
treatment start until discontinuation for any reason (Section 6.3).  The postdiscontinuation 
follow-up period begins the day after the patient and the investigator agree that the patient will 
no longer continue study treatment and is defined by the following periods:

The short term follow-up period begins 1 day after discontinuation of study 
treatment and lasts approximately 30 days (Visit 801).  

The long-term follow-up period begins 1 day after the short-term follow-up period 
(Visit 801) is completed and continues until death or study closure to collect survival 
data.

After discontinuation, tumor measurements will be performed as indicated in 
Section 8.3. Other study procedures will be performed as outlined in Attachment 1.
This study will be considered closed approximately 12 months from the date that the last patient 
was enrolled.  Patients who are benefitting from treatment may continue to receive study drug for 
long-term durations, even after the study has closed and final database lock has occurred in the 
continued-access period.  
Based on emerging preclinical and clinical data, the protocol may be amended as appropriate to 
reflect the most current scientific knowledge. Study design may be modified to reflect this data 
and scientific needs. This includes, and is not limited to, change in the study design, 
modifications of safety monitoring, addition of cohorts to study, and introduction of new 
schedules as single agent or in combination with other agents. 
Refer to Attachment 1 for the Study Schedule.

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Abbreviations:  approx = approximately; CLL= Chronic lymphocytic leukemia; GIST = 
gastrointestinal stromal tumors; ICD = intercellular domain; NK= natural killer; 
TIW = 3 times per week.
Figure JJCA.6.1.
Study design.
6.2.1. Continued-Access Period
All patients remaining on study treatment without disease progression following the final 
analysis will be able to enter the continued-access period of the study, which begins 
approximately 12 months after the last patient was enrolled and ends after the last patient 
discontinues study treatment and performs safety follow-up visit.  During the continued-access 
period, patients on study treatment who continue to experience clinical benefit may continue to 
receive study treatment until they meet discontinuation criteria.  The continued-access period 
includes a follow-up visit.  The follow-up visit begins 1 day after the patient and the investigator 
agree that the patient will no longer continue treatment in the continued-access period and lasts 

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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approximately 30 days.  If it is deemed to be in the best interest of the patient to start a new 
anticancer treatment prior to the scheduled end of the follow-up visit, the follow-up visit duration 
may be shortened.  In this case, the follow-up assessments should be completed prior to the 
initiation of the new therapy.
During the continued-access period, all AEs, SAEs, dose reductions, and study drug exposure 
will be collected on the case report form/electronic case report form (CRF/eCRF). 
SAEs will also be reported to Lilly Global Patient Safety and collected in the Lilly Safety System 
(LSS).  In the event that an SAE occurs, additional information (such as local laboratory results, 
concomitant medications, and hospitalizations) may be requested by Lilly in order to evaluate the 
reported SAE.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.  The Study 
Schedule (Attachment 1) describes all assessments for the continued-access period.
6.3.
Discontinuations
6.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is unintentionally enrolled, Lilly or its designee must be contacted.  In these 
rare cases, the investigator must obtain documented approval from Lilly to allow the patient to 
continue in the study.
In addition, patients will be discontinued from the study drug and from the study in the following 
circumstances:

Enrollment in any other clinical trial judged not to be scientifically or medically 
compatible with this study.

Investigator/Physician Decision
o
the investigator/physician decides that the patient should be withdrawn from the 
study
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the other agent

Patient Decision
o
the patient requests to be withdrawn from the study

Sponsor Decision
o
the investigator or 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

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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
The patient has evidence of symptomatic progression or confirmed objective progressive 
disease.  The determining factor for whether a patient can continue on study drug should 
be based on his/her clinical symptoms even if the patient has progressive disease based 
on radiological evidence.  The investigator may also take into consideration biomarker 
responses (PSA, AFP, etc).

The patient experiences unacceptable toxicity including, but not limited to, a Grade 4 
non-hematological toxicity or a toxicity that does not resolve to baseline within 3 weeks.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).
The reason and date for discontinuation will be collected for all patients.  Patients who 
discontinue will have follow-up procedures performed as shown in the Study Schedule 
(Attachment 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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7.
Treatment
7.1.
Materials and Supplies
LY3039478 will be supplied as 25 and 50-mg capsules in bottles for oral consumption.  
LY3039478 capsules should be stored at room temperature within the temperature range stated 
on the label.  Investigators should instruct patients to store the capsules at home in the original 
container and to keep out of the reach of children.  Capsules should be swallowed whole and 
should not be opened, crushed, or dissolved.
Prednisone will either be provided by Lilly or obtained locally as appropriate and required.
Clinical study materials provided by Lilly will be labeled according to the country’s regulatory 
requirements. 
7.2.
Study Drug Administration
The investigator or his/her designee is responsible for:

explaining the correct use of the investigational agent and planned duration of each 
individual’s treatment to the patient/legal representative,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensation, destruction, and collection, and

returning all unused medication to Lilly or its designee at the end of the study or if 
appropriate and instructed by Lilly, may be destroyed at the site per local regulations and 
standard operating procedures.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
7.2.1. Dosing Schedule
LY3039478 will be administered orally TIW during both the dose-escalation phase (Part A) and 
the dose-confirmation phase (Part B, C, D, and E) following 1 of these schedules (decision at 
investigator’s discretion):

Monday, Wednesday, Friday every week for a 28-day cycle

Tuesday, Thursday, Saturday every week for a 28-day cycle

Wednesday, Friday, Sunday every week for a 28-day cycle

Thursday, Saturday, Monday every week for a 28-day cycle
For Study Part F1, LY3039478 will be administered orally TIW following 1 of these schedules 
(decision at investigator’s discretion):

Monday, Wednesday, Friday every week for a 28-day cycle

Tuesday, Thursday, Saturday every week for a 28-day cycle

Wednesday, Friday, Sunday every week for a 28-day cycle

Thursday, Saturday, Monday every week for a 28-day cycle

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For Study Part F2, LY3039478 will be administered orally twice a week for 2 weeks in Cycle 1, 
followed by TIW dosing, following 1 of these schedules (decision at investigator’s discretion):

For Cycle 1: Monday and Friday for Weeks 1 and 2, followed by Monday, Wednesday, 
Friday for Weeks 3 and 4. For Cycle 2 and beyond: Monday, Wednesday, and Friday 
every week for a 28-day cycle.

For Cycle 1: Tuesday and Saturday for Weeks 1 and 2, followed by Tuesday, Thursday, 
Saturday for Weeks 3 and 4. For Cycle 2 and beyond: Tuesday, Thursday, Saturday 
every week for a 28-day cycle.

For Cycle 1: Wednesday and Sunday for Weeks 1 and 2, followed by Wednesday, 
Friday, Sunday for Weeks 3 and 4. For Cycle 2 and beyond: Wednesday, Friday, 
Sunday every week for a 28-day cycle.

For Cycle 1: Thursday and Monday for Weeks 1 and 2, followed by Thursday, Saturday, 
Monday for Weeks 3 and 4. For Cycle 2 and beyond: Thursday, Saturday, Monday 
every week for a 28-day cycle.
LY3039478 will be taken once per day on days of administration prior to a meal
(recommendation is within 30 minutes) on an empty stomach.  During all cycles, study drug 
should be taken at approximately the same time on the dosing days. Any deviations should be 
documented in the patient diary. If a patient misses or vomits a dose, that dose should be 
omitted. 
Twice daily (BID; 12 hours apart) administration of LY3039478 will be explored if deemed 
necessary.
Prednisone will be administered daily on Days 1 through 14 during Cycle 1 (Part F) at the 
dosage of 20 mg.
During Cycle 1 and Cycle 2, patients will record the time and amount of each dose in a patient 
diary. Clinic personnel will instruct patients to pay particularly close attention to record this 
information accurately on days of PK assessments (Attachment 3).
The patient or clinic personnel will record this information in the patient diary, and study 
monitors will cross-reference clinic records at the site to verify accuracy.
For Cycle 2 and beyond, a delay of ≤7 days in the start of a cycle (Dose 1) for justifiable reasons 
(for example, inclement weather, holidays, or weekends) other than toxicity will be permitted 
and does not constitute a protocol violation.
For Cycle 2 and beyond, a delay of ≤3 weeks in the start of a cycle (Dose 1) to allow for 
recovery from toxicity will be permitted and does not constitute a protocol violation (refer to 
Section 7.2.4.1.2).
7.2.2. Dose-Escalation Phase
7.2.2.1.
Dose-Escalation Method
In this study, dose escalation will be driven by safety using the 3+3 method.

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Each new dose level will have a minimum of 3 patients enrolled to it.  If 1 patient, at any dose 
level, experiences a DLT within the first cycle of LY3039478, then up to 3 additional patients 
will be enrolled at that dose level.  If a DLT is observed in 2 or more patients at any dose level, 
dose escalation will cease and either the previous dose level will be declared the MTD or, 
following discussions between the sponsor and investigators additional patients may be treated at 
intermediate doses between the previous and current dose levels.
Model-based analyses that incorporate prior expectations about the dose-toxicity curve will also 
be fitted to the data at the end of each cohort, which may be used by the investigators and Lilly 
clinical research physician (CRP) to help determine the next dose level.  Dose escalation will 
take into account PK and PD information when available.
Additional patients may therefore be enrolled at a specific dose level to characterize PK/PD.
Intermediate doses levels will be explored if deemed necessary after discussion between the 
sponsor and investigators.
Further details regarding the model based analyses will be provided in the statistical analysis 
plan.
7.2.2.2.
Criteria for Dose Escalation
Safety data, in particular AEs, will be the primary criteria for the dose escalation.  The dose will 
be escalated following assessment of toxicity using the standard scoring system, CTCAE version 
4.0, established by the NCI.  Any AEs related to LY3039478 will be considered as toxicities.
In addition, if available at the time of dose-escalation decision, PK (eg, Cmax, AUC, and 
apparent systemic clearance [CL/F]) and PD results will be used as secondary/supporting data 
for dose escalation. 
In the initial cohort only, the first patient will be observed for a dose-limiting toxicity (DLT)
(defined in Section 7.2.2.3) during 14 days before subsequent patients are treated at that dose 
level.  If the first patient does not experience a DLT during this period, subsequent patients in the 
initial cohort may be enrolled concurrently.  By contrast, if the first patient experiences a DLT 
during this period, subsequent patients will be enrolled sequentially after observation for DLT 
during 14 days of therapy.
In subsequent cohorts, based on the safety and PK results of the previous cohort, enrollment will 
occur concurrently unless the results of the previous cohort warrant a sequential enrollment.  The 
decision is made between the investigators and the sponsor.
Table JJCA.7.1 shows the proposed dose levels for the Part A dose-escalation portion with the 
predicted simulated exposure for LY3039478.  
Table JJCA.7.1 summarize recommended doses levels.  Intermediate dose levels of LY3039478
will be used if deemed appropriate based on agreement between the investigators and the 
sponsor.  LY3039478 will not be increased beyond 100%. Dose doubling between cohorts will 
cease if 1 patient in a cohort experiences a DLT or 2 patients in a cohort experience Grade 2 
adverse events.

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Table JJCA.7.1.
Proposed LY3039478 Dose-Escalation Scheme for 
Study I6F-MC-JJCA and Predicted Human Exposure- Part A
Dose Level
LY3039478 
Dose (mg)
Predicted Median 
AUC0-τ,ss 
(ngh/mL)
Predicted 5th and 95th
percentiles AUCτ,ss 
(ngh/mL)
-1a
1.25
54.9
29.2 – 95.9
1
2.5
112
60.9 – 193
2
5
229
114 – 393
3
10
433
233 – 768
4
20
882
494 – 1600
5
30
1320
725 – 2290
6
45
1990
1080 – 3450
7
60
2620
1440 – 4700
8
80 
3450 
1890 – 6260 
9
100
4400
2310 – 7650
Abbreviations:  AUC0-τ = area under the plasma concentration versus time curve from time 0 to the end of the 
dosing interval (τ; where τ = 48 hours); AUCτ,ss = area under the plasma concentration versus time curve over 
1 dosing interval at steady-state; DLT = dose-limiting toxicity.
a
Dose Level -1 to be used only in the event of DLTs experienced in Dose Level 1 necessitating a dose de-
escalation.
Table JJCA.7.2 shows the proposed dose levels for the Part F dose escalation.    
Table JJCA.7.2.
Proposed LY3039478 Dose-Escalation Scheme for 
Study I6F-MC-JJCA and Predicted Human Exposure- Part F
Dose Level
LY3039478 
Loading Dose 
(mg)
1
75
2
100
3
125
4
150
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
MTD is determined, as defined in Section 7.2.2.3.  If the MTD has not yet been achieved at the 
highest prespecified dose level, based on both safety and the available PK data, following 
discussion with investigators, additional dose levels may be investigated.
In this study, intrapatient dose escalation is not permitted and dose escalation to the next cohort 
cannot occur without prior discussion and agreement between the investigator and the 
responsible Lilly CRP.  The decision will be documented in writing.
7.2.2.3.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition 
DLT is defined as an AE during Cycle 1 that is related to LY3039478 and fulfills any 1 of the 
following criterion using the NCI CTCAE v 4.0:

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
CTCAE Grade 3 non-hematological toxicity.  Exceptions will be made for:

nausea, vomiting, or constipation that lasts <72 hours and that can be 
controlled with treatment
•
electrolyte disturbance that can be controlled with treatment
•
Diarrhea CTCAE Grade 3 for <5 days and that can be controlled with 
standard treatment

Transient (<7 days) Grade 3 elevations of ALT and/or AST, that are not 
accompanied by a Grade 2 bilirubin increase are considered an exception 
to the DLT criteria, unless there is a clear alternative cause (eg, worsening 
biliary obstruction) if agreed by the study investigator and Lilly 
CRP/clinical research scientist (CRS)

CTCAE Grade 4 hematological toxicity of >5 days duration

Any febrile neutropenia

Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia.

Any other significant toxicity deemed by the primary investigator and Lilly 
clinical research personnel to be dose limiting (for example, any toxicity that is 
possibly related to the study medication that requires the withdrawal of the patient 
from the study during Cycle 1).
Investigators, together with the Lilly CRP, can declare a DLT if a patient is experiencing 
increasing toxicity during treatment, and it becomes clear that it is not going to be possible to 
complete the treatment without exposing the patient to excessive risk.
A DLT-equivalent toxicity is defined as an AE occurring between Day 1 and Day 28 of any 
cycle (other than Cycle 1) for a patient enrolled in Part A or in any cycle (including Cycle 1) for 
a patient enrolled in Part B that would have met the criteria for DLT if it had occurred during 
Cycle 1 for a patient enrolled in Part A.
For the purpose of this study, the MTD is defined as the highest tested dose that has <33% 
probability of causing a DLT during Cycle 1.
7.2.3. Cohort-Expansion Phase 
Once the MTD has been defined, the cohort-expansion phase (Parts B, C, D, E, and F) will be 
opened. Part B will consist of up to 50 additional evaluable patients with molecularly defined 
mutations, amplification, or gene expressions related to Notch pathway. Part C will consist of 
approximately 65 patients with soft tissue sarcomas.  Part D will consist of approximately 
42 patients with specific tumor types that have molecularly defined mutations, amplification, or 
gene expressions related to Notch pathway.  Part E will consist of approximately 15 patients with 
adenoid cystic carcinoma. 
The dose studied in Parts B, C, D, and E was defined at the end of dose escalation after a safety, 
PK, and PD review.  The current dose is 50 mg TIW.

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Part F will explore 2 alternate dosing schedules, and once an MTD has been defined for each of 
these alternate schedules, a cohort expansion in approximately 15 leiomyosarcoma patients with 
alterations in the Notch pathway such as mutations, amplification, or gene expressions related to 
Notch pathway will be opened for each dosing schedule.
If DLT-equivalent toxicities in the first cycle (ie, toxicities that would meet the DLT criteria 
described in Section 7.2.2.3) occur in 33% or more of patients within this cohort expansion, then 
investigators and the Lilly CRP will assess the nature and severity of these toxicities. No 
additional patients will be accrued until this safety review is completed and a decision is made 
either to continue at the current dose or to de-escalate the dose and define a new dose for the 
expansion portion. The safety review and decision will be documented in writing.
7.2.4. Dose Adjustments and Delays
7.2.4.1.
Part A
7.2.4.1.1. Dose Adjustments within a Cycle
No dose adjustments will be allowed within a cycle.  If a patient treated at a given dose level 
experiences a DLT or a DLT-equivalent toxicity (DLET) (as defined in Section 7.2.2.3), then 
treatment will be suspended for that patient for the duration of the current cycle.  If a toxicity 
does not meet the criteria for a DLT in Cycle 1 (or a DLET) but nonetheless requires omission of 
dose(s) for tolerability, then dosing may resume at the same dose after the toxicity resolves to 
baseline; however, the dose(s) omitted for tolerability during a cycle will not be replaced.
7.2.4.1.2. Dose Adjustments between Cycles
Before the start of each cycle, hematological toxicities and nonhematological toxicities (except 
alopecia and fatigue) must resolve to baseline.  The start of a cycle may be delayed up to 14 days 
to allow sufficient time for recovery.  Patients experiencing Grade 4 nonhematological toxicity 
or not recovering from toxicity within 14 days should be discontinued from the study.
The dose for a patient should be reduced for all subsequent cycles of therapy, to the dose level 
administered in the previous cohort, if the investigator determines that it is in the best interest of 
the patient or if the patient experienced at least 1 of the following events:

DLT (in Cycle 1 for patients in Part A)

DLT-equivalent toxicity (in Cycle 2 or beyond for patients in Part A, or in any 
cycle for patients in Part B)

Omission of >7 doses in a single cycle for tolerability.
For such patients requiring a dose reduction, re-escalation to the original dose level is not 
permitted.  If a patient experiences a DLT-equivalent toxicity at the reduced dose level, then the 
patient will be discontinued from the study.  If a patient requires omission of >3 doses for 
tolerability at the reduced dose level, then treatment may continue if the investigator determines 
that the patient is receiving clinical benefit.  Dose reduction by ≥2 dose levels is not permitted, 
so patients requiring dose reduction by >1 dose level should be discontinued from the study.

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Diarrhea should be managed by standard treatments as per institutional guidelines.  Guidance for 
diarrhea standard management is provided in Attachment 9.
7.2.4.2.
Parts B, C, D, and E
7.2.4.2.1. Dose Adjustments within a Cycle
If a patient experiences a DLET (as defined in Section 7.2.2.3), then treatment should be 
suspended for that patient. If a toxicity does not meet the criteria for a DLET but nonetheless 
requires omission of dose(s) for tolerability, then dosing may resume at the same dose after the 
toxicity resolves to baseline; however, the dose(s) omitted for tolerability during a cycle will not 
be replaced.  
In either case, depending on the toxicities and whether the patient benefits from the treatment, 
dosing may resume at the given dose or a reduced dose and with or without allowed concomitant
medication after consultation with the Lilly CRP.
7.2.4.2.2. Dose Adjustments between Cycles

Nonhematologic toxicity must resolve to CTCAE Grade 0, 1, or baseline level before 
resuming treatment (with the exception of alopecia, fatigue, skin rash, nausea, vomiting, 
constipation, or diarrhea that can be controlled with treatment).  

Hematologic toxicity must resolve to a level that, in the opinion of the investigator, is 
reasonable to allow for continuation of treatment.

Patients who experience a DLET or do not recover from toxicity within the 3-week time 
frame may have the dosage reduced to 25 mg TIW. 

Reescalation to the previous dose is acceptable in the absence of continuing toxicities.  If 
subsequent LY3039478 dose reduction is required after reescalation, the patient should 
be maintained at the reduced dose level.
Adjustments to these dosing guidelines may be permitted following an evaluation of the patient’s 
condition, benefit of treatment, and consultation with the Lilly CRP.  All exceptions to these 
guidelines will be documented.
7.2.4.3.
Part F
7.2.4.3.1. Dose Adjustments within a Cycle
If a patient experiences a DLT or a DLET (as defined in Section 7.2.2.3), then treatment should 
be suspended for that patient.  If a toxicity does not meet the criteria for a DLT or DLET but 
nonetheless requires omission of dose(s) for tolerability, then dosing may resume at the same 
dose after the toxicity resolves to baseline; however, the dose(s) omitted for tolerability during a 
cycle will not be replaced.  
In either case, depending on the toxicities and whether the patient benefits from the treatment, 
dosing may resume at the given dose or a reduced dose and with or without allowed concomitant 
medication after consultation with the Lilly CRP.

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7.2.4.3.2. Dose Adjustments between Cycles

Nonhematologic toxicity must resolve to CTCAE Grade 0, 1, or baseline level before 
resuming treatment (with the exception of alopecia, fatigue, skin rash, nausea, vomiting, 
constipation, or diarrhea that can be controlled with treatment).  

Hematologic toxicity must resolve to a level that, in the opinion of the investigator, is 
reasonable to allow for continuation of treatment.

Patients who experience a DLET or do not recover from toxicity within the 3-week time 
frame may have the dosage reduced to the previous dose level. Patients in first dose level 
may be reduced to 50 mg TIW.  

A second dose reduction is allowed.

Reescalation to the previous dose is acceptable in the absence of continuing toxicities.  If 
subsequent LY3039478 dose reduction is required after reescalation, the patient should 
be maintained at the reduced dose level.
Adjustments to these dosing guidelines may be permitted following an evaluation of the patient’s 
condition, benefit of treatment, and consultation with the Lilly CRP.  All exceptions to these 
guidelines will be documented.
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3039478 in this study.  
For patients participating in Part A and the dose-escalation phase of Part F:  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 identification 
number assignment and cohort for each patient.  No dose escalations (that is, to the next cohort) 
can occur without prior discussion and agreement with the responsible Lilly CRP or CRS. For 
patients participating in Study Part F cohort expansion: upon confirmation of eligibility, the 
sponsor will assign the patient to a dosing schedule (F1 or F2). Further details on the method of 
assignment are documented in the Statistical Analysis Plan. If investigators have eligible 
patients who have consented concurrently, >3 patients may be entered at a particular dose level 
provided that accrual has not ceased due to excessive toxicity.  This enrollment procedure is 
allowed because of the advanced disease state of this patient population and the screening 
involved in defining eligibility.  This event should be approved by the sponsor following 
discussions with the investigators.
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
No other chemotherapy, immunotherapy, cancer-related hormone therapy, or experimental drugs 
will be permitted while the patients are on this study.  An exception will be made for prostate or 
breast cancer patients continuing gonadotropin-releasing hormone or luteinizing hormone-

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releasing hormone agonist therapy.  Palliative radiotherapy is allowed. In addition, any disease 
progression requiring other forms of specific antitumor therapy will also necessitate early 
discontinuation from the study.  Appropriate documentation for all forms of premedications, 
supportive care, and concomitant medications must be captured on the case report form.  
Patients should receive full supportive care with the exception that the routine use of granulocyte 
colony stimulating factors (G-CSF) is not permitted during this study.  Patients should not 
receive G-CSF prophylactically in any cycle.  G-CSFs may only be used for patients who have 
ANC<0.5 109, neutropenic fever, or documented infections while neutropenic.  G-CSFs must 
be discontinued at least 24 hours before the start of the next cycle of treatment.  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).  If 
clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008). 
For Study Parts A, B, C, D, and E, patients should not receive corticosteroids prophylactically 
with the intent of attenuating GI toxicity. However, corticosteroid therapy initiated before study 
entry for a preexisting condition may be continued. Corticosteroids may be used for treatment of 
GI toxicities if deemed necessary after agreement between the investigators and Lilly CRP.  As a 
guidance, standard treatments are provided in Attachment 9. For Study Part F, prednisone will 
be co-administered with LY3039478 as detailed in Section 7.2.1.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.6.
Treatment Compliance
Patient compliance with study drug(s) will be assessed at each visit by direct questioning,
counting returned tablets/capsules/packages, and reviewing patient diary.  Deviation(s) from the 
prescribed dosage regimen should be recorded on the case report form (eCRF).
The patient must take 75% of the intended dose to be deemed compliant with study drug 
administration.  Similarly, a patient may be considered noncompliant if he or she is judged by the 
investigator to have intentionally or repeatedly taken more than the prescribed amount of 
medication.  Any missed doses during a cycle will be omitted and not replaced.  In the event of a 
missed dose, a patient should resume and continue dosing, beginning with the next scheduled 
dose.  
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP or CRS before the final determination is made to discontinue 
the patient.  If a patient is discontinued due to study drug noncompliance, the patient may be 
replaced.

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7.6.1. Evaluable Patients
7.6.1.1.
Parts A, B, C, D, E, and F
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug, regardless of whether they are deemed 
evaluable for the assessment of a dose level.
Patients who are not evaluable for PK, but who complete 1 cycle of therapy, may be replaced 
upon consultation with the investigators and the Lilly CRP or CRS to ensure adequate PK data, 
unless accrual to that cohort has stopped due to a DLT.  Patients who are evaluable for PK are 
defined as those patients who have a sufficient number of PK samples to evaluate PK parameters 
after at least 1 dose. 
7.6.1.2.
Dose Escalation Only
Any patient who is discontinued from the study before completing Cycle 1 will be deemed non-
evaluable for assessment of a dose level, unless they experience a DLT prior to withdrawal. 
If the patient is noncompliant during Cycle 1 due to reasons other than drug-related toxicity, he 
or she will be considered nonevaluable and may be replaced.
Nonevaluable patients will be replaced to ensure that 3 patients complete 1 cycle of therapy at 
each dose level, 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 LY3039478 have been assessed in nonclinical toxicology studies 
and the results from these studies are detailed in the IB.  This Phase 1 study contains detailed 
safety monitoring that will permit initial characterization of the safety profile of LY3039478 in 
patients.  Study procedures and their timing, including collection of blood and urine samples, are 
described in the Study Schedule (Attachment 1).
Standard laboratory tests, including chemistry, hematology, coagulation and urinalysis panels, 
will be performed.  A serum pregnancy test will be administered if applicable.  Other clinical 
laboratory tests will also be collected.  Attachment 2 lists the specific tests that will be performed 
for this study.
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, all 
AEs that are serious 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.
Investigators or their designees must document their review of each laboratory report.
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 
an AE using the same guidelines and schedules as those for AEs.  Lack of drug effect is not an 
AE in clinical studies because the purpose of the clinical study is to establish drug effect.

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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 4.0.
The NCI CTCAE v 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  Any minor version of 
CTCAE v 4.0 (for example:  version 4.0) 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 NCI CTCAE v 4.0 criteria, the investigator will be responsible for 
selecting the appropriate system organ class and assessing severity grade based on the intensity 
of the event.  Note that both CTCAE term (actual or coded) and severity grade must be selected 
by study site personnel and collected on the 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(s) must be stopped immediately.
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  All AEs 
related to protocol procedures are reported to Lilly or designee.
If a patient's dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via designated data transmission methods 
the circumstances and data leading to any such dosage reduction or discontinuation of treatment. 
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and the 
AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and the 
AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.

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As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1.
Serious Adverse Events
Previously planned (prior to signing the informed consent form [ICF]) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course of the 
study.
Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in 
the patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs.
An SAE is any adverse event during this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. 
SAEs due to disease progression (including death) should not be reported as an SAE unless the 
investigator deems it to be related to the use of 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.  Alerts issued via telephone 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.  
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
8.1.2.2.1. Prior to Administration of Study Drug
AE and SAE collection begins after the patient has signed the ICF and has received study drug.  
If a patient experiences an AE or SAE after signing informed consent, but prior to receiving 
study drug, the event will NOT be collected unless the investigator believes the event may have 
been caused by a protocol procedure.

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8.1.2.2.2. On Study
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(s) or protocol procedures, occurring 
during the initial 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 
safety assessments is 30 days ± 3 days after the last dose of study drug 
Following the safety assessments, which mark the end of the initial follow-up visit (Visit 801), 
the patient will be discontinued from the study, unless there is an ongoing AE or SAE that is 
related to study drug or protocol procedure.  In this instance, the patient should be followed in 
subsequent follow-up visits until the event is resolved, the event is no longer considered to be 
drug- or procedure 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.
After the initial follow-up visit (Visit 801) AEs and SAEs are not required to be reported unless 
the investigator feels the events were related to either study drug or a protocol procedure.  Any
subsequent follow-up(s) will be no more than 30 ±3 days in duration.
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 (DCSI) in the IB and that the investigator identifies as 
related to study drug or procedure.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulatory regulations and the 
associated detailed guidances.
8.1.2.4.
Summary of Adverse Events and Serious Adverse Event Reporting 
Guidelines
The AE and SAE reporting guidelines are summarized in Table JJCA.8.1 and Attachment 4.

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Table JJCA.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study I6F-MC-JJCA
Timing
Types of AEs/SAEs Reported 
Prestudy (baseline assessments), per Section 8.1.2.2.1
Preexisting conditions
Procedure-related AEs/SAEs
On therapy, per Section 8.1.2.2.2
All AEs/SAEs regardless of relatedness
Follow-up Visit (Visit 801), per Section 8.1.2.2.3
All AEs/SAEs regardless of relatedness
Continued-access period
All AEs/SAEs regardless of relatedness
Continued-access period follow-up
All AEs/SAEs regardless of relatedness
Subsequent Follow-up visits, if necessary – no more than 
30 ±3 days in durationa
Ongoing or new AEs/SAEs related to study drug or 
protocol procedures
Long-term posttreatment discontinuation 
follow-upb
All AE and SAEs related to protocol procedures or 
study drug
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
a
Part A only.
b
Parts B, C, D, and E only.
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).  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  
Consecutive replicate ECGs (usually triplicates) will be obtained at approximately 1-minute 
intervals.  
ECGs may be obtained at additional times, when deemed clinically necessary.  Collection of 
more ECGs (more replicates) than expected at a particular time point is allowed to ensure high 
quality records.  
ECGs will initially be interpreted by a qualified physician (the investigator or qualified designee) 
at the site as soon after the time of ECG collection as possible, and ideally while the patient is 
still present, to determine whether the patient meets entry criteria at the relevant visit(s) and for 
immediate patient management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, 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 (for example, 

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demographics and study details) 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 ECG 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.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical scientist, and periodically review:

trends in safety data,

laboratory analytes including any analytes of special interest,

AEs 
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 
adverse events using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study and assessments.
Attachment 2 lists the specific tests that will be performed for this study. 
Attachment 3 specifies the PK/PD sampling schedules for this study.
Attachment 7 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.  Fewer invasive sampling may actually occur, but this will not 
require a protocol amendment.

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Venous blood samples will be drawn for measurement of relevant analytes in plasma; in 
addition, creatinine in serum will be measured after the first dose in Cycle 1 at all dose levels. 
Blood samples will be collected throughout the study. 
Instructions for the collection and handling of blood samples will be provided by the sponsor.
A maximum of 5 additional PK (blood) samples may be added or removed during the study if
warranted and agreed upon by both the investigator and sponsor.  Supplies required for the 
collection and shipment of the samples will be provided by the sponsor.
Sample handling and shipment to the central laboratory will occur per instructions given to the 
study site.  Plasma PK samples (from venous blood) will be analyzed at a laboratory designated 
by the sponsor. Plasma concentrations of LY3039478 will be quantified using validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay. All bioanalytical samples will 
be stored in the United States.
The remaining plasma from the samples collected for PK may be used for exploratory 
metabolism work as deemed appropriate by the sponsor. 
Urine will be collected after Dose 1 of Cycle 1 at all dose levels in Part A.  Total urine output for 
the first 8 to 10 hours post LY3039478 administration will be collected, pooled, and refrigerated.  
The final urine sample should be collected at the time that Dose 1, 8- to 10-hour PK sample is 
drawn (Sample #8), and urine collection should cease thereafter.  At the end of the 8- to 10-hour 
collection period, the total urine volume will be recorded, an aliquot sent for creatinine 
determination, and 2 approximately 10-mL samples will be stored frozen, and the remaining 
urine will be discarded.  Instructions for the collection and handling of urine samples will be 
provided by the sponsor.  Although every attempt should be made to collect urine from patients, 
failure to do so is not considered a protocol violation.
Urine will be used for exploratory quantification of LY3039478, creatinine, and exploratory 
metabolite identification at the discretion of the sponsor.  Urine concentrations of LY3039478 
will be quantified using validated LC-MS/MS assay.  Analytes will be quantified using assays 
deemed appropriate by the sponsor.  All urine samples will be stored in the United States.
The remaining urine from the samples collected for LY3039478 quantification may be used for 
exploratory metabolism work as deemed appropriate by the sponsor. 
Bioanalytical samples collected to measure study drug concentration and metabolism will be 
retained for a maximum of 2 years following last patient visit for the study.
8.2.1. Samples for Standard Laboratory Testing
Blood and urine samples will be collected at the times specified in the Study Schedule 
(Attachment 1). Routine clinical laboratory tests will be analyzed by a central laboratory 
selected by Lilly or local laboratory, depending on the tests.  Attachment 2 lists the specific tests 
that will be performed for this study.  Attachment 7 summarizes the blood volumes for all blood 
and urine sampling (screening, safety laboratories, and bioanalytical assays) during the study.

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Investigators must document their review of each laboratory safety report.
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 medically or 
scientifically appropriate.  When medical and 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. Pharmacokinetic Samples
PK samples will be collected as specified in the Pharmacokinetic Sampling Schedule 
(Attachment 3).
A maximum of 5 additional PK samples may be drawn during the study if warranted and agreed 
upon by both the investigator and sponsor.  
Plasma concentrations of LY3039478 will be quantified using validated LC-MS/MS assay.  All 
bioanalytical samples will be stored in the United States.  The remaining plasma samples 
collected for PK evaluation may be used for exploratory studies to assess the metabolism of 
LY3039478, which may involve sample pooling. These samples may be retained for a 
maximum of 2 years following the last patient visit for the study.
After the first dose in Cycle 1 at all dose levels in Part A, total urine output for the first 8 to 
10 hours will be collected and pooled for quantification of LY3039478, creatinine, and 
exploratory metabolite identification. Urine concentrations of LY3039478 will be quantified 
using validated LC-MS/MS assay.  All urine samples will be stored in the United States.
The remaining urine from the samples collected for LY3039478 quantification may be used for 
exploratory metabolism work as deemed appropriate by the sponsor.
Bioanalytical samples collected to measure study drug concentration and metabolism will be 
retained for a maximum of 2 years following last patient visit for the study.
8.2.3. Pharmacogenetic Samples
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 allow, a blood sample will be collected for pharmacogenetic (PGx) analysis.  It is a 
1-time collection, as noted in the Study Schedule (Attachment 1).
Samples will be stored and exploratory analysis may be performed to identify genetic variants 
that might play a role in tumor biology or to evaluate their association with observed clinical
outcomes to LY3039478.
In the event of an unexpected AE or the observation of unusual response, the samples may be 
genotyped and analysis may be performed to evaluate a genetic association with response to 

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LY3039478.  These investigations may be limited to a focused candidate gene study or, if 
appropriate, genome wide association studies may be performed to identify regions of the 
genome associated with the variability observed in drug response.  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.
Samples will be identified by the patient number (coded) and stored for up to 15 years after the 
last patient visit for the study at a facility selected by the sponsor.  The duration allows the 
sponsor to respond to regulatory requests related to the study drug.  The sample and any data 
generated from it can only be linked back to the patient by investigator site personnel.  
8.2.4. Exploratory Samples
8.2.4.1.
Blood Samples for Aβ Assays
Blood samples will be collected for exploratory analysis of circulating Aβ peptides (for example, 
Aβ(1-x) or peptide components thereof) before and after treatment with LY3039478.  These 
samples may be retained for a maximum of 15 years following the last patient visit for the study.  
Tests are run and confirmed promptly whenever medically or scientifically appropriate.  When 
medical and scientific circumstances warrant, however, it is acceptable to retain samples to batch 
the tests run.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.4.2.
Blood Samples
Exploratory biomarker studies may be performed on tissues and blood, for cytokeratin 18, RBM 
and potential epigenomic alterations associated with the host tumor (for example, microRNA 
expression arrays).
8.2.4.3.
Tumor and Skin Biopsies 
Throughout this study, archived tumor tissue obtained previously for diagnostic purposes (for 
example, at initial diagnosis) will be requested for biomarker research but is not required for 
study entry in Part A.  At baseline, before the patient received study drug for Parts B, C, D, E,
and F, a mandatory pretreatment formalin-fixed paraffin-embedded (FFPE) tumor tissue 
(paraffin blocks or unstained slides cut from that block) will be collected. For Study Part F, the 
tumor tissue sample is required to be obtained within 2 years of the date of enrollment if 
archival.  A fresh sample is required if no archival sample meeting that criteria can be located.  
Table JJCA.8.2 presents tumor and skin biopsy collection time points.

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Table JJCA.8.2.
Tumor and Skin Biopsy Time Points
Collection Time 
Point
Part A
Parts B, Ca, and Da
Part E and F
Baseline archived 
tissue collection
Optional
Mandatory
Mandatory
Pre-/Postdose tumor 
biopsies
Optional
Recommended/optional
Mandatory
Pre-/Postdose skin 
biopsies
Mandatory
Mandatory
Mandatory
a
LMS, GIST, liposarcoma, angiosarcoma, and mature T cell, B cell, or NK cell neoplasm patients enrolled under 
Amendment d will have mandatory sample collection at each time point. 
Pretreatment tumor biopsies and skin biopsies (as instructed by the laboratory manual) will be 
collected pre- and posttreatment for measuring various biomarkers, potentially including 
gene-expression profiling (GEP), as well as other exploratory biomarkers.  Additionally, optional 
skin biopsies and/or optional tumor biopsies at time of disease progression will be collected.  
Furthermore, skin and/or tumor biopsies may be performed if deemed necessary by the 
investigator.  The samples will be analyzed at laboratories using assays designated by the 
sponsor.  Sample handling and shipment to the central laboratory will occur per instructions 
given to the study site.
Stored tissue samples will retain the patient identifier (for example, trial patient numbers) and 
therefore will not be stored indefinitely.  Archived biopsy specimens submitted as an FFPE 
tissue block (or sectioned slides) will be returned to the sites by end of study or upon request.  
Tumor biopsy slides will be stored for a maximum of 15 years after last patient visit for the 
study; any sample remaining at that time will be destroyed.  Samples will be stored at a facility 
selected by the sponsor.
8.3.
Efficacy Evaluations
An objective of the study is to document any antitumor activity (secondary in Part A and 
coprimary for Parts B, C, D, E, and F).  Refer to Attachment 1 for details regarding the timing of 
specific efficacy measures.  
Each patient will be assessed by 1 or more of the following radiologic tests for tumor 
measurement:

computed tomography (CT) scan

magnetic resonance imaging (MRI)

chest x-ray

PET scan – mandatory for Part E and F, Part C patients with sarcoma (leiomyosarcoma, 
GIST, liposarcoma, and angiosarcoma), and Part D patients with mature T cell, B cell, or 
NK cell neoplasms enrolled under amendment d.

DCE-MRI 
Each patient’s full extent of disease will also be assessed with:  

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
applicable tumor measurement by RECIST 1.1 (Eisenhauer et al. 2009), Revised 
Response Criteria for Malignant Lymphoma (Cheson et al. 2007), Guidelines from the 
National Cancer Institute Working Group for CLL (Hallek et al. 2008), or the RANO 
criteria for glioblastoma (Wen et al. 2010).  For tumor measurement evaluations in 
patients with soft tissue sarcomas or HCC, Choi et al. 2007 will be used in addition to 
RECIST 1.1.

evaluation of tumor markers, if indicated

evaluation of performance status (refer to the ECOG scale, Attachment 5)
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. Responses of CLL patients are confirmed according to the Guidelines from the 
National Cancer Institute Working Group for CLL (Hallek et al. 2008). Partial metabolic 
response by PET scan is defined as a minimum of 15±25% in tumour [18F]-FDG SUV after one 
cycle of therapy, and greater than 25% after more than one treatment cycle and should be 
confirmed at least 4 weeks later, according to PET response criteria of the European 
Organization for Research and Treatment of Cancer (Young et al. 1999). If a patient is 
discontinued from the study, repeat radiology assessments may be omitted if clear clinical signs 
of progressive disease are present.
Table JJCA.8.3 defines the efficacy endpoints assessed during the study.
Table JJCA.8.3.
Definition of Efficacy Endpoints
Endpoint
Definition
Overall survival
The time from the date of study enrollment to the date of death from any cause
Progression-free 
survival
The time from the date of study enrollment to the date of first observation of objective 
progression or death from any cause  
Duration of response
The time from the date of first evidence of a confirmed complete or partial response to 
the date of objective progression or the date of death from any cause (whichever is 
earlier)
After patients have discontinued study treatment, they may receive additional anticancer therapy 
at the discretion of the investigator. For those patients who discontinue study treatment without 
objectively measured progressive disease, the investigative sites will continue to monitor patients 
approximately every 60 days (±14 days) to evaluate tumor response by the same method used at 
baseline and throughout the study, until objective progression or the patient starts a new 
anticancer therapy, or study closure. Once a patient has objective progression or starts a new 
anticancer therapy, they will be followed for OS approximately every 60 days (±14 days) until 
death or study closure.
Lilly or its designee will collect and store all tumor measurement images for patients enrolled in 
Parts B, C, D, E, and F.  A central review of imaging scans may be performed by Lilly or its 
designee.

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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 CRF or laboratory requisition form.  
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.

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9.
Data Management Methods
9.1.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection

conduct a quality review of the database 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable institutional 
review board (IRB)/ERBs with direct access to the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome measures (for example, a rating scale), a daily dosing schedule or an event 
diary. 
For data handled by a data management third party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred using standard Lilly file 
transfer processes.

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For data handled by the sponsor internally, CRF data and some or all data that are related will be 
managed by the sponsor and stored electronically in the sponsor’s system.
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.
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.
ECG data will be stored electronically in the central database system of Lilly’s central review 
organization.  Data will subsequently be transferred from the central review organization system 
to the Lilly generic labs system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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10. Data Analyses
10.1. General Considerations
Approximately 282 patients may be enrolled in this multicenter, open-label Phase 1 study with 
dose escalation followed by dose confirmation. 
During Part A dose escalation, approximately 55 patients will be enrolled into cohorts 
sequentially and without randomization to dose. The total sample size per cohort will be 
determined by DLTs. 
During the Part B cohort expansion, approximately 50 patients with molecularly defined 
mutations, amplification, or gene expression alterations related to Notch pathway will be 
enrolled.  This sample size is adequate to explore the PD effects and anti-tumor activity of 
LY3039478 in patients with molecular alterations related to the Notch pathway.  Given that 
deregulated Notch signaling is implicated in a number of malignancies (refer to Table JJCA.5.1), 
there was no statistical powering for this part of the study as it is exploratory in nature.
Part C will focus on approximately 65 patients with soft tissue sarcoma including approximately
25 patients with leiomyosarcoma. A sample size of 25 patients is considered sufficient to 
estimate response rates with adequate precision for this stage of development and to explore 
antitumor activity in subsets of interest (for example RB1 deletion status) (Table JJCA.10.1).
Part D of the study will include 5 cohorts, for patients with triple-negative breast cancer 
(approximately 8), cholangiocarcinoma (approximately 8), HCC (approximately 8), CLL 
(approximately 8), and mature T cell, B cell, or NK cell neoplasms (approximately 10) who have 
molecularly defined mutations, amplification, or gene expression alterations related to Notch 
pathway. Part E will focus on approximately 15 patients with adenoid cystic carcinoma. This 
sample size is adequate to explore PD effects and anti-tumor activity of LY3039478 in within 
each specific tumor type of interest.  
Part F will focus on approximately 55 patients. The total sample size during dose escalation will 
be determined by DLTs and is estimated to be approximately 10 to 15 patients for each schedule
(F1 and F2). The sample size of approximately 15 patients for each schedule (F1 and F2) in the 
expansion cohorts is adequate to explore anti-tumor activity of LY3039478 in patients with 
leiomyosarcoma.  
For guidance, example point estimates of incidence rates and corresponding 2-sided exact 95% 
confidence interval (CI) are provided in Table JJCA.10.1 for the proposed sample size of each 
tumor type in study Parts C, D, E, and F. The values are provided as a reference for estimation 
rather than a basis of any decision criteria.

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Table JJCA.10.1.
Estimated Exact 95% CI for Example Overall Response Rate for 
Proposed Sample Size 
Sample Size
Example Number of 
Responders (%)
Exact 95% CI 
for ORR (%)
5
1 (20%)
(1%, 72%)
3 (60%)
(15%, 95%)
8
2 (25%)
(3%, 65%)
5 (63%)
(24%, 91%)
10
2 (20%)
(3%, 56%)
6 (60%)
(26%, 88%)
15
3 (20%)
(4%, 48%)
9 (60%)
(32%, 84%)
20
4 (20%)
(6%, 44%)
12 (60%)
(36%, 81%)
25
5 (20%)
(7%, 41%)
15 (60%)
(39%, 79%)
Abbreviations:  CI = confidence interval; ORR = overall response rate.
Statistical analysis of this study will be the responsibility of Lilly. The analyses for this study 
will be descriptive, except for possible exploratory analysis as deemed appropriate. Data 
analyses will be provided by dose groups and study part and for all study patients combined 
wherever appropriate. For continuous variables, summary statistics will include number of 
patients, mean, median, standard deviation, minimum, and maximum. Categorical endpoints 
will be summarized using number of patients, frequency, and percentages. Missing data will not 
be imputed.
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
CRP or CRS, pharmacokineticist, and statistician.  The CRP or CRS and statistician will also be 
responsible for the appropriate conduct of an internal review for both the final study report and 
any study-related material to be authorized by Lilly for publication.
Exploratory analyses of the data not described below will be conducted as deemed appropriate.
10.1.1. 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.
10.1.2. Patient Characteristics
Patient characteristics will include a summary and listing of the following:

Patient demographics

Baseline disease characteristics

Prior disease-related therapies 

Concomitant medications.

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Other patient characteristics will be summarized as deemed appropriate. In addition, the 
numbers and percentages of patients reporting post-discontinuation therapies will be provided 
overall, by type of therapy (surgery, radiotherapy, systemic therapy), and by drug name.  
10.1.3. Safety Analyses
All patients who receive at least 1 dose of LY3039478 will be evaluated for safety and toxicity.  
AE terms and severity grades will be assigned by the investigator using CTCAE, Version 4.0.  
Safety parameters will be summarized separately by dose level.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

Dose adjustments

Laboratory values 

Vital signs 

DLTs at each dose level 

ECG readings.
10.1.4. Pharmacokinetic Analyses
PK analyses will be conducted on patients who receive at least 1 dose of the study drug and have 
samples collected.  
PK parameter estimates for LY3039478 will be calculated by standard noncompartmental 
methods of analysis.
The primary parameters for analysis will be Cmax, area under the plasma concentration-time 
curve from time zero to last measurable plasma concentration (AUC[0-tlast]), and area under the 
concentration-time curve from time zero to infinity or over 1 dosing interval at steady state 
(AUC[0-∞] or AUC,ss) of LY3039478.  Other noncompartmental parameters, such as time of 
t1/2, CL/F, and apparent volume of distribution (V/F) may be reported.  Additional exploratory 
analyses will be performed if warranted by data and other validated PK software programs (for 
example, NONMEM) may be used if appropriate and approved by Global Pharmacokinetic 
management.  The version of any software used for the analysis will be documented and the 
program will meet the Lilly requirements of software validation.
PK parameter estimates will be evaluated to delineate effects of dose proportionality.  Log-
transformed Cmax and AUC estimates will be assessed to estimate ratios of geometric means and 
the corresponding 90% CIs.
Exploratory renal clearance of LY3039478, as well as the accompanying creatinine clearance, 
will be calculated as the ratio of amount excreted/AUC, and will be compared to unbound 
glomerular filtration rate, estimated using creatinine renal clearance.

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The PK data will be combined, and analyses may be conducted to determine a relationship 
between exposure and PD/PGx effect data permitting. This model may be used to help reassess 
the dose cohort escalation as the study progresses. If deemed necessary, PK/PD modeling may 
be employed to evaluate variability in exposure, pharmacologic effects, and safety parameters.
10.1.5. Exploratory Biomarker Analyses
Biomarker data from all patients undergoing biomarker assessments will be analyzed using 
descriptive statistics.  These data may include, but are not limited to circulating Aβ peptides that 
are hypothesized to be related to safety, efficacy, drug disposition or pathways associated with 
the mechanism of action of LY3039478.
10.2. Efficacy
The study was not designed to make a formal efficacy assessment.  However, any tumor 
response data will be tabulated and summarized by study part, and further analyses will be 
conducted as warranted to explore patients grouped by mutation/amplification status and tumor 
type.
Overall response rate (ORR) is defined as the proportion of patients who achieve a complete 
response or partial response. Depending on the histology, tumor responses will be measured and 
recorded using the appropriate guidelines (RECIST 1.1 [Eisenhauer et al. 2009], Revised 
Response Criteria for Malignant Lymphoma [Cheson et al. 2007], the Guidelines from the 
National Cancer Institute Working Group for CLL [Hallek et al. 2008], or RANO criteria for 
glioblastoma [Wen et al. 2010]). 
For patients in study Part C, HCC patients from Part D, and leiomyosarcoma patients in Part F,
ORR defined using the Choi criteria (Choi et al. 2007) will be considered for response evaluation 
in addition to RECIST criteria. Modified response criteria incorporating changes in tumor 
density in addition to tumor size has been demonstrated to be a more sensitive prognostic marker 
for time to progression and disease specific survival in GIST sarcomas (Benjamin et al. 2007; 
Choi et al. 2007).
For Part E, Part C, and F patients with sarcoma (leiomyosarcoma, GIST, liposarcoma, and 
angiosarcoma), and Part D patients with mature T cell, B cell, or NK cell neoplasms enrolled 
under amendment d, PET maximum standardized uptake values (SUVmax) will also be 
analyzed, and metabolic responses defined using PET response criteria of the European 
Organisation for Research and Treatment of Cancer (Young et al. 1999).
For the purposes of statistical analysis, subjects will be grouped by mutation and/or 
amplification, and by tumor type. Where there are a small number of subjects (<4) with a 
particular tumor type or mutation/amplification, subjects may be pooled with other small groups 
for statistical analysis purposes. Change in tumor size (and/or change in tumor density) will be 
assessed in each patient with measurable disease using radiographic imaging, and is defined as 
the fold change from the baseline evaluation to the evaluation at the end of Cycle 2. Statistical 
analyses may be conducted utilizing analysis of covariance models with potential covariates 
including baseline measurements, mutations/amplification group, tumor type, ECOG status and 

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other covariates as deemed appropriate. Logistic regression analyses will also be utilized to 
estimate the ORR for each grouping of patients. Further exploratory analyses may utilize a 
Bayesian hierarchical model in order to explore response rates across each tumor type.
Descriptive analyses of duration of response, PFS, and OS will be conducted using the Kaplan-
Meier method.
10.3. Interim Analyses
During Part A, patient safety will be assessed prior to each dose escalation to ensure nothing 
precludes administration of larger doses to future study patients.  In addition to reviewing AEs 
and laboratory measurements, PK/PD profiles of LY3039478 will be reviewed per cohort. 
Based on these interim results, modifications (eg, reductions in dose increment) to the dose-
escalation strategy or other design elements may be made to ensure patient safety. The study 
investigators and the Lilly CRP will make the determination regarding dose escalation based 
upon their review of the safety/tolerability data and the PK data from the previous cohorts.  In 
addition, an interim review will be conducted prior to proceeding to Part B including safety, PK, 
and PD.  All relevant data will be reviewed to confirm the estimation of the MTD.  The decision 
to proceed to Part B will be made following discussions between the investigators and Lilly 
clinical research personnel.

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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 or legal representative 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. 
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are submitted to the ERB and 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.
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling and updates during the course of the study,

ICF, and 

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).
All or some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data.
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 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
Allenspach EJ, Maillard I, Aster JC, Pear WS. Notch signaling in cancer. Cancer Biol Ther. 
2002;1(5):466-476.
Artavani-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal 
integration in development. Science. 1999;284(5415):770-776.
Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, 
Charnsangavej C. We should desist using RECIST, at least in GIST. J Clin Oncol. 
2007;25(13):1760-1764.
Bhanushali AA, Babu S, Thangapandi VR, Pillai R, Chheda P, Das BR. Mutations in the HD and 
PEST domain of Notch-1 receptor in T-cell acute lymphoblastic leukemia: report of novel 
mutations from Indian population. Oncol Res. 2010;19(2):99-104.
[CGARN] Cancer Genome Atlas Research Network.  Integrated genomic analyses of ovarian 
carcinoma. Nature. 2011;474:609-615.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, 
Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai 
K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on 
Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-
586.
Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff 
DA, Benjamin RS. Correlation of computed tomography and positron emission tomography in 
patients with metastatic gastrointestinal stromal tumor treated at a single institution with 
imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 
2007;25(13):1753-1759.
De Salvo M, Raimondi L, Vella S, Adesso L, Ciarapica R, Verginelli F, Pannuti A, Citti A, 
Boldrini R, Milano GM, Cacchione A, Ferrari A, Collini P, Rosolen A, Bisogno G, Alaggio R, 
Inserra A, Locatelli M, Stifani S, Screpanti I, Miele L, Locatelli F, Rota R.  Hyper-activation
of Notch3 amplifies the proliferative potential of rhabdomyosarcoma cells.  PLoS One. 2014 
May 5;9(5):e96238. doi: 10.1371/journal.pone.0096238. eCollection 2014.
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.
Gast A, Scherer D, Chen B, Bloethner S, Melchert S, Sucker A, Hemminki K, Schadendorf D, 
Kumar R. Somatic alterations in the melanoma genome: a high-resolution array-based 
comparative genomic hybridization study. Genes Chromosomes Cancer. 2010;49(8):733-745.
Grabher C, von Boehmer H, Look AT. Notch 1 activation in the molecular pathogenesis of T-
cell acute lymphoblastic leukaemia. Nature Reviews Cancer. 2006;(6):347-359.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, 
Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic 
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IeM, Wang TL. Notch3 gene amplification in ovarian cancer. Cancer Res. 
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DA, Preije JMP, Velasco G, Gutierrez-Fernandez A, Costa D, Carrio A, Guijarro S, Enjuanes 
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Attachment 1.
Protocol JJCA Study Schedule

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Baseline Assessments
Relative Day Prior to Day 1 of 
Cycle 1
28
14
7
Comments
Informed consent 
X
Informed consent signed prior to performance of any 
protocol-specific tests/procedures.
Radiological tumor assessment
X
PET scan
X
Optionala
DCE-MRI 
X
Optional and not applicable for CLL patients
Medical history
X
Including alcohol/tobacco use and other relevant
habits assessments
Physical examination
X
Vital signs 
X
Including temperature, blood pressure, pulse rate, 
respiration rate
Height
X
ECOG performance status
X
Chest x-ray
X
May be omitted in patients having a chest CT for 
their radiological tumor assessment
ECG 
X
One set of triplicate ECGs, central
Hematology 
X
Local laboratory, for CLL patients includes 
immunophenotyping (see Attachment 2).
Coagulation (PT/INR, aPTT, 
fibrinogen)
X
Local laboratory
Serum chemistry 
X
Central laboratory
Urinalysis 
X
Local laboratory
Child-Pugh, BCLC, and CLIP 
staging 
X
Only for HCC patients in Part D (see Attachment 10, 
Attachment 11, and Attachment 12)
Tumor measurement (palpable or 
visible)
X
CTCAE v 4.0 grading (preexisting 
conditions)
X
To be reported only after study eligibility is 
confirmed.  See Section 8.1.2.2 for reporting 
expectations 
Concomitant medications
X
Tumor markers
X
If applicable, local laboratory
Blood PD biomarkers (A beta)
X
For Parts A and B only
Tumor biopsya
X
Screening for alterations of Notch 
pathway
X
Screening done locally, required only for Part B, D,
and F expansion cohort patients.  Performed at any 
time prior to ICF and study drug start.
Archived tumor sample
X
Paraffin-embedded tumor tissue, only after study 
eligibility is confirmed.
Pregnancy test 
X
Negative results prior to dosing required for women 
of childbearing potential
Skin biopsy
X
Marrow aspirate and biopsy, if 
clinically indicated
X
Only CLL patients, according to institutional 
guidelines, last results prior dosing
Cytogenetic tests (FISH)
X
Only CLL patients, if applicable, local laboratory

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Abbreviations:  aPTT = activated partial thromboplastin time; BCLC= Barcelona Clinical Liver Classification 
Table; CLIP = Cancer of the Liver Italian Scoring System; CLL = Chronic Lymphocytic Leukemia; 
CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; ECG = electrocardiogram;
ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridization; HCC = hepatocellular 
carcinoma; Meds = medications; PD = pharmacodynamic; PET = positron emission tomography; 
PT/INR = prothrombin time/international normalized ratio.
a
PET scan and tumor biopsy are mandatory for all patients in Part E, Part F, and LMS, GIST, liposarcoma, and 
angiosarcoma patients in Part C, and mature T cell, B cell, or NK cell neoplasm patients in Part D enrolled under 
Amendment d.

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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During and Poststudy Assessments for Parts A, B, C, D, E, and F1
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
LY3039478 therapya
X
X
X
X
X
X
X
X
X
X
X
X
Prednisone therapyp
X
X
X
X
X
X
Physical examination
X
X
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
X
X
X
ECOG performance status
X
X
X
X
CTCAE version 4.0 grading
X
X
X
Concomitant medications
X
X
X
Tumor measurement (palpable and visible)
X
DCE-MRI (optional)b
X
Central ECGc
X
Hematologyd
X
X
X
X
Serum chemistryd
X
X
Xe
X
Serum creatininec, d
X
ECG chemistryc, d
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
Tumor markerd
X
Pharmacogenetics sample (predose)
X
Blood PK samplingc
X
Xq
X
Tumor biopsyf
X
Skin biopsyc, g
X
Blood PD biomarkers (A beta-Parts A and 
B only)c
X
X
Blood PD biomarkers (RBM, 
cytokeratin 18, epigenomics) predose 
X
Urine (8- to 10-hour collection)c,h
X

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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During and Poststudy Assessments for Part F2
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose
10
LY3039478 therapy
X
X
X
X
X
X
X
X
X
X
Prednisonep
X
X
X
X
Physical examination
X
X
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
X
X
X
ECOG performance status
X
X
X
X
CTCAE version 4.0 grading
X
X
X
Concomitant medications
X
X
X
Tumor measurement (palpable and visible)
X
DCE-MRI (optional)b
X
Central ECGc
X
Hematologyd
X
X
X
X
Serum chemistryd
X
X
Xe
X
Serum creatininec, d
X
ECG chemistryc, d
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
Tumor markerd
X
Pharmacogenetics sample (predose)
X
Blood PK samplingc
X
Xr
Xs
Tumor biopsyf
X
Skin biopsyc, g
X
Blood PD biomarkers (RBM, 
cytokeratin 18, epigenomics) predose 
X

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Cycle 2
Week 1
Week 2
Week 3
Week 4
Study Procedures
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
LY3039478 therapya
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
X
ECOG performance status
X
X
CTCAE version 4.0 grading
X
X
Concomitant medications
X
X
Tumor measurement (palpable and visible)
X
ECGc
X
Radiological tumor assessmenti
X
PET scanj
X
Hematologyd
X
X
For CLL patients only:  
Immunophenotyping as per institutional 
guidelines (at end of every 2 cycles)
X
Serum chemistryd
X
X
ECG chemistryc,d predose
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
Tumor markerd
X
Blood PK samplingc predose
X
Blood PD biomarkers (A–beta- Part A and 
B only)c predose 
X
Blood PD biomarkers (RBM, 
cytokeratin 18, epigenomics) predose
X

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Cycle 3-n 
Visit
801
Follow-
upk
Week 1
Week 2
Week 3
Week 4
V801
V802-
XX
Study Procedures
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
LY3039478 therapya
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
X
ECOG performance status
X
X
X
CTCAE version 4.0 grading
X
X
Xl
Concomitant medications
X
Xm
Xm
Tumor measurement (palpable and visible)
X
Xn
Radiological tumor assessment
X
Xn
Hematologyd
X
X
X
For CLL patients only:  
immunophenotyping as per institutional 
guidelines (at end of every 2 cycles)
X
X
Serum chemistryd
X
X
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
Tumor markerd
X
X
Blood PD biomarkers (A –beta- Parts A 
and B only) predose
X
Blood PD biomarkers (RBM, 
cytokeratin 18, epigenomics) predose
X
Marrow aspirate and biopsy,
if clinically indicated for CLL patientso
X
Abbreviations:  aPTT = activated partial thromboplastin time; CLL= chronic lymphocytic leukemia; CTCAE = Common Terminology Criteria for Adverse 
Events; D = day; DCE-MRI= dynamic contrast-enhanced magnetic resonance imaging; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; PK = pharmacokinetic; PD = pharmacodynamic; PET = positron emission tomography; PT/INR = prothrombin time/international normalized ratio; 
RBM = Rules-Based Medicine; V = visit.

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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a
LY3039478 is to be administered 3 times per week through each 28-day cycle.  If assessments associated with a dose cannot be performed, the assessments 
may be performed either with the previous dose (if known in advance) or the next dose.  For start of Cycle 2 and beyond, refer to Section 7.2.1 and 
Section 7.2.4.1.2.
b DCE-MRI should be performed on a day when LY3039478 is given either at Dose 3, 4, or 5 and repeated at the discretion of the investigator.  DCE-MRI is 
not applicable for CLL patients.
c
For complete details, see Attachment 3.
d For central versus local laboratories, refer to Attachment 2.
e
Only for patients with ≥Grade 2 nausea, vomiting, or diarrhea.
f
Optional posttreatment tumor biopsy should be obtained (whenever clinically feasible) at Cycle 1, preferably 6 to 8 hours (±1 hour) after Dose 10.  Greater 
flexibility has been provided for the posttreatment tumor biopsy (between Doses 7 and 12, inclusive) compared to other Dose 10 visit assessments (between 
Doses 9 and 11, inclusive) to enable radiographic guidance and access to appropriate medical specialists; however, if this flexibility is exercised and the 
posttreatment tumor biopsy is obtained on a day other than the Dose 10 visit, then a single PK sample should be obtained as close as possible (for example, 3 
hours) to the time of the biopsy.  Additional optional tumor biopsies may be performed at time of disease progression and if deemed necessary by the 
investigator.  Tumor biopsy are mandatory for all patients in Part E, F, and LMS, GIST, liposarcoma, and angiosarcoma patients in Part C and mature T cell, 
B cell, or NK cell neoplasm patients in Part D enrolled under Amendment d.
g Skin biopsies are mandatory according to the schedule provided in Attachment 3.  Additional optional skin biopsies may be performed at time of disease 
progression and if deemed necessary by the investigator.
h Part A only.
i
Radiological assessment is performed at baseline (up to 28 days before the first dose), then at the end of Cycle 2 (no more than 10 days prior to Day 1 of 
Cycle 3), then every other cycle thereafter.  If a patient is discontinued from the study, repeat radiology may be omitted if progressive disease can be 
documented quantitatively with clinical measurements.
j
Optional during Cycle 2 (not limited to Dose 1) repeated at the discretion of the investigator. Mandatory for all patients in Part E and LMS, GIST, 
liposarcoma, and angiosarcoma patients in Part C, and mature T cell, B cell, or NK cell neoplasm patients in Part D enrolled after Amendment d.  Metabolic 
response by PET scan must be repeated for confirmation at least 4 weeks after initial response see Section 8.3. 
k Long-term follow-up for survival applies to Part B, C, D, E, and F only.
l
Collection of AEs and SAEs related to study treatment or study procedures only.
m collection of concomitant medication post-study treatment discontinuation must include any subsequent cancer treatment.
n Every 60 ( ±14) days and applies only to those patients who discontinue the study without progression or have not started another treatment regimen as 
outlined in Section 8.3.
o According to Guidelines from the National Cancer Institute Working Group for CLL, marrow aspirate and biopsy will be performed in CLL patients when a 
partial remission or complete remission is observed (to obtain bone marrow response information) and also 2 months after the last study drug treatment (to 
obtain duration of response).  Institutional guidelines will be followed.
p Prednisone given during Cycle 1 daily on Days 1-14 in Study Part F only as described in Section 7.2.1.
q For Part C, D, E, and dose-expansion patients in Part F1.
r
For Dose 5 in the dose-expansion part of F2 only.
s
For Dose 8 in the dose-escalation part of F2 only.

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Continued Access Schedule of Activities
Visit 501-n 
Follow-
upa
Week 1
Week 2
Week 3
Week 4
901
Study Proceduresb
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
LY3039478 therapy
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
Serum chemistry
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
ECOG performance status
X
AE collection (CTCAE version 4.0)
X
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology Group.
a
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the continued-access 
period and lasts approximately 30 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.
b
Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Attachment 2.
Protocol JJCA Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistrya,b:
Hemoglobin
Serum concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Phosphorus
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes 
Alanine aminotransferase (ALT)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Gamma-glutamyl transpeptidase (GGT)
Platelets
Blood urea nitrogen (BUN)
Reticulocytese
Prolymphocytese
Immunophenotyping, including B-cell 
lymphocytes and T-cell lymphocytes evaluation 
or based on institutional guidelines using for 
examples, CD5, CD19, CD20, CD23 and 
CD79be
Creatinine
Lipase
LDHe
Uric acid 
Calcium
Glucose random
Albumin 
Total protein
Coagulationa:
aPTT
ECG Chemistryb:
PT/INR
Lipase
Fibrinogen
Thyroid stimulating hormone (TSH)
Tri-iodothyronine (T3)
Urinalysisa:
Thyroxine (T4)
Albuminc
Glucose, randomc
Calciumc
Sodiumc
Potassiumc
Phosphorus
Magnesium
Serum creatinineb,d
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Urine leukocyte esterase
Tumor markersa
Serum pregnancy test (females with child-
bearing potential only)a
Biomarkersb (research laboratory tests)
Marrow aspirate and biopsye
Cytogenetics (FISH)e

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Abbreviations:  aPTT = activated partial thromboplastin time; ECG = electrocardiogram; FISH = fluorescence in 
situ hybridization; LDH = lactate dehydrogenase; PT/INR = international normalized ratio of prothrombin time; 
RBC = red blood cells; WBC = white blood cells.
a
Local or investigator-designated laboratory. 
b
Assayed by Lilly-designated laboratory.
c
Test not performed if both chemistry and ECG chemistry required at same time point.  See Attachment 3.
d
Test not performed if both chemistry and creatinine required at same time point.  See Attachment 3.
e
Tests performed for CLL patients only and tests performed at local laboratory.

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Attachment 3.
Protocol JJCA Pharmacokinetic and 
Pharmacodynamic Sampling Schedule

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part A, 10 Patients in Part B, and Dose-Escalation Patients 
in Part F1
PK 
Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478a
Urine Sampling 
Part A Onlya
Sampling Time 
for Serum 
Creatinine
Part A Only
PD Sampling 
Time for 
A(1-x)
(Parts A and 
B only)
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
Screening
Screening
2
1
1
Predose
0 to 8-10 hr pooled 
samples (end time 
of sample to 
coincide with PK 
blood draw)
Record total 
volume
Predose
Predose
Predose
3
1
1
0.5 hr
4
1
1
1 hr
1 hr
5
1
1
2 hr
2 hr
6
1
1
4 hr
4 hr
4 hr
4 hr
7
1
1
6-8 hr
6-8 hr
6-8 hr (±1 hour)
8
1
1
8-10 hr
8-10 hr
8-10 hr
9
1
1
24-30 hr
24-30 hr
24-30 hr
10
10
1
Predose
Predose
11
10
1
0.5 hr
12
10
1
1 hr
13
10
1
2 hr
2 hr
14
10
1
4 hr
4 hr
15
10
1
6-8 hr
6-8 hr
16
10
1
8-10 hr
8-10 hr
17
10
1
24-30 hr
24-30 hr
18
1
2
Predose
Predose
Predose
Abbreviations:  ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.
a
All urine needs to be collected between 0 and 8 to 10 hours.  The urine collection should cease at the time that the Dose 1, 8- to 10-hour PK sample is drawn 
(Sample 8).  The collected urine needs to be pooled and the total volume recorded.  From the pooled urine, 3 aliquots will be collected:  1) creatinine 
measurement, 2) approximately 10 mL to measure LY3039478 concentrations, and 3) approximately 10 mL to measure LY3039478 metabolites.  The rest of 
the urine will then be discarded.  During the 0- and 8- to 10-hour urine collection/pooling, the urine should not be frozen.  Sample 1 for creatinine should not 
be frozen, but the two 10-mL samples (Samples 2 and 3) should be frozen at the end of the collection period and should be shipped frozen.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule for Dose-Escalation Patients in Part F2
PK 
Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
2
1
1
Predose
Predose
3
1
1
0.5 hr
4
1
1
1 hr
5
1
1
2 hr
6
1
1
4 hr
4 hr
7
1
1
6-8 hr
6-8 hr (±1 hour)
8
1
1
8-10 hr
9
1
1
24-30 hr
24-30 hr
10
8
1
Predose
11
8
1
0.5 hr
12
8
1
1 hr
13
8
1
2 hr
14
8
1
4 hr
15
8
1
6-8 hr
16
8
1
8-10 hr
17
8
1
24-30 hr
18
1
2
Predose
Predose
Abbreviations:  ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule for the Remaining Patients in Part B Who Did Not Complete 
the Sampling Schedule for Part A
PK 
Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478
PD Sampling 
Time for 
A(1-x)
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
Screening
2
1
1
Predose
Predose
Predose
3
1
1
0.5 hr
4
1
1
1 hr
5
1
1
2 hr
2 hr
6
1
1
4 hr
4 hr
4 hr
7
1
1
6-8 hr
6-8 hr
6-8 hr (±1 hour)
8
1
2
Predose
Predose
Predose
Abbreviations:  ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Parts C, D, E, and Dose-Expansion Patients in Part F1
Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
2
1
1
Predose
Predose
3
1
1
1-3 hr
2 hr
4
1
1
4 hr
5
1
1
6-8 hr
6-8 hr (±1 hour)
6
7
1
Predose
7
1
2
Predose
Predose
Abbreviations:  ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule for Dose-Expansion Patients in Part F2
Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
2
1
1
Predose
Predose
3
1
1
1-3 hr
2 hr
4
1
1
4 hr
5
1
1
6-8 hr
6-8 hr (±1 hour)
6
5
1
Predose
7
1
2
Predose
Predose
Abbreviations:  ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Attachment 4.
Protocol JJCA Recommendations for 
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.

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Attachment 5.
Protocol JJCA Eastern Cooperative 
Oncology Group Performance Status
Eastern Cooperative Oncology Group Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out performance of a light or sedentary nature, for example,
light housework, office work
2
Ambulatory and capable of all selfcare but unable to carry out any 
work activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally 
confined to bed or chair
5
Dead
Reference:
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-655.

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Attachment 6.
Protocol JJCA Creatinine Clearance 
Formula
Note:  This formula is to be used for calculating CrCl from local laboratory results only.  
For serum creatinine 
concentration in mg/dL:
CrCl =
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
(mL/min)
0.81 serum creatinine 
(mol/L)
a age in years, weight (wt) in kilograms.
Reference:  
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
-OR-
GFR(mL/min/1.73m2) = 170 x [PCr]-0.999 x [age]-0.176
x [0.762 if patient is female] x [1.18 if patient is black]
x [SUN]-0.17 x [Alb]+0.318
PCr= Plasma Creatinine, mg/dL; SUN= Serum urea nitrogen, mg/dL; Alb= Serum albumin, g/dL
Reference:
Murray PT, Ratain MJ. Estimation of the glomerular filtration rate in cancer patients: a new 
formula for new drugs. Clin Oncol. 2003 Jul 15;21(14):2633-5.

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Attachment 7.
Protocol JJCA Sampling Summary
This table summarizes the maximum number of samples and volumes for all sampling and tests 
during the study.  Fewer samples may actually be taken, but this will not require a protocol 
amendment.
Protocol I6F-MC-JJCA Sampling Summary 
Purpose
Sample 
Type
Average Amount 
per Sample 
Maximum 
Number Samples
Maximum Total 
Amount
Screening testsa
Blood
4 mL
5
20 mL
Screening testsa
Urine
10 mL
1
10 mL
Standard testsa
V001 Cycle 1
Blood
4 mL
13
52 mL
Standard testsa
V002 Cycle 2
Blood
4 mL
7
28 mL
Standard testsa
V003 Cycle 3-n
Blood
4 mL
5
20 mL
Standard testsa
Follow-Up
Blood
4 ml
4
16 mL
Cardiac and renala
Blood
12 mL
4
48 mL
Drug concentration
Blood
2 mL
35
70 mL
Drug concentration
Urine
10 mL
3 
30 mL
Pharmacogenetic samples
Blood
10 mL
1
10 mL
Nonpharmacogenomic 
biomarkers
Blood
4 mL
6
24 mL
Skin biopsies
Tissue 
Biopsy
5 mm, 0.5 oz, 
1 cubic centimeter
2
10 mm
1.0 oz
2 cc
Tumor biopsies (optional)
Tissue 
Biopsy
5 mm, 0.5 oz, 
1 cubic centimeter
2
10 mm
1.0 oz
2 cc
Total 
Urine
40 mL
Total 
Tissue
20 mm
2.0 oz
4 cc
Total 
Blood
288 mL
Abbreviations:  V = visit.
a
Additional samples may be drawn if needed for safety purposes.

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Attachment 8.
Protocol JJCA Guidance on Alterations 
Related to Notch Pathway
Mutations
Notch-1
Notch-2
Notch-3
Notch-4
FBXW7
Amplifications
Notch-1
Notch-2
Notch-3
Jagged-1
Jagged-2
Gene and Protein Overexpression
Notch receptors 
Notch ligands
NICD (by IHC)

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Attachment 9.
Protocol JJCA Guidance for Diarrhea 
Management
First report of diarrhea:  

Obtain history of onset and duration of diarrhea to assess drug causality.

Description of number of stools and stool composition (eg, watery, blood, mucus in stool) 

Assess patient for fever, abdominal pain, cramps, distension, bloating, nausea, vomiting, 
dizziness, weakness (ie, rule out risk for sepsis, bowel obstruction, dehydration).

Medication profile (ie, to identify any diarrheogenic agents) 

Dietary profile (ie, to identify diarrhea-enhancing foods) 
Management of diarrhea 
General recommendations:  

Stop all lactose-containing products and alcohol.

Stop laxatives, bulk fiber (Metamucil®), and stool softeners (docusate sodium).

Drink 8 to 10 large glasses of clear liquids per day (water).

Eat frequent small meals (bananas, rice, applesauce, Ensure®, toast).

Stop high-osmolar food supplements (with fiber).
It is recommended that patients be provided loperamide tablets.  Patients are instructed on the 
use of loperamide at Cycle 1 in order to manage signs or symptoms of diarrhea at home.  Patients 
should be instructed to start oral loperamide (initial administration of 4 mg, then 2 mg every 
4 hours up to a maximum of 16 mg/day) at the first sign of loose stool or symptoms of 
abdominal pain.  These instructions should be provided at each cycle, and the site should ensure 
that the patient understood the instruction.  
Treatment of diarrhea Grade 1 or 2 
Diarrhea Grade 1 or 2 will be treated with standard loperamide (initial administration 4 mg, then 
2 mg every 4 hours [up to a maximum of 16 mg/day] or after each unformed stool). 
After 12 to 24 hours:  
Diarrhea resolved 

Continue instructions for dietary modification.

Gradually add solid foods to diet.

Discontinue loperamide after 12-hours diarrhea-free interval.
Diarrhea unresolved 
Persisting diarrhea Grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections, with monitoring of patient’s condition (to rule 
out dehydration, sepsis, or ileus) and medical check and selected workup if patient does 

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not need hospitalization.  Observe patient for response to antidiarrheal treatment.  
Persisting diarrhea Grade 3 or 4 may be treated with hospitalization, high dose 
loperamide (initial 4 mg, then 2 mg every 2 hours) and addition of opium tincture or 
dihydrocodeine tartrate tablets/injections, start of intravenous (IV) fluids and antibiotics 
as needed with monitoring of patients condition (to rule out dehydration, sepsis, ileus) 
medical check and workup (perform appropriate additional testing).  Observe patient for 
response. 
After 12 to 24 hours:  
Diarrhea resolved 

Continue instructions for dietary modification.

Gradually add solid foods to diet.

Discontinue loperamide and/or other treatment after 12-hours diarrhea-free interval.
Diarrhea unresolved 

If diarrhea is still persisting (NCI CTCAE Grades 1 and 2) after 2x 24 hours with 
high-dose loperamide and opiates, then admit to hospital and employ measures as 
for Grade 3 and 4 until diarrhea is resolved.

If diarrhea is still persisting and progressed to NCI Grades 3 and 4, employ 
measures described below. 
Treatment of diarrhea Grade 3 or 4 
Severe diarrhea Grade 3 or 4 may be treated with hospitalization, high-dose loperamide (initially
4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of IV fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus) medical check and workup 
Diarrhea workup and additional test).  Observe patient for response. 
After 12 to 24 hours:  

If diarrhea is still persisting, administer subcutaneous (SC) Sandostatin/octreotide 
(100 to 500 µg 3 times per day [TID]).

Continue IV fluids and antibiotics as needed.

If diarrhea Grade 3 or 4 is still persisting, patients should receive opium tincture or 
dihydrocodeine tartrate injections SC or intramuscular (IM).

If diarrhea Grade 3 or 4 is still persisting, SC Sandostatin/octreotide (500 to 1000 µg 
3 times daily [TID]) should be administered 

To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 
2 weeks. Treatment should be continued only when diarrhea resolved. 
Diarrhea workup 
Perform appropriate tests (Fine and Schiller 1999). 

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Spot stool analysis

Collect stool, separating it from urine (special containers; analysis immediately;
exceptionally, freeze samples).

Blood 

Fecal leukocytes (Wright's staining and microscopy) 

Clostridium difficile toxin 

Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immunosuppressed 
patients), plus Shigella and pathogenic Escherichia coli - enterotoxigenic, 
enterohemorrhagic etc., and possibly Aeromonas, Plesiomonas (if exposure to 
contaminated water is suspected) 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is 
likely to be fragile with evidence of colitis, and thus, great care and caution must be 
exercised in undertaking these invasive procedures. 

Gastroscopy to obtain jejunal fluid (ie, bacterial overgrowth for cultures and biopsy 
of proximal jejunum to assess extent of inflammatory jejunitis)

Sigmoidoscopy - reassessment of colitis
Reference
Fine KD, Schiller LR. AGA Technical Review on the Evaluation and Management of Chronic 
Diarrhea. Gastroenterology. 1999; 116:1464-1486.

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Attachment 10.
Protocol JJCA Child-Pugh Score
Child-Pugh Score
Clinical and Biochemical 
Parameters
Pointsa
1
2
3
Bilirubin (mg/dL)
<2
2-3
>3
Albumin (g/dL
>3.5
2.8-3.5
<2.8
Ascites
Absent
Moderate
Tense
Encephalopathy
Absent
Moderate (Stage I-II)
Severe (Stage III-IV)
Prothrombin time
    Sec prolonged
    %
    INRb
<4
>60
<1.7
4-6
40-60
1.7-2.3
>6
<40
>2.3
In case of primary biliary cirrhosis
1
2
3
Bilirubin (mg/dL)
<4
4-10
>10
Note: This table applies to hepatocellular carcinoma (HCC) patients only.
Abbreviations:  INR = international normalized ratio; Sec = second.
a
Total points:  5 to 6:  Child-Pugh class A; 7 to 9:  Child-Pugh class B; 10 to 15:  Child-Pugh class C.
b
INR is an expression of prothrombin time, corrected by the sensitivity of the reactiveness to anticoagulants, and 
should be validated as an alternative to prothrombin time in liver insufficiency.
Source:  Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg. 1973;60(8):646-649.

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Attachment 11.
Protocol JJCA Barcelona Clinic Liver 
Cancer Classification Table
Barcelona Clinic Liver Classification Table
Stage
Performance Status 
Test
Tumor Stage
Okuda Stage
Liver Function Status
A
0
Single
I-II
Child-Pugh A-B
B
0
Large multinodular
I-II
Child-Pugh A-B
C
1-2
Vascular invasion/
extrahepatic spread
I-II
Child-Pugh A-B
D
3-4
Any
III
Child-Pugh C
Note:  This table applies to hepatocellular carcinoma (HCC) patients only.  Stage A and B, all criteria should be 
fulfilled; Stage C and D, at least 1 criterion should be fulfilled.
Source:  Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907-1917.

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Attachment 12.
Protocol JJCA Cancer of the Liver Italian 
Program Scoring System
CLIP Scoring System
Variable
Score
Child-Pugh stage
  A
0
  B
1
  C
2
Tumor morphology
  Uninodular and extension ≤50%
0
  Multinodular and extension ≤50%
1
  Massive or extension >50%
2
AFP
  <400
0
  ≥400
1
Portal vein thrombosis
  No
0
  Yes
1
Note:  This table applies to hepatocellular carcinoma (HCC) patients only.
Abbreviations:  AFP = alpha-fetoprotein; CLIP = Cancer of the Liver Italian Program.
Source:  The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology. 2000;31(4):840-845

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Attachment 13.
Protocol JJCA Protocol Amendment 
I6F-MC-JJCA(e) Summary 
A Phase 1 Study of LY3039478 in Patients with Advanced 
or Metastatic Cancer
Overview
Protocol I6F-MC-JJCA, A Phase 1 Study of LY3039478 in Patients with Advanced or Metastatic 
Cancer, has been amended.  The new protocol is indicated by Amendment (e) and will be used to 
conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

the addition of Study Part F to explore 2 alternative dosing schedules

the addition of a continued-access period

Minor editorial changes were made for clarity and consistency.  

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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.

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Clinical Protocol Synopsis:  Study I6F-MC-JJCA
Name of Investigational Product:  LY3039478
Title of Study:  A Phase 1 Study of LY3039478 in Patients with Advanced or Metastatic Cancer
Number of Planned Patients:  Total study sample size will be approximately 
227282 patients, with approximately 55 patients in Part A and approximately 
172227 patients in Parts B, C, D, and E, and F.  
Phase of Development:  1
Length of Study:  
Planned first patient visit:  September 2012               Planned last patient visit:  December 2017  
Objectives:  
Primary:  Part A:  The primary objective of this study is to determine a recommended Phase 2 dose of 
LY3039478 that may be safely administered to patients with advanced or metastatic cancer.
Parts B, C, D, and E:  The primary objectives are to confirm the recommended Phase 2 dose of LY3039478 that 
may be safely administered to patients with specific tumor types and to document antitumor activity.
Part F:  The primary objective is to determine a recommended Phase 2 dose of LY3039478 that may be safely 
administered to patients according to 2 alternative dosing schedules with co-administration of prednisone and to 
document antitumor activity.
Secondary:  

To characterize the safety and toxicity profile of LY3039478 as assessed by National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0

To estimate the pharmacokinetic (PK) parameters of LY3039478

Part A:  To document any antitumor activity observed with LY3039478

Parts B, C, D, and E, and F:  To assess duration of response, progression-free survival (PFS), and overall 
survival (OS)
Exploratory:  

To explore renal clearance of LY3039478 and PK of LY3039478 metabolites in plasma and urine

To explore predictive biomarkers related to LY3039478

To explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of Notch activity
(Notch intracellular domain by immunohistochemistry or an alternative validated method) including 
cytokeratin 18 or Rules-Based Medicine

To explore the utility of positron emission tomography scan to assess treatment effect with LY3039478

To explore the utility of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to assess 
treatment effect with LY3039478
Study Design:  Phase 1, multicenter, nonrandomized, open-label, dose-escalation study followed by cohort 
expansion (Parts B, C, D, andE, and F) of oral LY3039478 in outpatients with advanced or metastatic cancer.  
Diagnosis and Main Criteria for Inclusion and Exclusions:  Men and women, aged ≥18 years, having advanced 
or metastatic cancer (solid tumor or lymphoma including chronic lymphocytic leukemia [CLL]) for which 
available standard therapies have failed.  For Part B, patients must have prescreened alterations in the Notch 
pathway such as mutations, amplification, or gene expressions related to Notch pathway.  Part C patients must 
have histological evidence of advanced or metastatic soft tissue sarcomas.  Part D patients must have advanced or 
metastatic cancer with specific tumor types harboring Notch molecular alterations including triple-negative breast 
cancer (ER-, PR-, HER2-), cholangiocarcinoma, hepatocellular carcinoma (HCC), CLL, and mature T cell, B cell, 
or Natural Killer (NK) cell neoplasms.  Part E patients must have advanced or metastatic adenoid cystic carcinoma 
(ACC).  Part F patients in the dose confirmation must have histological evidence of nonresectable or metastatic 
leiomyosarcoma with prescreened alterations in the Notch pathway such as mutations, amplification, or gene 
expressions related to Notch pathway.

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Test Product, Dosage, and Mode of Administration:  LY3039478, dose range 2.5 to 100 mg, given orally as 
capsules 3 times per week during a 28-day cycle.  In Study Part F, dosing schedules will utilize a loading dose 
(starting at 75 mg and escalating up to 150 mg) administered 3 times per week for 2 weeks during Cycle 1 
(schedule F1) or 2 times per week for 2 weeks during Cycle 1 (schedule F2), followed by 50 mg 3 times per week 
(TIW) from Week 3 onwards.  In Study Parts F1 and F2, prednisone will be co-administered for 2 weeks in Cycle 
1.
Planned Duration of Treatment:  Patients will receive 2 cycles (28 days each) of LY3039478 unless 1 or more of 
the criteria for discontinuation are fulfilled.  In Study Parts F1 and F2, prednisone will be co-administered with 
LY3039478 for 2 weeks in Cycle 1.  A patient may receive >2 cycles of treatment only if:  1) none of the criteria 
for discontinuation have been fulfilled and 2) the investigator determines that the patient is experiencing clinical 
benefit from treatment.  
Short-term follow-up period (postdiscontinuation):  30 days 
Long-term follow-up period (postdiscontinuation):  after the short-term follow-up through death or study closure.
Continued-access period:  All patients remaining on study treatment without disease progression following the 
final analysis will be able to enter the continued-access period of the study, which begins approximately 12 months 
after the last patient was enrolled and ends after the last patient discontinues study treatment and performs safety 
follow-up visit.
Criteria for Evaluation:  
   Safety:  NCI CTCAE, version 4.0, dose-limiting toxicities (DLT)
   Bioanalytical:  Plasma concentrations of LY3039478
   Efficacy:  Depending on the histology, efficacy will be assessed using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 for solid tumors (along with the Choi criteria for soft tissue sarcomas and HCC), the 
Revised Response Criteria for Malignant Lymphoma, the Guidelines from the National Cancer Institute Working 
Group for CLL, or the Response Assessment in Neuro-Oncology (RANO) criteria for glioblastoma.
Statistical Methods:  
   Safety:  Dose escalation will be driven by safety using the 3+3 method.  Model-based analyses that incorporate 
prior expectations about the dose-toxicity curve will be fitted to the data at the end of each cohort, which will be 
used by the investigators and the Eli Lilly and Company (Lilly) clinical research physician to determine the next 
dose level.  The maximum tolerated dose is defined as the highest tested dose that has <33% probability of causing 
a DLT during Cycle 1.
   Efficacy:  Tumor response data will be tabulated and summarized by study part.  For the purposes of statistical 
analysis, subjects will be grouped by mutation and/or amplification, and by tumor type.  Change in tumor size 
(and/or change in tumor density) will be analyzed by analysis of covariance models with potential covariates 
including baseline measurements, mutations/amplification group, tumor type, Eastern Cooperative Oncology 
Group performance status, and other covariates as deemed appropriate.  Logistic regression analyses will also be 
utilized to estimate the overall response rate for each grouping of patients.  Descriptive analyses of duration of 
response, PFS, and OS will be conducted using the Kaplan-Meier method.
   Pharmacokinetics:  PK parameters for LY3039478 will be analyzed by standard non-compartmental methods of 
analysis.
   Pharmacodynamics:  All PD data will be assessed.  Exploratory PK/PD analyses may be conducted to identify 
the exposure-biomarker response relationship. 
4.0 Abbreviations and Definitions
…
DLET
dose-limiting equivalent toxicity

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...
5.2.1. Primary Objective
…
Part F:  The primary objective is to determine a recommended Phase 2 dose of LY3039478 that 
may be safely administered to patients according to 2 alternative dosing schedules with co-
administration of prednisone and to document antitumor activity.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

•to characterize the safety and toxicity profile of LY3039478 as assessed by National 
Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.0

•to estimate the pharmacokinetic (PK) parameters of LY3039478

•Part A:  to document any antitumor activity observed with LY3039478

•Parts B, C, D, andE, and F:  to assess duration of response, progression-free survival 
(PFS) and overall survival (OS)
…
5.3.4. Biomarkers 
As part of an ongoing effort by Lilly to better understand how to predict which tumors are more 
likely to respond to LY3039478 treatment, the collection of samples to be stored for possible 
future biomarker research are a mandatory part of this study.
Biomarkers will be used to assess not only PD response to LY3039478 in plasma, surrogate 
tissues, and tumors, but also potential predictive markers of efficacy and/or patient tailoring.  
In Parts B, andD, and the Part F dose confirmation, patients will be entered based on screened 
molecular alteration related to Notch pathway.  
PD biomarkers will be measured before and after administration of study drug in plasma and 
skin throughout the study.  Whenever clinically feasible, biomarkers will be measured before and 
after administration of study drug in tumors during dose escalation and dose confirmation (Parts 
A, B, C, D, andE, and F).  Potential predictive biomarkers will be measured (when the assays 
become available) throughout the study in archived tumor tissue (for example, from prior biopsy) 
as well as before and after administration of study drug in both tumors and blood during dose 
confirmation.  
…
5.4.3. Rationale for (Amendment E)

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As of November 2015, approximately 40 patients have been treated at 75 mg TIW and 
62 patients have been treated at 50 mg TIW.  Review of safety data (treatment emergent adverse 
events, dose-limiting equivalent toxicities, and dose reductions) confirmed the 50-mg TIW 
schedule to be adequately tolerated.  Initial observations of metabolic responses were observed in 
patients treated at 100 mg, 75 mg, and 50 mg with exploratory analyses suggestive of a potential 
relationship to dose.  
Study Part F will be added in order to explore 2 alternative dosing schedules allowing a loading 
dose for 2 weeks in Cycle 1, followed by the current 50-mg TIW schedule.  Prednisone will be 
co-administered with LY3039478 during the loading dose period in order to mitigate potential 
GI toxicity.  Study Part F dose confirmation will enroll patients with histologic evidence of 
advanced or metastatic leiomyosarcoma with Notch molecular alterations in order to allow a 
homogeneous population to further characterize the clinical activity of LY3039478.  
In addition, a continued-access period was added to the protocol for patients who are benefitting 
from treatment after final database lock has occurred.  Minor editorial changes and clarifications 
have also been made.
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]
For all parts:  The patient must be, in the judgment of the investigator, an appropriate 
candidate for experimental therapy after available standard therapies have failed to provide 
clinical benefit for their advanced or metastatic cancer.
For Dose Escalation (Part A):  The patient must have histological or cytological evidence of 
cancer, either a solid tumor or a lymphoma, which is advanced or metastatic.
For Part B:  All patients must have histological evidence of their advanced or metastatic cancer 
and prescreened alterations in the Notch pathway such as mutations, amplification, or gene 
expressions related to Notch pathway (Attachment 8).  
For Part C:  All patients must have histological evidence of advanced or metastatic soft tissue 
sarcoma.  Eligible patients must have leiomyosarcoma, angiosarcoma, rhabdomyosarcoma, 
liposarcoma, pleomorphic sarcoma, or GIST.
For Part D:  All patients must have histological evidence of advanced or metastatic cancer and 
prescreened alterations in the Notch pathway such as mutations, amplification, or gene 
expressions related to Notch (Attachment 8).

Cohort 1:  Patients must have triple-negative breast cancer (ER-, 
PR-, HER2-).

Cohort 2:  Patients must have HCC.  These patients should have 
Child-Pugh stage A (Attachment 10).

Cohort 3:  Patients must have cholangiocarcinoma.

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
Cohort 4:  Patients must have CLL.

Cohort 5:  Patients must have mature T cell, B cell, or Natural 
Killer (NK) cell neoplasms
For Part E:  All patients must have histological evidence of advanced or 
metastatic adenoid cystic carcinoma (ACC).
For Part F:  All patients must have:   
Dose Escalation:  histological or cytological evidence of cancer, either a solid 
tumor or a lymphoma, which is advanced or metastatic.
Dose Confirmation:  histological evidence of nonresectable or metastatic 
leiomyosarcoma and prescreened alterations in the Notch pathway such as 
mutations, amplification, or gene expressions related to Notch pathway 
(Attachment 8).  
[2]
As defined by the Response Evaluation Criteria in Solid Tumors (RECIST 
1.1; Eisenhauer et al. 2009), the Revised Response Criteria for Malignant 
Lymphoma (Cheson et al. 2007), the Guidelines from the National Cancer 
Institute Working Group for CLL (Hallek et al. 2008), the Response 
Assessment in Neuro Oncology (RANO) criteria for glioblastoma (Wen et al. 
2010). 
For Dose Escalation (Part A):  Have measurable or nonmeasurable disease
For Parts B, C, D, andE, and F:  Have measurable disease or reliable 
biomarker measure (for example, prostate-specific antigen [PSA], CA125)
...
[10]
Females with childbearing potential must have a negative serum pregnancy test within 7 
days of the first dose of study drug and also must not be breastfeeding.
...
[21]
For Parts B, C, D, andE, and F:  Have available tumor tissue (archival or new biopsy)
...
6.2.
Summary of Study Design
Study JJCA is a multicenter, nonrandomized, open-label, dose-escalation Phase 1 study of oral 
LY3039478 in patients with advanced or metastatic cancer.  In Study Parts A, B, C, D, and E,
Eeligible patients will receive LY3039478 administered orally TIW during a 28-day cycle.  In 
Study Part F, eligible patients will receive LY3039478 administered orally during a 28-day 
cycle, according to 2 alternative dosing schedules, with co-administration of prednisone for 
2 weeks in Cycle 1. 
Patients will receive 2 cycles of LY3039478 unless 1 or more of the criteria for discontinuation 
(refer to Section 6.3.1) are fulfilled.  A patient may receive >2 cycles of treatment only if:  1) 

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none of the criteria for discontinuation have been fulfilled and 2) the investigator determines that 
the patient is experiencing clinical benefit from treatment.  The follow-up period for poststudy 
evaluation will be 30 days from the date of the last dose of study drug received.  
The study design consists of a dose-escalation phase (Part A), and a cohort-expansion phase 
(Parts B, C, D, and E), and a dose-escalation phase with alternative dosing schedules followed by 
a cohort-expansion phase (Part F).
…
Part B will focus focused on approximately 50 patients with tumors that have molecularly 
defined mutations, amplification, or gene expressions alterations related to Notch pathway or 
known activated Notch pathways.   
Part C will focus focused on approximately 65 patients with soft tissue sarcoma including 
patients with leiomyosarcoma (approximately 25), angiosarcoma (approximately 10), 
rhabdomyosarcoma (approximately 5), liposarcoma (approximately 10), pleomorphic sarcoma 
(approximately 5), and GIST (approximately 10). 
Part D will focus focused on approximately 42 patients with specific tumor types harboring 
Notch molecular alterations, including patients with triple negative breast cancer (ER-, PR-, 
HER2-) (approximately 8), cholangiocarcinoma (approximately 8), HCC (approximately 8), 
CLL (approximately 8), and mature T cell, B cell, or NK cell neoplasms (approximately 10).
Part E will focus focused on approximately 15 patients with adenoid cystic carcinoma.  
Part F will focus on approximately 55 patients with histologic evidence of advanced or 
metastatic cancer with expansion cohorts in patients with leiomyosarcoma and prescreened 
alterations in the Notch pathway.  Approximately 10 to 15 patients will be treated in a 
dose-escalation phase and approximately 15 patients in a cohort-expansion phase at the 
recommended Phase 2 dose according to the following 2 dosing schedules, to be conducted 
concurrently.
F1:  Dose escalation of a loading dose TIW for 2 weeks in Cycle 1 only followed by 50 mg TIW. 
Prednisone will be co-administered with LY3039478 for the first 2 weeks in Cycle 1 only.
F2:  Dose escalation of a loading dose twice a week for 2 weeks in Cycle 1 only followed by 
50 mg TIW.  Prednisone will be co-administered with LY3039478 for the first 2 weeks in 
Cycle 1 only. 
The total sample size for Parts A, B, C, D, andE, and F is estimated to be approximately 227282 
patients.  Further expansion is possible following the analysis of outcome.
…
This study will be considered closed approximately 12 months from the date that the last patient 
was enrolled.  Patients who are benefitting from treatment may continue to receive study drug for 
long-term durations, even after the study has closed and final database lock has occurred in the 
continued-access period.  In such cases, the sponsor may amend the protocol to allow for a safety 

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extension to follow such patients after the end of the trial or may open a substudy which would 
be defined in a subsequent amendment.
…
Abbreviations:  approx = approximately; CLL= Chronic lymphocytic leukemia; GIST = 
gastrointestinal stromal tumors; ICD = intercellular domain; NK= natural killer; 
TIW = 3 times per week.
6.2.1. Continued-Access Period
All patients remaining on study treatment without disease progression following the final 
analysis will be able to enter the continued-access period of the study, which begins 
approximately 12 months after the last patient was enrolled, and ends after the last patient 
discontinued study treatment and performs safety follow-up visit.  During the continued-access 
period, patients on study treatment who continue to experience clinical benefit may continue to 
receive study treatment until they meet discontinuation criteria.  The continued-access period 
includes a follow-up visit.  The follow-up visit begins 1 day after the patient and the investigator 
agree that the patient will no longer continue treatment in the continued-access period and lasts 
approximately 30 days.  If it is deemed to be in the best interest of the patient to start a new 
anticancer treatment prior to the scheduled end of the follow-up visit, the follow-up visit duration 
may be shortened.  In this case, the follow-up assessments should be completed prior to the 
initiation of the new therapy.
During the continued-access period, all AEs, SAEs, dose reductions, and study drug exposure 
will be collected on the case report form/electronic case report form (CRF/eCRF).
SAEs will also be reported to Lilly Global Patient Safety and collected in the Lilly Safety System 
(LSS).  In the event that an SAE occurs, additional information (such as local laboratory results, 
concomitant medications, and hospitalizations) may be requested by Lilly in order to evaluate the 
reported SAE.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.  The Study 
Schedule (Attachment 1) describes all assessments for the continued-access period.

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7.1.
Materials and Supplies
LY3039478 will be supplied as 25 and 50-mg capsules in bottles for oral consumption.  
LY3039478 capsules should be stored at room temperature within the temperature range stated 
on the label.  Investigators should instruct patients to store the capsules at home in the original 
container and to keep out of the reach of children.  Capsules should be swallowed whole and 
should not be opened, crushed, or dissolved.
Prednisone will either be provided by Lilly or obtained locally as appropriate and required.
Clinical study materials provided by Lilly will be labeled according to the country’s regulatory 
requirements.
...
7.2.1. Dosing Schedule
…
For Study Part F1, LY3039478 will be administered orally TIW following 1 of these schedules 
(decision at investigator’s discretion):
•
Monday, Wednesday, Friday every week for a 28-day cycle
•
Tuesday, Thursday, Saturday every week for a 28-day cycle
•
Wednesday, Friday, Sunday every week for a 28-day cycle
•
Thursday, Saturday, Monday every week for a 28-day cycle
For Study Part F2, LY3039478 will be administered orally twice a week for 2 weeks in Cycle 1, 
followed by TIW dosing, following 1 of these schedules (decision at investigator’s discretion):

For Cycle 1:  Monday and Friday for Weeks 1 and 2, followed by Monday, Wednesday, 
Friday for Weeks 3 and 4.  For Cycle 2 and beyond:  Monday, Wednesday, and Friday 
every week for a 28-day cycle.

For Cycle 1:  Tuesday and Saturday for Weeks 1 and 2, followed by Tuesday, Thursday, 
Saturday for Weeks 3 and 4.  For Cycle 2 and beyond:  Tuesday, Thursday, Saturday 
every week for a 28-day cycle.

For Cycle 1:  Wednesday and Sunday for Weeks 1 and 2, followed by Wednesday, 
Friday, Sunday for Weeks 3 and 4.  For Cycle 2 and beyond:  Wednesday, Friday, 
Sunday every week for a 28-day cycle.

For Cycle 1:  Thursday and Monday for Weeks 1 and 2, followed by Thursday, Saturday, 
Monday for Weeks 3 and 4.  For Cycle 2 and beyond:  Thursday, Saturday, Monday 
every week for a 28-day cycle.
…
Prednisone will be administered daily on Days 1 through 14 during Cycle 1 (Part F) at the 
dosage of 20 mg. 
…

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7.2.2.2.
Criteria for Dose Escalation
…
Table JJCA.7.1 shows the proposed dose levels for the Part A dose-escalation portion with the 
predicted simulated exposure for LY3039478.  
Table JJCA.7.1.
Proposed LY3039478 Dose-Escalation Scheme for Study I6F MC 
JJCA and Predicted Human Exposure- Part A
Dose Level
LY3039478 
Dose (mg)
Predicted Median 
AUC0-τ,ss 
(ngh/mL)
Predicted 5th and 95th
percentiles AUCτ,ss 
(ngh/mL)
-1a
1.25
54.9
29.2 – 95.9
1
2.5
112
60.9 – 193
2
5
229
114 – 393
3
10
433
233 – 768
4
20
882
494 – 1600
5
30
1320
725 – 2290
6
45
1990
1080 – 3450
7
60
2620
1440 – 4700
8
80 
3450 
1890 – 6260 
9
100
4400
2310 – 7650
...
Table JJCA.7.2 shows the proposed dose levels for the Part F dose escalation.    
Table JJCA.7.2.
Proposed LY3039478 Dose-Escalation Scheme for Study I6F MC 
JJCA and Predicted Human Exposure- Part F
Dose Level
LY3039478 
Loading Dose 
(mg)
1
75
2
100
3
125
4
150
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
MTD is determined, as defined in Section 7.2.2.3.  If the MTD has not yet been achieved at the 
highest prespecified dose level (100 mg), based on both safety and the available PK data, 
following discussion with investigators, the following additional dose levels may be investigated:  
120 mg, 140 mg, and 160 mg (Intermediate doses may be explored as previously described in the 
protocol)additional dose levels may be investigated.
7.2.2.3.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose Definition 
DLT is defined as an AE during Cycle 1 that is related to the study drugs LY3039478 and fulfills 
any 1 of the following criterion using the NCI CTCAE v 4.0:

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…
7.2.3. Cohort-Expansion Phase 
Once the MTD has been defined, the cohort-expansion phase (Parts B, C, D, and E, and F) will 
be opened.  Part B will consist of up to 50 additional evaluable patients with molecularly defined 
mutations, amplification, or gene expressions related to Notch pathway.  Part C will consist of 
approximately 65 patients with soft tissue sarcomas.  Part D will consist of approximately 
42 patients with specific tumor types that have molecularly defined mutations, amplification, or 
gene expressions related to Notch pathway.  Part E will consist of approximately 15 patients with 
adenoid cystic carcinoma.  
The dose studied in Parts B, C, D, and E was defined at the end of dose escalation after a safety, 
PK, and PD review.  The current dose is 50 mg TIW. 
Part F will explore 2 alternate dosing schedules, and once an MTD has been defined for each of 
these alternate schedules, a cohort expansion in approximately 15 leiomyosarcoma patients with 
alterations in the Notch pathway such as mutations, amplification, or gene expressions related to 
Notch pathway will be opened for each dosing schedule.
…
7.2.4.1.1.
Dose Adjustments within a Cycle
No dose adjustments will be allowed within a cycle.  If a patient treated at a given dose level 
experiences a DLT or a DLT-equivalent toxicity (DLET) (as defined in Section 7.2.2.3), then 
treatment will be suspended for that patient for the duration of the current cycle.  If a toxicity 
does not meet the criteria for a DLT in Cycle 1 (or a DLT-equivalent toxicity DLET) but 
nonetheless requires omission of dose(s) for tolerability, then dosing may resume at the same 
dose after the toxicity resolves to baseline; however, the dose(s) omitted for tolerability during a 
cycle will not be replaced.
7.2.4.1.2.
Dose Adjustments between Cycles
…
For such patients requiring a dose reduction, re-escalation to the original dose level is not 
permitted.  If a patient experiences a DLT-equivalent toxicity at the reduced dose level, then the 
patient will be discontinued from the study.  If a patient requires omission of >3 doses for 
tolerability at the reduced dose level, then treatment may continue if the investigator determines 
that the patient is receiving clinical benefit.  Dose reduction by >≥2 dose levels is not permitted, 
so patients requiring dose reduction by >1 dose level should be discontinued from the study.
…
7.2.4.2.2
Dose Adjustments between Cycles
…

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
If dosing is delayed for >3 weeks for treatment-related AEs, the patient should be 
withdrawn from the study treatment.  
…
7.2.4.3.
Part F
7.2.4.3.1.
Dose Adjustments within a Cycle
If a patient experiences a DLT or a DLET (as defined in Section 7.2.2.3), then treatment should 
be suspended for that patient.  If a toxicity does not meet the criteria for a DLT or DLET but 
nonetheless requires omission of dose(s) for tolerability, then dosing may resume at the same 
dose after the toxicity resolves to baseline; however, the dose(s) omitted for tolerability during a 
cycle will not be replaced.  
In either case, depending on the toxicities and whether the patient benefits from the treatment, 
dosing may resume at the given dose or a reduced dose and with or without allowed concomitant 
medication after consultation with the Lilly CRP.
7.2.4.3.2.
Dose Adjustments between Cycles

Nonhematologic toxicity must resolve to CTCAE Grade 0, 1, or baseline level before 
resuming treatment (with the exception of alopecia, fatigue, skin rash, nausea, vomiting, 
constipation, or diarrhea that can be controlled with treatment).  

Hematologic toxicity must resolve to a level that, in the opinion of the investigator, is 
reasonable to allow for continuation of treatment.

Patients who experience a DLET or do not recover from toxicity within the 3-week time 
frame may have the dosage reduced to the previous dose level.  Patients in first dose level 
may be reduced to 50 mg TIW.  

A second dose reduction is allowed.

Reescalation to the previous dose is acceptable in the absence of continuing toxicities.  If 
subsequent LY3039478 dose reduction is required after reescalation, the patient should 
be maintained at the reduced dose level.
Adjustments to these dosing guidelines may be permitted following an evaluation of the patient’s 
condition, benefit of treatment, and consultation with the Lilly CRP.  All exceptions to these 
guidelines will be documented.
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3039478 in this study.  
For patients participating in Part A and the cohort-escalation phase of Part F:  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 
identification number assignment and cohort for each patient.  No dose escalations (that is, to the 
next cohort) can occur without prior discussion and agreement with the responsible Lilly CRP or 

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CRS.  For patients participating in Study Part F cohort expansion:  upon confirmation of 
eligibility, the sponsor will assign the patient to a dosing schedule (F1 or F2).  Further details on 
the method of assignment are documented in the Statistical Analysis Plan.  If investigators have 
eligible patients who have consented concurrently, >3 patients may be entered at a particular 
dose level provided that accrual has not ceased due to excessive toxicity.  This enrollment 
procedure is allowed because of the advanced disease state of this patient population and the 
screening involved in defining eligibility.  This event should be approved by the sponsor 
following discussions with the investigators.
…
7.5.
Concomitant Therapy
…
For study Parts A, B, C, D, and E, pPatients should not receive corticosteroids prophylactically 
with the intent of attenuating gastrointestinal GI toxicity.  However, corticosteroid therapy 
initiated before study entry for a preexisting condition may be continued.  Corticosteroids may 
be used for treatment of GI toxicities if deemed necessary after agreement between the 
investigators and Lilly CRP.  As a guidance, standard treatments are provided in Attachment 9.  
For Study Part F, prednisone will be co-administered with LY3039478 as detailed in Section 
7.2.1.
…
7.6.1. Evaluable Patients
7.6.1.1.
Parts A, B, C, D, andE, and F
…
7.6.1.2.
Part A Dose Escalation Only
…
Table JJCA.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for Study 
I6F-MC-JJCA

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Timing
Types of AEs/SAEs Reported 
Prestudy (baseline assessments), per Section 8.1.2.2.1 
Preexisting conditions
Procedure-related AEs/SAEs
On therapy, per Section 8.1.2.2.2
All AEs/SAEs regardless of relatedness
Follow-up Visit (Visit 801), per Section 8.1.2.2.3
All AEs/SAEs regardless of relatedness
Continued-access period
All AEs/SAEs regardless of relatedness
Continued-access period follow-up
All AEs/SAEs regardless of relatedness
Subsequent Follow-up visits, if necessary – no more than 
30 ±3 days in durationa
Ongoing or new AEs/SAEs related to study drug or 
protocol procedures
Long-term posttreatment discontinuation 
follow-upb
All AE and SAEs related to protocol procedures or 
study drug
…
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.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical scientist, and periodically review:
•
trends in safety data,
•
laboratory analytes including any analytes of special interest,
•
AEs including monitoring of any AEs of special interest
…
8.2.4.3.
Tumor and Skin Biopsies
Throughout this study, archived tumor tissue obtained previously for diagnostic purposes (for 
example, at initial diagnosis) will be requested for biomarker research but is not required for 
study entry in Part A.  At baseline, before the patient received study drug for Parts B, C, D, 
andE, and F, a mandatory pretreatment formalin-fixed paraffin-embedded (FFPE) tumor tissue 
(paraffin blocks or unstained slides cut from that block) will be collected.  For Study Part F, the 
tumor tissue sample is required to be obtained within 2 years of the date of enrollment if 
archival.  A fresh sample is required if no archival sample meeting that criteria can be located.  
Table JJCA.8.2 presents tumor and skin biopsy collection time points.

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Table JJCA.12.1.
Tumor and Skin Biopsy Time Points
Collection Time 
Point
Part A
Parts B, Ca, and Da
Part E and F
Baseline archived 
tissue collection
Optional
Mandatory
Mandatory
Pre-/Postdose tumor 
biopsies
Optional
Recommended/optional
Mandatory
Pre-/Postdose skin 
biopsies
Mandatory
Mandatory
Mandatory
…
8.3.
Efficacy Evaluations
An objective of the study is to document any antitumor activity (secondary in Part A and 
coprimary for Parts B, C, D, andE, and F).  Refer to Attachment 1 for details regarding the 
timing of specific efficacy measures.  
Each patient will be assessed by 1 or more of the following radiologic tests for tumor 
measurement:

computed tomography (CT) scan

magnetic resonance imaging (MRI)

chest x-ray

PET scan – mandatory for Part E and F, Part C patients with sarcoma (leiomyosarcoma, 
GIST, liposarcoma, and angiosarcoma), and Part D patients with mature T cell, B cell, or 
NK cell neoplasms enrolled under amendment d. 
…
Lilly or its designee will collect and store all tumor measurement images for patients enrolled in 
Parts B, C, D, andE, and F.  A central review of imaging scans may be performed by Lilly or its 
designee.
…
10.1.
General Considerations
Approximately 182282 patients may be enrolled in this multicenter, open-label Phase 1 study 
with dose escalation followed by dose confirmation.  
…
Part F will focus on approximately 55 patients.  The total sample size during dose escalation will 
be determined by DLTs and is estimated to be approximately 10 to 15 patients for each schedule 
(F1 and F2). The sample size of approximately 15 patients for each schedule (F1 and F2) in the 
expansion cohorts is adequate to explore anti-tumor activity of LY3039478 in patients with 
leiomyosarcoma.  

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For guidance, example point estimates of incidence rates and corresponding 2-sided exact 95% 
confidence interval (CI) are provided in Table JJCA.10.1 for the proposed sample size of each 
tumor type in study Parts C, D, andE, and F.  The values are provided as a reference for 
estimation rather than a basis of any decision criteria.
…
10.2.
Efficacy
…
For patients in study Part C and, HCC patients from Part D, and leiomyosarcoma patients in 
Part F, ORR defined using the Choi criteria (Choi et al. 2007) will be considered for response 
evaluation in addition to RECIST criteria.  Modified response criteria incorporating changes in 
tumor density in addition to tumor size has been demonstrated to be a more sensitive prognostic 
marker for time to progression and disease specific survival in GIST sarcomas (Benjamin et al. 
2007; Choi et al. 2007).
For Part E, Part C, and F patients with sarcoma (leiomyosarcoma, GIST, liposarcoma, and 
angiosarcoma), and Part D patients with mature T cell, B cell, or NK cell neoplasms enrolled 
under amendment d, PET maximum standardized uptake values (SUVmax) will also be 
analyzed, and metabolic responses defined using PET response criteria of the European 
Organisation for Research and Treatment of Cancer (Young et al. 1999).
…

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Baseline Assessments
Relative Day Prior to Day 1 of 
Cycle 1
28
14
7
Comments
Informed consent 
X
Informed consent signed prior to performance of any 
protocol-specific tests/procedures.
Radiological tumor assessment
X
PET scan
X
Optionala
DCE-MRI 
X
Optional and not applicable for CLL patients 
Medical history
X
Including alcohol/tobacco use and other relevant 
habits assessments
Physical examination
X
Vital signs 
X
Including temperature, blood pressure, pulse rate, 
respiration rate
Height
X
ECOG performance status
X
Chest x-ray
X
May be omitted in patients having a chest CT for 
their radiological tumor assessment
ECG 
X
One set of triplicate ECGs, central
Hematology 
X
Local laboratory, for CLL patients includes 
immunophenotyping (see Attachment 2).
Coagulation (PT/INR, aPTT, 
fibrinogen)
X
Local laboratory
Serum chemistry 
X
Central laboratory
Urinalysis 
X
Local laboratory
Child-Pugh, BCLC, and CLIP 
staging 
X
Only for HCC patients in Part D (see Attachment 10, 
Attachment 11, and Attachment 12)
Tumor measurement (palpable or 
visible)
X
CTCAE v 4.0 grading (preexisting 
conditions)
X
To be reported only after study eligibility is 
confirmed.  See Section 8.1.2.2 for reporting 
expectations 
Concomitant medications
X
Tumor markers
X
If applicable, local laboratory
Blood PD biomarkers (A beta)
X
For Parts A and B only
Tumor biopsya
X
Screening for alterations of Notch 
pathway
X
Screening done locally, required only for Part B,and
D, and F expansion cohort patients.  Performed at 
any time prior to ICF and study drug start.
Archived tumor sample
X
Paraffin-embedded tumor tissue, only after study 
eligibility is confirmed.
Pregnancy test 
X
Negative results prior to dosing required for women 
of childbearing potential
Skin biopsy
X
Marrow aspirate and biopsy, if 
clinically indicated
X
Only CLL patients, according to institutional 
guidelines, last results prior dosing
Cytogenetic tests (FISH)
X
Only CLL patients, if applicable, local laboratory

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Abbreviations:  aPTT = activated partial thromboplastin time; BCLC= Barcelona Clinical Liver Classification 
Table; CLIP = Cancer of the Liver Italian Scoring System; CLL = Chronic Lymphocytic Leukemia; 
CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridization; HCC = hepatocellular 
carcinoma; Meds = medications; PD = pharmacodynamic; PET = positron emission tomography; 
PT/INR = prothrombin time/international normalized ratio. 
a
PET scan and tumor biopsy are mandatory for all patients in Part E, Part F, and LMS, GIST, liposarcoma, and 
angiosarcoma patients in Part C, and mature T cell, B cell, or NK cell neoplasm patients in Part D enrolled under 
Amendment d.

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LY3039478
During and Poststudy Assessments for Parts A, B, C, D, E, and F1
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
LY3039478 therapya
X
X
X
X
X
X
X
X
X
X
X
X
Prednisone therapyp
X
X
X
X
X
X
Physical examination
X
X
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
X
X
X
ECOG performance status
X
X
X
X
CTCAE version 4.0 grading
X
X
X
Concomitant medications
X
X
X
Tumor measurement (palpable and visible)
X
DCE-MRI (optional)b
X
Central ECGc
X
Hematologyd
X
X
X
X
Serum chemistryd
X
X
Xe
X
Serum creatininec, d
X
ECG chemistryc, d
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
Tumor markerd
X
Pharmacogenetics sample (predose)
X
Blood PK samplingc
X
Xq
X
Tumor biopsyf
X
Skin biopsyc, g
X
Blood PD biomarkers (A beta-Parts A and 
B only)c
X
X
Blood PD biomarkers (RBM, 
cytokeratin 18, epigenomics) predose 
X
Urine (8- to 10-hour collection)c,h
X

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During and Poststudy Assessments for Part F2
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
LY3039478 therapy
X
X
X
X
X
X
X
X
X
X
Prednisonep
X
X
X
X
Physical examination
X
X
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
X
X
X
ECOG performance status
X
X
X
X
CTCAE version 4.0 grading
X
X
X
Concomitant medications
X
X
X
Tumor measurement (palpable and visible)
X
DCE-MRI (optional)b
X
Central ECGc
X
Hematologyd
X
X
X
X
Serum chemistryd
X
X
Xe
X
Serum creatininec, d
X
ECG chemistryc, d
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
Tumor markerd
X
Pharmacogenetics sample (predose)
X
Blood PK samplingc
X
Xr
Xs
Tumor biopsyf
X
Skin biopsyc, g
X
Blood PD biomarkers (RBM, 
cytokeratin 18, epigenomics) predose 
X
…

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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f
Optional posttreatment tumor biopsy should be obtained (whenever clinically feasible) at Cycle 1, preferably 6 to 8 hours (±1 hour) after Dose 10.  Greater 
flexibility has been provided for the posttreatment tumor biopsy (between Doses 7 and 12, inclusive) compared to other Dose 10 visit assessments (between 
Doses 9 and 11, inclusive) to enable radiographic guidance and access to appropriate medical specialists; however, if this flexibility is exercised and the 
posttreatment tumor biopsy is obtained on a day other than the Dose 10 visit, then a single PK sample should be obtained as close as possible (for example, 3 
hours) to the time of the biopsy.  Additional optional tumor biopsies may be performed at time of disease progression and if deemed necessary by the 
investigator.  Tumor biopsy are mandatory for all patients in Part E, F, and LMS, GIST, liposarcoma, and angiosarcoma patients in Part C and mature T cell, 
B cell, or NK cell neoplasm patients in Part D enrolled under Amendment d.
…
k Long-term follow-up for survival applies to Part B, C, D, andE, and F only.
l
Collection of AEs and SAEs related to study treatment or study procedures only.
m collection of concomitant medication post-study treatment discontinuation must include any subsequent cancer treatment.
n Every 60 ( ±14) days and applies only to those patients who discontinue the study without progression or have not started another treatment regimen as 
outlined in Section 8.3.
o According to Guidelines from the National Cancer Institute Working Group for CLL, marrow aspirate and biopsy will be performed in CLL patients when a 
partial remission or complete remission is observed (to obtain bone marrow response information) and also 2 months after the last study drug treatment (to 
obtain duration of response).  Institutional guidelines will be followed.
p Prednisone given during Cycle 1 daily on Days 1-14 in Study Part F only as described in Section 7.2.1.
q For Part C, D, E, and dose-expansion patients in Part F1.
r
For Dose 5 in the dose-expansion part of F2 only.
s
For Dose 8 in the dose-escalation part of F2 only.

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Continued Access Schedule of Activities
Visit 501-n 
Follow-
upa
Week 1
Week 2
Week 3
Week 4
901
Study Proceduresb
Dose 
1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
LY3039478 therapy
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
Serum chemistry
X
X
Vital signs and weight 
(temperature, pulse rate, blood pressure, 
respiratory rate)
X
ECOG performance status
X
AE collection (CTCAE version 4.0)
X
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology Group.
a
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the continued-access 
period and lasts approximately 30 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.
b
Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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Attachment 3.
Protocol JJCA Pharmacokinetic and Pharmacodynamic Sampling Schedule
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part A and for, 10 Patients in Part B, and Dose-Escalation 
Patients in Part F1
PK 
Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478a
Urine Sampling 
Part A Onlya
Sampling Time 
for Serum 
Creatinine
Part A Only
PD Sampling 
Time for 
A(1-x)
(Parts A and 
B only)
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
Screening
Screening
2
1
1
Predose
0 to 8-10 hr pooled 
samples (end time 
of sample to 
coincide with PK 
blood draw)
Record total 
volume
Predose
Predose
Predose
3
1
1
0.5 hr
4
1
1
1 hr
1 hr
5
1
1
2 hr
2 hr
6
1
1
4 hr
4 hr
4 hr
4 hr
7
1
1
6-8 hr
6-8 hr
6-8 hr (±1 hour)
8
1
1
8-10 hr
8-10 hr
8-10 hr
9
1
1
24-30 hr
24-30 hr
24-30 hr
10
10
1
Predose
Predose
11
10
1
0.5 hr
12
10
1
1 hr
13
10
1
2 hr
2 hr
14
10
1
4 hr
4 hr
15
10
1
6-8 hr
6-8 hr
16
10
1
8-10 hr
8-10 hr
17
10
1
24-30 hr
24-30 hr
18
1
2
Predose
Predose
Predose

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Pharmacokinetic and Pharmacodynamic Sampling Schedule for Dose-Escalation Patients in Part F2
PK 
Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
2
1
1
Predose
Predose
3
1
1
0.5 hr
4
1
1
1 hr
5
1
1
2 hr
6
1
1
4 hr
4 hr
7
1
1
6-8 hr
6-8 hr (±1 hour)
8
1
1
8-10 hr
9
1
1
24-30 hr
24-30 hr
10
8
1
Predose
11
8
1
0.5 hr
12
8
1
1 hr
13
8
1
2 hr
14
8
1
4 hr
15
8
1
6-8 hr
16
8
1
8-10 hr
17
8
1
24-30 hr
18
1
2
Predose
Predose
Abbreviations:  ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Parts C, D, andE, and Dose-Expansion Patients in Part F1
…
Pharmacokinetic and Pharmacodynamic Sampling Schedule for Dose-Expansion Patients in Part F2

I6F-MC-JJCA(e) Phase 1 Oncology Protocol
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Sample 
Number
Dose 
Number
Cycle
PK Sampling 
Time for 
LY3039478
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Screening
1
Screening
2
1
1
Predose
Predose
3
1
1
1-3 hr
2 hr
4
1
1
4 hr
5
1
1
6-8 hr
6-8 hr (±1 hour)
6
5
1
Predose
7
1
2
Predose
Predose
Abbreviations:  ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.

Leo Document ID = ba3a4fa3-3d54-4049-89cc-212ae10ae1e6
Approver: 
Approval Date & Time: 08-Jul-2016 14:59:40 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Jul-2016 19:49:29 GMT
Signature meaning: Approved
PPD
PPD