Clinical trial NCT02836600
Conditions: Advanced Solid Tumor
Keywords: notch inhibitor
Sponsor: Eli Lilly and Company
Start date: 2016-09-09; Completion date: 2023-05-30
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the tolerability of the study drug LY3039478 in Japanese participants with advanced solid tumors.

Detailed description:

Arms: arm 1: Participants received 25 milligrams (mg) of LY3039478, administered orally three times per week (TIW) in a 28-day cycle, until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. arm 2: Participants received 50 mg of LY3039478, administered orally TIW in a 28-day cycle, until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met.
Interventions: intervention 1: LY3039478
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol Addendum I6F-JE-JJCC(b) 
A Phase 1 Study of LY3039478 in Japanese Patients with Advanced Solid Tumors 
NCT02836600 
Approval Date: 12-Apr-2019


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1.
Protocol I6F-JE-JJCC(b)
A Phase 1 Study of LY3039478 in Japanese Patients with 
Advanced Solid Tumors
Confidential Information
The information contained in this document 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.
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3039478
This Phase 1 study is a single center, nonrandomized, open-label, dose-escalation study of 
oral LY3039478 in Japanese patients with advanced and/or metastatic solid tumors.
Eli Lilly Japan K.K.
Chuo-ku, Kobe Japan
Protocol Electronically Signed and Approved by Lilly:  20-Apr-2016
Amendment (a) Electronically Signed and Approved by Lilly:  30-May-2016
Amendment (b) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 12-Apr-2019 GMT


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2.
Synopsis
This Phase 1 study is a single center, nonrandomized, single arm, open-label, dose-escalation
study of LY3039478 in Japanese patients with advanced solid tumors.


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Clinical Protocol Synopsis:  Study I6F-JE-JJCC
Name of Investigational Product: LY3039478
Title of Study:  A Phase 1 Study of LY3039478 in Japanese Patients with Advanced Solid Tumors
Number of Planned Patients:  9 to 12
Phase of Development:  1
Objectives:
The primary objective of this study is to evaluate the tolerability of LY3039478 up to the global recommended 
dose in Japanese patients with advanced solid tumors.
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3039478

to evaluate the pharmacokinetic (PK) parameters of LY3039478.

to document any antitumor activity observed with LY3039478.
The exploratory objectives of this study are:

to explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of Notch activity.

to evaluate tumor tissue and blood for biomarkers related to solid tumors, the Notch signaling pathway 
and drug target pathways, immune functioning, and mechanism of action of study drug, and their potential 
association with the study objectives.

to explore the utility of positron emission tomography scan to assess treatment effect with LY3039478.
Study Design:
Study I6F-JE-JJCC (JJCC) is a Phase 1, single center, nonrandomized, single-arm, open-label, dose-escalation
study of LY3039478 in Japanese patients with advanced solid tumors.  Study JJCC will consist of 2 dose levels, 25 
and 50 mg LY3039478 3 times per week (TIW; 3 or 6 patients per dose level).  Transition of dose level (from 25 to 
50 mg) will proceed if the frequency of dose-limiting toxicity (DLT) observed in Cycle 1 (28 days) is <33% of 
patients in the first dose level (25 mg).  Eligible patients will be treated with LY3039478 at the assigned dose.  
Treatment will continue until disease progression, development of unacceptable toxicity, or any other 
discontinuation criteria are met.
Diagnosis and Main Criteria for Inclusion and Exclusions:
Patients must be ≥20 years of age and have histological or cytological evidence of a diagnosis of solid tumor that is 
advanced and/or metastatic.  In the judgment of the investigator, patients must be appropriate candidates for 
experimental therapy after available standard therapies have failed or for whom standard therapy is not appropriate.  
Patients must have a performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale.  
Patients also must have adequate organ function, including hematologic, hepatic, and renal, and an estimated life 
expectancy of ≥12 weeks.
Patients may be excluded if they have received previous therapy for cancer within 14 or 21 days of the initial dose 
of study drug for a nonmyelosuppressive or myelosuppressive agents, respectively; have serious preexisting 
medical conditions; have current or recent (within 3 months of study drug administration) gastrointestinal disease 
with chronic or intermittent diarrhea; have an active bacterial, fungal, and/or known viral infection; or have known 
acute or chronic leukemia or current hematologic malignancies that may affect the interpretation of results.
Investigational Product, Dosage, and Mode of Administration:
LY3039478 25 and 50 mg, administered orally as capsules 3 times per week during a 28-day cycle.
Planned Duration of Treatment:
The planned duration of treatment is not fixed.  A cycle is defined as 28 days, and treatment will continue until 
disease progression, development of unacceptable toxicity, or any other discontinuation criteria are met.  
Follow-up: 30 days ±3 days after the patient and the investigator agree that the patient will no longer continue 
study treatment.
Criteria for Evaluation:
Safety:  National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.0 will be used for 
classifying or grading events and severity.  Medical Dictionary for Regulatory Activities will be used for coding 


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and summarizing reporting event terms. Safety measurements will include DLTs, serious adverse events (AEs), 
dose adjustments, laboratory tests, electrocardiograms (ECGs), and vital signs.
Bioanalytical:  Plasma and urine concentrations of LY3039478.
Efficacy:  Response Evaluation Criteria in Solid Tumors version 1.1 for solid tumors; Response Assessment in 
Neuro-Oncology criteria for glioblastoma.
Pharmacokinetics/Pharmacodynamics:  Maximum plasma concentration and area under the plasma concentration 
versus time curve.  In addition, half-life, apparent clearance, and apparent volume of distribution may be reported.
The PK data will be combined, and analyses may be conducted to determine a relationship between exposure and 
PD/pharmacogenetic effect data.
Statistical Methods:
Safety: Safety analyses will include summaries of the following:

DLTs at each dose level (using the DLT analysis set)

AEs, including severity, possible relationship to study drug and outcome

dose adjustments

laboratory values

vital signs and physical examination

ECG readings.
Efficacy: The study was not designed to make an efficacy assessment.  However, any tumor response data will be 
tabulated.
Pharmacokinetics: The PK parameters for LY3039478 will be calculated by standard noncompartmental 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 Japanese Patients with 
Advanced Solid Tumors
Section
Page
1.
Protocol I6F-JE-JJCC(b) A Phase 1 Study of LY3039478 in Japanese 
Patients with Advanced Solid Tumors.................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................5
4.
Abbreviations and Definitions...........................................................................................11
5.
Introduction ......................................................................................................................15
5.1.
Rationale and Justification for the Study ......................................................................15
5.2.
Objectives ....................................................................................................................16
5.2.1.
Primary Objective ................................................................................................16
5.2.2.
Secondary Objectives...........................................................................................16
5.2.3.
Exploratory Objectives.........................................................................................16
5.3.
General Introduction to LY3039478.............................................................................16
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................17
5.3.2.
Nonclinical Pharmacokinetics/Pharmacodynamics...............................................17
5.3.3.
Nonclinical Toxicology........................................................................................18
5.3.4.
Prior Clinical Experience .....................................................................................18
5.3.4.1.
Clinical Adverse Events with LY3039478 ......................................................18
5.3.4.2.
Clinical Pharmacokinetics with LY3039478 ...................................................19
5.3.4.3.
Clinical Absorption, Distribution, Metabolism, and 
Excretion........................................................................................................19
5.3.5.
Biomarkers...........................................................................................................19
5.4.
Rationale for Selection of Dose....................................................................................20
6.
Investigational Plan...........................................................................................................21
6.1.
Study Population..........................................................................................................21
6.1.1.
Inclusion Criteria .................................................................................................21
6.1.2.
Exclusion Criteria ................................................................................................22
6.2.
Summary of Study Design............................................................................................23
6.2.1.
Study Completion and End of Trial......................................................................24
6.3.
Discontinuation............................................................................................................24
6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................25
6.3.2.
Discontinuation of Patients from Study or Study Drug .........................................25
6.3.3.
Patients Lost to Follow-Up...................................................................................26


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6.3.4.
Discontinuation of Study Sites .............................................................................26
6.3.5.
Discontinuation of the Study................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Materials and Supplies .................................................................................................28
7.2.
Study Drug Administration ..........................................................................................28
7.2.1.
Dosing Schedule ..................................................................................................28
7.2.2.
Dose Escalation....................................................................................................29
7.2.2.1.
Dose-Limiting Toxicity Determination ...........................................................29
7.2.2.2.
Dose Escalation Method.................................................................................30
7.2.3.
Dose Adjustments and Delays..............................................................................31
7.2.3.1.
Dose Adjustments within Cycle 1...................................................................31
7.2.3.2.
Dose Adjustments within Cycle 2 and Beyond................................................31
7.2.3.3.
Dose Adjustments Between Cycles.................................................................32
7.3.
Method of Assignment to Treatment ............................................................................32
7.4.
Blinding .......................................................................................................................33
7.5.
Concomitant Therapy...................................................................................................33
7.6.
Treatment Compliance .................................................................................................33
7.6.1.
Evaluable Patients................................................................................................34
7.7.
Continued Access.........................................................................................................34
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................36
8.1.
Safety Evaluations........................................................................................................36
8.1.1.
Safety Data Collection and Review ......................................................................36
8.1.2.
Adverse Events ....................................................................................................36
8.1.2.1.
Serious Adverse Events ..................................................................................38
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................39
8.1.2.2.1.
Prior to Administration of Study Drug(s) ..................................................39
8.1.2.2.2.
On Study...................................................................................................39
8.1.2.2.3.
Follow-Up Visit........................................................................................39
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................40
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................40
8.1.3.
Vital Signs and Laboratory Measurements ...........................................................40
8.1.3.1.
Electrocardiograms.........................................................................................40
8.1.4.
Safety Monitoring ................................................................................................41
8.1.5.
Complaint Handling.............................................................................................42
8.2.
Sample Collection and Testing.....................................................................................42
8.2.1.
Samples for Standard Laboratory Testing.............................................................43
8.2.2.
Pharmacokinetic Samples.....................................................................................43


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8.2.3.
Pharmacogenomic Samples..................................................................................43
8.2.4.
Exploratory Samples ............................................................................................44
8.2.4.1.
Blood Samples for Amyloid Beta Assays........................................................45
8.2.4.2.
Blood Samples................................................................................................45
8.2.4.3.
Tumor and Skin Biopsies................................................................................45
8.3.
Efficacy Evaluations ....................................................................................................46
8.4.
Procedure/Sampling Compliance..................................................................................47
9.
Data Management Methods...............................................................................................48
9.1.
Data Quality Assurance................................................................................................48
9.2.
Data Capture Systems ..................................................................................................48
9.2.1.
Case Report Form ................................................................................................48
9.2.2.
Ancillary Data......................................................................................................49
10.
Data Analyses...................................................................................................................50
10.1. General Considerations ................................................................................................50
10.1.1.
Analysis Populations............................................................................................50
10.2. Patient Disposition .......................................................................................................50
10.3. Patient Characteristics ..................................................................................................51
10.4. Safety Analyses............................................................................................................51
10.5. Pharmacokinetic Analyses............................................................................................51
10.6. Pharmacokinetic/Pharmacodynamic Analyses..............................................................52
10.7. Efficacy........................................................................................................................52
10.8. Exploratory Biomarker Analyses..................................................................................52
10.9. Interim Analyses ..........................................................................................................52
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................53
11.1. Informed Consent.........................................................................................................53
11.2. Ethical Review.............................................................................................................53
11.3. Regulatory Considerations ...........................................................................................53
11.3.1.
Investigator Information.......................................................................................54
11.3.2.
Protocol Signatures ..............................................................................................54
11.3.3.
Final Report Signature .........................................................................................54
12.
References ........................................................................................................................55


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List of Tables
Table
Page
Table JJCC.1.
Adverse Event and Serious Adverse Reporting Guidelines for Study 
JJCC..............................................................................................................40
Table JJCC.2.
Tumor and Skin Biopsy Time Points .............................................................46


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List of Figures
Figure
Page
Figure JJCC.1.
Illustration of study design.............................................................................24
Figure JJCC.2.
Schema of dose level transition......................................................................31
Figure JJCC.3.
Continued access diagram..............................................................................35


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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JJCC Study Schedule.......................................................................57
Attachment 2.
Protocol JJCC Clinical Laboratory Tests........................................................65
Attachment 3.
Protocol JJCC Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenetic Sampling and Electrocardiogram Schedule.........................66
Attachment 4.
Protocol JJCC Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................68
Attachment 5.
Protocol JJCC Recommendations for Reporting Serious Adverse 
Events............................................................................................................69
Attachment 6.
Protocol JJCC Eastern Cooperative Oncology Group Performance 
Status.............................................................................................................70
Attachment 7.
Protocol JJCC Creatinine Clearance Formula.................................................71
Attachment 8.
Protocol JJCC Guidance for Diarrhea Management .......................................72
Attachment 9.
Protocol JJCC RECIST Criteria 1.1 ...............................................................75
Attachment 10.
Protocol I6F-JE-JJCC(b) Amendment Summary [A Phase 1 Study of 
LY3039478 in Japanese Patients with Advanced Solid Tumors]....................82


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4.
Abbreviations and Definitions
Term
Definition
Aβ
Amyloid-β
AE
adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal 
(investigational) product, whether or not related to the medicinal 
(investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
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, good 
clinical practice, and the applicable regulatory requirement(s).
ChE
cholinesterase
Cmax
maximum plasma concentration
CL/F
apparent systemic clearance
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.
eCRF
electronic case report form:  Sometimes referred to as clinical report form, an
electronic form for recording study participants’ data during a clinical study, as 
required by the protocol.
CRP
clinical research physician
CRS
clinical research scientist


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CSF
colony-stimulating factor
CSL
C-promoter binding factor-1 (CBF-1), Suppressor of Hairless (Su[H]), and 
lin-12 and glp-1 (LAG-1)
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DDI
drug-drug interaction
DLET
dose-limiting equivalent toxicity
DLL
Delta-like
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last 
patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least 1 dose of study treatment.
enter
Patients who are entered in the trial are those who have signed the informed 
consent form directly or through their legally acceptable representatives.
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.
F
oral absorption/bioavailability
FDP
fibrin/fibrinogen degradation products
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
hERG
human ether-a-go-go-related gene
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form


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ICH
International Conference on Harmonisation
ILD
interstitial lung disease
informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the 
trial that are relevant to the patient’s decision to participate.  Informed consent 
is documented by means of a written, signed and dated informed consent form.
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for data lock.
investigational 
product
A pharmaceutical form of an active substance or placebo being tested or used as 
a reference in a clinical trial.  Investigational product includes a product with a 
marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from 
the authorized form
2.
used for an unauthorized indication or
3.
used to gain further information about the authorized form.
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.
LC-MS/MS
liquid chromatography-tandem mass spectrometry
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous 
events occurring while using a drug/drug delivery system.
LDH
lactate dehydrogenase
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 
standard operating procedures, International Conference on Harmonisation 
Good Clinical Practice guidelines, and all applicable laws (for example, privacy 
and data protection) and regulations. 
MTD
maximum tolerated dose
NCI
National Cancer Institute
NICD
Notch intracellular domain
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
patient
A subject with a defined disease.
PD
pharmacodynamic(s)


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PD
progressive disease
PET
positron emission tomography
PK
pharmacokinetic(s)
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data.
SAC
Safety Assessment Committee
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.  In this 
study, screening involves invasive or diagnostic procedures and/or tests (for 
example, x-rays, blood draws).  For this type of screening, informed consent for 
these screening procedures and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study.
sponsor
The party who takes responsibility for the initiation, management and/or 
financing of a clinical study.
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TIW
3 times per week
tmax
time of maximal plasma concentration
TPO
third-party organization
ULN
upper limit of normal
V/F
apparent volume of distribution
WHO
World Health Organization


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A Phase 1 Study of LY3039478 in Japanese Patients with 
Advanced Solid Tumors
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 these 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 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.  
γ-Secretase is a high molecular weight multiprotein complex possessing protease activity against 
a number of type I membrane proteins, including amyloid precursor protein, ErbB4 receptor, and 
Notch receptors.  γ-Secretase cleavage of the Notch receptor results in the release of a peptide 
called the Notch intracellular domain (NICD) and translocation to the nucleus.  The NICD is 
important in regulating transcriptional activity through interactions with the transcription 
repressor C-promoter binding factor-1, Suppressor of Hairless, and lin-12 and glp-1 (CSL), also 
known as mammalian recombination signal-binding protein-Jκ.  Notch intracellular domain
binding to the CSL relieves suppressive function by displacing co-repressors and recruiting co-
activators 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).
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 γ-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; 


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CGARN 2011; Puente et al. 2011).  In summary, inhibition of Notch signaling constitutes an 
attractive strategy to provide therapeutic benefits to cancer patients.
Eli Lilly and Company (Lilly) has developed a potent small-molecule inhibitor of Notch, 
LY3039478, for the treatment of cancer.  The Phase 1 first-in-human Study I6F-MC-JJCA 
(JJCA) established a maximum tolerated dose (MTD) of 75 mg 3 times per week (TIW) on 
Days 1 through 28 of a 28-day cycle. However, a review of safety data showed significant dose 
reductions or omissions related to adverse events (AEs); therefore, the recommended dose was 
adjusted to 50 mg TIW.  This study in Japanese patients with advanced cancers, Study I6F-JE-
JJCC (JJCC), is a Phase 1 trial designed to confirm the safety and tolerability of LY3039478 up 
to the recommended dose, 50 mg TIW, which was established in Study JJCA.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.
5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to evaluate the tolerability of LY3039478 up to the global 
recommended dose in Japanese patients with advanced solid tumors.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3039478.

to evaluate the pharmacokinetic (PK) parameters of LY3039478.

to document any antitumor activity observed with LY3039478.
5.2.3. Exploratory Objectives
The exploratory objectives of this study are:

to explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of 
Notch activity.

to evaluate tumor tissue and blood for biomarkers related to solid tumors, the Notch 
signaling pathway and drug target pathways, immune functioning, and mechanism of 
action of study drug, and their potential association with the study objectives.

to explore the utility of positron emission tomography (PET) scan to assess treatment 
effect with LY3039478.
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.  


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More information about the known and expected benefits, risks and reasonably anticipated 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 
≤1nM 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% value for Notch-1 intracellular domain inhibition 
of 0.8 and 0.9 mg/kg, respectively, and threshold plasma concentration of the compound required 
to inhibit cleavage by 50% 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 produced optimal 
efficacy while balancing on-target gastrointestinal (GI) toxicity. Furthermore, coadministration 
of dexamethasone with LY3039478 significantly improved body weight loss and GI toxicity 
without negatively impacting antitumor 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 (F) 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 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 (for example, 
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 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 


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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 in mouse lung, as a surrogate tumor marker.  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 target tissues for toxicity that may be clinically 
relevant.  Based on results from the repeat-dose toxicity studies, the primary target organ for 
LY3039478 toxicity is the GI tract.  The mucoid enteropathy and all other toxicities were 
reversible or partially reversible following a 3-week recovery period in rats. Details and findings 
from the rat and dog studies are presented in the IB.
The intestinal toxicity in the toxicology studies was characterized by fecal abnormalities such as 
few/absent or watery feces in rats and soft, watery, mucoid, and discolored feces in dogs, and 
histologic changes described as a mucoid enteropathy.  Mucoid enteropathy is a known target-
mediated toxicity of Notch inhibitors (Milano et al. 2004).  Based on in vitro human ether-a-go-
go-related gene (hERG) results, there is no expected risk for QT prolongation by hERG 
inhibition.  In the 1-month dog study, 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 interval).  No evidence of mutagenicity or clastogenicity was 
observed in a bacterial mutagenicity (Ames) or in vitro chromosomal aberration assay, 
respectively.  In additional in vitro assays, LY3039478 was classified as a nonirritant and 
demonstrated no phototoxic potential.
5.3.4. Prior Clinical Experience
5.3.4.1.
Clinical Adverse Events with LY3039478
During the dose-escalation phase (Part A) of Phase 1 Study JJCA, 5 of the 55 patients (9.1%)
experienced dose-limiting toxicities (DLTs). Dose-limiting toxicities of Grade 4 
thrombocytopenia were experienced by 1 patient each in Cohort 4 (20 mg), Cohort 5 (30 mg), 
and Cohort 7 (60 mg). In 2 out of the 3 patients, the thrombocytopenia was associated with 
bleeding. Dose-limiting toxicities of Grade 3 colitis (1 patient) and Grade 3 nausea (not 
manageable with medical treatment) associated with Grade 3 fatigue (1 patient) were
experienced in Cohort 9 (100 mg). In addition, 1 patient in Cohort 7 (60 mg) experienced a
dose-limiting equivalent toxicity (DLET) of Grade 3 colitis during Cycle 2, and 1 patient in


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Cohort 9 (100 mg) experienced a DLET of Grade 3 fatigue during Cycle 4. The MTD was
established at 75 mg. During Part B of Study JJCA, 2 patients treated with 75 mg experienced 
DLETs of Grade 3 diarrhea and colitis during Cycle 1 (1 patient) and Grade 3 diarrhea during 
Cycle 2 (1 patient). Additional review of the safety data from Part B (25 patients) revealed 
Grade 3 and 4 AEs of diarrhea (5 patients); nausea (3 patients); and vomiting, colitis, and 
hypophosphatemia (2 patients each) that were assessed as possibly related to study drug by the 
investigator. In addition, approximately 30% of patients had dose reductions. These 
developments led to the reduction of the MTD to 50 mg. At the 50-mg dose level, preliminary 
safety data show a reduction in all GI toxicities (diarrhea, nausea, and vomiting) in both 
frequency and severity. In addition, there were no reports of colitis at the 50-mg dose level. 
There were fewer dose reductions and dose omissions necessary at 50 mg compared with 75 mg. 
The most frequent (≥10% of patients) treatment-emergent adverse events reported at the 50-mg 
dose level were:  diarrhea (14 patients, 39%); nausea and asthenia (8 patients each, 22%); and
vomiting, fatigue, decreased appetite, and dry skin (4 patients each, 11%).  The only Grade 3
events experienced at this dose level were stomatitis (1 report) and asthenia (2 reports).
5.3.4.2.
Clinical Pharmacokinetics with LY3039478
As of 06 January 2015, PK data for LY3039478 were available from 52 patients after a single 
dose and from 35 patients after multiple dosing, over a dose range of 2.5 to 100 mg in Cycle 1 
from Study JJCA.  After oral administration, tmax of LY3039478 was reached approximately 1 to 
2 hours postdose and the mean t1/2 was approximately 5 to 7 hours.  The PK of LY3039478 did 
not change upon multiple dosing, and there was little to no accumulation with the TIW dosing 
schedule.  A preliminary assessment of dose proportionality has been conducted for PK 
parameters (area under the plasma concentration versus time curve (AUC) from time zero to 
48 hours and maximum plasma concentration [Cmax]) after multiple dosing, and no deviations 
from linearity were observed across the dose range studied (2.5 to 100 mg).  The variability in 
exposures, assessed by percentage coefficient of variation, ranged from 30% to 90% for Cmax and 
AUC.  Preliminary analyses of urine data suggest that renal clearance contributed to 
approximately 20% of apparent plasma clearance of LY3039478.
5.3.4.3.
Clinical Absorption, Distribution, Metabolism, and Excretion
Preliminary human plasma and urine profiling indicated that LY3039478 is cleared by 
glucuronidation, by hydrolysis of the amide bond connecting the azepine ring to the aliphatic 
side chain, and by urinary excretion.  LY3039478 does not inhibit key CYPs or drug transporters 
in vitro.  LY3039478 is a weak inducer of CYP3A4 in vitro and is predicted to decrease the 
AUC of midazolam (a sensitive substrate of this enzyme) by 20%.  LY3039478 clearance 
mechanisms (urinary excretion of parent, glucuronidation, and amide hydrolysis) indicate low 
DDI potential.
5.3.5. Biomarkers
As part of an ongoing effort by Lilly to better understand the relationship between cancer, 
genetics, and response to therapy, this study will analyze biomarkers relevant to solid tumors, the 


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Notch signaling pathway and drug target pathways, immune functioning, mechanism of action of 
study drug, and their potential association with the objectives of the study. 
Pharmacodynamic 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.  Potential predictive 
biomarkers will be measured 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.
Additional details about sampling are provided in Section 8.2.4, Attachment 1, and Attachment 
3.
5.4.
Rationale for Selection of Dose
A dose range from 25 to 50 mg of LY3039478 administered orally TIW was selected based on 
the safety and PK data of Study JJCA.
During the dose escalation phase (Part A) of Study JJCA, doses between 2.5 and 100 mg TIW 
were investigated.  As described in Section 5.3.4.1, the MTD was determined to be 75 mg
initially, but a review of safety data showed significant dose reductions or omissions related to 
AEs; therefore, the recommended dose was adjusted to 50 mg.
The objective of Study JJCC is to confirm tolerability in patients up to the recommended dose, 
50 mg in TIW, as determined in Study JJCA.  The maximum dose level in Study JJCC is also 
50 mg.  To ensure the patients’ safety, the initial dose is 25 mg, which is 50% of the 
recommended dose in non-Japanese patients (50 mg).


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6.
Investigational Plan
6.1.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened; however, individuals who failed screening due to a minor deviation from the range 
of eligibility may be rescreened by agreement between the investigator and the sponsor.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
[1]
Have histological or cytological evidence of a diagnosis of solid tumor that is 
advanced and/or metastatic and must be, in the judgment of the investigator, an 
appropriate candidate for experimental therapy after available standard therapies 
have failed or for whom standard therapy would not be appropriate.
[2]
Have measurable and/or nonmeasurable disease as defined by the Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (Eisenhauer et 
al. 2009; refer to Attachment 9).
[3]
Are 20 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 × 109/L, platelets 
100 × 109/L, and hemoglobin 8 g/dL.

Hepatic:  bilirubin 1.5 × upper limit of normal (ULN), alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST) 3.0 × ULN.  
If the liver has tumor metastatic involvement, ALT and AST equaling 
5.0 × ULN are acceptable.

Renal:  calculated creatinine clearance ≥45 mL/min (refer to Attachment 7).
[6]
Have a performance status of 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Oken et al. 1982; refer to Attachment 6).
[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 or Grade ≤1, except alopecia).  
At the discretion of the investigator, patients with breast or prostate cancers 
progressing on hormone therapies may have that treatment continued while 
receiving study drug.


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[8]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[9]
Males must agree to use medically approved barrier contraceptive precautions 
during the study and for 3 months following the last dose of study drug.  This 
precaution should also be followed by vasectomized males.
Females of childbearing potential:  must agree to use medically approved 
contraceptive precautions during the study and for 3 months following the last 
dose of study drug, and must have had a negative serum or urine pregnancy test 
≤7 days before the first dose of study drug, and must also not be breastfeeding.  
If a female patient stops breastfeeding for the study entry, breastfeeding must 
cease from the day of the first study drug administration until at least 3 months 
after the last administration.
Acceptable methods of contraception include bilateral tubal ligation, condoms
with spermicide, intrauterine device that has been in place for at least 3 months 
before the first dose of study drug, or the oral contraceptive pill taken for at 
least 3 months before the first dose of study drug.
A woman of childbearing potential is defined as a premenopausal female.  The 
postmenopausal condition or post-menopause is defined as:
1)
at least 6 weeks after surgical bilateral oophorectomy that can be 
confirmed via medical history records
or
2)
spontaneous amenorrhea for at least 12 months, not induced by a 
medical condition such as anorexia nervosa nor induced by medication.
[10] Have an estimated life expectancy of ≥12 weeks, in the judgment of the 
investigator.
[11] Are able to swallow capsules.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[12]
Have received treatment with any study 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.
[13]
Have serious preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study.


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[14]
Have central nervous system (CNS) malignancy with the following exceptions:  

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 28 days prior 
to initial dosing (screening not required). Patients with brain edema should 
be excluded despite conditions.

Patients with glioblastoma; World Health Organization (WHO) Grade IV, or 
WHO Grade II or III glioma, are eligible.
[15]
Have known acute or chronic leukemia or current hematologic malignancies 
that, in the judgment of the investigator and sponsor, may affect the
interpretation of results.
[16]
Have received an autologous or allogeneic stem cell transplant.
[17]
Are pregnant or lactating.
[18]
Have an active bacterial, fungal, and/or known viral infection (for example, 
human immunodeficiency virus antibodies, active uncontrolled clinically 
serious hepatitis B virus or hepatitis C virus infection).  Screening is not 
required for enrollment.
[19]
Have current or recent (within 3 months of study drug administration) GI 
disease with chronic or intermittent diarrhea, or disorders that increase the risk 
of diarrhea, such as inflammatory bowel disease.  Nonchronic conditions (for 
example, infectious diarrhea) that are completely resolved for at least 1 week 
prior to starting study treatment are not exclusionary.
[20]
Have received prior treatment with a Notch inhibitor.
[21]
Have hepatocellular carcinoma.
[22]
Have persistent bleeding.
[23]
Have undergone major surgery within 28 days prior to first dose. If the 
procedure is minimally invasive (for example, tumor biopsy), the treatment 
should be initiated after the investigator confirms the hemostasis and does not 
anticipate any significant bleeding.
6.2.
Summary of Study Design
Study JJCC is a Phase 1, single center, nonrandomized, single-arm, open-label, dose-escalation 
study of LY3039478 in Japanese patients with advanced solid tumors.
Study JJCC will consist of 2 dose levels, 25 and 50 mg LY3039478 TIW (3 or 6 patients per 
dose level).  Transition of dose level (from 25 to 50 mg) will proceed if the frequency of DLT 
observed in Cycle 1 (28 days) is <33% of patients in the first dose level (25 mg). Figure JJCC.1
illustrates the study design.


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Eligible patients will be treated with LY3039478 at the assigned dose.  The planned duration of 
treatment is not fixed. Treatment will continue until disease progression, development of 
unacceptable toxicity, or any other discontinuation criteria are met (Figure JJCC.1).
Abbreviations:  DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology 
Group; N = number of patients or no; PD = progressive disease; PS = performance 
status; TIW = 3 times per week; Y = yes.
Figure JJCC.1.
Illustration of study design.
Refer to Attachment 1 for the Study Schedule.
6.2.1. Study Completion and End of Trial
Study completion will occur following the data cutoff date for the primary analysis of primary 
and secondary objectives.  The data cutoff date will be the time of when it is deemed that enough 
data is obtained for the analysis as determined by Lilly.  Investigators will continue to follow 
Study Schedule for each cycle (Attachment 1) for all patients until notified by Lilly that study 
completion has occurred.  The “end of trial” refers to the date of the last visit or last scheduled 
procedure for the last patient. “End of trial” occurs after study completion and after the last 
patient has discontinued study treatment and completed the final follow-up visit (including the 
final follow-up visit for the continued access period, if applicable) or has been declared lost to 
follow-up.
6.3.
Discontinuation
The reason for and date of discontinuation will be collected for all patients.  The Date of 
Discontinuation from study treatment is to be reported on the case report form (CRF).  Patients 


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who discontinue will have follow-up procedures performed as shown in the Study Schedule 
(Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
6.3.1. Discontinuation of Patients Inadvertently Enrolled
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor clinical research physician (CRP)/clinical research scientist (CRS) and the 
investigator to determine whether the patient may continue in the study, with or without 
investigational product.  Inadvertently enrolled patients may be maintained in the study and on 
investigational product when the sponsor CRP/CRS agrees with the investigator that it is 
medically appropriate for that patient.  The patient may not continue in the study with or without 
investigational product if the sponsor CRP/CRS does not agree with the investigator’s 
determination that it is medically appropriate for the patient to continue.  The investigator must 
obtain documented approval from the sponsor CRP/CRS to allow the inadvertently enrolled 
patient to continue in the study with or without investigational product.
6.3.2. Discontinuation of Patients from Study or Study Drug
Patients who are discontinued from the study drug will have follow-up procedures performed as 
shown in the Study Schedule (Attachment 1).
Patients will be discontinued from the study drug in the following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
the investigator/physician decides that the patient should be withdrawn from the 
study or study drug(s).
o
the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug(s) occurs prior to introduction of the other 
agent.

Patient Decision
o
the patient requests to be discontinued from the study or study drug.

Sponsor Decision


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o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP.

The patient becomes pregnant.

The patient has evidence of progressive disease by radiological assessments
(RECIST v1.1).  However, the patient may continue the study drug if, in the opinion of 
the investigator, the patient will clinically benefit from continuation of study drug, 
following discussion and approval by the sponsor. The patient will re-sign the informed 
consent form (ICF) for the continuation of study treatment.

The patient has evidence of deteriorating clinical symptoms of progressive disease.

The patient experiences unacceptable toxicity including, but not limited to, a Grade 4 
nonhematological toxicity or a toxicity that does not resolve to baseline or Grade 1 within 
3 weeks.

The patient, treated at 25 mg TIW, experiences a toxicity requiring dose reduction.
However, the patient may continue after the toxicity has recovered to baseline or Grade 1
if, in the opinion of the investigator, the patient will clinically benefit from continuation 
of study drug. The dosing schedule for resuming study treatment at 25 mg can be 
modified after agreement with the sponsor, while safety assessment will be maintained as 
Attachment 1.  The patient will re-sign the ICF for the continuation of study treatment.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).
An exception to these discontinuation criteria may be granted in rare circumstances where the 
patient has a serious or life-threatening condition for which there is no effective alternative 
therapy and, in the opinion of the investigator, is receiving benefit from study drug.  In these rare 
cases, the investigator must obtain documented approval from sponsor to allow the patient to 
continue study treatment and the patient will re-sign the ICF for the continuation of study 
treatment.
6.3.3. Patients Lost to Follow-Up
A patient would be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
6.3.4. 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 discontinuation of study site participation necessary for any 
scientific, medical, safety, regulatory, ethical, or other reasons consistent with applicable laws, 
regulations, and GCP.


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6.3.5. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges discontinuation of the study 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- or 50-mg capsules in bottles for oral consumption.  
LY3039478 capsules should be stored at room temperature as 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 not be opened, crushed, or dissolved.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agents and planned duration of each 
individual’s treatment to the site personnel.

verifying that instructions are followed properly.

maintaining accurate records of study drug dispensation, and collection, and returning or 
destroying all unused medication to Lilly or its designee at the end of the study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
7.2.1. Dosing Schedule
LY3039478 will be administered orally TIW as stated in Attachment 1.  A cycle is defined as 
28 days. In principle, the patients will be admitted to the investigational site for 4 weeks through 
the entire Cycle 1. However, if the investigator judges that the patient can be managed on an 
outpatient basis based on the safety evaluation results, the patient may be discharged on or after 
Day 15.
The following are examples; the schedule will be determined at the investigator’s discretion.

Monday, Wednesday, and Friday every week, for a 28-day cycle.

Tuesday, Thursday, and Saturday every week, for a 28-day cycle.

Wednesday, Friday, and Sunday every week, for a 28-day cycle.

Thursday, Saturday, and Monday every week, for a 28-day cycle.

Friday, Sunday, and Tuesday every week, for a 28-day cycle.
LY3039478 will be taken once per day on days of administration prior to a meal 
(recommendation is 30 minutes prior) on an empty stomach.  During all cycles, study drug 
should be taken at approximately the same time on the dosing days.  If a patient misses or vomits 
a dose, that dose should be omitted.


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The patient will be instructed to record time and amount of each dose in the patient diary through 
entire study and study monitors will cross-reference clinic records at the site to verify accuracy.
7.2.2. Dose Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
tolerability of LY3039478 for 50 mg TIW is confirmed.
Safety data, in particular AEs, will be the primary criteria for the dose escalation.  In addition, if 
available at the time of dose escalation decision, PK results (for example, Cmax and AUC) may 
be used as secondary/supporting data for dose escalation. If there are patients who are
considered nonevaluable for DLT, safety data from such patients should also be reviewed for the 
dose escalation decision.
Based on the ongoing safety reviews, modifications to the dose escalation strategy or other 
design elements may be made via protocol amendment to ensure patient safety.
7.2.2.1.
Dose-Limiting Toxicity Determination
Dose-limiting toxicity is defined as an AE during Cycle 1 (first 28 days) that is related to study 
drug and fulfills any one of the following criteria using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v 4.0:

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
-
asymptomatic electrolyte disturbance that can be controlled with treatment
-
Grade 3 diarrhea, stomatitis, or mucositis that lasts <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, unless there is a clear alternative 
cause (for example, worsening biliary obstruction) if agreed by the study 
investigator and Lilly CRP/CRS
-
tumor lysis/necrosis syndrome

CTCAE Grade 4 hematological toxicity of >5 days duration

CTCAE Grade ≥3 anemia which requires a transfusion of packed red blood cells

Any febrile neutropenia

Neutropenia that requires treatment with granulocyte-colony stimulating factors (G-
CSFs). However, the investigators and Lilly clinical research personnel will 
comprehensively determine the dose-limiting toxicity based on the clinical course of the 
patient, including laboratory test results.


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
CTCAE Grade 3 thrombocytopenia with bleeding, Grade 3 thrombocytopenia which 
requires platelet transfusion, or Grade 4 thrombocytopenia

Any other significant toxicity deemed by the investigators 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)
Dose-limiting toxicity will be confirmed based on the agreement between the primary 
investigator and the sponsor, with a consultation with the Safety Assessment Committee (SAC)
as needed.  
7.2.2.2.
Dose Escalation Method
In this study, dose escalation will be driven by safety using the 3+3 method.  Dose escalation 
will proceed as follows:
Dose Level 1 (25 mg):

3 patients will be enrolled.  If 1 out of 3 evaluable patients for DLT experience a DLT, 
3 additional patients will be enrolled in the same dose level.

If 0 out of 3, or 1 out of 6 evaluable patients for DLT experience a DLT, the dose will be 
escalated to Dose Level 2.

If dose escalation is made based on 3 evaluable patients in Dose Level 1 and Dose Level 
2 is judged as intolerable, an additional 3 patients will be enrolled in Dose Level 1 and 
tolerability of Dose Level 1 will be evaluated based on a total of 6 patients’ data.
Dose Level 2 (50 mg):

6 patients will be enrolled.  If ≤1 out of 6 evaluable patients for DLT experience a DLT, 
the dose will be judged as tolerable.
All dose levels:

If 2 patients experience DLTs at any given dose, the sponsor will examine the safety data 
and consult with the SAC as needed.  With the consultation, the sponsor and the primary 
investigator will decide if the dose is intolerable or additional patients will be enrolled to 
the same dose level.

If ≥3 patients experience DLTs at any given dose, it will be judged that the dose is not 
tolerable for Japanese patients.
An evaluable patient for DLT is defined as a patient who takes ≥75% of the planned dose in 
Cycle 1 (first 28 days) or a patient who experiences DLT in Cycle 1 (first 28 days).  A patient 
who takes <75% in Cycle 1 due to reasons other than drug-related toxicity (for example, early 
discontinuation due to progressive disease) will be considered nonevaluable for DLT and 
replaced by a new patient. If a patient takes <75% in Cycle 1 due to drug-related toxicities, the 
investigators and Lilly clinical research personnel will discuss whether the toxicities could be 


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deemed to be dose-limiting, and will consult with the SAC if needed. If it is not considered DLT, 
the patient is deemed to be nonevaluable for DLT and will be replaced by a new patient.
The reason for taking <75% of the planned dose needs to be documented appropriately and may 
be confirmed by the sponsor.
Dose escalation decisions will be made by agreement between the primary investigator and the 
sponsor, with a consultation with the SAC as needed.  Additional patients may be enrolled at a 
specific dose level to characterize PK/PD or safety profile.
Figure JJCC.2 illustrates the dose level transition method and tolerability confirmation.
Abbreviations:  DLT = dose-limiting toxicity; SAC = Safety Assessment Committee.
Figure JJCC.2.
Schema of dose level transition.
7.2.3. Dose Adjustments and Delays
7.2.3.1.
Dose Adjustments within Cycle 1
If a patient experiences a DLT, the patient should be discontinued from study treatment, unless, 
in the opinion of the investigator, the patient can clinically benefit from continuation of 
LY3039478 at a reduced dose level after the toxicity has recovered to baseline or Grade 1. For 
patients receiving Dose Level 1 (25 mg TIW), study treatment at 25 mg can be resumed and the 
dosing schedule may be modified, while safety assessment will be maintained as described in the 
Study Schedule (Attachment 1).  For these situations, agreement between the investigator and the 
sponsor is required and the patient will re-sign the ICF for the continuation of study treatment.
If a patient experiences a toxicity which does not meet the criteria for a DLT, but requires dose 
omission in the opinion of investigator, the dose can be omitted. Dosing may resume at the same 
dose after the toxicity resolves to baseline or Grade 1; however, the dose(s) omitted for 
tolerability during a cycle will not be replaced.
7.2.3.2.
Dose Adjustments within Cycle 2 and Beyond
If a patient treated at a given dose level experiences a DLET, the treatment will be discontinued
for that patient. The dose may be resumed at a reduced dose level after the toxicity resolves to 


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baseline or Grade 1 if the investigator determines that it is in the best interest of the patient. For
patients receiving 25 mg, the dosing schedule for resuming study treatment can be modified, 
while safety assessment will be maintained as described in the Study Schedule (Attachment 1).
For these situations, agreement between the investigator and the sponsor is required and the 
patient will re-sign the ICF for the continuation of study treatment.  
If a patient experiences a toxicity which does not meet the criteria for a DLET, but requires dose 
omission in the opinion of the investigator, the dose can be omitted. Dosing may resume at the 
same dose level after the toxicity resolves to baseline or Grade 1; however, the dose(s) omitted 
for tolerability during a cycle will not be replaced.  A DLET is defined as an AE occurring in any 
cycle (other than Cycle 1) that would have met the criteria for DLT if it had occurred during 
Cycle 1.
7.2.3.3.
Dose Adjustments Between Cycles
Before the start of each cycle, hematological and nonhematological toxicities (except alopecia 
and fatigue) must resolve to baseline or Grade 1.  The start of a cycle may be delayed up to 
3 weeks to allow sufficient time for recovery.  Patients not recovering from toxicity to baseline 
or Grade 1 within 3 weeks after development should be discontinued from study treatment.
The dose for a patient in Dose Level 2 should be reduced for all subsequent cycles of therapy to 
Dose Level 1 in the cases below:  
1.
if the investigator determines that it is in the best interest of the patient, or 
2.
if the patient experiences dose omission of >7 doses in a single cycle due to toxicities which 
are not considered DLTs/DLETs.
If a patient requires omission of >3 doses for tolerability at the reduced dose level in a single 
cycle, the patient should be discontinued from study treatment. 
Study treatment should be discontinued for patients started at 25 mg TIW who experience a 
toxicity requiring dose reduction. For such patients who experience toxicities that may cause 
discontinuation from study treatment as noted above, the dosing may be resumed at a reduced 
dose level after the toxicities have recovered to baseline or Grade 1 if, in the opinion of the 
investigator, those patients can clinically benefit from continuation of study drug.  For patients at 
25 mg, the dosing schedule for resuming study treatment can be modified while safety 
assessment will be maintained as described in the Study Schedule (Attachment 1). For the
exceptions noted above, agreement between the investigator and the sponsor are required and the 
patient will re-sign the ICF for the continuation of study treatment.
For patients requiring a dose reduction, re-escalation to the original dose level is not permitted.
A delay in the start of a cycle due to holidays, weekends, bad weather, or other unforeseen 
circumstances will be permitted up to 3 working days.
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3039478 in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted between 


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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/CRS.
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, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while patients are on this study. An exception will be made 
for prostate or breast cancer patients continuing gonadotropin-releasing hormone or luteinizing 
hormone-releasing hormone agonist therapy.  The need for any form of radiotherapy (except 
palliative) will be cause for early discontinuation from the study.  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 CRF.
Patients should receive full supportive care, with the exception that the routine use of 
granulocyte-colony stimulating factors (G-CSFs) is not permitted during this study. Patients 
should not receive G-CSFs prophylactically in any cycle.  Granulocyte-colony stimulating 
factors may only be used for patients who have ANC<0.5 × 109/L, neutropenic fever, or 
documented infections while neutropenic and 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, transfusions may be used according to ASCO guidelines (Schiffer et al. 2001; 
Rizzo et al. 2008).
Diarrhea should be managed by standard treatments as per institutional guidelines.  Guidance for 
diarrhea standard management is provided in Attachment 8.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.6.
Treatment Compliance
Patient compliance with study drug will be assessed at Day 1 of each cycle (other than Cycle 1)
by direct questioning or counting returned capsules, and reviewing patient diary.  More frequent 


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assessment may be performed if necessary.  Deviation(s) from the planned dosage regimen 
should be recorded on the CRF.
The patient must take 75% of the intended dose in a single cycle 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 planned
amount of study drug.  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/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.
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have 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 Cycle 1, may be replaced upon 
consultation with the investigator and the Lilly CRP/CRS to ensure adequate PK data, unless 
accrual to that cohort has stopped due to a DLT.
Any patient who is discontinued from study treatment before completing Cycle 1 will be deemed 
nonevaluable 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 may be replaced to ensure that the required number of patients complete 
Cycle 1, unless accrual to that cohort has stopped due to a DLT.
7.7.
Continued Access
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks.  
The continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
Patients who are in 30-day follow-up when the continued access period begins will continue in 
30-day follow-up until the 30-day follow-up visit is completed.
The patient’s continued access will end when a criterion for discontinuation is met (Section 6.3).  
Continued access follow-up will begin the day after the patient and the investigator agree to 
discontinue study treatment and lasts 30 (±3) days.


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Study procedures during continued access period are described in the Study Schedule (Continued 
Access) (Attachment 1).
Figure JJCC.3.
Continued access diagram.


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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 completed dose-escalation phase (Part A) of Phase 1 Study JJCA; 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 Japanese 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 or urine 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,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be study drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
For interstitial lung disease (ILD) and suspected ILD cases being diagnosed after starting the 
study drug, external specialists may evaluate related examination results, such as image data.  
The investigator will provide the test results, including imaging examination and pathological 
examination, upon request of the sponsor.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  Table
JJCC.1 presents a summary of AE and SAE reporting guidelines.
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 


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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.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect.
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE v 4.0.
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 4.03) may be used for this study.  Minor CTCAE v 4.0 
updates from the NCI will not necessitate a protocol amendment. For AEs without matching 
terminology within the 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 CRF.  This collection is in addition to verbatim text 
used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities dictionary.
Cases of pregnancy that occur following maternal or paternal exposures to study drug during the 
study and for 3 months following the last administration of the investigational product should be 
reported.  Data on fetal outcome and breastfeeding should be collected, if feasible, for regulatory 
reporting and drug safety evaluation.
Upon documentation of pregnancy, the patient must be removed from the study and treatment 
with study drug(s) must be stopped immediately.
For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition,
all AEs related to protocol procedures are reported to Lilly or designee.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via designated data transmission methods 
the circumstances and data leading to any such dosage reduction or discontinuation of treatment.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to study drug via designated data transmission methods.


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The investigator decides whether he or she interprets the observed AEs as either related to 
disease, study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.
8.1.2.1.
Serious Adverse Events
Planned (prior to signing the ICF) surgeries should not be reported as SAEs unless the 
underlying medical condition has worsened during the course of the study.
Planned hospitalizations or procedures for underlying preexisting conditions that are already 
recorded in the patient’s medical history at the time of study enrollment should not be considered 
SAEs.  Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
Serious adverse events due to disease progression, including death, should not be reported unless
the investigator deems them to be possibly related to the study drug.


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Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they
are to be immediately followed with official notification on study-specific SAE forms/electronic 
case report form (eCRF).  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
If an investigator becomes aware of SAEs occurring after the patient’s participation in the study
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor and the SAEs will be entered in the
Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.  Recommendations for reporting SAEs are provided in Attachment 5.
8.1.2.2.1. Prior to Administration of Study Drug(s)
Adverse event 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.
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.
This applies to the continued access period.
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 follow-up visit must be reported to Lilly or its designee.  The follow-up visit starts 
following the day after the patient and investigator agree to discontinue the 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 patient and 
the investigator agree that the patient will no longer continue study treatment.
Following the safety assessments, which mark the end of the 30-day follow-up visit, 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 related to 


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study drug or protocol procedure, 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 30-day follow-up visit, AEs and SAEs are not required to be reported unless the 
investigator judges whether the events have been related to either study drug or a protocol 
procedure.
This applies to the continued access follow-up in the continued access period. 
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 or 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 AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JJCC.1.
Table JJCC.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study JJCC
Timing
Types of AEs/SAEs Reported 
Prestudy (baseline assessments), per Section 8.1.2.2.1
Preexisting conditions
Procedure-related AEs/SAEs
On study, per Section 8.1.2.2.2
All AEs/SAEs regardless of relatedness
30-day follow-up visit, per Section 8.1.2.2.3
All AEs/SAEs regardless of relatedness
Subsequent follow-up visits, if necessary
Ongoing or new AEs/SAEs related to study drug, or 
protocol procedures
Abbreviations:  AE = adverse event; SAE = serious adverse event.
8.1.3. Vital Signs and Laboratory Measurements
8.1.3.1.
Electrocardiograms
For each patient, a 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1) and the Pharmacokinetic, Pharmacodynamic, and Pharmacogenetic Sampling 
and Electrocardiogram Schedule (Attachment 3).  Patients must be supine for approximately 5 to 
10 minutes before ECG collection and remain supine but awake during ECG collection.  
Consecutive replicate ECGs (triplicates) will be obtained at approximately 1-minute intervals. It 
is highly recommended that ECGs are recorded before collecting any blood for safety or PK 
tests.
Electrocardiograms 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.


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Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria 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. Any new clinically relevant findings should 
be reported as an AE.
All digital ECGs designated for central evaluation and over-read will be electronically 
transmitted to a central ECG laboratory designated by Lilly. For central ECGs, a cardiologist at 
the central ECG laboratory will conduct a full over-read on 1 of the replicates (including all 
intervals). A report based on data from this over-read will be issued to the investigative site.  For 
each set of replicates, the cardiologist will determine the RR and QT intervals and heart rate on 
the ECGs that were not fully over-read.  These data are not routinely reported back to the 
investigative site. All data from the over-reads will be placed in the Lilly database for analytical 
and study report purposes.  However, any clinically significant finding that was not present on 
the fully over-read ECG will be reported to the investigator and to Lilly.  It is recognized that 
ECG interpretations by the investigator (or qualified designee) and by the cardiologist at the 
central ECG laboratory may be different. When there are differences in ECG interpretation 
between the investigator (or qualified designee) and the cardiologist at the central ECG 
laboratory, the investigator’s (or qualified designee’s) interpretation will be used for study entry 
and immediate patient management.  Interpretations from the cardiologist at the central ECG 
laboratory will be used for data analysis and report writing purposes.  The investigator (or 
qualified designee) must document the final over-read ECG report issued by the central ECG 
laboratory, and any alert reports.
8.1.4. Safety Monitoring
The Lilly CRP/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 research 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


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
If a study patient experiences elevated ALT ≥5 × ULN and elevated total bilirubin 
≥2 × ULN, clinical and laboratory monitoring should be initiated by the investigator. 

For patients entering the study with ALT >3 × ULN, monitoring should be triggered at 
ALT ≥2 × baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 4).
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated AEs using 
the study-specific complaint forms provided for this purpose.

faxing the completed complaint form within 24 hours to Lilly or its designee.
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
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, pharmacogenetic, ECG, and blood plasma biomarker
sampling schedule for this study.
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.  
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.


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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.
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 scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Pharmacokinetic Samples
Pharmacokinetic samples will be collected as specified in the Pharmacokinetic,
Pharmacodynamic, and Pharmacogenetic Sampling and Electrocardiogram 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 a validated liquid 
chromatography-tandem mass spectrometry (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, 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 a 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 investigational product concentration and 
metabolism will be retained for a maximum of 2 years following last patient visit for the study.
8.2.3. Pharmacogenomic 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 


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regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.  
This will be a 1-time collection, as noted in the Study Schedule (Attachment 1 and Attachment 
3).
Pharmacogenetic biomarker samples of 10 mL will be collected in this study.  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 pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to 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.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis. These results may not 
be disclosed to patients, because this research is exploratory and the outcome based on the 
research may not be sufficiently validated to disclose to the patients. When a patient withdraws 
his/her consent and requests to discard these samples (for example, blood or deoxyribonucleic 
acid), the samples will be destroyed. Analysis results which are available before the consent 
withdrawal may be published in articles or other disclosures without an identifiable individual 
patient.
The samples will be coded with the patient number and stored for up to 15 years after the last 
patient visit for the study at a facility selected by the sponsor.  The samples and any data 
generated from them can only be linked back to the patient by investigator site personnel. The 
duration allows the sponsor to respond to regulatory requests related to the study drug.
8.2.4. Exploratory Samples
Required samples for biomarker research to be collected from all patients in this study are the 
following:

blood samples (see Sections 8.2.4.1 and 8.2.4.2)

tumor tissue (archived or newly biopsied) and skin biopsies (see Section 8.2.4.3)
Samples for biomarker research will be collected as specified in Attachment 3, where local 
regulations allow.  These samples are also described in the following subsections.
It is possible that biomarker data for patients in the study has already been generated from 
samples that were collected and analyzed prior to enrolling in this trial.  This may include data 
generated from genetic analyses. If available, these data may be requested from medical records 
for use in the research described in Sections 8.2.4.1 through 8.2.4.3.


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8.2.4.1.
Blood Samples for Amyloid Beta Assays
Blood samples will be collected for exploratory analysis of circulating Amyloid-β (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 60 days after the testing lab has 
released the 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.  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
Blood samples for nonpharmacogenetic biomarker research will be collected as specified in
Attachment 1 and Attachment 3, where local regulations allow.
Blood samples will be examined for biomarkers related to solid tumors, the Notch signaling 
pathway and drug target pathways, immune functioning, variable response to LY3039478, 
mechanism of action of study drug, and/or for research-related methods, or validating diagnostic 
tools or assays.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs/institutional review boards (IRBs) impose 
shorter time limits, at a facility selected by Lilly.  This retention period enables use of new 
technologies, response to questions from regulatory agencies, and investigation of variable 
response that may not be observed until later in the development of LY3039478 or after 
LY3039478 becomes commercially available.
8.2.4.3.
Tumor and Skin Biopsies
Samples will be examined for biomarkers related to the Notch signaling pathway and drug target 
pathways, immune functioning, variable response to LY3039478, and mechanism of action of 
study drug or disease state, and to correlate these markers to clinical outcome and/or for 
research-related methods, or validating diagnostic tools or assays.
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. Skin biopsy is mandatory and collected as specified in Attachment 1 and 
Attachment 3. Collection of tumor biopsies collected pre- and posttreatment is optional.
Table JJCC.2 presents tumor and skin biopsy collection times. Tumor biopsy must be collected 
only if the investigator does not anticipate any significant bleeding post-treatment. If the 
investigator considers a high risk of significant bleeding, the procedure should be omitted.


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Table JJCC.2.
Tumor and Skin Biopsy Time Points
Collection Time Point
Requirement
Baseline archived tumor tissue collection
Optional
Pre-/postdose tumor biopsies
Optional
Pre-/postdose skin biopsies
Mandatory
In addition to the required and optional biopsies and biomarker sample collections, patients may 
be asked to undergo collection of an additional biopsy specimen and blood sample after 
treatment with the study drug has been initiated, including potentially after disease progression.  
Such additional biopsies are optional and should be performed only if clinically feasible.  If these 
additional samples are requested, they will be used to further investigate biomarkers that may 
explain treatment response and resistance mechanisms.
Formalin-fixed paraffin-embedded tumor tissue should be provided as a block or unstained 
slides.  Due diligence should be used to make sure that tumor sample (not a normal adjacent or a 
tumor margin sample) is provided.  Pathology reports accompanying archival tissue may also be 
requested.  The report must be coded with the patient number.  Personal identifiers, including the 
patient’s name and initials, must be removed from the institutional pathology report prior to 
submission.  Archival blocks will be sectioned and returned to the study site.  Slides and tissue 
samples collected on-study will not be returned.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility 
selected by Lilly.  This retention period enables use of new technologies, response to questions 
from regulatory agencies, and investigation of variable response that may not be observed until 
later in the development of LY3039478 or after LY3039478 becomes commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  However, existing technologies, including mutation profiling, copy number 
variability, gene expression, multiplex assays, and/or immunohistochemistry may be performed 
on these tissue samples to assess potential associations with these biomarkers and clinical 
outcomes.
8.3.
Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1
for details regarding the timing of specific efficacy measures.
Each patient will be assessed by 1 or more of the following radiologic tests for tumor 
measurement (computed tomography [CT] scan or magnetic resonance imaging is mandatory):

CT scan

magnetic resonance imaging

chest x-ray (may be omitted in patients having a chest CT for their radiological tumor 
assessment)


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
PET scan (optional).
Each patient’s full extent of disease will also be assessed with:

applicable tumor measurement, including overall response rate by RECIST v1.1 
(Eisenhauer et al. 2009; Attachment 9) or the Response Assessment in Neuro-
Oncology criteria for glioblastoma (Wen et al. 2010)

applicable tumor measurement by PET response criteria of the European 
Organization for Research and Treatment of Cancer (Young et al. 1999) if 
performed

evaluation of tumor markers, if indicated

evaluation of performance status (refer to the ECOG scale, Attachment 6).
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.
Endpoint
Definition
Overall response rate
Solid tumor measurement by RECIST v1.1 (Eisenhauer et al. 2009)
Evaluation of tumor markers
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 lab requisition form.
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.


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9.
Data Management Methods
9.1.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide 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 ERBs/IRBs 
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 a daily 
dosing schedule or an event diary.
For data handled by a data management third-party organization (TPO), CRF data will be 
managed and stored in the electronic data capture system.  Subsequent to the final database lock, 
validated data will be transferred using standard Lilly file transfer processes.


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9.2.2. Ancillary Data
Data managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system.  Data will subsequently be transferred 
from the central vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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10. Data Analyses
10.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.  The analyses for this study 
will be descriptive, except for possible exploratory analysis as deemed appropriate.
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. Analysis Populations
Each analysis is done on a specific analysis population. The analysis populations are defined as 
follows:

Efficacy Analyses Set: All patients who have received at least 1 dose of study drug and 
who are evaluable for the assessment of a dose level will form the efficacy analysis set.  
This population will be used in all efficacy reporting and analyses.

Safety Analyses Set: 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, will 
form the safety analysis set.  This population will be used in all safety reporting and 
analyses.

DLT Analyses Set: All patients in safety analysis set who are deemed evaluable for the 
assessment of DLT will form the DLT analyses set. The following patients will not be 
considered as evaluable for DLT:
o
Any patients who are discontinued from the study before completing 1 cycle of 
LY3039478 treatment will be deemed nonevaluable for assessment of a dose level, 
unless they experience a DLT prior to withdrawal.
o
If a patient is noncompliant during Cycle 1 due to reasons other than drug-related 
toxicity, he or she will be considered nonevaluable and may be replaced.

PK/PD Analyses Set: All patients who have received at least 1 dose of the study drug 
and have had sufficient postdose samples collected to allow estimation of PK parameters 
will form the PK/PD analyses set.  This population will be used in all PK/PD reporting 
and analyses.
10.2. Patient Disposition
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.


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10.3. Patient Characteristics
Patient characteristics will include a summary of the following:

patient demographics (including age, sex, screening height and weight, and screening 
body mass index)

baseline disease characteristics

prior disease-related therapies

concomitant medications.
Other patient characteristics will be summarized as deemed appropriate.
10.4. Safety Analyses
All patients who receive at least 1 dose of LY3039478 will be evaluated for safety and toxicity.  
Adverse event terms and severity grades will be assigned by the investigator using CTCAE v 
4.0.  Note that any minor version of CTCAE v 4.0 (for example, CTCAE v 4.03) may be used for 
this study.
Safety analyses will include summaries of the following:

DLTs at each dose level (using the DLT analysis set; see Section 10.1.1)

AEs, including severity and possible relationship to study drug

dose adjustments

laboratory values

vital signs and physical examination

ECG readings.
10.5. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of the 
study drug and have had samples collected.
Pharmacokinetic parameter estimates for LY3039478 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax and AUC from time zero to infinity or over 
1 dosing interval at steady state (AUCτ,ss) of LY3039478.  Other noncompartmental parameters, 
such as time of t1/2, apparent systemic clearance, and apparent volume of distribution 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.


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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.
10.6. Pharmacokinetic/Pharmacodynamic Analyses
The PK data will be combined, and analyses may be conducted to determine a relationship 
between exposure and PD/pharmacogenetic 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.
10.7. Efficacy
The study was not designed to make a formal efficacy assessment.  However, any tumor 
response data will be tabulated.
10.8. 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.
10.9. Interim Analyses
Interim access to safety data, including DLTs, will be performed during the study.  In order to 
assess DLTs, which is key to proceed with dose escalation or to determine a tolerable dose, a 
DLT evaluation form at Dose Level 1 and Dose Level 2 will be prepared.  Therefore, no
database lock activities on safety CRF pages are mandatory.
Interim analyses for safety and PK may be conducted after all patients receiving Dose Level 2 
complete Cycle 1 (DLT evaluation period).
Additional interim analyses may be conducted when deemed necessary (for example, in case of a 
safety concern).
If it is deemed that enough data is obtained to assess the primary objective and the secondary 
objectives, a clinical study report might be created before the last patient visit.  In this case, all 
data until the data cutoff date will be used for the analysis of safety, efficacy, PK, and PD
biomarkers.  All data defined in the protocol will continue to be collected from patients on 
treatment after the data cutoff date.  These data may be reported separately and the analyses on 
all patients, including these data, may not be performed.


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11. Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. Informed Consent
The investigator 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 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

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
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 investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
If multiple sites participate in the study, the investigator with the most qualified patients will 
serve as the final report coordinating investigator and will sign the clinical study report for this 
study.  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 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 sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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12. References
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Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
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Fine KD, Schiller LR. AGA technical review on the evaluation and management of chronic 
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Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, Jacobs RT, Zacco A, 
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Murray PT, Ratain MJ. Estimation of the glomerular filtration rate in cancer patients: a new 
formula for new drugs. Clin Oncol. 2003;21(14):2633-2635.
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Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, Escaramis G, Jares P, Bea
S, Gonzalez-Diaz M, Bassaganyas L, Baumann T, Juan M, Lopez-Guerra M, Colomer D, 
Tubío JM, Lopez C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernandez JM, Puente 
DA, Freije JM, Velasco G, Gutierrez-Fernandez A, Costa D, Carrio A, Guijarro S, Enjuanes A, 
Hernandez L, Yagüe J, Nicolas P, Romeo-Casabona CM, Himmelbauer H, Castillo E, Dohm 
JC, de Sanjose S, Piris MA, de Alava E, San Miguel J, Royo R, Gelpí JL, Torrents D, Orozco 
M, Pisano DG, Valencia A, Guigo R, Bayes M, Heath S, Gut M, Klatt P, Marshall J, Raine K, 
Stebbings LA, Futreal PA, Stratton MR, Campbell PJ, Gut I, Lopez-Guillermo A, Estivill X, 
Montserrat E, Lopez-Otín C, Campo E. Whole-genome sequencing identifies recurrent 
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Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev 
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Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, 
Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, 
Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response 
assessment criteria for high-grade gliomas: response assessment in neuro-oncology working 
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Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P. 
Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and 
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Cancer. 1999;35(13):1773-1782.


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Attachment 1.
Protocol JJCC Study Schedule


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Study Entry (Screening and Baseline) to Cycle 1 Assessments
Cycle/Visit
Screening/Baseline
Cycle 1
Day Relative to Day 1 in Each Cycle
≤28
≤14
≤7
Week 1
Week 2
Week 3
Week 4
1
3
5
8
10
12
15
17
19
22
24
26
LY3039478 therapy (dose)a
1
2
3
4
5
6
7
8
9
10c
11
12
Informed consent
X
Medical history
X
Physical examination
X
X
X
X
X
X
X
X
X(±3)
Vital signs and weight
X
X
X
X
X
X
X
X
X(±3)
Height
X
ECOG performance status
X
X
X
X
X
X
X
X
X(±3)
ECG
X
X
X
Hematology/serum chemistry
X
X
X
X
X
X
X
X
X(±3)
Coagulation
X
X
X
X
X
X
X
X
X(±3)
Urinalysis
X
X
X
X
X
X
X
X
X(±3)
Pregnancy test (if applicable)
X
Serum creatinine
X
X
ECG chemistry
X
X
Blood PD biomarkers (Aβ)
X
X
X
Blood for exploratory biomarker research (predose)
X
Urine collection (0 to 8-10 hours)
X
Blood PK sampling
X
X
Pharmacogenetic sampling
X
Radiological tumor assessment (CT/MRI)
X
Tumor biopsy (optional)
X
X
Tumor marker (if applicable)
X
X(±3)
Tumor measurement (palpable or visible if applicable)
X
Archival tumor tissue sample (optional)
X
Skin biopsy (mandatory)
X
X
Chest X-ray
X
PET scan (optional)
X
CTCAE grading
X
Concomitant medications
X
Dispense/return LY3039478, diary/drug accountability
X


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Cycle 2 Assessments
Cycle/Visit
Cycle 2
Day Relative to Day 1 in Each Cycle
Week 1
Week 2
Week 3
Week 4
1b
3
5
8
10
12
15
17
19
22
24
26
LY3039478 therapy (dose)a
1
2
3
4
5
6
7c
8
9
10c
11
12
Physical examination
X
X(±3)
Vital signs and weight
X
X(±3)
ECOG performance status
X
X(±3)
ECG
X
Hematology/serum chemistry
X
X(±3)
Coagulation
X
X(±3)
Urinalysis
X
X(±3)
ECG chemistry
X
Blood PD biomarkers (Aβ) (predose)
X
Blood PD biomarkers for exploratory biomarker 
research (predose)
X
Blood PK sampling (predose)
X
Tumor marker (if applicable)
X(±3)
Radiological tumor assessment (CT/MRI)
X
No more than 10 days prior 
to Day 1 of Cycle 3
Tumor measurement (palpable or visible if applicable)
Chest X-ray
PET scan (optional)
X
CTCAE grading
X
Concomitant medications
X
Dispense/return LY3039478, diary/drug accountability
X


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Cycle 3 to Follow-up Assessments
Cycle/Visit
Cycle 3-n
30-day 
Follow-
up
Visitd
Day Relative to Day 1 in Each Cycle
Week 1
Week 2
Week 3
Week 4
1b
3
5
8
10
12
15
17
19
22
24
26
LY3039478 therapy (dose)a
1
2
3
4
5
6
7c
8
9
10
11
12
Physical examination
X
X
Vital signs and weight
X
X
ECOG performance status
X
X
Hematology/serum chemistry
X
X(±3)
X
Coagulation
X
X(±3)
X
Urinalysis
X
X(±3)
X
Blood PD biomarkers (Aβ) (predose)
X
X
Blood PD biomarkers  for exploratory biomarker 
research (predose)
X
X
Tumor marker (if applicable)
X(±3)
X
Radiological tumor assessment (CT/MRI)
X(±3)
Xe
Tumor measurement (palpable or visible if applicable)
X(±3)
Xe
Chest X-ray
X(±3)
Xe
CTCAE grading
X
X
Concomitant medications
X
X
Dispense/return LY3039478, diary/drug accountability
X
Abbreviations:  Aβ = Amyloid-β; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; MRI = magnetic resonance imaging; PD = pharmacodynamic; PET = positron emission tomography; PK = pharmacokinetic
a
LY3039478 is to be administered 3 times per week through each 28-day cycle.
b
A delay in the start of a cycle due to holidays, weekends, bad weather, or other unforeseen circumstances will be permitted up to 3 working days.
c
The doses need to be done on the planned date.
d
30-day follow-up visit to occur 30 days (±3) after the patient and the investigator agree that the patient will no longer continue study treatment.
e
For patients who discontinue study treatment without objectively measured progressive disease, subsequent assessments are not required.  Refer to comments for those 
assessments in the table below for details.


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Assessment
Comments
Informed consent
Informed consent form must be signed before performing any protocol procedure.
Medical history
Including alcohol/tobacco use and other relevant habits assessments.  Also, any preexisting and pretreatment toxicity (treatment- or disease-related) 
should be documented and recorded as part of the pretreatment (baseline) medical history.
Physical examination
Physical exam per local practice needs to be performed prior to drug administration at each scheduled time point. 
Vital signs and weight
Including temperature, blood pressure, pulse rate, respiration rate.
Height
Height measurements to be performed at baseline only.
ECOG performance 
status
Assessment needs to be completed prior to drug administration at each scheduled time point.
ECG
For Screening/ Baseline:
One set of triplicate ECGs, central.
For Cycle 1:
Perform central triplicate ECGs at 1, 2, 4, and 24 to 30 hours postdose for Dose 1 (Day 1).
Perform central triplicate ECG at 1, 2, 4, and 24 to 30 hours postdose for Dose 10 (Day 22).
For Cycle 2:
Perform central triplicate ECG prior to start of treatment.
Refer to Attachment 3 for detailed time points.
Hematology/serum 
chemistry
Conducted at local laboratory.  Refer to Attachment 2 for details.  It is acceptable to use the test results of the hematology/chemistry laboratory values 
obtained during screening if the tests have been performed within 3 days before Day 1 of Cycle 1.  It is also acceptable to use the test results if the tests 
have been performed within 3 days before Day 1 of each cycle. 
Coagulation
aPTT, PT/INR, fibrinogen, fibrin/fibrinogen degradation products (FDP), and D-dimer.  Conducted at local laboratory.  It is acceptable to use the test 
results of the coagulation values obtained during screening if the tests have been performed within 3 days before Day 1 of Cycle 1.  It is also acceptable 
to use the test results if the tests have been performed within 3 days before Day 1 of each cycle.
Serum creatinine
Conducted at local laboratory.  Performed at screening/baseline, predose, 1, 4, and 8 to 10 hours postdose.
ECG chemistry
Conducted at local laboratory.  Refer to Attachment 2 and Attachment 3 for details.
Pregnancy test (if 
applicable)
Serum or urine pregnancy test will be conducted at local laboratory at screening/baseline.  Negative results prior to dosing required for women of 
childbearing potential.
Urinalysis
Conducted at local laboratory.  Refer to Attachment 2 for details.  It is acceptable to use the test results obtained during screening if the tests have been 
performed within 3 days before Day 1 of Cycle 1.  It is also acceptable to use the test results if the tests have been performed within 3 days before 
Day 1 of each cycle.


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Assessment
Comments
Urine collection
All urine will 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 number 8; refer to Attachment 3).  The collected urine will 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.  Urine sample number 1 for creatinine should not be frozen, but the two 10-mL samples (urine sample number 2 and 3) should be frozen at the 
end of the collection period and should be shipped frozen.
Blood PD biomarkers 
(Aβ)
Assayed by Lilly-designated laboratory.  Refer to Attachment 3 for detailed time points.
Blood PD biomarkers 
for exploratory 
biomarker research
Collected predose at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and 30-day follow-up visit, and assayed by Lilly-designated laboratory.  Refer to 
Attachment 3 for detailed time points.
PK sampling
Assayed by Lilly-designated laboratory.  Refer to Attachment 3 for detailed time points.
Pharmacogenetic 
sampling
Assayed by Lilly-designated laboratory.  This is a 1-time sample which may be taken prior to start of treatment (Cycle 1 predose).
Skin biopsy
Mandatory.  Collected at baseline/screening and postdose (6 to 8 hours after Dose 1).  Additional optional skin biopsies may be performed at time of 
disease progression and if deemed necessary by the investigator.  The samples will be analyzed at laboratories using assays designated by Lilly. 
Archival tumor tissue 
sample (optional)
Optional.  Request archived paraffin-embedded tumor tissue, but only after study eligibility is confirmed.  The archived tumor samples can be shipped 
anytime during the study.  Availability of archived tissue is optional for participation in this study but is highly encouraged.  If archived tumor is not 
available, it will not constitute a protocol deviation.
Tumor biopsy (optional)
Optional. Collected at baseline/screening and posttreatment tumor biopsy should be obtained (whenever clinically feasible) at Cycle 1, preferably 6 to 
8 hours after Dose 10 (Day 22).  Greater flexibility has been provided for the posttreatment tumor biopsy (between Doses 7 and 12, inclusive) 
compared to other Dose 10 visit assessments (±3 days of planned visit) 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 Cycle 1 Day 22 (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 must be collected only if the investigator does not 
anticipate any significant bleeding post-treatment. If the investigator considers a high risk of significant bleeding, the procedure should be omitted.
Tumor marker (if 
applicable)
Optional.  Conducted at local laboratory, if applicable.


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Assessment
Comments
Radiological tumor 
assessment (CT/MRI)
Radiological assessment is performed at baseline (up to 28 days before the first dose but the assessment obtained prior to informed consent may be used 
as the baseline assessment provided they were performed within 28 days of Cycle 1 Day 1), then at the end of Cycle 2 (no more than 10 days prior to 
Day 1 of Cycle 3[inclusive]).  If the start of Cycle 3 is delayed, then it is not necessary to perform the assessment again in the time window of 10 days 
prior to Day 1 of Cycle 3.  After Cycle 4 (inclusive), radiological assessment is performed at Day 15 of every other cycle.  Radiological assessment 
performed out of time window (±3 days of planned date) due to logistical reasons or patient safety concerns may not be considered as a deviation but 
the investigator should make every effort to conduct as close to the time window as possible.  For patients who discontinue study treatment without 
objectively measured progressive disease, the radiological tumor assessment is not required. If the result of assessment is available by 30- day follow-
up visit, it should be reported.
Tumor measurement 
(palpable or visible)
Performed at the same timing as radiological tumor assessment.  Visible tumor (such as skin lesions) should be documented by photography and each 
photographic image of the tumor should include a ruler.
PET scan
Optional.  Performed locally at baseline/screening and during Cycle 2 (not limited to Dose 1) repeated at the discretion of the investigator.
Chest X-ray
The chest X-ray will be measured on the same date as radiological tumor assessment. May be omitted in patients having a chest CT scan for their 
radiological tumor assessment
CTCAE grading
Refer to Section 8.1.2 for reporting guidelines.
Concomitant 
medications
Performed throughout study. 
Collection of concomitant medication post-study treatment discontinuation, including subsequent cancer treatment, will last until the end of 30-day
follow-up visit.
Dispense/return
LY3039478, diary/drug
accountability
Performed at the end of each cycle or the start of each cycle, and the end of study treatment.
Abbreviations:  Aβ = Amyloid-β; aPTT = activated partial thromboplastin time; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG 
= electrocardiogram; ECOG = Eastern Cooperative Oncology Group; MRI = magnetic resonance imaging; PD = pharmacodynamic; PET = positron emission tomography; PK 
= pharmacokinetic; PT/INR = prothrombin time/international normalized ratio.


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Continued Access
Cycle/Visit
Cycle n
30-day 
Follow-
up
Visitc
Day Relative to Day 1 in Each Cycle
Week 1
Week 2
Week 3
Week 4
1b
3
5
8
10
12
15
17
19
22
24
26
LY3039478 therapy (dose)a
1
2
3
4
5
6
7
8
9
10
11
12
CTCAE grading
X
X
Dispense/return LY3039478, diary/drug accountability
X
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a
LY3039478 is to be administered 3 times per week through each 28-day cycle.
b
A delay in the start of a cycle due to holidays, weekends, bad weather, or other unforeseen circumstances will be permitted up to 3 working days.
c
30-day follow-up visit to occur 30 days (±3) after the patient and the investigator agree that the patient will no longer continue study treatment.
Note: Efficacy assessments will be done at the investigator’s discretion based on the standard of care.
Assessment
Comments
CTCAE grading
Refer to Section 8.1.2 for reporting guidelines.
Dispense/return
LY3039478, diary/drug
accountability
Performed at the end of each cycle or the start of each cycle, and the end of study treatment.
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events.


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Attachment 2.
Protocol JJCC Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Serum concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Phosphorus
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes
ALT
Eosinophils
AST
Basophils
GGT
Platelets
BUN
Reticulocytes
Creatinine
Lipase
Coagulationa
Uric acid
aPTT
Calcium
PT/INR
Glucose, random
Fibrinogen
Albumin
D-dimer
Total protein
Fibrin/fibrinogen degradation products (FDP)
Lactate dehydrogenase (LDH)
Cholinesterase (ChE)
Urinalysisa
ECG Chemistrya
Specific gravity
Lipasec
pH
Thyroid stimulating hormone (TSH) 
Protein
Free tri-iodothyronine (fT3)
Glucose
Free thyroxine (fT4)
Ketones
Albuminc
Blood
Glucose, randomc
Calciumc
Serum or urine pregnancy test (females with 
child-bearing potential only) a
Sodiumc
Potassiumc
Phosphorusc
Tumor markersa
Magnesium
Biomarkersb (research laboratory tests)
Serum creatininea,d
Pharmacogenomicb
Pharmacokineticb
Abbreviations:  ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; ECG = electrocardiogram; GGT = gamma glutamyl transferase; 
PT/INR = prothrombin time/international normalized ratio; 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.


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Attachment 3.
Protocol JJCC Pharmacokinetic,
Pharmacodynamic, and Pharmacogenetic Sampling and 
Electrocardiogram Schedule


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Cycle
Dose 
Number
(Day)
Sample 
Number
PK 
Sampling 
Timea
Urine 
Samplinga
Serum 
Creatinine 
Sampling 
Time
PD Aβ (1-x) 
Sampling Time
PD biomarkers 
for exploratory 
biomarker 
research
PD Skin 
Biopsies 
Sampling 
Time
Pharmaco-
genetic 
Sampling
Time
ECG with 
ECG  
Chemistry
Screening
Screening
1
Screening
Screening
Screening
Screening
1
1
(Day 1)
2
Predose
0 to 8-10-hr 
pooled 
samples 
(end time 
of sample 
to coincide 
with PK 
blood 
draw).
Predose
Predose
Predose
Predose
Predose
3
0.5 hr
4
1 hr
1 hr
1 hr
5
2 hr
2 hr
2 hr
6
4 hr
4 hr
4 hr
4 hr
7
6-8 hr
6-8 hr
6-8 hr
8
8-10 hr
8-10 hr
8-10 hr
9
24-30 hr
24-30 hr
24-30 hr
10
(Day 22)
10
Predose
Predose
Predose
11
0.5 hr
12
1 hr
1 hr
13
2 hr
2 hr
2 hr
14
4 hr
4 hr
4 hr
15
6-8 hr
6-8 hr
16
8-10 hr
8-10 hr
17
24-30 hr
24-30 hr
24-30 hr
2
1
(Day 1)
18
Predose
Predose
Predose
Predose
3
1
(Day 1)
19
Predose
Predose
30-day Follow-up visit
20
Same time as other 
safety assessment
Same time as other 
safety assessment
Abbreviations:  Aβ = Amyloid-β; ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic;.
a
All urine will be collected between 0 and 8-10 hours.  The urine collection should cease at the time that the Dose 1, 8- to 10-hour PK sample is drawn (Sample number 8).  The 
collected urine will 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.  Urine sample number 1 for creatinine should not be frozen, but the two 10-mL samples (urine sample number 2 
and 3) should be frozen at the end of the collection period and should be shipped frozen.


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Attachment 4.
Protocol JJCC Hepatic Monitoring Tests 
for Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Recommended Autoimmune Serologya
AST
Anti-nuclear antibody
GGT
Anti-smooth muscle antibody
CPK 
Anti actin antibody
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by central laboratory or local/investigator-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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


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Attachment 6.
Protocol JJCC Eastern Cooperative 
Oncology Group Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out performance of a light or sedentary nature, for example,
light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair
5
Dead
Reference:  Oken et al. 1982.


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Attachment 7.
Protocol JJCC 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.
Abbreviations:  CrCl = creatinine clearance; wt = weight (in kilograms).
Reference:  Cockcroft and Gault 1976.
-OR-
GFR(mL/min/1.73m2) = 170 × [PCr]-0.999 × [age]-0.176
× [0.762 if patient is female] × [1.18 if patient is black]
× [SUN]-0.17 × [Alb]+0.318
Abbreviations:  PCr= plasma creatinine, mg/dL; SUN= serum urea nitrogen, mg/dL; Alb= serum albumin, 
g/dL.
Reference:  Murray and Ratain 2003.


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Attachment 8.
Protocol JJCC Guidance for Diarrhea 
Management
Diarrhea should be managed by standard treatments as per institutional guidelines.  Guidance 
used in the phase 1 study (JJCA) for diarrhea standard management is provided as below.
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, and 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 should 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).


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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 should 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 
not need hospitalization.  Observe patient for response to antidiarrheal treatment.  
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 48 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 intravenous (IV) fluids and antibiotics as needed with monitoring of 
patients condition (to rule out dehydration, sepsis, ileus) medical check and workup.  Observe 
patient for response.
After 12 to 24 hours:

If diarrhea is still persisting, administer subcutaneous (SC) Sandostatin/octreotide 
(100 to 500 g 3 times per day [TID]).

Continue IV fluids and antibiotics as needed.


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
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 g 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).
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.


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Attachment 9.
Protocol JJCC RECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST):  Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis,  inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:  

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.


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


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


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


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


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


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


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Attachment 10. Protocol I6F-JE-JJCC(b) Amendment 
Summary [A Phase 1 Study of LY3039478 in Japanese 
Patients with Advanced Solid Tumors]
Overview
Protocol I6F-JE-JJCC [A Phase 1 Study of LY3039478 in Japanese Patients with Advanced 
Solid Tumors] has been amended.  The new protocol is indicated by Amendment (b) and will be 
used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Section 2: Deleted the Length of the Study since it is defined in the protocol 
separate brochure separately.

Section 6.2.1.: Clarified the definition of the study completion and the end of the trial.

Sections 7.7.: Added new section for the continued access.

Section 8.1.2.2.2. and Section 8.1.2.2.3.: Added the Adverse Event and Serious 
Adverse Event Reporting during the continued access.

Attachment 1.: Added new table for the continued access.

Minor editorial changes were made for clarity.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2. Synopsis
[…]
Length of Study:
Planned first patient visit: July 2016
Planned last patient visit:  April 2017 (End of study is defined as the last visit or last scheduled 
procedure shown in the Study Schedule for the last active patient in the study.)
6.2.1 Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) after all patients have completed treatment and their safety summary visit.  Study 
completion will occur following the data cutoff date for the primary analysis of primary and 
secondary objectives.  The data cutoff date will be the time of when it is deemed that enough 
data is obtained for the analysis as determined by Lilly.  Investigators will continue to follow 
Study Schedule for each cycle (Attachment 1) for all patients until notified by Lilly that study 
completion has occurred.  The “end of trial” refers to the date of the last visit or last scheduled 
procedure for the last patient.  “End of trial” occurs after study completion and after the last 
patient has discontinued study treatment and completed the final follow-up visit (including the 
final follow-up visit for the continued access period, if applicable) or has been declared lost to 
follow-up.
7.7 Continued Access
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks.  
The continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
Patients who are in 30-day follow-up when the continued access period begins will continue in 
30-day follow-up until the 30-day follow-up visit is completed.
The patient’s continued access will end when a criterion for discontinuation is met (Section 6.3).  
Continued access follow-up will begin the day after the patient and the investigator agree to 
discontinue study treatment and lasts 30 (±3) days.
Study procedures during continued access period are described in the Study Schedule (Continued 
Access) (Attachment 1).


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Figure JJCC.3.
Continued access diagram.
8.1.2 Adverse Events
[…]
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.
8.1.2.2.2 On Study
[…]
This applies to the continued access period.
8.1.2.2.3 Follow-Up Visit
[…]
This applies to the continued access follow-up in the continued access period.


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Attachment 1. Protocol JJCC Study Schedule
[…]
Continued Access
Cycle/Visit
Cycle n
30-day 
Follow-
up
Visitc
Day Relative to Day 1 in Each Cycle
Week 1
Week 2
Week 3
Week 4
1b
3
5
8
10
12
15
17
19
22
24
26
LY3039478 therapy (dose)a
1
2
3
4
5
6
7
8
9
10
11
12
CTCAE grading
X
X
Dispense/return LY3039478, diary/drug accountability
X
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a
LY3039478 is to be administered 3 times per week through each 28-day cycle.
b
A delay in the start of a cycle due to holidays, weekends, bad weather, or other unforeseen circumstances will be permitted up to 3 working days.
c
30-day follow-up visit to occur 30 days (±3) after the patient and the investigator agree that the patient will no longer continue study treatment.
Note: Efficacy assessments will be done at the investigator’s discretion based on the standard of care.
Assessment
Comments
CTCAE grading
Refer to Section 8.1.2 for reporting guidelines.
Dispense/return
LY3039478, diary/drug
accountability
Performed at the end of each cycle or the start of each cycle, and the end of study treatment.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events.


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Attachment 4.  Protocol JJCC Clinical Laboratory Tests
[…]
a
Assayed by central laboratory or local/investigator-designated laboratory.
[…]


Leo Document ID = 326cc5d2-f45e-4c84-8361-a44e70b76af6
Approver: 
Approval Date & Time: 12-Apr-2019 01:52:39 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 12-Apr-2019 03:49:40 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Protocol Addendum I6F-JE-JJCC (3) 
A Phase 1 Study of LY3039478 in Japanese Patients with Advanced Solid Tumors 
NCT02836600 
Approval Date: 02-April-2019


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1.
Statistical Analysis Plan:
I6F-JE-JJCC:  A Phase 1 Study of LY3039478 in Japanese 
Patients with Advanced Solid Tumors
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Generic Name (LY3039478) Indication studied
This Phase 1 study is a single center, nonrandomized, open-label, dose-escalation study of 
oral LY3039478 in Japanese patients with advanced and/or metastatic solid tumors.
Eli Lilly Japan K.K.
Chuo-ku, Kobe Japan
Protocol I6F-JE-JJCC
Phase 1
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:  22 July
2016.
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly:  26 April
2017.
Statistical Analysis Plan Version 3 electronically signed and approved by Lilly on date 
provided below.
I6F-JE-JJCC Statistical Analysis Plan Version 3
Approval Date: 02-Apr-2019 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: I6F-JE-JJCC:  A Phase 1 Study of 
LY3039478 in Japanese Patients with Advanced Solid Tumors...........................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Exploratory Objectives...................................................................................................6
5.
Study Design.......................................................................................................................7
5.1.
Summary of Study Design..............................................................................................7
5.2.
Determination of Sample Size ........................................................................................7
5.3.
Method of Assignment to Treatment ..............................................................................8
6.
A Priori Statistical Methods ................................................................................................9
6.1.
General Considerations ..................................................................................................9
6.2.
Adjustments for Covariates ..........................................................................................10
6.3.
Handling of Dropouts or Missing Data.........................................................................10
6.4.
Multiple Comparisons/Multiplicity...............................................................................10
6.5.
Use of an “Efficacy Subset” of Patients........................................................................11
6.6.
Patient Disposition .......................................................................................................11
6.7.
Patient Characteristics ..................................................................................................11
6.8.
Treatment Compliance .................................................................................................11
6.9.
Concomitant Therapy...................................................................................................11
6.10. Efficacy Analyses ........................................................................................................12
6.10.1.
Efficacy Definitions .............................................................................................12
6.10.2.
Efficacy Analyses ................................................................................................13
6.11. Safety Analyses............................................................................................................13
6.11.1.
Extent of Exposure...............................................................................................13
6.11.2.
Dose-Limiting Toxicity........................................................................................13
6.11.3.
Adverse Events ....................................................................................................14
6.11.4.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................15
6.11.5.
Clinical Laboratory Evaluation.............................................................................15
6.11.6.
Vital Signs and Other Physical Findings...............................................................15
6.11.7.
Electrocardiograms ..............................................................................................15
6.11.8.
Subgroup Analyses ..............................................................................................16
I6F-JE-JJCC Statistical Analysis Plan Version 3


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6.12. Protocol Violations.......................................................................................................16
6.13. Interim Analyses and Data Monitoring.........................................................................16
6.14. Annual Report Analyses...............................................................................................16
6.15. Clinical Trial Registry Analyses...................................................................................17
7.
References ........................................................................................................................18
I6F-JE-JJCC Statistical Analysis Plan Version 3


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Table of Contents
Figure
Page
Figure JJCC.1.
Illustration of study design...............................................................................7
I6F-JE-JJCC Statistical Analysis Plan Version 3


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3.
Revision History
SAP Version 1 was approved prior to the first visit when a subject receives study drug or any 
other protocol intervention.
SAP Version 2 was approved prior to the data base lock. The main objective of this revision was 
to removed PET metabolic response analysis since the desired results cannot be obtained through 
programing.  It was also updated to remove the summary table for tumor markers, the napoleon 
plot for the treatment duration, and the plot for the vital signs because it was determined that the 
listings are sufficient.  The summary of laboratory parameters was also clarified, and the 
category for toxicity grade for overall adverse event summary table was modified from “grade 3 
or 4” to “grade >= 3”.
SAP Version 3 was approved prior to the data base lock.  It was updated to correct the categories
of absolute QTcF value.  Several other changes were made to clarify the definition.
I6F-JE-JJCC Statistical Analysis Plan Version 3


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to evaluate the tolerability of LY3039478 up to the global 
recommended dose in Japanese patients with advanced solid tumors.
4.2.
Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3039478,

to evaluate the pharmacokinetic (PK) parameters of LY3039478

to document any antitumor activity observed with LY3039478.
4.3.
Exploratory Objectives
The exploratory objectives of this study are:

to explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of 
Notch activity.

to evaluate tumor tissue and blood for biomarkers related to solid tumors, the Notch 
signaling pathway and drug target pathways, immune functioning, and mechanism of 
action of study drug, and their potential association with the study objectives.

to explore the utility of positron emission tomography (PET) scan to assess treatment 
effect with LY3039478.
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5.
Study Design
5.1.
Summary of Study Design
Study JJCC is a Phase 1, single center, nonrandomized, single-arm, open-label, dose-escalation 
study of LY3039478 in Japanese patients with advanced solid tumors.
Study JJCC will consist of 2 dose levels, 25 and 50 mg LY3039478 TIW (3 or 6 patients per 
dose level).  Transition of dose level (from 25 to 50 mg) will proceed if the frequency of dose-
limiting toxicity (DLT) observed in Cycle 1 (28 days) is <33% of patients in the first dose level 
(25 mg).  Figure JJCC.1 illustrates the study design.
Eligible patients will be treated with LY3039478 at the assigned dose.  The planned duration of 
treatment is not fixed.  Treatment will continue until disease progression, development of 
unacceptable toxicity, or any other discontinuation criteria are met (Figure JJCC.1).
Abbreviations:  DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology 
Group; N = number of patients or no; PD = progressive disease; PS = performance 
status; TIW = 3 times per week; Y = yes.
Figure JJCC.1.
Illustration of study design.
5.2.
Determination of Sample Size
The sample size will primarily be determined by the incidence of DLTs in patients in each dose 
level.  Following a 3+3 dose escalation scheme, the sample size calculation assumes that dose 
level 1 will include 3 to 6 patients and dose level 2 will have 6 patients as shown in the Figure 
JJCC.1.  This sample size was not based on a statistical power calculation.
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5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3039478 in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted between 
the investigational site and the Lilly clinical research personnel to confirm that each patient 
meets all enrollment criteria.  Upon confirmation of eligibility, the sponsor will confirm the dose, 
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 
clinical research physician (CRP)/clinical research scientist (CRS).
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.
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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
CRP or CRS, pharmacokineticist, and statistician.  The CRP or CRS and statistician will also be 
responsible for the appropriate conduct of an internal review for both the final study report and 
any study-related material to be authorized by Lilly for publication.
The analyses for this study will be descriptive, except for possible exploratory analysis as 
deemed appropriate.  Data analyses will be provided by assigned dose level.
In general, continuous variables will be presented using the mean, standard deviation (SD),
median, minimum, maximum and number of patients with an observation (n).  For categorical 
variables, the population size (N), the number of events (n), the number of subjects with events 
(n) and the percentage of subjects with events are usually reported.  
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate and they will be planned in this SAP in advance.
The following data handling conventions will be used in the analysis.  
Term
Definition or Rule
Relative Study Day
If assessment is on or after date of first dose then 
(date of assessment) – (date of first study drug dose) +1
If assessment precedes first dose of drug then 
(date of assessment) – (date of first study drug dose)
There is no study day 0.  Study day 1 is the date of first dose and study day -1 is the day 
before the first dose.
Cycle Day
If assessment is on or after date of first dose in cycle then 
(date of assessment) – (date of first study drug dose in cycle) +1
There is no cycle day 0.  Cycle day 1 is the date of first dose in that cycle.
Duration of treatment
(Date of Day 1 of last cycle + 28 – Date of Day 1 of Cycle 1) / 7
Baseline
For change from baseline analyses, baseline value is defined as the last reported measure 
on or before the first dose date (prior to the dose administration), unless otherwise 
specified.
Entered
Patients who have signed the informed consent document directly or through their 
legally acceptable representatives.
Enrolled 
Patients who have been assigned to study treatment and have received at least 1 dose of 
study treatment.  
Efficacy Analyses Set
In principle, all patients who are enrolled in this study.  A patient who are considered 
nonevaluable for the assessment of a dose level might be excluded from the efficacy 
analysis set.  In this case, the nonevaluable condition will be specified before the data 
base lock.
Safety Analyses Set
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.
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DLT Analyses Set
All patients who are deemed evaluable for DLT assessment.  The evaluable patients must
taken ≥75% of the assigned dose in Cycle 1 (first 28 days) or experienced a DLT in 
Cycle 1 (first 28 days).
PK/PD Analyses Set
All patients who have received at least 1 dose of the study drug and have had sufficient 
postdose samples collected to allow estimation of PK parameters will form the PK/PD 
analyses set.
Screen Failures
Patients who have signed informed consent, do not meet eligibility criteria and are not 
enrolled.
6.2.
Adjustments for Covariates
Given the small sample size, no formal analysis investigating the impact of covariates is planned.
6.3.
Handling of Dropouts or Missing Data
Missing data, except for dates, will not be imputed.  They will be kept as missing in the data 
analyses, except for dates when used in calculations of relative study day, for which sponsor 
reporting standards will be utilized for imputation rules, defined as:  

The birth date will be imputed by assigning month and day with July 1st to calculate age.

For the missing date of relative study day, the following imputation methods will be used:
o
If only the day of the month is unknown, the 15th of the month will be used.
o
If both the day and the month are unknown, July 1st will be used.

When expanding the concomitant therapy, and previous therapy records across visits, the 
following imputation methods will be used:
o
For start date, 

If the day component is unknown, then the 1st of the month will be used.

If the month are unknown, then January will be used.

If both the day and the month are unknown, January 1st will be used.

If the day, the month and the year are unknown, the date will be missing.
o
For end date, 

If the day component is unknown, then the 30th of the month will be used.

If the month are unknown, then December will be used.

If both the day and the month are unknown, December 30th will be used.

If the day, the month and the year are unknown, the date will be missing.  
Partial dates should be reported in all listings and not the imputed date.
Analyses of response will include all patients with measureable disease.  Analyses of change in 
tumor size will include only patients with measureable disease and evaluable target lesion 
measures at baseline and at least one post-treatment visit.
6.4.
Multiple Comparisons/Multiplicity
No formal hypothesis testing is planned for this study; thus, there will be no adjustments for 
multiplicity.
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6.5.
Use of an “Efficacy Subset” of Patients
Analyses of disposition will use all patients entered in to the study.  Analyses of efficacy and 
safety analyses will utilize the efficacy analyses set and safety analysis set, respectively.  
Analyses will be reported according to patients assigned dose level.  
6.6.
Patient Disposition
Frequency distributions of the enrolled patients and patients in the efficacy analyses set, the 
safety analyses set, the DLT analyses set, and PK/PD analyses set will be summarized.
Summary of the screen failure and reason will be provided.
A detailed description of patient disposition will be provided for all patients entered into the 
study.  It will include a summary of the number and percentage of patients treated and 
completing the study, or discontinuing (overall and by reason for discontinuation, if known).  
Reason for discontinuation from both study treatment and study will be listed by the pre-
determined categories.  
A list of deaths and reasons for death will be provided.  Reasons for death will also be 
summarized, including the specific adverse event (AE) preferred term if reason for death is AE.
6.7.
Patient Characteristics
Patient demographic and baseline disease characteristics will be summarized.  Patient 
demographics will include age, sex, race, height, country, and screening weight and body mass 
index.  Baseline disease characteristics will include Alcohol use, Tobacco use, ECOG 
performance status, disease stage period, initial pathological diagnosis, histopathological 
diagnosis grade and TNM at diagnosis.
6.8.
Treatment Compliance
Treatment compliance will be summarized for safety analysis set.  Treatment compliance 
information will be collected through pill counts at each visit, and the number of tablets taken 
relative to the number expected to be taken will be listed.  
Percent compliance is calculated from dispensed and returned capsules as:  
(actual drug taken (mg)) / (total drug (mg) prescribed)*100
where total drug prescribed is the drug assigned excluding dose omissions and accounting for 
dose adjustments.
6.9.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization (WHO) drug dictionary.  All concomitant medications will be summarized.  
If concomitant medication use is due to an AE, the associated AE will also be listed.
A separate listing of transfusions will be listed.
Prior therapies, including systemic therapy, radiotherapy and surgeries will be summarized.
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Any post-treatment therapies following discontinuation will also be listed.
6.10. Efficacy Analyses
The study was not designed to make a formal efficacy assessment.  However, any tumor 
response data will be summarized and listed for efficacy analyses set.
6.10.1. Efficacy Definitions
The following definitions for efficacy endpoints will be used:
Overall response rate (ORR) is the proportion of efficacy patients who achieved a complete 
response (CR) or partial response (PR) out of all efficacy patients.  Depending on the histology, 
tumor responses will be measured and recorded using the appropriate guidelines [RECIST 1.1 
(Eisenhauer et al. 2009), the Response Assessment in Neuro-Oncology criteria for glioblastoma 
(Wen et al. 2010)].  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.  For patients who discontinue study treatment without objectively 
measured progressive disease, the radiological tumor assessment is not required.
Best response is determined from a sequence of responses assessed.  Two objective status 
determinations of CR before progression are required for a best response of CR.  Two 
determinations of PR or better before progression, but not qualifying for a CR, are required for a 
best response of PR.
Change in tumor size will be assessed in each patient with measurable disease using 
radiographic imaging.  Tumor size is the sum of the tumor measurements for target lesions at 
each tumor evaluation.  Change in tumor size is defined as the percent change in tumor size from 
the baseline evaluation to the minimum post-dose evaluation.  Other definitions of change in 
tumor size may be explored (including specific time points, and AUC formulations).
Duration of Response will be calculated for ORR and is defined only for responders.  It is 
measured from the date of first evidence of a confirmed response to the date of first progression 
of disease or the date of death due to any cause, whichever is earlier.  For each patient who is not 
known to have died or to have had a progression of disease as of the data-inclusion cut-off date, 
duration of response will be censored at the date of last objective response assessment prior to 
the date of any subsequent systemic anticancer therapy.
Duration of Stable Disease will be calculated only for patients with best response of stable 
disease.  It is measured from the date of start of treatment to the date of first progression of 
disease or the date of death due to any cause, whichever is earlier.  For each patient who is not 
known to have died or to have had a progression of disease as of the data-inclusion cut-off date, 
duration of stable disease will be censored at the date of last objective response assessment prior 
to the date of any subsequent systemic anticancer therapy.
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6.10.2. Efficacy Analyses 
Tumor markers and disease progression data will be listed.
Reported lesion data (target/ non-target or measurable/ nonmeasurable) and investigator 
assessment of response will be listed.
The following efficacy endpoints, detailed in Section 6.10.1 will be summarized as appropriate:  

Overall response rate

Best overall response

Change in tumor size.  A waterfall plot of change in tumor size will be produced.  All 
patients with at least one target lesion measurement will be represented in the plot.

PET parameters will be listed.  Change in SUVmax will be presented using a waterfall 
plot for patients with evaluable baseline and post-treatment PET imaging data, if data 
warrant.

Duration of response

Duration of stable disease
6.11. Safety Analyses
All safety summaries and analyses will be based upon the safety analysis set.  Safety data will be 
summarized with patient counts and percentages in each dose level.  
Details of the analyses are described in the following sections.
6.11.1. Extent of Exposure
A summary of exposure will be provided, including cycle received, cumulative dose and 
duration on therapy.  
A summary of dose intensity will also be provided.  Dose intensity is calculated as:
(actual cumulative dose taken (mg)) / (duration of treatment (week))
A summary of relative dose intensity will also be provided.  Percent relative dose intensity is 
calculated as:
(actual amount of drug taken(mg)) / (amount of drug prescribed (mg))*100
A summary of dose adjustments will be provided, including dose omissions and dose reductions, 
and the corresponding reasons for dose adjustment.  If the reason for dose adjustment is due to an 
AE, the associated AE will be provided.  
6.11.2. Dose-Limiting Toxicity
Dose-limiting toxicities will be summarized for DLT analysis set.  Dose escalation will be driven 
for each treatment combination using the 3+3 method.  Dose-limiting equivalent toxicity (DLET)
will also be summarized for safety analysis set.
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6.11.3. Adverse Events
A listing of all AEs by patient will be presented.  This listing will include patient number, AE 
(reported term and preferred term [PT]), event start and end dates, Common Terminology 
Criteria for Adverse Events (CTCAE) grade, relationship to study treatment/procedure, 
seriousness, and outcome.  A listing of serious AEs (SAEs) will be produced using the similar 
format.
An overall summary will be provided for AEs.  The number and percent of evaluable patients 
will be summarized for each category below.  The summary will provide counts for all AEs, and 
AEs related to study treatment.  

Patients with at least one treatment-emergent AE (TEAE)

Patients with at least one grade >= 3 TEAE

Patients with at least one SAE

Patients who discontinued due to AE

Patients who discontinued due to SAE

Patients who died due to AE on study treatment

Patients who died due to AE within 30 days of discontinuation from study treatment
Treatment-emergent adverse events (TEAE) are defined as follows:

Any event that first occurred or worsened in severity after baseline, based on the
MedDRA LLT term and CTCAE severity grade.  This means that any episode of the 
same AE with the same grade as at baseline that starts after the first dose of study 
treatment will not be defined as treatment-emergent, even if now considered drug related.

Or any pre-existing condition [PEC] (emerged prior to signing the informed consent) or 
any AE (emerged after signing the informed consent) that was still present prior to the 
first dose but has increased in severity (CTCAE grade) following the start of study 
treatment, regardless of causality.
As per Lilly’s standard operating procedures, all “related”, “probably related,” “possibly 
related,” or “does not know” AEs and SAEs will be defined as related to study treatment.
MedDRA v19.0 (or higher) will be used when reporting AEs by MedDRA terms.  TEAEs and 
TEAEs related to study treatment will be summarized by System Organ Class [SOC] and by 
decreasing frequency of PT within SOC.
TEAEs will be summarized by CTCAE grade, including the total for maximum Grade 3 and 4, 
and Grade 3, 4 and 5.  These summaries will be provided for events regardless of study treatment
causality, and repeated for events deemed by the investigator to be related to study treatment.
Medical history and PECs will be summarized.  
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6.11.4. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
All deaths recorded in this study will be included as part of the complete AE listing, where 
appropriate, and listed separately.  A summary of deaths may be presented for all patients on 
therapy if there are a sufficient number of events for this to be deemed useful.
Serious AEs will be summarized by decreasing frequency of PT within SOC.  The summary will 
be provided for events regardless of study treatment causality, and repeated for events deemed 
by the investigator to be related to study treatment.  
6.11.5. Clinical Laboratory Evaluation
Listings of all laboratory results will be provided (using SI units [International System of Units], 
when available), for hematology, coagulation, urinalysis, ECG chemistry, clinical chemistry and 
hepatic monitoring.  
Laboratory analytes below/above quantifiable levels (data in the database recorded as “<x” and 
“>x) will be reported as such in listings, and imputed to the lower or upper limit of quantification 
in any summaries or analyses.  
A calculated CTCAE grade using CTCAE v4.0 (or higher) will be provided for all laboratory 
results, which can be used independently of clinical judgment to determine a CTCAE severity 
grade.  Shift tables of graded laboratory parameters from baseline to the worst value on the study
will be generated.
All laboratory parameters may be plotted by time.
6.11.6. Vital Signs and Other Physical Findings
All vital sign data will be listed and will include height, weight, respiratory rate, temperature, 
blood pressure, pulse rate and ECOG performance status.
6.11.7. Electrocardiograms
Electrocardiogram (ECG) assessment of normality and clinical significance will be listed.  Three 
replicate ECGs will be obtained at each time point.  The average of them will be used for 
analysis, if applicable.  If missing values exist, the average will be derived without the missing 
values.
QT analyses will be performed with Fridericia correction (QTcF).  QTcF based on each read is
calculated as follows:

QTcF = QT / RR1/3
ECG parameters including QTcF and time-matched plasma concentration of LY3039478 will be 
listed.  In the listing, QTcF values which meet following criteria will be indicated,

Absolute QTcF value:  >450 msec, >480 msec, >500 msec

Change from baseline in QTcF value:  >30 msec, >60 msec
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Change from baseline in QTcF will be plotted against the time-matched plasma concentration of 
LY3039478, if appropriate.  A linear regression model will be used to investigate the relationship 
between the QTcF changes and the concentration of LY3039478 and the fitted model and the 
90% confidential/prediction band will also be shown in this plot if warranted by the data.
6.11.8. Subgroup Analyses
Subgroup analyses are not preplanned, but some subgroup analyses may be conducted, if needed.  
6.12. Protocol Violations
Important protocol deviations will be listed by pre-determined categories (e.g.,
inclusion/exclusion criteria, non-compliance with protocol procedures, drug dosage/intervention,
use of excluded treatments, informed consent/assent process, continuing after meeting
withdrawal criteria, or other).
6.13. Interim Analyses and Data Monitoring
Interim access to safety data, including DLTs, will be performed during the study.  In order to 
assess DLTs, which is key to proceed with dose escalation or to determine a tolerable dose, a 
DLT evaluation form at Dose Level 1 and Dose Level 2 will be prepared.  Therefore, no 
database lock activities on safety CRF pages are mandatory.
Interim analyses for safety and PK may be conducted after all patients receiving Dose Level 2 
complete Cycle 1 (DLT evaluation period).
Additional interim analyses may be conducted when deemed necessary (for example, in case of a 
safety concern).
If it is deemed that enough data is obtained to assess the primary objective and the secondary 
objectives, a clinical study report might be created before the last patient visit.  In this case, all 
data until the data cutoff date will be used for the analysis of safety, efficacy, PK, and PD 
biomarkers.  All data defined in the protocol will continue to be collected from patients on 
treatment after the data cutoff date.  These data may be reported separately and the analyses on 
all patients, including these data, may not be performed.
6.14. Annual Report Analyses
The datasets including the following tables and listings will be generated for the Development 
Safety Update Report (DSUR) reports based on the resource document ‘Statistical Guidance and 
Mock Tables for the Development Safety Update Report (DSUR) and Periodic Safety Update 
Report (PSUR) / Periodic Benefit Risk Evaluation Report (PBRER)’:
•
Summary of patients demographics by age and gender
•
Summary of patients demographics by racial groups
•
Summary of cumulative patient exposure information
•
Listing of patients who died
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•
Listing of patients who discontinued study drugs or study due to AEs
Investigator’s Brochure (IB) related analyses may be conducted at the same time as the DSUR 
analyses if applicable.
6.15. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.  
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized:  by dose level, by 
MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a TEAE.

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth.  
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7.
References
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.
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, 
Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, 
Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response 
assessment criteria for high-grade gliomas: response assessment in neuro-oncology working 
group. J Clin Oncol. 2010; 28(11):1963-1972.
I6F-JE-JJCC Statistical Analysis Plan Version 3


Leo Document ID = a6da5cbf-9272-4271-96d1-94151ae306c7
Approver: 
Approval Date & Time: 02-Apr-2019 04:03:50 GMT
Signature meaning: Approved
PPD