A Phase 1b Study of LY3039478 in Combination With Other Anticancer Agents in Patients With Advanced or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor, Breast Cancer, Colon Cancer, Cholangiocarcinoma, Soft Tissue Sarcoma
Sponsor: Eli Lilly and Company

Protocol I6F-MC-JJCD(a) 
 
 
A Phase 1b Study of LY3039478 in Combination with Other Anticancer Agents in Patients with 
Advanced or Metastatic Solid Tumors 
 
NCT02784795 
 
Approval Date: 15-Mar-2016 
 
 
 

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1.
Protocol I6F-MC-JJCD(a)
A Phase 1b Study of LY3039478 in Combination with 
Other Anticancer Agents in Patients with Advanced or 
Metastatic Solid Tumors
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3039478, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act (FOIA) Exemption 4.
LY3039478
Study I6F-MC-JJCD (JJCD) is a multicenter, nonrandomized, open-label, Phase 1b study 
consisting of 5 separate, parallel dose escalations in patients with advanced/metastatic 
cancer from a variety of solid tumors followed by a dose-confirmation phase in specified 
tumor types.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 17 December 2015.
Amendment (d) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 15-Mar-2016 GMT

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2.
Synopsis
Clinical Protocol Synopsis:  Study I6F-MC-JJCD
Name of Investigational Product:  LY3039478
Title of Study:  A Phase 1b Study of LY3039478 in Combination with Other Anticancer Agents in Patients with 
Advanced or Metastatic Solid Tumors.
Number of Planned Patients:  Total study sample size will be approximately 
163 patients.  
Phase of Development:  1b
Length of Study:  
Planned first patient visit:  June 2016    Planned last patient visit:  June 2018 
Objectives:  
Primary:  
The primary objective of this study is to determine the recommended Phase 2 dose of LY3039478 in individual 
combinations with other anticancer agents.
Secondary:  

to characterize the safety and toxicity profile of LY3039478 in combination with other anticancer agents 
as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0

to estimate the pharmacokinetic (PK) parameters of LY3039478 in combination with other anticancer 
agents 

to estimate the PK parameters of taladegib and its active metabolite LSN3185556, in combination with 
LY3039478

to estimate the PK parameters of LY3023414 in combination with LY3039478

to estimate the PK parameters of abemaciclib and its major active metabolites LSN2839567 and 
LSN3106726, in combination with LY3039478

to document any antitumor activity observed with LY3039478 in combination with other anticancer 
agents

to assess duration of response and progression free survival (PFS)
Exploratory:  

to explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of Notch activity or 
other study drugs 

to explore the utility of positron emission tomography (PET) scan to assess treatment effect with 
LY3039478 in combination with other anticancer agents

to explore predictive biomarkers related to induction of cytochrome P450 (CYP) enzymes, such as 
cortisol and 6β-hydroxycortisol

to evaluate tumor tissue and blood for biomarkers related to the Notch signaling pathway and drug target 
pathways, immune functioning, mechanism of action of study drug(s) or disease state, and their potential 
association with the objectives of the study
Study Design:  Study I6F-MC-JJCD (JJCD) is a multicenter, nonrandomized, open-label, Phase 1b study 
consisting of 5 separate, parallel dose escalations in patients with advanced/metastatic cancer from a variety of 
solid tumors followed by a dose-confirmation phase in specified tumor types.  
Part A:  In the dose-escalation phase of Part A, eligible patients will receive LY3039478 given orally, 3 times per 
week (TIW) in combination with a hedgehog/Smoothened (Smo) antagonist (taladegib [LY2940680]) given orally, 
daily (QD) on a 28-day cycle.  A single dose of taladegib will also be given on Day 1 during a 3-day lead-in period 
(dose-escalation phase only) for PK evaluation.  In the dose-confirmation phase of Part A, approximately 
10 patients with breast cancer (that have mutations, amplification, or gene expression alterations related to Notch 
pathway) and 10 patients with soft tissue sarcomas will be treated.
Part B:  In the dose-escalation phase of Part B, eligible patients will receive LY3039478 given orally, TIW in 
combination with a class I phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) 

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
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(PI3K/mTOR) inhibitor (LY3023414) given orally, every 12 hours on a 28-day cycle.  A single dose of 
LY3023414 will also be given on Day 1 during a 3-day lead-in period (dose-escalation phase only) for PK 
evaluation.  In the dose-confirmation phase of Part B, approximately 10 patients each with advanced or metastatic 
colon cancer or soft tissue sarcoma will be treated.  Colon cancer patients have to have mutations, amplification, or 
gene expression alterations related to Notch pathway.
Part C:  In the dose-escalation phase of Part C, eligible patients will receive LY3039478 given orally, TIW in 
combination with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (abemaciclib [LY2835219]) given orally, 
every 12 hours on a 28-day cycle.  A single dose of abemaciclib will also be given on Day 1 during a 3-day lead-in 
period (dose-escalation phase only) for PK evaluation.  In the dose-confirmation phase of Part C, approximately 
15 patients with metastatic breast cancer that have mutations, amplification, or gene expression alterations related 
to Notch pathway will be treated.
Part D:  In the dose-escalation phase of Part D, eligible patients will receive LY3039478 given orally, TIW in 
combination with cisplatin and gemcitabine given as intravenous (IV) infusions on Days 1 and 8 of a 21-day cycle.  
In the dose-confirmation phase of Part D, approximately 15 patients with cholangiocarcinoma that have mutations, 
amplification, or gene expression alterations related to Notch pathway will be treated.  
Part E:  In the dose-escalation phase of Part E, eligible patients will receive LY3039478 given orally, TIW in 
combination with gemcitabine and carboplatin given as IV infusions on Days 1 and 8 of a 21-day cycle.  In the 
dose-confirmation phase of Part E, approximately 15 patients with triple negative breast cancer (TNBC) (estrogen 
receptor negative [ER-], progesterone receptor negative [PR-], human epidermal growth factor receptor 2 negative 
[HER2-]) that have mutations, amplification, or gene expression alterations related to Notch pathway will be 
treated.
Diagnosis and Main Criteria for Inclusion and Exclusions:  Adult patients (≥18 years of age) who are 
appropriate candidates for experimental treatment with adequate organ function and performance status, have
histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is unresectable or 
metastatic.  In the dose-confirmation phase of the study, all patients must have measurable disease as defined by 
the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).  In Part A dose confirmation:  all patients 
must have histological evidence of unresectable or metastatic soft tissue sarcoma or breast cancer. Breast cancer 
patients must have prescreened alterations related to Notch pathway.  For Part B dose confirmation:  all patients 
must have histological evidence of unresectable or metastatic colon cancer or soft tissue sarcoma.  Colon cancer 
patients must have prescreened alterations related to Notch pathway.  For Part C dose confirmation:  all patients 
must have histological evidence of unresectable or metastatic breast cancer and must have prescreened alterations 
related to Notch pathway. For Part D dose confirmation:  all patients must have histological evidence of 
cholangiocarcinoma, prescreened alterations related to Notch pathway, and must not have received >1 line of prior 
systemic therapy for metastatic or resectable disease.  For Part E dose confirmation:  all patients must have 
histological evidence of locally advanced unresectable or metastatic TNBC, prescreened alterations related to 
Notch pathway, and not have received >2 lines of prior systemic treatment for unresectable or metastatic TNBC.  
All patients must have available tumor tissue (archived or newly biopsied).  Patients with serious concomitant 
systemic disorders including malabsorptive syndromes, enteropathies, gastroenteritis (acute or chronic), or diarrhea 
(acute or chronic), who have received other investigational product within 14 days, have symptomatic central 
nervous system malignancy or metastases, acute leukemia, active infection including human immunodeficiency 
virus, cardiac disease, or a second primary malignancy that may affect the interpretation of results will be excluded 
from treatment.  For Part B only; patients with insulin-dependent diabetes mellitus or a history of gestational 
diabetes mellitus will be excluded from treatment.
Test Product, Dosage, and Mode of Administration:  LY3039478, dose range 25-50 mg, given orally as 
capsules TIW during a 21- or 28-day cycle.

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Planned Duration of Treatment:  
The planned duration of treatment is not fixed; patients will remain on study drug therapy until they fulfill 1 of the 
criteria for treatment discontinuation.  
Short-term follow-up period (postdiscontinuation):  30 days 
Long-term follow-up period (postdiscontinuation):  after the short-term follow-up through death or study closure.
Reference Therapy, Dose, and Mode of Administration:  

Taladegib will be supplied as 100-mg tablets in bottles for oral consumption.  

LY3023414 will be supplied as 25-mg, 100-mg, or 200-mg capsules or 100-mg, 150-mg, or 200-mg 
tablets.  

Abemaciclib will be supplied as 50-mg hypromellose capsules.

Gemcitabine will be dosed at 1000 mg/m2 on Days 1 and 8 of each 21-day cycle as an IV infusion.

Cisplatin will be dosed at 25 mg/m2 on Days 1 and 8 of each 21-day cycle as an IV infusion.

Carboplatin will be dosed at area under the plasma concentration-time curve (AUC) 2 on Days 1 and 8 of 
each 21-day cycle as an IV infusion.
Criteria for Evaluation:  
   Safety:  Safety will be evaluated based on recorded adverse events (AEs), physical examinations, vital sign 
measurements, electrocardiograms (ECGs), and clinical laboratory assessments.  AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  AEs and clinical laboratory values will be graded using 
NCI CTCAE v4.0.
   Bioanalytical:  Plasma concentrations of LY3039478, taladegib and its active metabolite LSN3185556,
abemaciclib and its active metabolites LSN2839567 and LSN3106726, LY3023414, gemcitabine, cisplatin, and 
carboplatin.
   Efficacy:  Depending on the histology, efficacy will be assessed using RECIST 1.1 for solid tumors.
Statistical Methods:  
   Safety:  Safety analyses will include listings and/or summaries of the following:

AEs, treatment-emergent AEs (TEAEs), and dose-limiting toxicities (DLTs)

drug exposure

dose adjustments

laboratory measures

vital signs

ECG readings
   Efficacy:  The study was not designed to make an efficacy assessment.  However, any tumor response data will 
be tabulated.  Descriptive analyses of duration of response and PFS will be conducted using the Kaplan-Meier 
method.
   Pharmacokinetics:  PK parameters for LY3039478, taladegib and its active metabolite LSN3185556, 
LY3023414, abemaciclib and its active metabolites LSN3106726 and LY2839567, gemcitabine, cisplatin, and 
carboplatin will be analyzed by standard noncompartmental methods of analysis.
   Pharmacodynamics:  Biomarker data from all patients undergoing biomarker assessments will be analyzed using 
descriptive statistics.  

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
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3.
Table of Contents
A Phase 1b Study of LY3039478 in Combination with Other 
Anticancer Agents in Patients with Advanced or Metastatic 
Solid Tumors
Section
Page
1.
Protocol I6F-MC-JJCD(a) A Phase 1b Study of LY3039478 in 
Combination with Other Anticancer Agents in Patients with 
Advanced or Metastatic Solid Tumors.................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................5
4.
Abbreviations and Definitions...........................................................................................12
5.
Introduction ......................................................................................................................19
5.1.
Rationale and Justification for the Study ......................................................................19
5.1.1.
Rationale for Combination with Taladegib ...........................................................20
5.1.2.
Rationale for Combination with LY3023414........................................................20
5.1.3.
Rationale for Combination with Abemaciclib.......................................................21
5.1.4.
Rationale for Combination with Cisplatin and Gemcitabine .................................22
5.1.5.
Rationale for Combination with Gemcitabine and 
Carboplatin ..........................................................................................................22
5.2.
Objectives ....................................................................................................................23
5.2.1.
Primary Objective ................................................................................................23
5.2.2.
Secondary Objectives...........................................................................................23
5.2.3.
Exploratory Objectives.........................................................................................23
5.3.
General Introduction to LY3039478.............................................................................24
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................24
5.3.2.
Human Pharmacokinetics.....................................................................................25
5.3.3.
Pharmacodynamics ..............................................................................................26
5.4.
General Introduction to Taladegib ................................................................................26
5.4.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................26
5.4.2.
Clinical Summary ................................................................................................27
5.5.
General Introduction to LY3023414.............................................................................27
5.5.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................28
5.5.2.
Clinical Summary ................................................................................................28
5.6.
General Introduction to Abemaciclib............................................................................29
5.6.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................29
5.6.2.
Clinical Summary ................................................................................................30

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5.7.
Rationale for Selection of Doses for LY3039478 and Other 
Anticancer Agents........................................................................................................31
5.8.
Rationale for Amendment (a).......................................................................................32
6.
Investigational Plan...........................................................................................................33
6.1.
Study Population..........................................................................................................33
6.1.1.
Inclusion Criteria .................................................................................................33
6.1.2.
Exclusion Criteria ................................................................................................35
6.2.
Summary of Study Design............................................................................................36
6.2.1.
Study Completion and End of Trial......................................................................38
6.2.2.
Continued Access Period......................................................................................38
6.3.
Discontinuations ..........................................................................................................39
6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................39
6.3.2.
Discontinuation of Patients from Study or Study Drug .........................................39
6.3.3.
Discontinuation of Study Sites .............................................................................40
6.3.4.
Discontinuation of the Study................................................................................40
7.
Treatment..........................................................................................................................41
7.1.
Materials and Supplies .................................................................................................41
7.2.
Study Drug Administration ..........................................................................................42
7.2.1.
Dosing Schedule ..................................................................................................42
7.2.1.1.
LY3039478 in Combination with Taladegib (Part A)......................................43
7.2.1.2.
LY3039478 in Combination with LY3023414 (Part B)...................................43
7.2.1.3.
LY3039478 in Combination with Abemaciclib (Part C)..................................44
7.2.1.4.
LY3039478 in Combination with Cisplatin and 
Gemcitabine (Part D)......................................................................................44
7.2.1.5.
LY3039478 in Combination with Gemcitabine and 
Carboplatin (Part E)........................................................................................45
7.2.2.
Dose Escalation....................................................................................................45
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................47
7.2.3.
Dose-Confirmation Phase.....................................................................................48
7.2.4.
Dose Adjustments and Delays..............................................................................49
7.2.4.1.
LY3039478 ....................................................................................................49
7.2.4.1.1.
Dose Adjustments within a Cycle .............................................................49
7.2.4.1.2.
Dose Adjustments between Cycles............................................................49
7.2.4.2.
Dose Adjustments with Taladegib ..................................................................50
7.2.4.3.
Dose Adjustments with LY3023414 ...............................................................50
7.2.4.4.
Dose Adjustments with Abemaciclib ..............................................................51
7.2.4.5.
Dose Adjustments with Cisplatin and Gemcitabine.........................................52
7.2.4.6.
Dose Adjustments with Gemcitabine and Carboplatin.....................................53

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7.3.
Method of Assignment to Treatment ............................................................................54
7.4.
Blinding .......................................................................................................................55
7.5.
Concomitant Therapy...................................................................................................55
7.6.
Treatment Compliance .................................................................................................56
7.6.1.
Evaluable Patients................................................................................................56
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................57
8.1.
Safety Evaluations........................................................................................................57
8.1.1.
Safety Data Collection and Review ......................................................................57
8.1.2.
Adverse Events ....................................................................................................57
8.1.2.1.
Serious Adverse Events ..................................................................................59
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................60
8.1.2.2.1.
Prior to Administration of Study Drug(s) ..................................................60
8.1.2.2.2.
On Therapy...............................................................................................60
8.1.2.2.3.
Follow-Up Visit........................................................................................60
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................61
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................61
8.1.3.
Other Safety Measures .........................................................................................62
8.1.3.1.
Electrocardiograms.........................................................................................62
8.1.4.
Safety Monitoring ................................................................................................63
8.1.5.
Complaint Handling.............................................................................................64
8.2.
Sample Collection and Testing.....................................................................................64
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................64
8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................65
8.2.3.
Pharmacogenetic Samples....................................................................................65
8.2.4.
Exploratory Samples ............................................................................................66
8.2.4.1.
Blood Samples for Aβ Assays.........................................................................66
8.2.4.2.
Samples for Assessing CYP3A Induction .......................................................66
8.2.4.3.
Blood Samples for Biomarker Research..........................................................67
8.2.4.4.
Tumor Tissue and Skin Biopsies.....................................................................67
8.3.
Efficacy Evaluations ....................................................................................................68
8.4.
Procedure/Sampling Compliance..................................................................................69
9.
Data Management Methods...............................................................................................70
9.1.
Data Quality Assurance................................................................................................70
9.2.
Data Capture Systems ..................................................................................................70
9.2.1.
Case Report Form ................................................................................................70
9.2.2.
Ancillary Data......................................................................................................71

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10.
Data Analyses...................................................................................................................72
10.1. General Considerations ................................................................................................72
10.2. Patient Disposition .......................................................................................................72
10.3. Patient Characteristics ..................................................................................................73
10.4. Safety Analyses............................................................................................................73
10.5. Pharmacokinetic Analyses............................................................................................73
10.6. Pharmacokinetic/Pharmacodynamic Analyses..............................................................74
10.7. Efficacy........................................................................................................................74
10.8. Tailoring Biomarker Analyses......................................................................................74
10.9. Interim Analyses ..........................................................................................................74
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................75
11.1. Informed Consent.........................................................................................................75
11.2. Ethical Review.............................................................................................................75
11.3. Regulatory Considerations ...........................................................................................75
11.3.1.
Investigator Information.......................................................................................76
11.3.2.
Protocol Signatures ..............................................................................................76
11.3.3.
Final Report Signature .........................................................................................76
12.
References ........................................................................................................................77

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List of Tables
Table
Page
Table JJCD.7.1. Dose Regimens..............................................................................................43
Table JJCD.7.2. Proposed Dose-Escalation Scheme for Part A................................................46
Table JJCD.7.3. Proposed Dose-Escalation Scheme for Part B ................................................46
Table JJCD.7.4. Proposed Dose-Escalation Scheme for Part C ................................................47
Table JJCD.7.5. Proposed LY3039478 Dose-Escalation Scheme for Part D ............................47
Table JJCD.7.6. Proposed LY3039478 Dose-Escalation Scheme for Part E.............................47
Table JJCD.7.7. Dose Adjustments for Taladegib....................................................................50
Table JJCD.7.8. Dose Adjustments for LY3023414.................................................................51
Table JJCD.7.9. Dose Adjustments of Abemaciclib.................................................................52
Table JJCD.7.10. Cisplatin and Gemcitabine Dose Adjustment for Toxicity..............................53
Table JJCD.7.11. Dose Modification Based on Neutrophil and/or Platelet Count on Day 
of Treatment (Day 1 and Day 8) ....................................................................54
Table JJCD.7.12. Dose Modification Based on Common Toxicity Criteria................................54
Table JJCD.8.1. Adverse Event and Serious Adverse Reporting Guidelines for 
Study JJCD....................................................................................................62
Table JJCD.8.2. Tumor and Skin Biopsy Time Points .............................................................67
Table JJCD.8.3. Definition of Efficacy Endpoints ...................................................................68
Table JJCD.10.1. Estimated Incidence Rate and Its 2-Sided 95% Confidence Interval...............72

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List of Figures
Figure
Page
Figure JJCD.1.
Illustration of study design for Protocol I6F-MC-JJCD. .................................38

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List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JJCD Study Schedule.......................................................................80
Attachment 2.
Protocol JJCD Clinical Laboratory Tests .......................................................87
Attachment 3.
Protocol JJCD Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................88
Attachment 4.
Protocol JJCD Pharmacokinetic, Pharmacodynamic, and 
Electrocardiogram with Electrocardiogram Chemistry Sampling 
Schedule........................................................................................................89
Attachment 5.
Protocol JJCD Recommendations for Reporting Serious Adverse 
Events..........................................................................................................100
Attachment 6.
Protocol JJCD Eastern Cooperative Oncology Group Performance 
Status...........................................................................................................101
Attachment 7.
Protocol JJCD Creatinine Clearance Formula ..............................................102
Attachment 8.
Protocol JJCD Guidance on Alterations Related to Notch Pathway..............103
Attachment 9.
Protocol JJCD Guidance for Diarrhea Management.....................................104
Attachment 10.
CYP3A4 Inhibitors, Inducers, and Substrates for LY3023414 (Part B) ........107
Attachment 11.
Drugs Associated with QT Interval Prolongation for LY3023414 
(Part B)........................................................................................................109
Attachment 12.
Protocol JJCD Protocol Amendment 
I6F-MC-JJCD(a) Summary 
A Phase 1b Study of LY3039478 in Combination with Other 
Anticancer Agents in Patients with Advanced or Metastatic Solid 
Tumors........................................................................................................110

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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
AFP
alpha-fetoprotein
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APP
amyloid precursor protein
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
assent
Agreement from a minor or other individual who is not legally capable of 
providing consent, but who can understand the circumstances and potential risks 
involved in participating in a study.  
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC(0-48hr)
area under the plasma concentration-time curve from time zero to 48 hours
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to last 
measurable plasma concentration
audit
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s).
bDNA
branched-chain deoxyribonucleic acid
BID
twice daily
BUN
blood urea nitrogen
CBF-1
C-promoter binding factor-1

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CCND1
Cyclin D1
CDK
cyclin-dependent kinase
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL/F
apparent systemic clearance
Cmax
maximum plasma concentration
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated
complaint
Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
CPK
creatine phosphokinase
CRF/eCRF
case report form/electronic case report form:  Sometimes referred to as clinical 
report form, a printed or electronic form for recording study participants’ data 
during a clinical study, as required by the protocol.
CRP
clinical research physician
CRS
clinical research scientist
CSC
cancer stem cell
CSF
colony stimulating factor(s)
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
cytochrome P450
DLET
dose-limiting equivalent toxicity
DLL
Delta-like ligand

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DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGF
epidermal growth factor
EGFR
epidermal growth factor receptor
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.
ER-
estrogen receptor negative
ERB/IRB
ethical review board/institutional review board:  A board or committee 
(institutional, regional, or national) composed of medical and nonmedical 
members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical study are protected.
FFPE
formalin-fixed paraffin-embedded
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factor(s)
GFR
glomerular filtration rate
GGT
gamma-glutamyl transpeptidase
GI
gastrointestinal
GMP
good manufacturing practice
GnRH
gonadotropin-releasing hormone
GSI
gamma secretase inhibitor
HbA1C
glycosylated hemoglobin
HER2-
human epidermal growth factor receptor 2 negative
HES1
hairy and enhancer of split-1
IB
Investigator’s Brochure

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IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMS
isotope dilution mass spectrometry
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 datalock.
investigational 
product (IP)
A pharmaceutical form of an active ingredient 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.
IV
intravenous
Ki
inhibition constant
LC-MS/MS
liquid chromatography-tandem mass spectrometry
legal 
representative
An individual, judicial, or other body authorized under applicable law to 
consent on behalf of a prospective patient, to the patient’s participation in the 
clinical study.
LSS
Lilly Safety System:  Global safety database that tracks and reports serious 
adverse and spontaneous events occurring while using a drug/drug delivery 
system.
MATE1
multidrug and toxin extrusion protein 1
MedDRA
Medical Dictionary for Regulatory Activities
monitor
A person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local SOPs (if any), and global Medical SOPs.  
Monitors are trained on the investigational product(s), the protocol, informed 
consent document, any other written information provided to subjects, relevant 
SOPs, International Conference on Harmonisation Good Clinical Practice 
guidelines (ICH-GCP), and all applicable laws (for example, privacy and data 
protection) and regulations.  

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MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
mTOR
mammalian target of rapamycin
NCI
National Cancer Institute
NHS
National Health Service (England)
NICD
Notch intracellular domain
NRARP
Notch-Regulated Ankyrin Repeat
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)
PDX
patient-derived xenograft
PET
positron emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PK
pharmacokinetic(s)
PR-
progesterone receptor negative
PSA
prostate-specific antigen
PT/INR
prothrombin time/international normalized ratio
PTEN
phosphatase and tensin homolog
Q2D
every other day
QD
daily
Rb
retinoblastoma
RBC
red blood cells (erythrocytes)
RBP-J
recombination signal-binding protein-J
RECIST
Response Evaluation Criteria in Solid Tumors

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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.
re-screen
to screen a patient who was previously declared a screen failure for the same 
study
RP2D
recommended Phase 2 dose
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 tests (for 
example, skin biopsy, 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.
screen failure
A patient who does not meet one or more criteria required for participation in a 
trial
SE
standard error
Shh-CM
sonic hedgehog conditioned media
Smo
smoothened
sponsor
The party who takes responsibility for the initiation, management and/or 
financing of a clinical study.
study completion
This study will be considered complete once it is deemed that sufficient data are 
obtained to assess the primary and secondary objectives.
Su[H]
Suppressor of Hairless
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life
TACE
tumor necrosis factor-α converting enzyme
T-ALL
T-cell acute lymphoblastic leukemia/lymphoma
TEAE
treatment-emergent adverse event
TIW
3 times per week
Tmax
time to maximum observed plasma concentration
TNBC
triple negative breast cancer
TPO
third-party organization
TSH
thyroid stimulating hormone

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ULN
upper limit of normal
US
United States
WBC
white blood cells (leukocytes)
WHO
World Health Organization

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

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An oncogenic role for Notch was first reported as the result of a chromosomal translocation 
occurring in a patient with T-cell leukemia (Grabher et al. 2006).  Overexpression of NICD in 
hematopoietic progenitor cells of mice recapitulated this phenomenon, as they developed T-cell 
leukemia similar to humans.  Furthermore, treatment of these cells with the -secretase inhibitor 
prevented their cell growth.  Besides T-cell leukemia, there is increasing evidence that Notch 
signals are oncogenic in other cancers through multiple mechanisms including receptor 
amplification and overexpression of ligands and/or receptors.  Deregulated Notch signaling due 
to mutation or overexpression of ligands and/or receptors is implicated in a number of 
malignancies including lymphoid leukemias, melanoma, glioblastoma, and cancers of the breast, 
ovary, cholangiocarcinoma, lung, pancreas, colon, head and neck, cervix, and kidney (Koch and 
Radtke 2007; CGARN 2011; Puente et al. 2011).  In summary, inhibition of Notch signaling 
constitutes an attractive strategy to provide therapeutic benefits to cancer patients.
This Phase 1b study will assess the safety of a Notch inhibitor (LY3039478) in combination with 
different agents in order to determine the recommended Phase 2 dose of LY3039478 in 
combinations with those different anticancer agents as outlined in Figure JJCD.1.
5.1.1.
Rationale for Combination with Taladegib
The presence of small populations of cells with stem-like characteristics (cancer stem cells 
[CSCs]) is established in most malignancies, although the origin and plasticity of these cells is 
not fully understood.  Experimental models show that CSCs seem to be more resistant to 
chemotherapy and radiotherapy than “differentiated” tumor cells. CSCs typically demonstrate 
persistent activation of one or more highly conserved signal transduction pathways involved in 
development and tissue homeostasis, including the Notch, hedgehog, and Wnt pathways (Takebe 
et al. 2015).
Results from mainly preclinical models examining combination approaches to overcome the 
crosstalk among Notch, hedgehog, and Wnt pathways, as well as other signaling pathways, have 
shown promising results (Takebe et al. 2015). LY3039478 has shown significant antitumor 
activity when combined with taladegib (LY2940680) – a hedgehog/Smoothened (Smo) inhibitor 
in a leiomyosarcoma xenograft model (data on file).  
Clinically, a previous Notch and hedgehog inhibitors combination showed a good safety profile 
and clinical activity in patients with advanced sarcoma (Gounder et al. 2012). 
In summary, the combination of LY3039478 and taladegib is an attractive regimen to target 
CSCs.
5.1.2.
Rationale for Combination with LY3023414
LY3023414 is an orally available, dual kinase inhibitor of class I phosphatidylinositol 3-kinase
(PI3K) and the mammalian target of rapamycin (mTOR). The PI3K/mTOR pathway has been 
reported as activated in >70% of human cancers and has emerged as a promising target for 
anticancer therapies.  PI3K/mTOR signaling plays a central role in regulating physiological 
processes such as growth, survival, proliferation, and metabolism, and in the development of 
malignant disease (Bjornsti and Houghton 2004; Samuels and Ericson 2006).

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There are several mechanisms that lead to aberrant activation of this pathway, including 
mutations of growth factor receptors, PIK3CA, and loss of the tumor suppressor, phosphatase 
and tensin homolog (PTEN) (Stambolic et al. 1998; Courtney et al. 2010).  PTEN loss has been 
also described as a resistance mechanism to other targeted therapies. For example, T-cell acute 
lymphoblastic leukemia/lymphoma (T-ALL) loss of PTEN is a common event and is associated 
with resistance to Notch inhibition (Palomero et al. 2007). Mutational loss of PTEN induces 
resistance to NOTCH1 inhibition in T-cell leukemia.  Furthermore, Notch induces upregulation 
of the phosphatidylinositol 3-kinase and protein kinase B (PI3K-AKT) pathway via Hairy and 
enhancer of split-1 (HES1), which negatively controls the PTEN expression. LY302314 has 
demonstrated activity in preclinical tumor xenograft models with PTEN loss (manuscript 
submitted). When LY3039478 is administered in combination with LY3023414 (currently in 
Phase 2 development), a synergistic inhibition of tumor growth in A2780 ovarian carcinoma 
xenograft model is shown.  This suggests that simultaneous inhibition of Notch and PI3K 
signaling can provide improved therapeutic benefits in solid tumors such as ovarian cancer (data 
on file).  
Based on this, Study I6F-MC-JJCD (JJCD) will evaluate the novel/novel combination of 
LY3039478 and LY3023414 in patients with advanced cancer.
5.1.3.
Rationale for Combination with Abemaciclib
The cell cycle is the process by which mammalian cells replicate their deoxyribonucleic acid 
(DNA) and undergo cellular division.  The mammalian cell cycle has 4 phases:  S phase, where 
DNA replication occurs; G2 phase, where the cell prepares for mitosis; M (mitosis) phase, where 
the replicated DNA and cellular components are divided to form 2 daughter cells; and G1 phase, 
where cells commit to another round of DNA and cellular replication. Defects in the pathways 
that regulate cell proliferation in response to mitogenic signaling and other extracellular stimuli 
such as cell density and nutrients are a hallmark of cancer cells (Hanahan and Weinberg 2000), 
and the G1 cell cycle restriction point (R) is believed to be essential to maintaining control of 
proliferation (Blagosklonny and Pardee 2002; Ortega et al. 2002).  A primary mechanism 
controlling cell cycle progression through the restriction point is the cyclin-dependent kinase 4/6 
(CDK4/6) pathway (CDK4/6-cyclinD-INK4-Rb) and the importance of this pathway in 
regulating cell proliferation is highlighted by inactivation of restriction point control in a 
majority (>85%) of human tumors including breast cancer (Malumbres and Barbacid 2001).  
Notch signaling also plays a role in cell cycle. For instance, in human T-cell malignancies, 
Notch signaling regulates expression of key cell cycle regulatory proteins such as Cyclin D3, 
CDK4, and CDK6 for the progression of cells from G1 to S phase (Joshi et al. 2009).
Furthermore, gamma secretase inhibitor (GSI)-induced G1 arrest can be partially rescued by 
ectopic expression of CDK4 or CDK6. Rao et al. (2009) demonstrated that GSI and CDK4 
inhibitor produced synergistic growth inhibition of T-ALL cells through induction of CDK 
inhibitors CDKN2D (p19(INK4d)) and CDKN1B (p27(Kip1)), leading to derepression of 
retinoblastoma (Rb) tumor suppressor protein and subsequent exit from the cell cycle.  
Consistent with these reports, we observed that LY3039478 in combination with abemaciclib,

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a CDK4/6 inhibitor currently in Phase 3 development, inhibits tumor growth in Colo-205 (human 
colorectal) and NCI-H2122 (human adenocarcinoma of lung) xenograft models.
In summary, the combination of LY3039478 and abemaciclib is an attractive regimen to target 
the cell cycle.
5.1.4.
Rationale for Combination with Cisplatin and Gemcitabine 
A cisplatin and gemcitabine regimen is widely used for the treatment of different cancers.  
In cholangiocarcinoma, ABC-02, the first randomized, controlled Phase 3 study for cancers of 
the biliary tract, established a benefit for the addition of cisplatin to gemcitabine treatment as 
compared to single agent gemcitabine, with an improved rate of tumor control (81.4% vs 71.8%, 
p=.049) and a median overall survival of 11.7 months vs 8.1 months (hazard ratio 0.64; 95% 
confidence interval [CI] 0.52 to 0.80; p<.001) (Valle et al. 2010).  These results provided 
evidence for recent treatment guidelines for advanced cholangiocarcinoma that recommend the 
use of the gemcitabine and cisplatin (Eckel et al. 2011; NCCN 2015).  The gemcitabine and 
cisplatin dosing regimen used in the ABC-02 trial consisted of repeating cycles of cisplatin 
(25 mg/m2) followed by gemcitabine (1000 mg/m2) with each drug administered on Days 1 and 
8 every 3 weeks (Valle et al. 2010).
In a cholangiocarcinoma transgenic mouse model, the expression of the NOTCH1 NICD in 
mouse livers resulted in the formation of intrahepatic cholangiocarcinomas. Results suggested 
that intrahepatic cholangiocarcinoma can originate from this cell type as these tumors displayed
features of bipotential hepatic progenitor cells. According to Zender et al. (2013), human and 
mouse cholangiocarcinomas were characterized by high expression of the cyclin E protein. 
Cyclin E gene was identified as a direct transcriptional target in the pathway for Notch signaling.  
Inhibiting the -secretase activity in human cholangiocarcinoma xenotransplants resulted in 
downregulation of cyclin E expression, induction of apoptosis, and tumor remission in vivo 
(El Khatib et al. 2013; Zender et al. 2013).
The demonstrated efficacy of cisplatin and gemcitabine, the nonoverlapping toxicity profile, and 
role of Notch signaling in cholangiocarcinoma make cisplatin and gemcitabine an attractive 
regimen to combine with LY3039478.  
5.1.5.
Rationale for Combination with Gemcitabine and Carboplatin
Triple negative breast cancer (TNBC) is an aggressive histological subclass of breast cancer that 
is extremely aggressive and accounts for an excessive amount of metastatic disease cases and 
patient deaths.  Given the aggressive nature of TNBC and the need for tumor response in most 
cases, a multidrug regimen is preferred over a single-drug regimen in this subclass of patient
(Andre and Zielinski 2012). A gemcitabine and carboplatin combination is among the proposed
regimens for treatment of TNBC (O’Shaughnessy et al. 2011).  
Next-generation sequencing has been used to identify Notch mutations in a large collection of 
diverse solid tumors. Stoeck et al. (2014) reported that NOTCH1 and NOTCH2 rearrangements 
leading to constitutive receptor activation were confined to TNBC.  In addition, the TNBC cell 

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lines with NOTCH1 alterations associated with high levels of activated NOTCH1were 
responsive to a γ-secretase inhibitor in vitro and in vivo , whereas cell lines with NOTCH2 
alterations were resistant to GSI.  Immunohistochemical staining of N1ICD in TNBC xenografts 
established a connection between responsiveness and expression levels of the direct Notch target 
gene HES4, which correlated with outcome in patients with TNBC (Stoeck et al. 2014).
An additional study by Robinson et al. (2011) demonstrated that Notch family genes have a
meaningful effect on breast epithelial cells.  Furthermore, this study showed that various breast 
cancer cell lines that have Notch gene rearrangements are unique in their sensitivity to the
inhibition of Notch signaling (Robinson et al. 2011).
Based on these data, the combination of a Notch inhibitor with standard chemotherapy is an 
attractive regimen in TNBC.
5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to determine the recommended Phase 2 dose of 
LY3039478 in individual combinations with other anticancer agents.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3039478 in combination with other 
anticancer agents as assessed by National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0

to estimate the pharmacokinetic (PK) parameters of LY3039478 in combination with 
other anticancer agents

to estimate the PK parameters of taladegib and its active metabolite LSN3185556, in 
combination with LY3039478

to estimate the PK parameters of LY3023414 in combination with LY3039478

to estimate the PK parameters of abemaciclib and its major active metabolites 
LSN2839567 and LSN3106726, in combination with LY3039478

to document any antitumor activity observed with LY3039478 in combination with other 
anticancer agents

to assess duration of response and progression-free survival (PFS) 
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 or other study drugs

to explore the utility of positron emission tomography (PET) scan to assess treatment 
effect with LY3039478 in combination with other anticancer agents

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
to explore predictive biomarkers related to induction of cytochrome P450 (CYP) 
enzymes, such as cortisol and 6β-hydroxycortisol

to evaluate tumor tissue and blood for biomarkers related to the Notch signaling pathway
and drug target pathways, immune functioning, mechanism of action of study drug(s) or 
disease state, and their potential association with the objectives of the study
5.3.
General Introduction to LY3039478
LY3039478 is a potent Notch inhibitor being developed for the treatment of patients with cancer.  
LY3039478 prevents release of the NICD by inhibiting proteolytic activity of -secretase 
complex and thereby decreasing Notch signaling and its downstream biologic effects.  
LY3039478 has been shown to inhibit Notch signaling in cell lines representing a number of 
different solid tumors and leukemia.  
In nonclinical studies, the gastrointestinal (GI) tract is the key target organ for toxicity, which is 
also reflected in the current clinical safety observations.  
As of June 2015, the most commonly reported treatment-emergent adverse events (TEAEs), 
occurring in ≥10% of patients and possibly related to LY3039478 were diarrhea (48 patients, 
49.5%); vomiting (38 patients, 39.2%); nausea (34 patients, 35.1%); asthenia (28 patients, 
28.9%); decreased appetite (23 patients, 23.7%); hypophosphatemia (18 patients, 18.6%); dry 
skin (14 patients, 14.4%); dry mouth and mucosal inflammation (13 patients each, 13.4%);
weight decreased (12 patients, 12.4%); and alanine aminotransferase (ALT) increased, alopecia, 
and hair color changes (10 patients each, 10.3%).  Most of the TEAEs were mild or moderate in 
severity.  Hypophosphatemia was noted to be the most frequently reported Grade 3 TEAE 
(8 patients, 8.2%), with only 1 TEAE reported as serious.    
More information about the known and expected benefits, risks and reasonably anticipated 
adverse events (AEs) may be found in the Investigator’s Brochure (IB).  Information on AEs 
expected to be related to the investigational product may be found in Section 7 (Development 
Core Safety Information) of the IB.  Information on serious AEs (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.
More detailed information about the known and expected benefits and risks of LY3039478 may 
be found in the following:  Protocol Section 5.1 or in the IB.
5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
LY3039478 is a potent Notch inhibitor with a half-maximal inhibitory concentration (IC50) of 
≤1 nM in the majority of tumor cell lines tested for its ability to inhibit NOTCH1 cleavage.
LY3039478 potently inhibits Notch cleavage and downstream Notch signaling in lung and skin 
of Balb/C mice in a dose-dependent manner with a threshold dose concentration of the 
compound required to inhibit cleavage by 50% (TED50) value for N1ICD inhibition of 0.8 and 

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0.9 mg/kg, respectively, and threshold plasma concentration of the compound required to inhibit 
cleavage by 50% (TEC50) value of 6.2 and 6.6 ng/mL, respectively.
Doses of 7 to 10 mg/kg with an intermittent schedule of every other day (Q2D) produced optimal 
efficacy while balancing on-target GI toxicity. LY3039478 also inhibited NOTCH1 cleavage 
and downstream 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:  EL1986 and EL1989 adenocarcinoma of colon, EL1997 
triple negative invasive ductal carcinoma of breast, EL2144 brain metastases from 
adenocarcinoma of colon, and EL2056 glioblastoma; and cell-line–derived xenograft tumors:  
A2780 ovarian carcinoma, U-87 MG glioblastoma, HCT-116 and SW480 colon carcinoma, and 
K562 chronic myelogenous leukemia.  
Furthermore, LY3039478 has shown significant antitumor activity when combined with 
taladegib (LY2940680) in a leiomyosarcoma xenograft model.  In a proof-of-concept study using 
an ovarian cancer patient-derived xenograft (PDX) model (n=1 mouse per model), LY3039478 
in combination with carboplatin and paclitaxel was significantly better in 13/26 PDX models 
compared to single agent LY3039478 or chemotherapy alone (data on file).
5.3.2. Human Pharmacokinetics
As of 06 January 2015, PK data for LY3039478 were available from 52 patients on Day 1 and 
35 patients on Day 22 over a dose range of 2.5 to 100 mg in Cycle 1 from the first in human 
Study I6F-MC-JJCA (JJCA).  After oral administration, maximum plasma concentrations (Cmax) 
of LY3039478 were reached approximately 1 to 2 hours postdose.  The mean half-life (t1/2) was 
approximately 5 to 7 hours, suggesting little to no accumulation upon multiple dosing with a 
3-times-per-week (TIW) dosing schedule.  The area under the plasma concentration-time curve 
(AUC) from time zero to 48 hours (AUC[0-48hr]) after multiple dosing was similar to AUC from
time zero to infinity (AUC[0-]) after the first dose, indicating that the PK of LY3039478 did not 
change with time.  A preliminary assessment of dose proportionality has been conducted for PK 
parameters (AUC[0-48hr] and Cmax) on Day 22 of dosing in Cycle 1, and no deviations from 
linearity were observed across the dose range studied (2.5 to 100 mg).  The variability in 
exposures, as assessed by percentage coefficient of variation (CV), ranged from 30% to 90% for 
both Cmax and AUC.  Preliminary analyses of urine data suggest that renal clearance contributed 
to approximately 20% of apparent plasma clearance of LY3039478.
In primary cultured hepatocytes using incubation concentrations up to 100 µM, LY3039478 is a
mild inducer of CYP3A, with an estimated concentration yielding half the maximum effect 
(EC50) and maximum induction ratio (Emax) of 10 µM and 6.4-fold, respectively. Using a static 
model, the exposure of midazolam is predicted to be reduced by 20% after a dose of 75 mg 
LY3039478. In humans, the maximum tested dose was 100 mg and the Cmax was approximately 
2.3 µM.

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5.3.3. Pharmacodynamics
-Secretase is a multiprotein complex possessing protease activity against a number of type I 
membrane proteins including Notch receptors and APP.  Proteolytic cleavage of Notch receptors 
and APP by -secretase results in production of cleaved proteins NICD and Aβ, respectively.  
LY3039478 is a potent inhibitor of -secretase activity; and therefore, LY3039478 is expected to 
inhibit production of Aβ in addition to NICD.  Quantification of circulating Aβ in plasma was
used as a surrogate biomarker to determine PD effect of LY3039478 in patients.  The effect of 
LY3039478 on plasma Aβ concentrations follows an approximate dose related trend, with 
approximately 80% reductions in plasma Aβ observed from 45 mg to 100 mg.  
Additionally, expression of Notch regulated genes was assessed to monitor PD effect of 
LY3039478 in skin.  Skin samples were collected prior to and after approximately 6 hours of 
LY3039478 treatment.  Expressions of HES1, Cyclin D1 (CCND1), and Notch-Regulated 
Ankyrin Repeat (NRARP) were reduced; trending in a dose proportional manner.  Maximum 
inhibition of HES1 and NRARP occurred between 45 and 100 mg of LY3039478.
5.4.
General Introduction to Taladegib
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 investigational product 
may be found in Section 7 (Development Core Safety Information) of taladegib IB.  Information 
on SAEs expected in the study population independent of drug exposure and that will be 
assessed by the sponsor in aggregate, periodically during the course of the study, may be found 
in Section 6 (Effects in Humans) of the IB.  The information in the following sections provides a
brief summary.
5.4.1. Mechanism of Action and In Vitro/In Vivo Activity
Smo, a distant relative of G protein coupled receptors, is a key regulator of Hh signaling.  
Taladegib binds to the Smo receptor and competitively inhibits binding of 3H-2406189, an 
agonist to hSmo.  
Using an in vitro competitive binding assay, inhibitory concentration and binding constant were 
calculated based on the competitive displacement of radioligand.  LY2940680-Hydrochloride 
binds to human Smo receptor and inhibits binding of 3H-2406189, a known hSmo agonist, to 
hSmo with 76.4 ± 75.3 nM inhibition constant (Ki; n=4, geometric mean ± standard error [SE]) 
and 144 ± 143 nM IC50(n=4, geometric mean ± SE).  
To determine biological activity of taladegib in mouse cells, Gli-luciferase activity was 
quantified in mouse mesenchymal C3H10T1/2 cell line stimulated with sonic hedgehog 
conditioned media (Shh-CM).  LY2940680-Hydrochloride inhibited Hh signaling activity in 
mouse C3H10T1/2cells with an IC50 of 11.2 ± 5.33 nM (n=8, geometric mean ± SE).
To determine biological activity of taladegib in human cells, Gli1 transcript levels were 
quantified in human Daoy tumor cell line stimulated with Shh-CM.  LY2940680-Hydrochloride 
inhibited Hh signaling activity in human Daoy cells, with an IC50 of 2.22 ± 1.14 nM (n=8, 

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geometric mean ± SE) as determined by measurement of Gli1 messenger ribonucleic acid 
(mRNA) using branched-chain DNA (bDNA) assay technology.  
5.4.2. Clinical Summary
To date, the initial monotherapy study, Study I4J-MC-HHBB, has treated 84 patients at doses 
ranging from 50 mg to 600 mg daily.  The MTD was established at 400 mg as an oral daily dose.  
The most frequently occurring TEAEs (≥10% of patients) were dysgeusia (47.6%), nausea 
(46.4%), fatigue (45.2%), muscle spasms (39.3%), decreased appetite (32.1%), vomiting 
(28.6%), alopecia (27.4%), decreased weight (23.8%), myalgia (16.7%), diarrhea (15.5%), 
asthenia (10.7%), and constipation (10.7%).  Hyponatremia (n=1) was the only Grade 4 TEAE 
considered possibly related to taladegib treatment by the investigators; this event was also 
reported as serious.  Other Grade 3 TEAEs occurring in at least 2 patients and considered 
possibly related to taladegib treatment by the investigators were muscle spasms (n=4); fatigue 
(n=3); and nausea, vomiting, dysgeusia, asthenia, and myalgia (n=2 each).
A monotherapy, dose-escalation study in Japanese patients (Study I4J-MC-HHBH) has treated 
15 patients with doses ranging from 100 mg to 400 mg daily.  In this study, the most frequently 
reported TEAEs (≥10% of patients) considered possibly related to taladegib treatment were 
dysgeusia (n=11); decreased appetite (n=8); fatigue and nausea (n=6 each); vomiting (n=5); 
alopecia (n=4); pyrexia (n=3); and weight decreased, dehydration, muscular weakness, and 
insomnia (n=2 each).
After single- and multiple-dose administration, taladegib levels reach Cmax after approximately 
3 hours, with food appearing to have no impact on rate or extent of absorption. The mean value 
for the apparent clearance is 10 L/hr (75% CV); indicating that taladegib is slowly eliminated 
from the plasma. The mean value for the apparent volume of distribution is 248 L (47% CV). 
The mean taladegib t1/2 after multiple-dose administration across all doses is estimated to be 
approximately 22 hours (range:  5 to 55, 61% CV). The accumulation ratio is approximately 
2.1 between Day 1 and Day 15 (range:  0.7 to 4.8, 40% CV). A substrate depletion approach 
using recombinant human CYPs was used to identify the CYPs metabolizing taladegib and 
LSN3185556, and to predict the relative contributions of these CYPs to microsomal CYP-
mediated clearance. For both taladegib and LSN3185556, this approach indicated that CYP3A4 
was responsible for 100% of the hepatic CYP-mediated clearance of the respective compounds.  
5.5.
General Introduction to LY3023414
More detailed 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 
investigational product may be found in Section 7 (Development Core Safety Information) of 
LY3023414 IB.  Information on SAEs expected in the study population independent of drug 
exposure and that will be assessed by the sponsor in aggregate, periodically during the course of 
the study, may be found in Section 6 (Effects in Humans) of the IB.  The information in the 
following sections provides a brief summary.

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5.5.1. Mechanism of Action and In Vitro/In Vivo Activity
LY3023414 is a potent selective inhibitor of the Class I PI3K isoforms, mTOR, and DNA-PK, 
with selectivity in kinase enzyme assays as an ATP competitive inhibitor of PI3Kα (Ki 8.5 nM).  
LY3023414 has inhibitory activity against PI3K/mTOR pathway targets in vitro and in vivo as 
measured by phosphoprotein levels from cultured cells and tumor xenografts.  LY3023414 has 
antiproliferative and cell-cycle arresting effects in cultured cancer cells, and anti-angiogenesis 
activity via inhibition of in vitro vascular cord formation.  
5.5.2. Clinical Summary
Study I6A-MC-CBBA (CBBA) is an ongoing dose-escalation study for daily (QD) and 
twice-daily (BID) dosing of LY3023414 followed by expansion cohorts for different tumor types 
and LY3023414 combination treatments.
In the dose-escalation phase of Study CBBA, dose-limiting toxicities (DLTs) for BID dosing 
were observed in 3 out of 4 patients at the 250-mg BID dose level (Grade 4 hypophosphatemia, 
Grade 3 fatigue, Grade 3 mucositis) and in 1 out of 6 patients at the 200-mg BID dose level
(Grade 2 nausea).  Therefore, a dose of 200-mg LY3023414 was defined as the maximum 
tolerated dose (MTD) for BID dosing.  
As of 08 June 2015, of the 72 patients who received at least 1 dose of LY3023414, 61 patients 
(84.7%) had at least 1 possibly study drug-related TEAE (all grades).  The most commonly 
reported TEAEs (that is, occurring in ≥10% of patients) considered as possibly related to study 
drug(s) across all study parts in Study CBBA were nausea (41.7%), fatigue (31.3%), vomiting 
(34.7%), diarrhea (18.1%), stomatitis (16.7%), and decreased appetite (16.7%).  Most of these 
TEAEs (58.3%) were mild or moderate in severity.
For patients receiving LY3023414 monotherapy at doses up to and including the MTD (total 
n=60 patients, including 35 patients who received 200 mg BID monotherapy), 14 possibly 
related Grade 3 TEAEs have been reported including fatigue (n=3), hyperglycemia (n=2), and 
maculo-papular rash (n=2).  
PK analyses showed a dose-proportional increase in LY3023414 exposures (AUC) at tolerated 
dose levels with a t1/2 of 1.9 hours and a clearance following oral administration of 82 L/hr.  
Midazolam PK data indicated that LY3023414 is a weak inhibitor of CYP3A4.  In vitro 
metabolism data indicate that LY3023414 is likely primarily metabolized in humans by 
CYP3A4. Biomarker assessment demonstrated dose-related target inhibition as measured by 
p4EBP1 inhibition in peripheral mononuclear cells at LY3023414 doses ≥150 mg.  
Eleven of 47 patients (23%) had a decrease in their target lesions.  A durable partial response, 
according to Response Evaluation Criteria in Solid Tumors (RECIST), was observed in an 
endometrial cancer patient harboring PIK3R1 and PTEN mutations.  The remaining 10 patients 
had a decrease in their target lesions by up to 29%.  
Considering safety, PK/PD, and preliminary anti-tumor results, a dose of 200-mg LY3023414 
BID was determined as the recommended Phase 2 dose for LY3023414 monotherapy.  

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LY3023414 is currently being evaluated in additional Phase 2 studies for castration-resistant 
prostate cancer patients in combination with enzalutamide and squamous non-small cell lung 
cancer (NSCLC) patients in combination with the epidermal growth factor receptor (EGFR)
targeting antibody necitumumab.  
5.6.
General Introduction to Abemaciclib
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 investigational product 
may be found in Section 7 (Development Core Safety Information) of abemaciclib IB.  
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate, periodically during the course of the study, may be 
found in Section 6 (Effects in Humans) of the IB.  The information in the following sections 
provides a brief summary.
5.6.1. Mechanism of Action and In Vitro/In Vivo Activity
Abemaciclib mesylate is a potent inhibitor of CDK4 and CDK6 that is selective over other CDKs 
at the enzyme (3 orders of magnitude more selective for CDK4 compared to CDK1) and cellular 
level.  This is demonstrated in Colo 205 cells by potent cellular inhibition of Rb phosphorylation 
(pSer780, IC50=120 ± 36 nM) and by exclusive G1 cell cycle arrest (indicated by accumulation 
of cells with 2N DNA content) up to 6 µM concentration.  Studies in other cancer cell models 
have confirmed and demonstrated that abemaciclib mesylate inhibits CDK4/6 to induce G1 arrest 
specifically in Rb+ cell lines versus lines, which lack functional Rb (Rb-).  Using in vitro kinase 
panel screening, abemaciclib mesylate also demonstrates inhibition (IC50 <0.3 µM) of the 
human protein kinases hCDK9, hPIM1, hPIM2, hHIPK2, hDYRK2, GSK3β, hCDK5/P35, and 
CK2; however, the reversible G1 arrest seen in vitro and in vivo indicates that the CDK4/6 
activity of abemaciclib mesylate predominates over these other activities.
The phenotypic selectivity for a G1 arrest is also demonstrated in animal studies.  In these 
studies, in vivo target inhibition was measured in human Colo 205 xenografts with an assay 
monitoring both biochemical and phenotypic inhibition of CDK4/6.  Rb phosphorylation at 
serine 780 (pRb) is a specific marker for CDK4/6 inhibition and also a phenotypic marker for G1 
arrest, while TopoIIα is a specific marker for cells in S phase and pHH3 is a marker for cells in 
M phase.  Inhibition of CDK4/6 associated with reduced pRb and a sustained G1 arrest is 
indicated by strong inhibition of all markers.  The capacity of abemaciclib mesylate to inhibit 
CDK4/6 in vivo is illustrated by the sustained PD response in mouse Colo 205 xenograft model, 
in which a 50-mg/kg oral dose resulted in ≥50% inhibition of Rb phosphorylation for 1 to 
24 hours after dosing.  This effect also correlated with an inhibition of cell cycle progression as 
indicated by the potent suppression of pRb, TopoIIα, and pHH3 observed at 24 hours following 
dosing.  A dose response for inhibition was observed in these studies such that the threshold 
effective doses for 70% inhibition (TED70) for pRb and TopoIIα inhibition 24 hours after oral 
dosing were 14.1 and 14.3 mg/kg, respectively.  

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5.6.2. Clinical Summary
As of December 2015, 572 patients were treated with abemaciclib across 6 clinical studies.  
Abemaciclib has been given as monotherapy, in combination with endocrine therapy, and in 
combination with chemotherapeutic agents. Cumulatively in all of these groups, the most 
common TEAEs (≥10% of patients) possibly related to study drug included diarrhea (73.3%), 
fatigue (48.6%), nausea (48.3%), neutropenia (32.9%), vomiting (25.3%), decreased appetite 
(25.2%), thrombocytopenia (22.9%), anemia (22.4%), leukopenia (20.3%), abdominal pain 
(18.2%), and blood creatinine increased (14.0%).  
Grade 3 TEAEs possibly related to study drug included neutropenia (13.8%); diarrhea (13.6%); 
leukopenia and fatigue (7.7% each); thrombocytopenia (5.1%); anemia (4.7%); nausea (3.0%); 
lymphopenia (2.8%); hypokalemia (1.4%); abdominal pain, decreased appetite, and vomiting 
(1.2% each); ALT increased and blood creatinine increased (0.9% each); dehydration, febrile 
neutropenia, and stomatitis (0.7% each); AST increased, confusional state, hyponatremia, lung 
infection, and rash (0.5% each); hypophosphatemia, hypotension, international normalized ratio 
increased, and pneumonitis (0.3% each); and acute kidney injury, aphasia, arthralgia, chronic 
kidney disease, colitis, dermatitis acneiform, dyspnea, gait disturbance, gamma-glutamyl 
transpeptidase (GGT) increased, hematotoxicity, hematuria, hypertension, infection, infusion 
related reaction, liver function text abnormal, lymphorrhea, malaise, muscular weakness, pain, 
pancreatitis, pruritus, pyrexia, skin infection, somnolence, syncope, and upper-airway cough 
syndrome (0.2% each).  In addition, Grade 3 scrotal infection was experienced by 1 patient 
(0.7% by total male population).  
Grade 4 TEAEs possibly related to study drug included neutropenia (5.2%); thrombocytopenia 
(1.4%); leukopenia (0.9%); anemia and GGT increased, (0.3% each); and cardiogenic shock, 
febrile neutropenia, hypertriglyceridemia, hypokalemia, lymphopenia, sepsis, stress 
cardiomyopathy (0.2% each).  
Grade 5 TEAE of sepsis (0.3%) and sudden death (0.2%) that were possibly related to study drug 
were reported. 
Treatment-emergent CTCAE central laboratory toxicities of increased creatinine were reported 
in 93% of patients (N=572) who received abemaciclib therapy.  Mean serum creatinine rises, to 
approximately 15% to 40% above baseline, occurred during Cycle 1 in most of the patients 
exposed to abemaciclib and were maintained during treatment.  A decrease in serum creatinine to 
near baseline was observed following treatment discontinuation, indicating that the serum 
creatinine increase observed is reversible.  Concomitant increases in mean blood urea nitrogen 
(BUN) were typically not observed in patients exposed to abemaciclib.  In vitro studies have 
indicated that abemaciclib and its major metabolites (LSN2839567 and LSN3106726) inhibit the 
renal transporter, multidrug and toxin extrusion protein 1 (MATE1), at clinically relevant 
concentrations.  Thus, increases in serum creatinine observed following dosing with abemaciclib, 
in the absence of simultaneous increases in BUN or development of an abnormal urinalysis, are 
most likely due to inhibition of its tubular secretion via MATE1 and may not reflect a decline in 
renal function, making serum creatinine level an unreliable measurement for renal function.  

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Investigators should be aware that serum creatinine increases may be a consequence of receiving 
abemaciclib.  If deterioration of renal function is suspected, measures other than those relying on 
assessment of serum creatinine should be used to determine renal function.  
PK data for abemaciclib after a single oral dose administration were available from 222 patients 
dosed over a total dose range of 50 to 275 mg. The exposure of abemaciclib increased in a dose 
proportional manner; however, statistical significance at the 90% confidence level could not be 
established. The time course of abemaciclib concentration in plasma is characterized by a slow 
absorption, with a median time to maximum observed plasma concentration (Tmax) ranging from 
4 to 6 hours postdose. The mean t1/2 ranged from 17 to 38 hours across the dose range tested but 
there was no consistent trend with dose, suggesting no dose-dependent change in CL.  
A substrate depletion assay used to identify the CYP enzymes metabolizing abemaciclib and its 
major active metabolites LSN2839567 and LSN3106726, indicate that CYP3A is primarily 
involved in the CYP-mediated metabolism and is responsible for over 99% of the CYP-mediated 
microsomal clearance of abemaciclib, LSN2839567, and LSN3106726.  In Study I3Y-MC-JPBF, 
coadministration of abemaciclib with rifampin, a strong CYP3A inducer, reduced abemaciclib 
exposure by over 90%.  
5.7.
Rationale for Selection of Doses for LY3039478 and Other 
Anticancer Agents
During the dose-escalation phase (Part A) of Phase 1 Study JJCA, 5 of the 55 patients (9.1%) 
experienced DLTs.  DLTs 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.  DLTs 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 
Cohort 9 (100 mg) experienced a DLET of Grade 3 fatigue during Cycle 4.  The MTD was 
established at 75 mg TIW.
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 Grades 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 TIW.  
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) TEAEs reported at the 
50-mg dose level were: diarrhea (14 patients, 39%); nausea and asthenia (8 patients each, 22%);

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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).  
The starting dose for LY3039478 is 50% of the monotherapy recommended dose (25 mg).  
LY3039478 will be escalated up to 50 mg.
For Part A, the starting dose for taladegib is 50% of the monotherapy recommended dose 
(200 mg). Taladegib will be escalated up to 400 mg.
For Part B, the starting dose for LY3023414 is 75% of the monotherapy recommended dose 
(150 mg BID).  LY3023414 will be escalated up to 200 mg.
For Part C, the starting dose for abemaciclib is 50% of the monotherapy recommended dose 
(100 mg BID).  Abemaciclib will be escalated up to 150 mg BID.
For Parts D and E, the dose regimens of cisplatin/gemcitabine and gemcitabine/carboplatin will 
be the standard regimens used for treatment of cholangiocarcinoma and TNBC, respectively.
5.8.
Rationale for Amendment (a)
This study was amended at the request of the Food and Drug Administration (FDA) to clarify 
inclusion criteria, some criteria for DLTs (Section 7.2.2.1), and the definition for MTD.  Minor 
editorial changes and clarifications have also been made.  

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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 be 
re-screened. Individuals may be re-screened up to 3 times.  Each time re-screening is performed, 
the individual must sign a new informed consent form (ICF) and will be assigned a new 
identification number.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
[1]
For all parts:  The patient must be, in the judgment of the investigator, an 
appropriate candidate for experimental therapy after available standard 
therapies (per available local guidelines) have failed to provide clinical benefit 
for their advanced or metastatic cancer.

For dose escalation for all combinations:  The patient must have 
histological or cytological evidence of cancer, either a solid tumor or a 
lymphoma, which is unresectable or metastatic.

For Part A dose confirmation: All patients must have histological 
evidence of unresectable or metastatic soft tissue sarcoma or breast cancer. 
Breast cancer patients must have prescreened mutations, amplification, or 
gene/protein expression alterations related to Notch pathway
(Attachment 8).

For Part B dose confirmation:  All patients must have histological evidence of 
unresectable or metastatic colon cancer or soft tissue sarcoma. Colon cancer 
patients must have prescreened mutations, amplification, or gene/protein 
expression alterations related to Notch pathway (Attachment 8).  

For Part C dose confirmation:  All patients must have histological 
evidence of unresectable or metastatic breast cancer and prescreened 
mutations, amplification, or gene/protein expression alterations related to 
Notch pathway (Attachment 8).  

For Part D dose confirmation: All patients must have histological 
evidence of cholangiocarcinoma and prescreened mutations, amplification, 
or gene/protein expression alterations related to Notch pathway 
(Attachment 8). Patients must not have received >1 line of prior systemic 
therapy for metastatic or resectable disease (that is, patients may have 
received adjuvant gemcitabine and then later gemcitabine/cisplatin for 
recurrent metastatic disease).

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
For Part E dose confirmation: All patients must have histological 
evidence of locally advanced unresectable or metastatic TNBC and 
prescreened mutations, amplification, or gene/protein expression 
alterations related to Notch pathway (Attachment 8). Patients must not 
have received >2 lines of systemic treatment for unresectable or metastatic
TNBC.
[2]
For dose confirmation (all parts):  Have measurable disease (as defined by the 
RECIST guideline [RECIST 1.1; Eisenhauer et al. 2009]).
[3]
Are 18 years of age.
[4]
Have given written informed consent prior to any study-specific procedures
[5]
Have adequate organ function, including:

Hematologic:  Absolute neutrophil count (ANC) 1.5 x 109/L, platelets 
100 x 109/L, and hemoglobin 8 g/dL or >5 mmol/L. Patients may 
receive erythrocyte transfusions to achieve this hemoglobin level at the 
discretion of the investigator; however, initial study drug treatment must 
not begin earlier than the day after the erythrocyte transfusion.

Hepatic:  Bilirubin 1.5 times upper limit of normal (ULN), ALT and 
aspartate aminotransferase (AST) 2.5 times ULN.  If the liver has tumor 
involvement, AST and ALT equaling 5 times ULN are acceptable.

Renal:  calculated creatinine clearance >60 mL/min (Attachment 7).

For Part B only: have fasting glucose ≤140 mg/dL and glycosylated 
hemoglobin (HbA1c) ≤7 g/dL.
[6]
Have a performance status of 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (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) except for residual alopecia.  
At the discretion of the investigator, patients with breast or prostate cancers 
progressing on luteinizing hormone-releasing hormone (LHRH) or
gonadotropin-releasing hormone (GnRH) therapies may have that treatment 
continued while receiving study drug.
[8]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[9]
Males and females with reproductive potential must agree to use highly 
effective methods of birth control during the study and for 12 weeks following 
the last dose of the study drugs or country requirements, whichever is longer.

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Women of child-bearing potential must test negative for pregnancy within 
7 days of enrollment based on a serum pregnancy test and also must not be 
breastfeeding
[10] Have an estimated life expectancy ≥12 weeks.
[11] Are able to swallow capsules and tablets.
[12] Have available tumor tissue (archived or newly biopsied).
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.  
[13] Have received treatment within 14 days of the initial dose of study drug with 
an investigational product or nonapproved use of a drug or device (other than 
the study drug/device used in this study) for non-cancer indications or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.  
[14] Have a serious concomitant systemic disorder (for example, active infection 
including human immunodeficiency virus, or cardiac disease) that, in the 
opinion of the investigator, would compromise the patient’s ability to adhere 
to the protocol.
[15] Have symptomatic central nervous system (CNS) malignancy or metastasis 
(screening not required).  

Patients with treated CNS metastases are eligible for this study if they are 
not currently receiving corticosteroids and/or anticonvulsants, and their 
disease is asymptomatic and radiographically stable for at least 60 days.

Patients with glioblastoma, World Health Organization (WHO) Grade 4, 
or WHO Grade 2 or 3 glioma are eligible.
[16] Have current acute leukemia.
[17] Have a second primary malignancy that, in the judgment of the Investigator 
and sponsor, may affect the interpretation of results.
[18] 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.  
[19] Part B only: Have insulin-dependent diabetes mellitus or a history of 
gestational diabetes mellitus. Patients with a type 2 diabetes mellitus are 
eligible if adequate control of blood glucose level is obtained by oral 
antidiabetics as documented by HbA1c ≤7%.  
[20] Part B only:  Have QTc interval of >470 msec.

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[21] Part B dose expansion only:  Prior treatment with a PI3K/mTOR inhibitor.
6.2.
Summary of Study Design
Study JJCD is a multicenter, nonrandomized, open-label, Phase 1b study consisting of 
5 separate, parallel dose escalations in patients with advanced/metastatic cancer from a variety of 
solid tumors followed by a dose-confirmation phase in specified tumor types (Figure JJCD.1).  
Additional parts exploring other combinations such as ramucirumab combination and/or 
immuno-oncology agents may be added in the future and will require a protocol amendment.
Part A:  A single dose of taladegib will be given on Day 1 during a 3-day lead-in period
(dose-escalation phase only) in order to evaluate the effects of LY3039478 on the PK of 
taladegib and its active metabolite LSN3185556 (see Section 5.3.2).  In the dose-escalation phase 
of Part A, eligible patients will receive LY3039478 given orally TIW in combination with a 
hedgehog/Smo antagonist (taladegib [LY2940680]) given orally QD on a 28-day cycle. In the 
dose-confirmation phase of Part A, approximately 10 patients with breast cancer (that have 
mutations, amplification, or gene/protein expression alterations related to Notch pathway) and 
10 patients with soft tissue sarcomas will be treated.
Part B: A single dose of LY3023414 will be given on Day 1 during a 3-day lead-in period
(dose-escalation phase only) in order to evaluate the effects of LY3039478 (a mild inducer of 
CYP3A) on the PK of LY3023414 (see Section 5.3.2).  In the dose-escalation phase of Part B, 
eligible patients will receive LY3039478 given orally TIW in combination with a PI3K/mTOR
inhibitor (LY3023414) given orally, every 12 hours on a 28-day cycle.  In the dose-confirmation 
phase of Part B, approximately 10 patients each with advanced or metastatic colon cancer or soft 
tissue sarcoma will be treated. Colon cancer patients have to have mutations, amplification, or 
gene/protein expression alterations related to Notch pathway.
Part C:  A single dose of abemaciclib will be given on Day 1 during a 3-day lead-in period
(dose-escalation phase only) in order to evaluate the effects of LY3039478 on the PK of 
abemaciclib and its metabolites LSN2839567 and LSN3106726 (see Section 5.3.2).  In the 
dose-escalation phase of Part C, eligible patients will receive LY3039478 given orally TIW in 
combination with a CDK4/6 inhibitor (abemaciclib [LY2835219]) given orally, every 12 hours
on a 28-day cycle. In the dose-confirmation phase of Part C, approximately 15 patients with 
metastatic breast cancer that have mutations, amplification, or gene/protein expression alterations 
related to Notch pathway will be treated.
Part D:  In the dose-escalation phase of Part D, eligible patients will receive LY3039478 given 
orally TIW in combination with cisplatin and gemcitabine given as intravenous (IV) infusions on 
Days 1 and 8 of a 21-day cycle.  In the dose-confirmation phase of Part D, approximately 
15 patients with cholangiocarcinoma that have mutations, amplification, or gene/protein
expression alterations related to Notch pathway will be treated.
Part E:  In the dose-escalation phase of Part E, eligible patients will receive LY3039478 given 
orally TIW in combination with gemcitabine and carboplatin given as IV infusions on Days 1 
and 8 of a 21-day cycle.  In the dose-confirmation phase of Part E, approximately 15 patients 

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with TNBC (estrogen receptor negative [ER-], progesterone receptor negative [PR-], human 
epidermal growth factor receptor 2 negative [HER2-]) that have mutations, amplification, or 
gene/protein expression alterations related to Notch pathway will be treated.
The total sample size is estimated to be approximately 163 patients. Further details are provided 
in Section 10.1.
The planned duration of treatment is not fixed; patients will remain on study drug therapy until 
they fulfill 1 of the criteria for treatment discontinuation.  The treatment period will be defined as 
the time from treatment start until discontinuation from treatment for any reason (Section 6.3.2).  
The postdiscontinuation follow-up period begins the day after the patient and the investigator 
agree that the patient will no longer continue study treatment and is defined by the following 
periods:

The short term follow-up period begins 1 day after the patient and investigator agree 
that the patient will no longer continue treatment and lasts approximately 30 days 
(Visit 801).  

The long-term follow-up period begins 1 day after the short-term follow-up period 
(Visit 801) is completed and continues until death or study closure to collect PFS data
(Visit 802-80X).

After discontinuation, tumor measurements will be performed as indicated in 
Section 8.3. Other study procedures will be performed as outlined in Attachment 1.
This study will be considered closed once it is deemed that sufficient data are obtained to assess 
the primary and the secondary objectives, estimated to be approximately 12 months from the 
date that the last patient was enrolled.  This will ensure that the primary objective and the 
secondary objectives are met for the purpose of the clinical study report. For PFS, in the event 
that the data are not mature enough to characterize the entire survival curve, a landmark analysis 
at 12 months will be done for the purpose of the clinical study report. Patients who are 
benefitting from treatment may continue to receive study drug for long-term durations, even after 
the study has closed and final database lock has occurred, in the continued access period.  
Based on emerging preclinical and clinical data, the protocol may be amended as appropriate to 
reflect the most current scientific knowledge.  Study design may be modified to reflect these data 
and scientific needs.  This includes, and is not limited to, change in the study design, 
modifications of safety monitoring, addition of cohorts to study, and introduction of new 
schedules as single agent or in combination with other agents.  
Refer to Attachment 1 for the Study Schedule.

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Figure JJCD.1.
Illustration of study design for Protocol I6F-MC-JJCD.
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]) following the final analysis.  “End of trial” refers to the date of the last visit or last 
scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up.
6.2.2. Continued Access Period
All patients remaining on study treatment without disease progression following the final 
analysis will be able to enter the continued access period of the study.  The continued access
period begins after study completion and ends at the end of trial.  During the continued access
period, patients on study treatment who continue to experience clinical benefit may continue to 
receive study treatment until disease progression, death, unacceptable toxicity, or start of new 
anticancer treatment.  The continued access period includes a follow-up visit.  The follow-up 
visit begins 1 day after the patient and the investigator agree that the patient will no longer 
continue treatment in the continued access period and lasts approximately 30 days.  If it is 

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
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LY3039478
deemed to be in the best interest of the patient to start a new anticancer treatment prior to the 
scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this case, 
the follow-up assessments should be completed prior to the initiation of the new therapy.
During the continued access period, all AEs, SAEs, study drug dosing, and dose reduction of 
treatment will be collected on the case report form/electronic case report form (CRF/eCRF).  
SAEs will also be reported to Lilly Global Patient Safety and collected in the Lilly Safety System
(LSS).  In the event that an SAE occurs, additional information (such as local laboratory results, 
concomitant medications, and hospitalizations) may be requested by Lilly in order to evaluate the 
reported SAE.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.
6.3.
Discontinuations
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) and the investigator to determine whether the 
patient may continue in the study, with or without investigational product.  Inadvertently 
enrolled patients may be maintained in the study and on investigational product when the Lilly
CRP agrees with the investigator that it is medically appropriate for that patient. The patient 
may not continue in the study with or without investigational product if the Lilly CRP does not 
agree with the investigator’s determination that it is medically appropriate for the patient to 
continue. The investigator must obtain documented approval from the Lilly CRP 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 early will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
In addition, patients will be discontinued from the study drug and from the study in the following 
circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
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o
the investigator/physician decides that the patient should be discontinued from the 
study or study drug(s)
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug(s) 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
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 good clinical practice (GCP).

The patient has evidence of progressive disease or confirmed objective progressive 
disease.  The determining factor for whether a patient can continue on study drug should 
be based on his/her clinical symptoms even if the patient has progressive disease based 
on radiological evidence.  The investigator may also take into consideration biomarker 
responses (prostate-specific antigen [PSA], alpha-fetoprotein [AFP], etc).

The patient experiences unacceptable toxicity including, but not limited to, a Grade 4 
nonhematological toxicity or a toxicity that does not resolve to baseline within 21 days.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).
The reason for and date of discontinuation will be collected for all patients.  The Date of 
Discontinuation (for any of the above reasons) from study treatment is to be reported on the 
CRF.  Patients who discontinue will have follow-up procedures performed as shown in the Study 
Schedule (Attachment 1).
6.3.3. 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.
6.3.4. 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- and 50-mg capsules in bottles for oral consumption.  
LY3039478 capsules should be stored at room temperature within the temperature range stated 
on the label.  Investigators should instruct patients to store the capsules at home in the original 
container and to keep out of the reach of children.  Capsules should not be opened, crushed, or 
dissolved.
Taladegib will be supplied as 100-mg tablets in bottles for oral consumption.  Taladegib tablets
should be stored within the temperature range stated on the label.  Investigators should instruct 
patients to store the tablets at home in the original container and to keep out of the reach of 
children.  Tablets should not be crushed or dissolved.
LY3023414 will be supplied as 25-mg, 100-mg, or 200-mg capsules or 100-mg, 150-mg, or 
200-mg tablets for oral consumption. LY3023414 should be stored within the temperature range 
stated on the label.  Investigators should instruct patients to store the capsules/tablets at home in 
the original container and to keep out of the reach of children.  Capsules should not be opened, 
crushed, or dissolved.
Abemaciclib will be supplied as 50-mg hypromellose capsules and should be stored within the 
temperature range stated on the label.  Investigators should instruct patients to store the capsules 
at home in the original container and to keep out of the reach of children.  Capsules should not be 
opened, crushed, or dissolved.
Gemcitabine will be supplied in commercially available dosage forms and provided according to 
the country’s regulatory requirements.  Gemcitabine should be stored and prepared in accordance 
with the package insert.  
Carboplatin will be supplied in commercially available dosage forms and provided according to 
the country’s regulatory requirements.  Carboplatin should be stored and prepared in accordance 
with the package insert.  
Cisplatin will be supplied in commercially available dosage forms and provided according to the 
country’s regulatory requirements.  Cisplatin should be stored and prepared in accordance with 
the package insert.  
Clinical trial materials will be labeled according to the country’s regulatory requirements, and 
Lilly will perform the labeling and the final packaging of the study medications under good 
manufacturing practice (GMP) conditions.  All study drugs should be stored within the 
temperature range stated on the label.

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7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agent(s) and planned duration of each 
individual’s treatment to the patient/legal representative,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensation 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(s) so that the situation can be assessed.
7.2.1. Dosing Schedule
LY3039478 will be administered orally TIW in all parts (in both the dose-escalation phases and 
the dose-confirmation phases) according to the schedule shown below.

Monday, Wednesday, Friday every week for a 21- or 28-day cycle

Tuesday, Thursday, Saturday every week for a 21- or 28-day cycle

Wednesday, Friday, Sunday every week for a 21- or 28-day cycle

Thursday, Saturday, Monday every week for a 21- or 28-day cycle 
Patients will receive LY3039478 orally TIW.  LY3039478 will be taken once per day on days of 
administration prior to a meal (recommendation is within 30 minutes) on an empty stomach.  
During all cycles, study drug should be taken at approximately the same time on the dosing days.  
Any deviations should be documented in the patient diary.  If a patient misses or vomits a 
LY3039478 dose, that dose should be omitted.  
In all study parts during Cycles 1 and 2, patients will record the time and amount of each dose of 
LY3039478 in a patient diary, additionally the amount of each dose of taladegib, LY3023414, 
and abemaciclib should be recorded by patients in the diary for doses associated with PK 
sampling days. For Cycle 3 and beyond, the first and last dose dates for each drug in each 
individual cycle will be documented.  
Clinic personnel will instruct patients to pay particularly close attention to and record this 
information accurately on days of PK assessments (Attachment 4).
The patient or clinic personnel will record this information in the patient diary, and study 
monitors will cross-reference clinic records at the site to verify accuracy.
For Cycle 2 and beyond, a delay of ≤7 days in the start of a cycle (Dose 1) for justifiable reasons 
(for example, inclement weather, holidays, or weekends) other than toxicity will be permitted 
and does not constitute a protocol violation.
For Cycle 2 and beyond, a delay of ≤21 days in the start of a cycle (Dose 1) to allow for recovery 
from toxicity will be permitted and does not constitute a protocol violation (refer to 
Section 7.2.4.1.2).

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Dose regimens are shown in Table JJCD.7.1.
Table JJCD.7.1.
Dose Regimens
Treatment
Regimen
Part A:  LY3039478 + taladegib
1 cycle = 28 days
Single dose of taladegib given on Day 1 during a 3-day lead-in period (only 
for Part A dose escalation)
LY3039478 dose-escalation dose TIW, Days 1 to 28
Taladegib dose-escalation dose QD, Days 1 to 28
Part B:  LY3039478 + LY3023414
1 cycle = 28 days
Single dose of LY3023414 given on Day 1 during a 3-day lead-in period (only 
for Part B dose escalation)
LY3039478 dose-escalation dose TIW, Days 1 to 28
LY3023414 dose-escalation dose BID, Days 1 to 28
Part C:  LY3039478 + abemaciclib
1 cycle = 28 days
Single dose of Abemaciclib given on Day 1 during a 3-day lead-in period 
(only for Part C dose escalation)
LY3039478 dose-escalation dose TIW, Days 1 to 28
Abemaciclib dose-escalation dose BID, Days 1 to 28
Part D:  LY3039478 + 
cisplatin/gemcitabine
1 cycle = 21 days
LY3039478 dose-escalation dose TIW, Days 1 to 21
Cisplatin 25 mg/m2, Days 1 and 8 of a cycle.
Gemcitabine 1000 mg/m2, Days 1 and 8 of a cycle
Part E:  LY3039478 + 
gemcitabine/carboplatin
1 cycle = 21 days
LY3039478 dose-escalation dose TIW, Days 1 to 21
Gemcitabine 1000 mg/m2, Days 1 and 8 of a cycle
Carboplatin AUC 2, Days 1 and 8 of a cycle
Abbreviations:  AUC = area under the plasma concentration-time curve; BID = twice daily; QD = daily; 
TIW = 3 times per week.
7.2.1.1.
LY3039478 in Combination with Taladegib (Part A)
Patients enrolled in Part A for the dose-escalation phase only will receive a single dose of 
taladegib on Day 1 during a 3-day lead-in period.
LY3039478 will be given orally TIW in combination with taladegib given orally QD.  
LY3039478 and taladegib should be taken at approximately the same time on the dosing days.
Drugs will be taken as specified above prior to a meal (recommendation is at least 30 minutes
prior) on an empty stomach.  During all cycles, any study drug deviations should be documented 
in the patient diary for both drugs.  If a patient misses or vomits a dose, that dose should be 
omitted. 
7.2.1.2.
LY3039478 in Combination with LY3023414 (Part B)
Patients enrolled in Part B for the dose-escalation phase only will receive a single dose of 
LY3023414 on Day 1 during a 3-day lead-in period.
LY3039478 will be given orally TIW in combination with LY3023414 given orally BID.  
LY3039478 and LY3023414 should be taken at approximately the same time on the dosing days
when applicable.

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LY3023414 will be taken as a chronic/continuous treatment approximately every 12 hours with a 
full glass of water. Patients should not consume food for approximately 1 hour before taking 
each dose of LY3023414 (if feasible). Patients should swallow LY3023414 as a whole
capsule/tablet and should not chew or crush them  If the patient misses a dose of LY3023414, the 
patient should take the dose as soon as possible, but not less than 6 hours before the next dose is 
scheduled.  If the next dose is to be taken in less than 6 hours or the patient vomits a dose, the 
patient should skip the missed dose and take the next dose as scheduled.
During all cycles, any study drug deviations should be documented in the patient diary for both 
drugs.  
7.2.1.3.
LY3039478 in Combination with Abemaciclib (Part C)
Patients enrolled in Part C for the dose-escalation phase only will receive a single dose of 
abemaciclib on Day 1 during a 3-day lead-in period.
LY3039478 will be given orally TIW in combination with abemaciclib given orally BID.  
LY3039478 and abemaciclib should be taken at approximately the same time on the dosing days
when applicable.
Abemaciclib will be taken as a chronic/continuous treatment every 12 hours.  During all cycles, 
any study drug deviations should be documented in the patient diary for both drugs.  If a patient 
misses or vomits a dose, that dose should be omitted.  
7.2.1.4.
LY3039478 in Combination with Cisplatin and Gemcitabine (Part D)
Patients will receive LY3039478 orally TIW.  On Days 1 and 8 of each 21-day cycle, 
LY3039478 should be given before the cisplatin and gemcitabine infusions. 
Patients enrolled in Part D will receive LY3039478 in combination with cisplatin and 
gemcitabine.  Patients will receive 25 mg/m2 cisplatin on Days 1 and 8 of each 21-day cycle. 
Cisplatin should be administered following the institutional-approved protocols for pre- and 
posthydration together with standard-of-care premedication.  All concomitant medications, 
including premedication, should be recorded on the CRF. Suggested administration is on an 
outpatient basis as a 1.5-hour IV infusion (1 liter of 0.9% saline including cisplatin, 20 mmol of 
potassium chloride, and 8 mmol of magnesium sulfate over 1 hour followed by 500 mL of 0.9% 
saline over 30 minutes).  The dose of cisplatin is to remain constant unless dose modification is 
required (see Section 7.2.4).  The dose of cisplatin administered should be rounded to the nearest 
1 mg.  Treatment should continue on schedule if possible, but a variance of ±2 days may be 
allowed to accommodate holidays and clinic scheduling conflicts.  
Patients will receive 1000 mg/m2 gemcitabine administered over 30 minutes on Days 1 and 8 of 
each 21-day treatment cycle.  Investigators should consult the approved gemcitabine package 
insert for complete packaging and labeling information.  The gemcitabine infusion should start 
immediately following the cisplatin dose.
If applicable, after discontinuation of gemcitabine or cisplatin patients may continue to receive 
treatment with LY3039478 as a single agent if they are deriving clinical benefit.

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7.2.1.5.
LY3039478 in Combination with Gemcitabine and Carboplatin (Part E)
Patients will receive LY3039478 orally TIW.  On Days 1 and 8 of each 21-day cycle, 
LY3039478 should be given before the gemcitabine and carboplatin infusions. 
Patients enrolled in Part E will receive LY3039478 in combination with gemcitabine and 
carboplatin.  Patients will receive 1000 mg/m2 gemcitabine administered over 30 minutes on 
Days 1 and 8 of each 21-day treatment cycle.  Investigators should consult the approved 
gemcitabine package insert for complete packaging and labeling information.
Patients will receive carboplatin dosed at AUC 2 IV over 30 minutes on Days 1 and 8 of each 
21-day treatment cycle.  Investigators should consult the approved carboplatin package insert for 
complete packaging and labeling information.  
At sites where serum creatinine is determined by a method standardized to the isotope dilution 
mass spectrometry (IDMS) reference material, the estimated glomerular filtration rate (GFR) 
used in the Calvert formula to calculate AUC-based dosing should not exceed 125 mL/min.  All 
United States (US) and any other outside the US (OUS) site where the IDMS method is available 
should calculate carboplatin doses based upon serum creatinine values that were measured by the 
IDMS method.  At sites where the IDMS method is not available, for the estimated GFR used to 
calculate the Calvert formula, all sites should use the method of serum creatinine measurement 
and carboplatin dosing that is aligned with local practice standard of care.
The site is responsible to consult the local laboratory to determine what method of serum 
creatinine measurement is used by that laboratory.
If applicable, after discontinuation of gemcitabine or carboplatin patients may continue to 
receive treatment with LY3039478 as a single agent if they are deriving clinical benefit.
7.2.2. Dose Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
MTD of each combination with LY3039478 is determined.
In this study, dose escalation will be driven by safety using the 3+3 method.  
Each new dose level will have a minimum of 3 patients enrolled to it.  If 1 patient, at any dose 
level, experiences a DLT within the first cycle of LY3039478, then up to 3 additional patients 
will be enrolled at that dose level.  If a DLT is observed in 2 or more patients at any dose level,
dose escalation will cease and either the previous dose level will be declared the MTD or, 
following discussions between the sponsor and investigators additional patients may be treated at 
intermediate doses between the previous and current dose levels.
In addition, if available at the time of dose-escalation decision, PK (Cmax, AUC, and apparent 
systemic clearance [CL/F]) results will be used as secondary/supporting data for dose escalation.
Additional patients may therefore be enrolled at a specific dose level to characterize PK/PD, 
provided the observed DLT rate does not exceed 33%.

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No dose escalation can occur without prior discussion and agreement between the investigator 
and the Lilly CRP; the decision will be documented in writing.  
Based on the ongoing safety reviews, modifications to the dose-escalation strategy or other 
design elements may be made via protocol amendment to ensure patient safety.  
During dose escalation, the starting dose LY3039478 will be 25 mg TIW.  This dose was defined 
from Study JJCA, and data will be evaluated on an ongoing basis until the MTD is determined.  
Table JJCD.7.2 shows the proposed dose levels for LY3039478 in combination with taladegib 
for Part A.  
Table JJCD.7.3 shows the proposed dose levels for LY3039478 in combination with LY3023414 
for Part B.
Table JJCD.7.4 shows the proposed dose levels for LY3039478 in combination with abemaciclib 
for Part C.
Table JJCD.7.5 shows the proposed dose levels for LY3039478 in combination with cisplatin 
and gemcitabine for Part D.
Table JJCD.7.6 shows the proposed dose levels for LY3039478 in combination with gemcitabine 
and carboplatin for Part E.
Intermediate/other dose levels will be explored if deemed necessary after discussion between the 
sponsor and investigators and taking into account patient safety and PK/PD information.
Table JJCD.7.2.
Proposed Dose-Escalation Scheme for Part A
Dose Level
LY3039478 
Dose (mg)
Taladegib Dose 
(mg)
1
25
200
2
50
200
3
50
400
Table JJCD.7.3.
Proposed Dose-Escalation Scheme for Part B
Dose Level
LY3039478 
Dose (mg)
LY3023414 Dose 
(mg)
1
25
150 BID
2
50
150 BID
3
50
200 BID
Abbreviation:  BID = twice daily.

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Table JJCD.7.4.
Proposed Dose-Escalation Scheme for Part C
Dose Level
LY3039478 
Dose (mg)
Abemaciclib 
Dose (mg)
1
25
100 BID
2
50
100 BID
3
50
150 BID
Abbreviation:  BID = twice daily.
Table JJCD.7.5.
Proposed LY3039478 Dose-Escalation Scheme for Part D
Dose 
Level
LY3039478 
Dose (mg)
Gemcitabine
Dose (mg/m2)
D1, D8
Cisplatin
Dose (mg/m2)
D1, D8
1
25
1000
25
2
50
1000
25
Abbreviation:  D = Day.
Table JJCD.7.6.
Proposed LY3039478 Dose-Escalation Scheme for Part E
Dose 
Level
LY3039478 
Dose (mg)
Gemcitabine
Dose (mg/m2)
D1, D8
Carboplatin
Dose (AUC)
D1, D8
1
25
1000
2
2
50
1000
2
Abbreviations:  AUC = area under the plasma concentration-time curve; D = Day.
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition
A DLT is defined as an AE during Cycle 1 that is related to LY3039478, taladegib, LY3023414,
or abemaciclib and fulfills any 1 of the following criterion using the NCI CTCAE v 4.0:

CTCAE Grade 3 nonhematological toxicity.  Exceptions will be made for:
o
Grade 3 nausea, vomiting, or constipation that lasts ≤72 hours and that can be 
controlled with treatment or Grade 4 vomiting or constipation that lasts ≤24 hours 
and that can be controlled with treatment
o
Grade 3 electrolyte disturbance that can be controlled with treatment.  Grade 4 
electrolyte disturbance lasting more than 24 hours will be considered a DLT
o
Diarrhea CTCAE Grade 3 for 4 days or less and that can be controlled with 
standard treatment
o
Transient (<7 days) Grade 3 elevations of ALT and/or AST that are not 
accompanied by a Grade 2 bilirubin increase are considered an exception to the 
DLT criteria, unless there is a clear alternative cause for example, worsening 

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
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biliary obstruction) if agreed by the study investigator and Lilly CRP/clinical 
research scientist (CRS)

CTCAE Grade 4 anemia

CTCAE Grade 4 neutropenia or leukopenia of >5-days duration 

Any febrile neutropenia

Grade 3 thrombocytopenia with clinically significant bleeding or Grade 4 
thrombocytopenia

Inability to start Cycle 2 within 3 weeks of the expected date because of persistent 
toxicity related to LY3039478, taladegib, LY3023414, or abemaciclib

Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting (for example, any toxicity that is possibly related 
to the study medication that requires the withdrawal of the patient from the study during 
Cycle 1)

Exceptions to the DLT criteria for Part B include:
o
Grade 3 fasting hyperglycemia that resolves to ≤Grade 2 within 7 days
o
Grade 4 hyperglycemia lasting <24 hours 
o
Grade 3 mucositis that resolves to ≤Grade 2 within 7 days.  Grade 4 mucositis of 
any duration will be considered a DLT
o
Grade 3 fatigue that resolves to ≤Grade 2 within 5 days
o
Grade 3 hypertriglyceridemia or hyperlipidemia without optimal treatment
Investigators, together with the Lilly CRP, can declare a DLT if a patient is experiencing 
increasing toxicity during treatment, and it becomes clear that it is not going to be possible to 
complete the treatment without exposing the patient to excessive risk.
A DLET is defined as an AE occurring between Day 1 and Day 21/28 of any cycle (other than 
Cycle 1) for a patient enrolled in the dose-escalation phase of Parts A, B, and C or in any cycle 
(including Cycle 1) for a patient enrolled in the dose-confirmation phase of Parts A, B, and C
that would have met the criteria for DLT if it had occurred during Cycle 1 for a patient enrolled 
in the dose-escalation phase of Parts A, B, and C.
For the purpose of this study, the MTD is defined as the highest tested dose that has 
<33% probability of causing a DLT during Cycle 1 in a cohort of at least 6 patients.
Determination of the recommended dose will take into account toxicities beyond Cycle 1, PK, 
and dose modifications of standard chemotherapy.
7.2.3. Dose-Confirmation Phase 
For each combination in the dose-escalation phase, there will be a dose-confirmation phase in 
specific tumor types.  Patients in the dose-confirmation phase will be treated at a dose no greater 
than the defined MTD from the dose-escalation phase.  Should a DLET occur in more than one 
third of patients at any time during the confirmation phase, Lilly clinical personnel and study 
investigators will meet and assess the severity and nature of the DLETs.  A decision will be 
made to continue at the current dose or to de-escalate the dose and define a new dose for the 
expansion phase.  This review and decision will be documented in writing.

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7.2.4. Dose Adjustments and Delays
7.2.4.1.
LY3039478
7.2.4.1.1. Dose Adjustments within a Cycle
Dose adjustments within Cycle 1 should be avoided if possible.  If a dose adjustment or delay is 
required during Cycle 1 of treatment in dose-escalation phase of the study, the patient will be 
allowed to continue but may be replaced if deemed appropriate by the Lilly CRP and 
investigator.  
If a patient treated at a given dose level experiences a DLT or a DLET (as defined in 
Section 7.2.2.1), then treatment will be suspended for that patient. Dosing may restart after 
recovery from toxicity at a lower dose after consultation between the investigator and Lilly CRP.  
If a toxicity does not meet the criteria for a DLT in Cycle 1 (or a DLET) but nonetheless requires 
omission of dose(s) for tolerability, then dosing may resume at the same dose or reduced dose 
after the toxicity resolves to baseline; however, the dose(s) omitted for tolerability during a cycle 
will not be replaced.
7.2.4.1.2. Dose Adjustments between Cycles
Nonhematologic toxicity must resolve to CTCAE Grade 0, 1, or baseline level before resuming 
treatment (with the exception of alopecia, fatigue, skin rash, nausea, vomiting, constipation, or 
diarrhea that can be controlled with treatment). The start of a cycle may be delayed up to 
21 days to allow sufficient time for recovery.  Patients experiencing Grade 4 nonhematological 
toxicity or not recovering from toxicity within 21 days should be discontinued from the study.  
Hematologic toxicity must resolve to CTCAE Grade 0, 1, or baseline level before resuming 
treatment.
The dose for a patient should be reduced for all subsequent cycles of therapy, to the dose level 
administered in the previous cohort, if the investigator determines that it is in the best interest of 
the patient or if the patient experienced at least 1 of the following events:

DLT or DLET

Omission of >7 doses in a single cycle for tolerability.
For such patients requiring a dose reduction, re-escalation to the original dose level is not 
permitted.  If a patient experiences a DLET at the reduced dose level, then the patient will be 
discontinued from the study.  If a patient requires omission of >3 doses for tolerability at the 
reduced dose level, then treatment may continue if the investigator determines that the patient is 
receiving clinical benefit.  Dose reduction by >1 dose level is not permitted; patients requiring 
dose reduction by >1 dose level should be discontinued from the treatment.
Diarrhea should be managed by standard treatments as per institutional guidelines.  Guidance for 
diarrhea standard management is provided in Attachment 9.

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7.2.4.2.
Dose Adjustments with Taladegib
Dose adjustments within Cycle 1 should be avoided if possible.  If a dose adjustment or delay is 
required during Cycle 1 of treatment during the dose-escalation phase, the patient will be 
allowed to continue but may be replaced if deemed appropriate by the Lilly CRP and 
investigator.  Dose adjustments and delays are allowed after Cycle 1 of treatment, as deemed 
appropriate by the investigator.  See Table JJCD.7.7 for specific dose-reduction guidance 
relating to nonhematologic toxicities.  All dose adjustments and delays are to be documented in 
the eCRFs.  
Patients who do recover within the approximately 14-day time frame may have their dose 
reduced.  Patients in Cohort 1 of Part A who do not recover within this approximately 14-day 
time frame should discontinue taladegib.  Re-escalation to the previous dose is acceptable in the 
absence of continuing toxicity.  If subsequent dose reduction is required after re-escalation, the 
patient must be maintained at the reduced dose level for all remaining cycles. Patients may have 
more than 1 dose reduction; however, the lowest dose that may be administered is 100 mg of 
taladegib.
If a dose is missed, it will not be made up.  If a patient has not taken ≥80% of the required doses 
in the first cycle, the patient will be deemed noncompliant/nonevaluable and will be replaced.  
The patient, however, will be permitted to continue on study.  If the patient experiences a DLT, 
the cohort will be expanded as described in Section 7.2.2.
If the offending study drug is discontinued because of unacceptable toxicity, the patient may 
continue single-agent treatment with LY3039478.  
Table JJCD.7.7.
Dose Adjustments for Taladegib
Toxicity/CTCAE Grade
Percent of Previous Dose
(Taladegib)
Grades 0–2
100%
Grade 2 dysgeusia lasting longer than 4 weeksa
50%
Grade 2 muscle cramping lasting longer than 4 weeksa
50%
Any Grade 3 or 4 nonhematologic toxicities not specified above
50%
Recurrence of any Grade 3 or 4 toxicity after 2 dose reductions
Discontinueb
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events.
a At investigator’s discretion; however, the dose may be reduced sooner than 4 weeks if it is determined to be 
intolerable.
b Discontinue patient from study treatment.
7.2.4.3.
Dose Adjustments with LY3023414
Dose adjustments for LY3023414 will follow the same principle guidance as outlined for 
LY3039478 in Section 7.2.4.1.  
Dose adjustments in Cycle 1 should be avoided if possible.  If a dose adjustment or delay is 
required during Cycle 1 of treatment in the dose-escalation phase of the study, the patient will be 

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allowed to continue if an AE has resolved sufficiently but may be replaced if deemed appropriate 
by the Lilly CRP and investigator.  
In Cycle 2 and beyond, dose adjustments and delays are allowed as deemed appropriate by the 
investigator. If a patient treated at a given dose level experiences a DLT or a DLET (as defined 
in Section 7.2.2.1), then treatment will be suspended for that patient.  Dosing may restart after 
recovery from toxicity at a lower dose after consultation between the investigator and Lilly CRP.  
If a toxicity does not meet the criteria for a DLT in Cycle 1 (or a DLET) but nonetheless requires 
omission of dose(s) for tolerability, then dosing may resume at the same dose or reduced after 
the toxicity resolves to baseline; however, the dose(s) omitted for tolerability or missed doses 
during a cycle will not be replaced.  Dose omissions within a cycle do not alter the start of the 
next scheduled cycle.  
Doses of LY3023414 may be adjusted according to Table JJCD.7.8. If the patient is receiving 
the lowest allowable dose and experiences an AE requiring a dose reduction, LY3023414 should 
be discontinued.  Re-escalation of study drug(s) may be considered if clinically warranted, 
following discussion and approval by the CRP.  Re-challenge of patients with dose-reduced 
study drug(s) following recovery from Grade 4 AEs may be considered on a case-by-case basis 
in consultation with the CRP.  Any patient requiring an AE-related dose delay of more than 
21 days after Cycle 1 from the intended day of the next scheduled dose due to a study drug 
related AE should be discontinued from the study, unless discussed with the Lilly CRP.
Table JJCD.7.8.
Dose Adjustments for LY3023414
Dose Level
LY3023414
1
150 mg BID
2
100 mg BID
Abbreviation:  BID = twice daily.
If the offending study drug is discontinued because of unacceptable toxicity, the patient may 
continue single-agent treatment with LY3039478.  
If consistent dose omissions of LY3023414 are required because of toxicity during combination 
therapy, a less frequent dosing schedule of LY3023414 may be instituted.  This decision will be 
made following discussions with the investigators and the Lilly CRP and will be documented in 
writing. 
7.2.4.4.
Dose Adjustments with Abemaciclib
Dose adjustments are allowed both within a cycle and between cycles.
If a patient experiences Grade 4 hematologic toxicity possibly related to abemaciclib, then 
dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 2) and 
the dose of abemaciclib must be reduced as outlined in Table JJCD.7.9.

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If a patient experiences >Grade 3 nonhematologic toxicity possibly related to abemaciclib, then 
dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 1) and 
the dose of abemaciclib must be reduced as outlined in Table JJCD.7.9.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea)
possibly related to abemaciclib that does not resolve with maximal supportive measures within 
7 days to either baseline or Grade 1, then dosing may be suspended (until the toxicity resolves to 
either baseline or at least Grade 1) and the dose of abemaciclib may be reduced as outlined in 
Table JJCD.7.9.
If a patient who, in the judgment of the investigator, is receiving clinical benefit from study 
therapy requires further dose reduction than is outlined in Table JJCD.7.9, then the investigator 
must discuss with the Lilly CRP prior to any further dose reduction.  For patients requiring dose 
reduction(s), re-escalation to a prior dose level is permitted only after consultation with the Lilly 
CRP.
Dose omissions are allowed within a cycle. If a patient requires omission of more than 25% of 
doses during a cycle for tolerability, then treatment may continue if the investigator determines 
the patient is receiving clinical benefit.
Patients requiring dose reduction by >2 dose levels should be discontinued from the treatment.  
Patients may remain on single agent treatment with LY3039478.
Table JJCD.7.9.
Dose Adjustments of Abemaciclib
Dose Adjustment levels
Oral Dose
Frequency
1
100 mg
Every 12 hours
2
50 mg
Every 12 hours
7.2.4.5.
Dose Adjustments with Cisplatin and Gemcitabine 
Initiation of a new cycle with cisplatin requires an ANC of at least 1,000/µL, platelets of at least 
75,000/µL, and resolution of nonhematologic toxicities to CTCAE v 4.0 Grade 0, 1, or baseline 
(except alopecia and fatigue).
Resolution of toxicity is required to occur within 3 weeks of the intended start of the cycle, 
otherwise cisplatin therapy should be discontinued.  Patients discontinuing cisplatin therapy may 
be allowed to continue LY3039478 and gemcitabine if they are receiving clinical benefit.
Resolution of toxicity is required to occur within 3 weeks of the intended start of the cycle, 
otherwise gemcitabine therapy should be discontinued.  Patients discontinuing gemcitabine 
therapy may be allowed to continue LY3039478 and cisplatin if they are receiving clinical 
benefit.
Cisplatin and gemcitabine therapy will not be delayed for LY3039478-related toxicity and the 
patient will continue to receive regularly scheduled infusions of cisplatin and gemcitabine.  If 
LY3039478 is terminated for LY3039478-related toxicity after a minimum of 4 cycles, cisplatin 
or gemcitabine may be continued as monotherapy or in combination until progression of disease.  

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Patients will continue their scheduled evaluation visits according to the Study Schedule 
(Attachment 1) until progression of disease.
In the case of cisplatin or gemcitabine non-GI-related toxicity, LY3039478 will not be delayed 
and the planned schedule for administration should be maintained.  If cisplatin or gemcitabine is 
terminated for non-GI-related toxicity, LY3039478 may be continued if clinically indicated
(Table JJCD.7.10).
Table JJCD.7.10.
Cisplatin and Gemcitabine Dose Adjustment for Toxicity
Event
Cisplatin Dose
Gemcitabine Dose
In 
previous 
cycle
Febrile neutropenia or 
Grade 4 ANC ≥7 days
Dose at 75% of prior dose.  Prior to treatment toxicity should have 
recovered to ≤ Grade 2 and ANC ≥1000/µL and platelets ≥75,000/µL.
Consider growth factor support per ASCO guidelines.
Current or 
prior cycle
Cisplatin or gemcitabine 
associated Grade 3-4 non-
hematologic AE
Treatment with cisplatin and/or gemcitabine should be deferred until 
recovery, and then continued with an appropriate dose reduction, 
adjustment of mitigatable factors, or discontinued as clinically indicated.
Bilirubin >1.6 mg/dL 
(>27 µmol/L)
Initiate gemcitabine dose at 
800 mg/m2. May reduce further 
for hematologic AEs as defined 
below
ANC 
(/µL)
Platelets 
(/µL)
Day 1
>1000 
to 
<1500
and
≥100,000
Dose at 100% dose.  
Dose at 100% dose.  
500 to 
1000
or
50,000 to 
<100,000
Give 100% of dose
Give 75% of prior dose.
<500
or
<50,000
Postpone until ANC >1000/µL or platelets > 100,000/µL.  If longer than 
1 week resume dosing in next cycle with a 75% dose reduction.
Day 8
>1000 
to 
<1500
and
≥100,000
Dose at 100% of prior dose.  
Dose at 100% of prior dose.  
500 to 
1000
or
50,000 to 
<100,000
Give 100% of dose.
Administer 75% of prior dose; 
continue this reduced dose in next 
cycle.  
<500
or
<50,000
Hold for recovery.  At next cycle, 
restart at 75% of prior dose.
Hold for recovery.  At next cycle, 
restart at 75% of prior dose.
Abbreviations:  AE = adverse event; ANC = absolute neutrophil count; ASCO = American Society for Clinical 
Oncology.
7.2.4.6.
Dose Adjustments with Gemcitabine and Carboplatin
A cycle may be delayed up to 21 days to allow a patient sufficient time for recovery from 
toxicity related to study treatment.  Before the start of each cycle, hematologic toxicities must 
resolve according to the guidelines in Table JJCD.7.11 and Table JJCD.7.12.  Nonhematologic 
toxicities must resolve to the patient’s baseline CTCAE grade or lower.  A cycle may be delayed 
by 7 days to accommodate a patient’s schedule or for other unforeseen circumstances.  

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Treatment delays between cycles that fulfill these criteria do not constitute a protocol violation.  
Patients who require a delay in treatment of more than 21 days for toxicity will be required to 
discontinue study treatment and enter the postdiscontinuation follow-up period (Section 6.2).  
Table JJCD.7.11.
Dose Modification Based on Neutrophil and/or Platelet Count on 
Day of Treatment (Day 1 and Day 8)
Neutrophil Count 
(/µL)
Platelet Count 
(/µL)
Dose Modification on Count Recovery
Carboplatin Dose
Gemcitabine Dose
≥1000
and
>100,000
100%
100%
500-1000
or
50,000-100,000
100% or delay
75% or delay based on clinical 
assessment
<500
or
<50,000
Delay
Stop this cycle if Day 8
Table JJCD.7.12.
Dose Modification Based on Common Toxicity Criteria
Toxicity
Definition
Dose Adjustment
Febrile neutropenia
ANC <500/µL plus fever requiring
IV antibiotics hospitalization
Give a 20% reduction for all future doses of 
carboplatin and gemcitabine
Other toxicities
Grade 3/4 toxicity (except alopecia)
Delay treatment. Resume with 20% dose reduction 
of carboplatin and/or gemcitabine provided toxicity 
has resolved to Grade 1 or less.  If further toxicity 
occurs, an additional reduction may be made after 
discussion with consultant.
Abbreviations:  ANC = absolute neutrophil count; IV = intravenous.
Gemcitabine and carboplatin therapy will not be delayed for LY3039478-related toxicity and the 
patient will continue to receive regularly scheduled infusions of gemcitabine and carboplatin.  If 
the LY3039478 is terminated for LY3039478-related toxicity after a minimum of 4 cycles, 
gemcitabine (or carboplatin) may be continued as monotherapy or in combination with 
carboplatin until progression of disease.  Patients will continue their scheduled evaluation visits 
according to the Study Schedule (Attachment 1) until progression of disease.
In the case of gemcitabine or carboplatin non-GI-related toxicity, LY3039478 will not be 
delayed and the planned schedule for administration should be maintained.  If a delay of more 
than 3 weeks is required for recovery of gemcitabine- or carboplatin-related toxicity, or more 
than 2 dose reductions of gemcitabine or carboplatin are necessary, the patient should 
discontinue treatment with gemcitabine and carboplatin.  If gemcitabine or carboplatin is 
terminated for non-GI-related toxicity, LY3039478 may be continued if clinically indicated.  
7.3.
Method of Assignment to Treatment
Before each patient’s enrollment into the study, an eligibility check must be conducted between 
the investigational site and the Lilly clinical research personnel to confirm that each patient 
meets all enrollment criteria.  Upon confirmation of eligibility, the sponsor will confirm the dose 
and identification number assignment, study part, and cohort for each patient.  No dose 

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escalations (that is, to the next cohort) can occur without prior discussion and agreement with the 
responsible Lilly CRP or CRS.  
If investigators have eligible patients who have consented concurrently, more than 3 patients 
may be entered at a particular dose level provided that accrual has not ceased due to excessive 
toxicity.  This enrollment procedure is allowed because of the advanced disease state of this 
patient population and the screening involved in defining eligibility.  This event should be 
approved by the sponsor following discussions with the investigators.
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
No other chemotherapy, immunotherapy, cancer-related hormone therapy, or experimental drugs 
will be permitted while the patients are on this study.  An exception will be made for prostate 
cancer patients continuing GnRH agonist therapy or breast cancer patients continuing 
antiestrogen therapy (for example, an aromatase inhibitor).  Patients participating in Parts A, B,
and C of the study (LY3039478 + taladegib, LY3023414, or abemaciclib, respectively) should 
not take any concomitant medications that are strong CYP3A4 inhibitors or inducers.  In 
addition, patients receiving LY3023414 (Part B) should avoid concomitant medication known to 
be sensitive substrates of CYP3A4 (for example, simvastatin, lovastatin, buspirone), cleared by 
CYP3A4 that have a narrow therapeutic range, or cause QTc interval prolongations (refer to 
Attachment 10 and Attachment 11 for further details).  Palliative radiotherapy is allowed.  In 
addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study.  Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the CRF.  
Patients should receive full supportive care with the exception that the routine use of granulocyte 
colony stimulating factors (G-CSF) is not permitted during this study.  Patients should not 
receive G-CSF prophylactically in any cycle.  G-CSF may be used only for patients who have 
ANC <0.5 109, neutropenic fever, or documented infections while neutropenic.  Use of G-CSF 
must be discontinued at least 24 hours before the start of the next cycle of treatment.  Should the 
use of hematopoietic colony-stimulating factors (CSF) be necessary, follow the American 
Society of Clinical Oncology (ASCO) recommendations for the use of CSFs (Smith et al. 2015).  
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008).
Patients should not receive corticosteroids prophylactically with the intent of attenuating GI
toxicity.  However, corticosteroid therapy initiated before study entry for a preexisting condition 
may be continued.  Corticosteroids may be used for treatment of GI toxicities if deemed 
necessary after agreement between the investigators and Lilly CRP.  As a guidance, standard 
treatments are provided in Attachment 9.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.

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7.6.
Treatment Compliance
Patient compliance with study drug(s) will be assessed at each visit by direct questioning or 
counting returned tablets/capsules, reviewing patient diary.  Deviation(s) from the prescribed 
dosage regimen should be recorded on the CRF.
The patient must take 75% of the intended dose to be deemed compliant with study drug 
administration.  Similarly, a patient may be considered noncompliant if he or she is judged by the 
investigator to have intentionally or repeatedly taken more than the prescribed amount of drug(s). 
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP or CRS before the final determination is made to discontinue 
the patient.
Some of the anticancer treatments will be administered intravenously at the investigational site, 
under the direction of the investigator.  As a result, a patient’s compliance with study drug 
administration is ensured.  Patients should attend scheduled clinic visits and must comply with 
study criteria under their control.  Deviation(s) from the prescribed dosage regimen should be 
recorded on the CRF.  
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug, regardless of whether they are deemed 
evaluable for the assessment of a dose level.
Any patient who is discontinued from the study before completing 1 cycle of LY3039478 
treatment will be deemed nonevaluable for assessment of a dose level, unless they experience a 
DLT prior to withdrawal.
Patients who receive all doses of LY3039478 but discontinue from study treatment before the 
end of Cycle 1 will be considered evaluable for the assessment of a dose level provided it can be 
documented whether the patient did or did not experience a DLT within 21 or 28 days of Cycle 1 
Day 1.
If the patient is noncompliant during Cycle 1 because of 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 enough patients complete 1 cycle of 
therapy at each dose level, unless accrual to that cohort has stopped because of a DLT.
Patients who are not evaluable for PK, but who complete 1 cycle of therapy, may be replaced 
upon consultation with the investigator(s) and the Lilly CRP or CRS to ensure adequate PK data, 
unless accrual to that cohort has stopped because of a DLT.

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8. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
The safety and tolerability of LY3039478 have been assessed in nonclinical toxicology studies 
and the results from these studies are detailed in the IB.  This Phase 1 study contains detailed 
safety monitoring that will allow additional characterization of the safety profile of LY3039478
in patients.  Study procedures and their timing, including collection of blood and urine samples, 
are described in the Study Schedule (Attachment 1).
Standard laboratory tests, including chemistry, hematology, coagulation, and urinalysis panels 
will be performed.  A serum pregnancy test will be administered if applicable.  Other clinical 
laboratory tests will also be collected.  Attachment 2 lists the specific tests that will be performed 
for this study.
8.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1). 
Table JJCD.8.1 presents a summary of AE and SAE reporting guidelines.  Table JJCD.8.1 also 
shows which database or system is used to store AE and SAE data.
8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from 
laboratory tests, vital sign measurements, and so on that occur should also be reported to Lilly or 

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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. All AEs observed will 
be graded using CTCAE v 4.0.  Any minor version of CTCAE v 4.0 may be used for this study.  
Minor CTCAE v 4.0 updates from the NCI will not necessitate a protocol amendment. For AEs 
without matching terminology within the NCI CTCAE v 4.0 criteria, the investigator will be 
responsible for selecting the appropriate system organ class and assessing severity grade based 
on the intensity of the event.  Note that both CTCAE term (actual or coded) and severity grade 
must be selected by study site personnel and collected on the CRF.  This collection is in addition 
to verbatim text used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breastfeeding should be collected, if feasible, for regulatory 
reporting and drug safety evaluation.
Upon documentation of pregnancy, the 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 protocol procedure and 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, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1.
Serious Adverse Events
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs.  Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
SAEs due to disease progression, including death, should not be reported unless the investigator
deems them to be possibly related to the study drug.
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 

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are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAEs are 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 LSS.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
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 
LSS.
8.1.2.2.1. Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the ICF.  For patients who do not enroll in the trial (that is, 
have not received at least 1 dose of LY3039478, taladegib, LY3023414, abemaciclib, 
gemcitabine, carboplatin, and/or cisplatin), only AEs and SAEs related to protocol procedures 
are required to be collected.  
8.1.2.2.2. On Therapy
All AEs and SAEs, regardless of relatedness to study drug(s), or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study drug 
until the patient and the investigator agree that the patient will no longer continue any study 
treatment.
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 (Visit 801) must be reported to Lilly or its designee.  The follow-up 
visit starts 1 day after the patient and the investigator agree that the patient will no longer 
continue any study treatment and lasts approximately 30 days.  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 any study treatment.
Following the safety assessments, which mark the end of the follow-up visit (Visit 801), the 
patient will be discontinued from the study, unless there is an ongoing AE or SAE that is 
possibly related to study drug.  In this instance, the patient should be followed in subsequent 
follow-up visits until the event is resolved, the event is no longer considered to be drug-related, 

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the event becomes stable or returns to baseline, a new treatment is initiated for the patient, or the 
patient dies or is lost to follow-up.
If it is deemed to be in the best interest of the patient to start a new anticancer treatment prior to 
the scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this 
case, the follow-up assessments should be completed prior to the initiation of the new therapy.
After the follow-up visit (Visit 801), AEs are not required to be reported unless the investigator 
feels the AEs were related to either study drug or a protocol procedure.  If an investigator 
becomes aware of an SAE believed to be related to protocol procedures or study drug, the
investigator should report the SAE to the sponsor, and the SAE will be entered in the LSS.  
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the
Development Core Safety Information in the IB and that the investigator identifies as related to 
study drug or procedure.  The US 21 Code of Federal Regulations (CFR) 312.32, the European 
Union Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national 
regulatory requirements in participating countries require the reporting of SUSARs.  Lilly has 
procedures that will be followed for the recording and expedited reporting of SUSARs that are 
consistent with global regulatory regulations and the associated detailed guidances.
8.1.2.4.
Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JJCD.8.1 and Attachment 5.

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Table JJCD.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study JJCD
Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of informed 
consent and ends just before the 
first dose of study drug)
Preexisting conditions
All AEs
All SAEs regardless of relatedness 
X
X
X
X
On therapy
(Starts at first dose of study drug[s]
and ends when the patient and the 
investigator agree that the patient 
will no longer continue any study 
treatment)
All AEs
All SAEs regardless of relatedness
X
X
X
Follow-up visit (Visit 801)
(Starts the day after the patient and 
the investigator agree that the 
patient will no longer continue any 
study treatment and ends when end 
of study safety assessments are 
completed in 30 days OR the 
planned end of the cycle)
All AEs
All SAEs regardless of relatedness
X
X
X
Continued access period
All AEs 
All SAEs regardless of relatedness
X
X
X
Continued access period follow-up
All AEs 
All SAEs regardless of relatedness
X
X
X
Subsequent follow-up visits, if 
necessary for patient monitoring 
Ongoing AEs possibly related to study 
drug(s), or protocol procedures
All SAEs related to protocol procedures 
or study drug
X
X
X
Patient no longer on study
All SAEs related to protocol procedures 
or study drug of which the investigator 
becomes aware
X
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
8.1.3. Other Safety Measures
8.1.3.1.
Electrocardiograms
For each patient, a 12-lead digital electrocardiogram (ECG) will be collected according to the 
Study Schedule (Attachment 1).  Patients must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection.  
Consecutive replicate ECGs (usually triplicates) will be obtained at approximately 1-minute 
intervals.  

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ECGs may be obtained at additional times, when deemed clinically necessary.  Collection of 
more ECGs (more replicates) than expected at a particular time point is allowed to ensure high 
quality records.  
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the patient is still 
present, to determine whether the patient meets entry criteria at the relevant visit(s) and for 
immediate patient management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will then conduct a full overread on 1 of the replicate ECGs 
(including all intervals).  A report based on data from this overread will be issued to the 
investigative site.  For each set of replicates, the RR and QT intervals and heart rate will be 
determined on the ECGs that were not fully overread.  These data are not routinely reported back 
to the investigative site.
All data from the overreads will be placed in the Lilly database for analytical and study report 
purposes.  Any clinically significant finding that was not present on the fully overread ECG but 
was present on the partially overread ECG (where only RR, QT, and heart rate is assessed) will 
be reported to the investigator and to Lilly.  If 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 subject 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 his/her review of 1 of the replicate ECGs 
printed at the time of collection, the final overread ECG report issued by the central ECG 
laboratory, and any alert reports.
8.1.4. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study.  
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or CRS, and periodically review:

trends in safety data,

laboratory analytes,

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
AEs, 

If a study patient experiences elevated ALT 5 times ULN and elevated total 
bilirubin 2 times ULN, clinical and laboratory monitoring should be initiated by 
the investigator  

For patients entering the study with ALT 3 times ULN, monitoring should be 
triggered at ALT 2 times ULN baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 3).
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 combination 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 and assessments in this study.
Attachment 2 lists the specific tests that will be performed for this study.
Attachment 4 specifies the PK/PD sampling schedule for this study.  
8.2.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.
Investigators must document their review of each laboratory safety report.
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 

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are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Samples for Drug Concentration Measurements 
Pharmacokinetics
Pharmacokinetic samples will be collected as specified in Attachment 4.
Additional PK samples may be drawn during the study if warranted and agreed upon by both the 
investigator and sponsor.  
Plasma concentrations of LY3039478, taladegib and its active metabolite (LSN3185556),
abemaciclib and its active metabolites (LSN3106726 and LSN2839567), LY3023414, 
gemcitabine, cisplatin, and carboplatin will be quantified using validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay.  All bioanalytical samples will 
be stored in a facility chosen by the sponsor.  The remaining plasma samples collected for PK 
evaluation may be used for exploratory studies to assess the metabolism of LY3039478 and/or 
taladegib, which may involve sample pooling.  These samples may be retained for a maximum of 
1 year following the last patient visit for the study.
After the first dose in Cycle 1 at all dose levels during dose escalation, total urine output for the 
first 6 to 8 hours will be collected and pooled for quantification of LY3039478, creatinine, and 
exploratory metabolite identification.  Urine concentrations of LY3039478 will be quantified 
using validated LC-MS/MS assay.  All urine samples will be stored in a facility chosen by the 
sponsor.  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 and/or protein binding will be retained for a maximum of 1 year following last 
patient visit for the study.
8.2.3. Pharmacogenetic Samples
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetics analysis.  
This is a 1-time collection, as noted in the Study Schedule (Attachment 1).
Samples will be stored and exploratory analysis may be performed to identify genetic variants 
that might play a role in tumor biology or to evaluate their association with observed clinical 
outcomes to study drugs.
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 study drugs.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide association studies may be performed to 

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identify regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.  
The samples will be will be coded with the patient number and stored for up to a maximum of 
15 years after the last patient visit for the study at a facility selected by the sponsor.  The samples
and any data generated from them can only be linked back to the patient by investigator site 
personnel.  The duration allows the sponsor to respond to regulatory requests related to the study 
drug.  
8.2.4. Exploratory Samples
Collection of samples for biomarker research is a component of this study. The following blood 
and tumor tissue samples will be collected.
Required samples for biomarker research to be collected from all patients in this study:

blood samples

skin biopsies

archived tumor tissue
These samples are described in the following sections.
It is possible that biomarker data 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, this data may be requested from medical records for use in the research 
described in the following sections.
8.2.4.1.
Blood Samples for Aβ Assays
Blood samples will be collected for exploratory analysis of circulating Aβ peptides (for example, 
Aβ[1-x] or peptide components thereof) before and after treatment with LY3039478 during the 
dose-escalation phases of the study (all parts).  Samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Tests are run and confirmed 
promptly whenever medically or scientifically appropriate.  When medical and scientific 
circumstances warrant, however, it is acceptable to retain samples to batch the tests run.  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.
Samples for Assessing CYP3A Induction
Blood samples will be collected for the exploratory analysis of cortisol concentrations in plasma. 
Urine samples collected will also be used for the exploratory analysis of 6β-hydroxy-cortisol 
excreted in urine.  Samples will be retained for a maximum of 1 year following last patient visit 
for the study.

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8.2.4.3.
Blood Samples for Biomarker Research
In blood, an evaluation of analytes related to the mechanism of action of study drugs, Notch and
signaling pathways of study drugs or downstream effects, and specific tumor cancer 
pathobiology may be evaluated to assess any potential correlation with response to study drugs.  
The analyses of these samples may be focused, but not limited to, gene expression panels, 
proteomics, enzyme-linked immunosorbent assay and/or sequencing approaches .  
Samples may be stored for a maximum of 15 years following last patient visit for the trial.
8.2.4.4.
Tumor Tissue and Skin Biopsies
Throughout this study, archived tumor tissue obtained previously for diagnostic purposes (for 
example, at initial diagnosis) will be requested for biomarker research. At baseline, a mandatory 
pretreatment formalin-fixed paraffin-embedded (FFPE) tumor tissue (paraffin blocks or 
unstained slides cut from that block) will be collected.  Tumor biopsies and skin biopsies (as 
instructed by the laboratory manual) will be collected pre- and posttreatment for measuring 
various biomarkers. Table JJCD.8.2 presents tumor and skin biopsy collection time points.  
Table JJCD.8.2.
Tumor and Skin Biopsy Time Points
Collection Time Point
Dose Escalation 
Parts A, B, C, D, and E
Dose Confirmation
Parts A, B, C, D, and E
Baseline archived tissue collection (FFPE)
Mandatory
Mandatory
Pre-/postdose tumor biopsies
Recommended
Recommended
Pre-/postdose skin biopsies
Mandatory
Mandatory
Disease progression
Recommended
Recommended
Abbreviation:  FFPE = formalin-fixed paraffin-embedded.
The archived tissue samples, tumor biopsies, and/or skin biopsies may be analyzed for 
biomarkers that may include, but are not limited to, mechanism of action of study drugs, Notch
signaling pathways or related pathway activation, immune functioning, and specific tumor 
cancer pathobiology.  Mutation profiling, copy number variability, and gene/protein expression
profiling may be performed on these samples to assess potential associations with these 
biomarkers and clinical outcomes.  
Additionally, optional skin biopsies and/or optional tumor biopsies at time of disease progression 
will be collected.  Furthermore, skin and/or tumor biopsies may be performed if deemed 
necessary by the investigator.  The samples will be analyzed at laboratories using assays 
designated by the sponsor.  Sample handling and shipment to the central laboratory will occur 
per instructions given to the study site. Details for the handling and shipping of the tumor tissue 
will be provided by the sponsor in a separate document. The tissue samples will be obtained 
using appropriate method. However, cytological or fine-needle aspiration specimens are not 
acceptable. Due diligence should be used to ensure that tumor specimen (not normal adjacent or 
tumor margins) is provided. Pathology reports accompanying the tissue may also be requested. 
Each sample will be labeled with patient number and tissue of origin and be stored for up to 

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15 years after the last patient visit at a facility selected by the sponsor. Any whole block 
submitted will be returned to the site.
8.3.
Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1
for details regarding the timing of specific efficacy measures.  
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement:

Computed tomography (CT) scan

Magnetic resonance imaging (MRI)

PET scan (pre- and postdose [Attachment 1]).
Each patient’s full extent of disease will also be assessed with:  

Tumor measurement by RECIST 1.1 (Eisenhauer et al. 2009). For tumor 
measurement evaluations in patients with soft tissue sarcomas, Choi et al. (2007) 
response criteria will be used in addition to RECIST 1.1. Response Assessment 
in Neuro-Oncology (RANO) criteria will be used for glioblastoma patients 
(Wen et al. 2010)

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.  If a patient is discontinued from the study, repeat radiology assessments may be 
omitted if clear clinical signs of progressive disease are present.
Table JJCD.8.3 defines the efficacy endpoints assessed during the study.
Table JJCD.8.3.
Definition of Efficacy Endpoints
Endpoint
Definition
Progression-free 
survival (PFS)
The time from the date of study enrollment to the date of first observation of objective 
progression or death from any cause.  
Duration of response
The time from the date of first evidence of a confirmed complete or partial response to 
the date of objective progression or the date of death from any cause (whichever is 
earlier).
After patients have discontinued study treatment, they may receive additional anticancer therapy 
at the discretion of the investigator.  For those patients who discontinue study treatment without 
objectively measured progressive disease, the investigative sites will continue to monitor patients 
approximately every 60 days (±14 days) to evaluate tumor response by the same method used at 

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baseline and throughout the study, until objective progression or the patient starts a new 
anticancer therapy, or study closure.  
Lilly or its designee will collect and store all tumor measurement images for patients enrolled in 
dose-confirmation phases of Parts A, B, C, D, and E.  A central review of imaging scans may be 
performed by Lilly or its designee.
8.4.
Procedure/Sampling Compliance
Every attempt will be made to enroll patients who have the ability to understand and comply 
with instructions.  Noncompliant patients may be discontinued from the study.
The collection times of safety assessments, PK samples, PD samples, and efficacy measurements 
are given as targets, to be achieved within reasonable limits.  The scheduled time points may be 
subject to minor alterations; however, the actual collection time must be correctly recorded on 
the CRF or laboratory requisition form.  
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.

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

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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.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  
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
The total sample size is estimated to be approximately 163 patients. To determine the 
recommended Phase 2 dose (RP2D) of LY3039478 in combination with other anticancer agents, 
an adequate sample size is required.  A sufficient sample size will allow for an accurate 
evaluation of the relationship between exposure and toxicity, as well as an evaluation of the 
relationship between exposure and pharmacological effects using descriptive statistics and 
appropriate modeling techniques, if data warrant.  
A total of 10 (Parts A and B) or 15 (Part C) patients with a given tumor type treated at the RP2D 
in dose confirmation can provide adequate precision for the estimated incidence rate of the 
following quantities of interest: (1) patients having a specified AE or (2) patients showing a 
response (partial response/complete response) to treatment.  With a total sample size of 
N=10-15, the 95% CI is approximately equal to the observed incidence rate 15% to 35%.  
Example point estimates of incidence rates and corresponding 2-sided 95% CIs are summarized 
in Table JJCD.10.1.  The values are provided as a reference for estimation rather than a basis of 
any decision criteria.  
Table JJCD.10.1.
Estimated Incidence Rate and Its 2-Sided 95% Confidence Interval
N=10
N=15
Num. of 
Cases
Est. 
Rate
95% CIa
Num. of 
Cases
Est. 
Rate
95% CIa
Lower Limit
Upper Limit
Lower Limit
Upper Limit
0
0.0
0.0
0.31
0
0.0
0.0
0.22
2
0.20
0.03
0.56
3
0.20
0.04
0.48
3
0.30
0.07
0.65
5
0.33
0.12
0.62
5
0.50
0.19
0.81
8
0.53
0.27
0.79
7
0.70
0.35
0.93
11
0.73
0.45
0.92
Abbreviations:  CI = confidence interval; Est = estimated; Num = number.
a
95% Clopper-Pearson interval for binomial distribution with sample size of 10 to 15 patients.
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.
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/listing of the following:

Patient demographics will be reported

Baseline disease characteristics

Prior disease-related therapies 

Concomitant medications.
Other patient characteristics will be summarized as deemed appropriate. In addition, 
postdiscontinuation therapies will be recorded and summarized by type of therapy (surgery, 
radiotherapy, systemic therapy) and by drug name.  
10.4. Safety Analyses
All patients who receive at least 1 dose of LY3039478 will be evaluated for safety and toxicity.  
AE terms and severity grades will be assigned by the investigator using CTCAE, v 4.0.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

dose adjustments

laboratory values 

vital signs 

DLTs at each dose level 

ECG readings.
10.5. Pharmacokinetic Analyses
PK analyses will be conducted on patients who have received at least 1 dose of the study drug 
and have had samples collected.  
PK parameter estimates for LY3039478, taladegib and its active metabolite (LSN3185556), 
LY3023414, abemaciclib and its active metabolites (LSN3106726 and LSN2839567), 
gemcitabine, carboplatin, and cisplatin will be calculated by standard noncompartmental 
methods of analyses where data allow.
The primary parameters for analysis will be (Cmax, AUC from time zero to last measurable 
plasma concentration (AUC0-tlast,), and AUC from time zero to infinity (AUC0-∞).  Other 
noncompartmental parameters, such as t1/2, CL/F, and apparent volume of distribution (V/F) 
may be reported.  Additional exploratory analyses will be performed if warranted by data and 
other validated PK software programs (for example, NONMEM®) may be used if appropriate 
and approved by Global Pharmacokinetic management.  The version of any software used for the 
analysis will be documented and the program will meet the Lilly requirements of software 
validation.
PK parameter estimates will be evaluated to delineate effects of the following drug interactions: 
LY3039478 with taladegib compared to taladegib alone, LY3039478 with LY3023414 compared 
to LY3023414 alone, and LY3039478 with abemaciclib compared to abemaciclib alone.  

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Log-transformed Cmax and AUC estimates will be assessed using mixed effect models with 
random patient effect, to estimate ratios of geometric means and the corresponding 90% CIs.
10.6. Pharmacokinetic/Pharmacodynamic Analyses 
The PK data will be combined and analyses may be conducted to determine a relationship 
between exposure and PD effect (for example, Aβ[1-x]), data permitting. This model may be 
used to help reassess the dose cohort escalation as the study progresses.
10.7. Efficacy
The study was not designed to make an efficacy assessment.  However, any tumor response data 
will be tabulated. Descriptive analyses of duration of response and PFS will be conducted using 
the Kaplan-Meier method.
10.8. Tailoring Biomarker Analyses
Efficacy measures may be summarized descriptively within subgroups of patients. Those may 
be characterized by the types of Notch pathway alterations. Exploratory analyses may be applied 
to correlate Notch pathway biomarkers with clinical outcome. If applicable, a subset of potential 
predictive biomarkers associating with interpretable clinical benefit may be further examined 
with biological evidence.
10.9. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the sponsor will determine if it is necessary to amend the protocol.
Because this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
study, until the MTDs are determined for each treatment arm. The purpose of these 
cohort-by-cohort reviews is to evaluate the safety data at each dose level and determine if a DLT 
has been observed that would suggest the MTD has been met or exceeded.  The investigators and 
the Lilly study team will make the determination regarding dose escalation based upon their 
review of the safety and tolerability data as described in this protocol.  
Safety and/or PK data will be reviewed during the study if needed for dose escalation, 
modifications to the dose-escalation strategy, or other design elements.
After all patients who are deemed evaluable for the assessment of dose levels complete the DLT 
evaluation period or the MTD is determined, an interim safety and PK analysis may be 
conducted for planning next studies.  
If it is deemed that enough data are 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.  
In this protocol, the term “informed consent” includes all consent and assent given by patients or 
their legal representatives.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline 
on GCP.  
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
11.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 
2) the ICH GCP Guideline [E6]
3) applicable laws and regulations.

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The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data.
11.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
11.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
11.3.3. Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most analyzable patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.

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12. References
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Joshi I, Minter LM, Telfer J, Demarest RM, Capobianco AJ, Aster JC, Sicinski P, Fauq A, 
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Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, 
Penninger JM, Siderovski DP, Mak TW. Negative regulation of PKB/Akt-dependent cell 
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Garrett-Engelee PW, Kluk M, Laskey J, Haines BB, Moskaluk C, Zawel L, Fawell S, 
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Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, 
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Attachment 1.Protocol JJCD Study Schedule

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Baseline Assessments
Relative Day Prior to Day 1 of 
Cycle 1
28
14
7
Comments
Informed consent 
X
Informed consent signed prior to performance of any 
protocol-specific tests/procedures
Radiological tumor assessment
X
PET scan
X
Optional
Medical history
X
Including alcohol/tobacco use and other relevant 
habits assessments
Physical examination
X
Vital signs 
X
Including temperature, blood pressure, pulse rate, 
respiration rate
Height
X
ECOG performance status
X
ECG 
X
One set of triplicate ECGs, central
Hematology 
X
Local laboratory 
Coagulation (PT/INR, aPTT, 
fibrinogen)
X
Central laboratory
Serum chemistry 
X
Central and local laboratorya
HbA1c 
X
Part B only; central and local laboratorya
Cystatin C 
X
Part C only
Urinalysis 
X
Local laboratory
Tumor measurement (palpable or 
visible)
X
CTCAE version 4.0 grading 
(preexisting conditions)
X
To be reported only after study eligibility is confirmed  
See Section 8.1.2 for reporting expectations 
Concomitant medications
X
Tumor markers
X
If applicable, local laboratory
Blood PD biomarkers (Aβ[1-x])b
X
Tumor biopsy
X
Predose tumor biopsy is recommended
Screening for alterations of Notch 
pathway
Screening done locally, any time prior to study drug 
therapy in all dose-confirmation phases except for soft 
tissue sarcoma in Part Ac
Archived tumor sample
Paraffin-embedded tumor tissue (block or unstained 
slides) will be collected only after study eligibility is 
confirmedc
Pregnancy test 
X
Negative results prior to dosing required for women of 
childbearing potential
Skin biopsy
X
Abbreviations:  aPTT = activated partial thromboplastin time; CTCAE = Common Terminology Criteria for 
Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
HbA1c = glycosylated hemoglobin; PD = pharmacodynamic; PET = positron emission tomography; 
PT/INR = prothrombin time/international normalized ratio. 
a
Patient eligibility and management is based on local laboratory results only unless the investigator chooses to use 
the central laboratory for such a purpose. 
b
Only during dose-escalation phase (all parts).
c
To be performed prior to study drug dosing.

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During and Poststudy Assessments - Parts A, B, and C
Cycle 1
3-Day 
Lead-In
Week 1
Week 2
Week 3
Week 4
Study Procedures
Single dose 
Taladegib,
LY3023414, or
Abemaciclib
on Day 1a
Day 1 of 
LY3039478
Combination
Day 8 of 
LY3039478
Combination
Day 15 of 
LY3039478
Combination
Day 22 of 
LY3039478
Combination
Physical examination
X
X
X
X
X
Vital signs and weight (temperature, pulse rate, blood 
pressure, respiratory rate)
X
X
X
X
X
ECOG performance status
X
X
X
X
X
CTCAE version 4.0 grading
X
X
X
X
Concomitant medications
X
X
X
X
X
Central ECGb
X
X
PET scanc
X
Hematologyd
X
X
X
X
X
Serum chemistryd
X
X
X
X
X
Cystatin C (for Part C only)
X
X
X
X
X
HbA1c (for Part B only)
X
ECG chemistryb,d
X
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
X
Tumor markerd
X
X
Pharmacogenetics sample (predose)
X
Blood PK samplingb
X
X
X
X
Tumor biopsy, recommendede
X
Skin biopsyb,f
X
Blood PD biomarkers (Aβ[1-x]) during dose escalation 
only)b,g
X
X
Blood exploratory circulating biomarkers predose 
X
Urine (8-hour collection)b,g
X
X

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During and Poststudy Assessments - Parts A, B, and C
Cycle 2
Cycle 3-n
Visit
801
Follow-
Upi
Week 1
Week 2
Week 3
Week 4
Week 1
Week 2
Week 3
Week 4
V801
V802-
XX
Study Procedures
Day 1
Day 8
Day 15
Day 22
Day 1
Day 8
Day 15
Day 22
Physical examination
X
X
X
X
Vital signs and weight (temperature, pulse 
rate, blood pressure, respiratory rate)
X
X
X
X
ECOG performance status
X
X
X
X
X
CTCAE version 4.0 grading
X
X
X
X
Xj
Concomitant medications
X
X
X
X
X
X
X
X
X
Xk
Tumor measurement (palpable and visible)
X
X
Xl
ECGb
X
Radiological tumor assessmenth
X
X
Xl
PET scanc
X
X
Hematologyd
X
X
X
X
X
Cystatin C (for Part C only)
X
X
X
X
X
HbA1c (for Part B only)
X
X
X
Serum chemistryd
X
X
X
X
X
ECG chemistryb,d
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
X
Tumor markerd
X
X
X
Blood PK samplingb predose
X
Blood PD biomarkers (Aβ[1-x])-during dose 
escalation only)b,g predose 
X
X
Blood exploratory circulating biomarkers 
predose
X
X
X

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During and Poststudy Assessments - Parts D and E
Cycle 1
Cycle 2
Week 1
Week 2
Week 3
Week 1
Week 2
Week 3
Study Procedures
Day 1
Day 8
Day 15
Day 1
Day 8
Day 15
Physical examination
X
X
X
X
X
Vital signs and weight (temperature, pulse rate, 
blood pressure, respiratory rate)
X
X
X
X
X
ECOG performance status
X
X
X
X
X
CTCAE version 4.0 grading
X
X
X
X
Concomitant medications
X
X
X
X
X
Tumor measurement (palpable and visible)
X
Central ECGb
X
X
Radiological tumor assessmenth
X
PET scanc
X
X
Hematologyd
X
X
X
X
X
X
Serum chemistryd
X
X
X
X
X
X
ECG chemistryb,d
X
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
Tumor markerd
X
X
Pharmacogenetics sample (predose)
X
Blood PK samplingb
X
X
X
Tumor biopsy, recommendede
X
Skin biopsyb,f
X
Blood PD biomarkers (Aβ[1-x]) during dose 
escalation only)b,g
X
X
X
Blood exploratory circulating biomarkers 
predose 
X
X
Urine (6- to 8-hour collection)b,g
X
X

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During and Poststudy Assessments - Parts D and E
Cycle 3-n
Visit 801
Follow-Upi
Week 1
Week 2
Week 3
V801
V802-XX
Study Procedures
Day 1
Day 8 
Day 15
Physical examination
X
X
Vital signs and weight (temperature, pulse rate, blood 
pressure, respiratory rate)
X
X
ECOG performance status
X
X
X
CTCAE version 4.0 grading
X
X
Xj
Concomitant medications
X
X
Xk
Tumor measurement (palpable and visible)
X
Xl
Radiological tumor assessmenth
X
Xl
PET scanc
X
Hematologyd
X
X
X
X
Serum chemistryd
X
X
X
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
Tumor markerd
X
X
Blood PD biomarkers (Aβ[1-x])-during dose escalation 
only)b,g predose 
X
Blood exploratory circulating biomarkers predose
X
Abbreviations:  AE = adverse event; aPTT = activated partial thromboplastin time; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HbA1c = glycosylated hemoglobin; PD = pharmacodynamic; 
PK = pharmacokinetic; PET = positron emission tomography; PT/INR = prothrombin time/international normalized ratio; RBM = Rules-Based Medicine; 
SAE = serious adverse event; V = visit.
a
Three-day lead-in period only occurs during the dose-escalation phase of Parts A, B, and C.
b
For complete details, see Attachment 4.
c
Optional (not limited to Dose 1) repeated at the discretion of the investigator (can be performed ±2 days).
d
For central versus local laboratories, refer to Attachment 2. 
e
Optional posttreatment tumor biopsy should be obtained (whenever clinically feasible) at Cycle 1, preferably 6 to 8 hours (±1 hour) after Dose 10.  Greater 
flexibility has been provided for the posttreatment tumor biopsy (between Doses 7 and 12, inclusive) compared to other Dose 10 visit assessments (between 
Doses 9 and 11, inclusive) to enable radiographic guidance and access to appropriate medical specialists.  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.

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f
Skin biopsies are mandatory according to the schedule provided in Table JJCD.8.2.  Additional optional skin biopsies may be performed at time of disease 
progression and if deemed necessary by the investigator.
g
Only in dose-escalation phase for all study parts. 
h
Radiological assessment is performed at baseline (up to 28 days before the first dose), then at the end of Cycle 2 (no more than 10 days prior to Day 1 of
Cycle 3), then every other cycle thereafter (no more than 10 days prior to Day 1 of the next cycle).  If a patient is discontinued from the study, repeat 
radiology may be omitted if progressive disease can be documented quantitatively with clinical measurements.
i
Long-term follow-up for PFS applies to dose-confirmation phase for all study parts.
j
Collection of AEs and SAEs related to study treatment or study procedures only.
k
Postdiscontinuation therapies and outcome of treatment will be recorded.
l
Every 60 (±14) days and applies only to those patients in the dose-confirmation phase for all study parts who discontinue the study without progression or 
have not started another treatment regimen as outlined in Section 8.3.

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Attachment 2.Protocol JJCD Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya,b
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Total bilirubin
Neutrophils
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Gamma-glutamyl transpeptidase (GGT)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatinine
Lipase
Coagulationb
Lactate dehydrogenase (LDH)
aPTT
Uric acid
PT/INR
Calcium
Fibrinogen
Phosphorus
Glucose, random (fasted for Part B)
Urinalysisa
Albumin
Specific gravity
Total protein
pH
Creatinine clearance
Protein
Serum or urine pregnancy test (females only)a
Glucose
Ketones
ECG Chemistryb
Blood
Urine leukocyte esterase
Thyroid-stimulating hormone (TSH)
Free tri-iodothyronine (T3)
HbA1c (for Part B only)
Free thyroxine (T4)
Calciumc
Cystatin C (for Part C only)
Sodiumc
Potassiumc
Tumor Markersa
Phosphorus
Magnesium
Biomarkersb
Abbreviations:  aPTT = activated partial thromboplastin time; ECG = electrocardiogram; HBA1c = glycosylated 
hemoglobin; PT/INR = international normalized ratio of prothrombin time; RBC = red blood cells; WBC = white 
blood cells.
a
Local or investigator-designated laboratory. Local safety laboratory results can be obtained up to 1 day before 
the scheduled time point.
b
Assayed by Lilly-designated laboratory.
c
Test not performed if both chemistry and ECG chemistry required at same time point.  See Attachment 4.

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Attachment 3.Protocol JJCD 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
Antinuclear antibodya
AST
GGT
Anti-smooth muscle antibodya
CPK 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transpeptidase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 4.Protocol JJCD Pharmacokinetic,
Pharmacodynamic, and Electrocardiogram with 
Electrocardiogram Chemistry Sampling Schedule

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Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part A Dose Escalation – LY3039478 + Taladegib
PK 
Sample 
Number
Cycle
Day of 
LY3039478
Combination
Sampling 
Time (hr) for 
LY3039478
Sampling 
Time (hr) for 
Taladegib/
LSN3185556
Sampling 
Time (hr) 
for Aβ
Sampling 
Time for 
Plasma 
Cortisol
Sampling 
Time for 
Urine
PD Sampling 
Time for Skin 
Biopsies
ECG with
ECG
Chemistry
1
Lead in
-3
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
screening
predose
2
Lead in
-3
0.5 
3
Lead in
-3
1
4
Lead in
-3
2
5
Lead in
-3
4
6
Lead in
-3
6
7
Lead in
-3
8
8
Lead in
-2
24-30
9
1
1
predose
predose
10
1
22
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
predose
11
1
22
0.5
0.5 
0.5
12
1
22
1
1
1
13
1
22
2
2
2
2 hr
14
1
22
4
4
4
15
1
22
6
6
6
6-8 hr
(±1 hr)
16
1
22
8
8
8
17
1
22
same time as 
taladegib 
predose 
sample
predose 
same time as 
taladegib 
predose 
sample
same time as 
taladegib 
predose 
sample
same time as 
taladegib 
predose sample
18
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part A Dose Confirmation – LY3039478 + Taladegib
PK 
Sample 
Number
Cycle
Day
PK Sampling 
Time (hr) for
LY3039478
Sampling Time (hr) 
for 
Taladegib/LSN3185556
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG
Chemistry
1
1
15
predose
predose
screening
predose
2
1
22
predose
predose
3
1
22
0.5
0.5
4
1
22
1-2
1-2
2 hr
5
1
22
3-4
3-4
6-8 hr (±1 hour)
6
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr= hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part B Dose Escalation – LY3039478 + LY3023414
PK Sample 
Number
Cycle
Day of 
LY3039478
Combination
Sampling 
Time (hr) 
for 
LY3039478
Sampling 
Time (hr) 
for 
LY3023414
Sampling 
Time (hr) 
for Aβ
Sampling 
Time for 
Plasma 
Cortisol 
Sampling 
Time for 
Urine 
PD 
Sampling 
Time for 
Skin 
Biopsies
ECG with 
ECG
Chemistry
1
Lead in
-3
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
screening
predose
2
Lead in
-3
0.5 
3
Lead in
-3
1
4
Lead in
-3
2
5
Lead in
-3
4
6
Lead in
-3
6
7
Lead in
-3
8
8
Lead in
-2
24-30
9
1
1
predose
predose
10
1
22
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
predose
11
1
22
0.5
0.5 
0.5
12
1
22
1
1
1
13
1
22
2
2
2
2 hr
14
1
22
4
4
4
15
1
22
6
6
6
6-8 hr
(±1 hr)
16
1
22
8
8
8
17
1
22
24-30
24-30
24-30 hr
24-30 hr
18
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr= hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part B Dose Confirmation – LY3039478 + LY3023414
PK 
Sample 
Number
Cycle
Day
PK Sampling 
Time (hr) for 
LY3039478
Sampling Time 
(hr) for 
LY3023414
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG
Chemistry
1
1
15
predose
predose
screening
predose
2
1
22
predose
predose
3
1
22
0.5
0.5
4
1
22
1-2
1-2
2 hr
5
1
22
3-4
3-4
6-8 hr (±1 hr)
6
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr= hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part C Dose Escalation – LY3039478 + Abemaciclib
PK Sample 
Number
Cycle
Day of 
LY3039478 
Combination
Sampling 
Time (hr) 
for 
LY3039478
Sampling 
Time (hr) for 
Abemaciclib,
LSN3106726,
LSN2839567
Sampling 
Time (hr) 
for Aβ
Sampling 
Time for 
Plasma 
Cortisol 
Sampling 
Time for 
Urine 
PD 
Sampling 
Time for 
Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Lead in
-3
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
screening
predose
2
Lead in
-3
0.5 
3
Lead in
-3
1
4
Lead in
-3
2
5
Lead in
-3
4
6
Lead in
-3
6
7
Lead in
-3
8
8
Lead in
-2
24-30
9
1
1
predose
predose
10
1
22
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
predose
11
1
22
0.5
0.5 
0.5
12
1
22
1
1
1
13
1
22
2
2
2
2 hr
14
1
22
4
4
4
15
1
22
6
6
6
6-8 hr
(±1 hr)
16
1
22
8
8
8
17
1
22
24-30
24-30
24-30 hr
24-30 hr
18
2
1
predose
predose
Predose
Abbreviations: ECG = electrocardiogram; hr= hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part C Dose Confirmation – LY3039478 + Abemaciclib
PK 
Sample 
Number
Cycle
Day
PK Sampling 
Time (hr) for 
LY3039478
Sampling Time (hr) 
for Abemaciclib, 
LSN3106726, 
LSN2839567
PD Sampling 
Time for Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
1
15
predose
predose
screening
predose
2
1
22
predose
predose
3
1
22
0.5
0.5
4
1
22
1-2
1-2
2 hr
5
1
22
3-4
3-4
6-8 hr (±1 hr)
6
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule (hours):  Part D Dose Escalation –
LY3039478 + Cisplatin/Gemcitabine
PK 
Sample 
Number
Cycle
Day
Sampling 
Time for 
LY3039478
Sampling 
Time for 
Cisplatin
(Relative to 
Start of 
Infusion)
Sampling 
Time for
Gemcitabine 
(Relative to 
Start of 
Infusion)
Sampling 
Time for Aβ
(Relative to 
LY3039478)
Sampling 
Time for 
Plasma 
Cortisol 
(Relative to 
LY3039478)
Sampling 
Time for 
Urine
(Relative to 
LY3039478)
PD Sampling 
Time for 
Skin 
Biopsies 
(Relative to 
LY3039478)
ECG with 
ECG 
Chemistry 
(Relative to 
LY3039478)
1
screening
predose
predose
2
1
1
predose
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
3
1
1
0.5
0.5 (end of 
infusion)
4
1
1
1
1.5 (end of 
infusion)
1
5
1
1
2
2
2
6
1
1
4
4
4
4
7
1
1
6-8
6
6
6-8
8
1
1
24-30
9
1
15
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
10
1
15
0.5
0.5
11
1
15
1
1
12
1
15
2
2
13
1
15
4
4
14
1
15
6-8
6-8
15
1
15
24-30
24-30
16
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule (hours):  Part D Dose Confirmation –
LY3039478 + Cisplatin/Gemcitabine
PK 
Sample 
Number
Cycle
Day
PK Sampling Time 
for LY3039478
Sampling Time for 
Cisplatin (Relative to 
Start of Infusion)
Sampling Time for 
Gemcitabine
(Relative to Start of 
Infusion)
PD Sampling Time 
for Skin Biopsies 
(Relative to 
LY3039478)
ECG with 
ECG Chemistry 
(Relative to 
LY3039478)
1
1
1
predose
predose
predose
predose
predose
2
1
1
0.5
-
0.5 (end of infusion)
3
1
1
1-2
1.5 (end of infusion)
1-2
4
1
1
3-4
3-4
3-4
6-8
4
5
1
15
predose
6
2
1
predose
predose
Abbreviations: ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule (hours):  Part E Dose Escalation –
LY3039478 + Gemcitabine/Carboplatin
PK 
Sample 
Number
Cycle
Day
PK Sampling 
Time for 
LY3039478
Sampling 
Time for 
Gemcitabine
(Relative to 
Start of 
Infusion)
Sampling 
Time for 
Carboplatin
(Relative to 
Start of 
Infusion)
Sampling 
Time for Aβ
(Relative to 
LY3039478)
Sampling 
Time for 
Plasma 
Cortisol
(Relative to 
LY3039478)
Sampling 
Time for 
Urine
(Relative to 
LY3039478)
PD Sampling 
Time for 
Skin Biopsies
(Relative to 
LY3039478)
ECG with 
ECG 
Chemistry
(Relative to 
LY3039478)
1
-
-
screening
predose
predose
2
1
1
predose
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
3
1
1
0.5
0.5 (end of 
infusion)
0.5 (end of 
infusion)
4
1
1
1
1
1
5
1
1
2
2
2
2
6
1
1
4
4
4
7
1
1
6-8
6
6
6-8
8
1
1
24-30
9
1
15
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
10
1
15
0.5
0.5
11
1
15
1
1
12
1
15
2
2
13
1
15
4
4
14
1
15
6-8
6-8
15
1
15
24-30
24-30
16
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic.

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Pharmacokinetic and Pharmacodynamic Sampling Schedule (hours):  Part E Dose Confirmation –
LY3039478 + Gemcitabine/Carboplatin
PK 
Sample 
Number
Cycle
Day
PK Sampling Time 
for LY3039478
Sampling Time for 
Gemcitabine (Relative 
to Start of Infusion)
Sampling Time for 
Carboplatin (Relative 
to Start of Infusion)
PD Sampling Time 
for Skin Biopsies
(Relative to 
LY3039478)
ECG with 
ECG Chemistry
(Relative to 
LY3039478)
1
1
1
predose
predose
predose
predose
predose
2
1
1
0.5
0.5 (end of infusion)
0.5 (end of infusion)
3
1
1
1-2
1-2
1-2
2
4
1
1
3-4
3-4
3-4
6
5
1
15
predose
6
2
1
predose
predose
Abbreviations: ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic.

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

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Attachment 6.Protocol JJCD 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 selfcare.  Totally confined to bed or chair
5
Dead
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and 
response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5(6):649-655.

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Attachment 7.Protocol JJCD Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.  
For serum creatinine concentration in mg/dL:
CrCl =
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
(mL/min)
0.81 serum creatinine 
(mol/L)
a Age in years, weight (wt) in kilograms.
Source:  Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron.
1976;16(1):31-41.
-OR-
GFR(mL/min/1.73m2) = 170 x [PCr]-0.999 x [age]-0.176
x [0.762 if patient is female] x [1.18 if patient is black]
x [SUN]-0.17 x [Alb]+0.318
Abbreviations:  GFR = glomerular filtration rate; PCr = plasma creatinine, mg/dL; SUN = serum urea 
nitrogen, mg/dL; Alb = serum albumin, g/dL.
Source:  Murray PT, Ratain MJ. Estimation of the glomerular filtration rate in cancer patients: a new 
formula for new drugs. J Clin Oncol. 2003;21(14):2633-2635.

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

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

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Diarrhea unresolved 
Persisting diarrhea Grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections, with monitoring of patient’s condition (to rule 
out dehydration, sepsis, or ileus) and medical check and selected workup if patient does 
not need hospitalization.  Observe patient for response to antidiarrheal treatment.  
Persisting diarrhea Grade 3 or 4 may be treated with hospitalization, high dose 
loperamide (initial 4 mg, then 2 mg every 2 hours) and addition of opium tincture or 
dihydrocodeine tartrate tablets/injections, start of intravenous (IV) fluids and antibiotics 
as needed with monitoring of patients condition (to rule out dehydration, sepsis, ileus) 
medical check and workup (perform appropriate additional testing).  Observe patient for 
response. 
After 12 to 24 hours:  
Diarrhea resolved 
o
Continue instructions for dietary modification. 
o
Gradually add solid foods to diet. 
o
Discontinue loperamide and/or other treatment after 12-hours diarrhea-free 
interval. 
Diarrhea unresolved 
o
If diarrhea is still persisting (National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE] Grades 1 and 2) after 
2x 24 hours with high-dose loperamide and opiates, then admit to hospital and 
employ measures as for Grade 3 and 4 until diarrhea is resolved. 
o
If diarrhea is still persisting and progressed to NCI Grades 3 and 4, employ 
measures described below. 
Treatment of Diarrhea Grade 3 or 4 
Severe diarrhea Grade 3 or 4 may be treated with hospitalization, high-dose loperamide (initially
4 mg, then 2 mg every 2 hours) and addition of opium tincture or dihydrocodeine tartrate 
tablets/injections, start of IV fluids and antibiotics as needed with monitoring of patients 
condition (to rule out dehydration, sepsis, ileus), medical check, and workup 
Diarrhea workup and additional test).  Observe patient for response. 
After 12 to 24 hours:  
o
If diarrhea is still persisting, administer subcutaneous (SC) 
Sandostatin/octreotide (100 to 500 µg 3 times per day [TID]). 
o
Continue IV fluids and antibiotics as needed. 
o
If diarrhea Grade 3 or 4 is still persisting, patients should receive opium tincture 
or dihydrocodeine tartrate injections SC or intramuscular (IM). 

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o
If diarrhea Grade 3 or 4 is still persisting, SC Sandostatin/octreotide (500 to 
1000 µg TID) should be administered.
o
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
o
Collect stool, separating it from urine (special containers; analysis immediately; 
exceptionally, freeze samples). 
o
Blood.
o
Fecal leukocytes (Wright’s staining and microscopy).
o
Clostridium difficile toxin.
o
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. 
o
Gastroscopy to obtain jejunal fluid (that is, bacterial overgrowth for cultures and 
biopsy of proximal jejunum to assess extent of inflammatory jejunitis).
o
Sigmoidoscopy - reassessment of colitis.
Reference
Fine KD, Schiller LR. AGA Technical review on the evaluation and management of chronic 
diarrhea. Gastroenterology. 1999;116(6):1464-1486.

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Attachment 10.
CYP3A4 Inhibitors, Inducers, and 
Substrates for LY3023414 (Part B)

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Strong 
CYP3A4 
Inhibitors
Moderate 
CYP3A4 
Inhibitors
Strong 
CYP3A4 
Inducers
Moderate 
CYP3A4 
Inducers
CYP3A4 
Substrates with 
Narrow 
Therapeutic 
Range
Sensitive CYP3A4 Substrates
boceprevir
amprenavir
avasimibe
bosentan
alfentanil
alfentanil
lopinavir
clarithromycin
aprepitant
carbamazepine
efavirenz
astemizole
aprepitant
lovastatin
conivaptan
atazanavir
phenytoin
etravirine
cisapride
budesonide
lurasidone
grapefruit juice
ciprofloxacin
rifampin
modafinil
cyclosporine
buspirone
maraviroc
indinavir
darunavir/ritonavir
St. John’s wort
nafcillin
dihydroergotamine
conivaptan
midazolam
itraconazole
diltiazem
ergotamine
darifenacin
nisoldipine
ketoconazole
erythromycin
fentanyl
darunavir
quetiapine
lopinavir/ritonavir
fluconazole
pimozide
dasatinib
saquinavir
mibefradil
fosamprenavir
quinidine
dronedarone
sildenafil
nefazodone
grapefruit juice
sirolimus
eletriptan
simvastatin
nelfinavir
imatinib
tacrolimus
eplerenone
sirolimus
posaconazole
verapamil
terfenadine
everolimus
tolvaptan
ritonavir
felodipine
tipranavir
saquinavir
indinavir
triazolam
telaprevir
fluticasone
vardenafil
telithromycin
voriconazole
Source:  Food and Drug Administration Drug Development and Drug Interactions page. Table of substrates, inhibitors, and inducers. 
Food and Drug Administration website. Available at: http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm. Accessed October 13, 2015.  

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Attachment 11.
Drugs Associated with QT Interval 
Prolongation for LY3023414 (Part B)
Drugs with a Risk of Torsades de Pointes
amiodarone
clarithromycin
halofantrine
pentamidine
terfenadine
arsenic trioxide
cisopyramide
haloperidol
pimozide
thioridazine
astemizole
dofetilide 
ibutilide
probucol
vandetanib
bepridil
domperidone
levomethadyl
procainamide
chlorpromazine
droperidol
mesoridazine
quinidine
cisapride
citalopram
erythromycin
flecainide
methadone
moxifloxacin
sotalol
sparfloxacin
Drugs with a Possible Risk of Torsades de Pointes
alfuzosin
felbamate
lithium
ranolazine
voriconazole
amantadine
fingolimod
moexipril/HCTZ
risperidone
ziprasidone
atazanavir
foscarnet
nicardipine
roxithromycin
azithromycin
chloral hydrate
clozapine
dolasetron
dronedarone
eribulin
escitalopram
fosphenytoin
gatifloxacin
gemifloxacin
granisetron
indapamide
isradipine
lapatinib
nilotinib
octreotide
ofloxacin
ondansetron
oxyytocin
paliperidone
perflutren lipid microspheres
sertindole
sunitinib
tacrolimus
tamoxifen
telithromycin
tizanidine
vardenafil
famotidine
levofloxacin
quetiapine
venlafaxine
Drugs with a Conditional Risk of Torsades de Pointes
amitriptyline
doxepin
itraconazole
ritonavir
trimipramine
ciprofloxacin
fluconazole
ketoconazole
sertraline
clomipramine
fluoxetine
nortriptyline
solifenacin
desipramine
galantamine
paroxetine
trazodone
diphenhydramine
imipramine
protriptyline
trimethoprim-Sulfa
Reference
Arizona Cert Center for Education and Research on Therapeutics page. QT Drug Lists web site. 
Available at: http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm#. Accessed 
October 13, 2015.

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Attachment 12.
Protocol JJCD Protocol Amendment 
I6F-MC-JJCD(a) Summary 
A Phase 1b Study of LY3039478 in Combination with Other 
Anticancer Agents in Patients with Advanced or Metastatic 
Solid Tumors
Overview
Protocol I6F-MC-JJCD, A Phase 1b Study of LY3039478 in Combination with Other Anticancer 
Agents in Patients with Advanced or Metastatic Solid Tumors, has been amended.  The new 
protocol is indicated by Amendment (a) 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:

Clarification to some inclusion criteria

Clarification to some dose-limiting toxicity (DLT) criteria

Clarification to the definition of maximum tolerated dose (MTD)

Change of wording from extension period to continued access period

Removal of the provision that patients must sign new informed consent forms (ICFs) to 
enter the continued access period

Clarification to the dosage strengths of LY3023414

Clarification of the dose adjustments between cycles

Clarification for electrocardiograms
Minor editing and formatting changes were also made.

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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.
2.0.
Synopsis
…
Diagnosis and Main Criteria for Inclusion and Exclusions:  Adult patients (≥18 years of age) who are 
appropriate candidates for experimental treatment with adequate organ function and performance status, have 
histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is advanced unresectable
or metastatic.  In the dose-confirmation phase of the study, all patients must have measurable disease as defined by 
the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).  In Part A dose confirmation:  all patients 
must have histological evidence of advanced unresectable or metastatic soft tissue sarcoma or breast cancer.  
Breast cancer patients must have prescreened alterations related to Notch pathway.  For Part B dose confirmation:  
all patients must have histological evidence of advanced unresectable or metastatic colon cancer or soft tissue 
sarcoma.  Colon cancer patients must have prescreened alterations related to Notch pathway.  For Part C dose 
confirmation:  all patients must have histological evidence of advanced unresectable or metastatic breast cancer 
and must have prescreened alterations related to Notch pathway.  For Part D dose confirmation:  all patients must 
have histological evidence of cholangiocarcinoma, prescreened alterations related to Notch pathway, and must not 
have received >1 line of prior systemic therapy for metastatic or resectable disease.  For Part E dose confirmation:  
all patients must have histological evidence of locally advanced unresectable or metastatic TNBC, prescreened 
alterations related to Notch pathway, and not have received >2 lines of prior systemic treatment for unresectable or 
metastatic TNBC.  All patients must have available tumor tissue (archived or newly biopsied).  Patients with 
serious concomitant systemic disorders including malabsorptive syndromes, enteropathies, gastroenteritis (acute or 
chronic), or diarrhea (acute or chronic), who have received other investigational product within 14 days, have 
symptomatic central nervous system malignancy or metastases, acute leukemia, active infection including human 
immunodeficiency virus, cardiac disease, or a second primary malignancy that may affect the interpretation of 
results will be excluded from treatment.  For Part B only; patients with insulin-dependent diabetes mellitus or a 
history of gestational diabetes mellitus will be excluded from treatment.
…
5.8.
Rationale for Amendment (a)
This study was amended at the request of the Food and Drug Administration (FDA) to clarify 
inclusion criteria, some criteria for DLTs (Section 7.2.2.1), and the definition for MTD.  Minor 
editorial changes and clarifications have also been made.  
6.1.1.
Inclusion Criteria
…
[1]
For all parts:  The patient must be, in the judgment of the investigator, an 
appropriate candidate for experimental therapy after available standard 
therapies (per available local guidelines) have failed to provide clinical benefit 
for their advanced or metastatic cancer.

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
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
For dose escalation for all combinations:  The patient must have 
histological or cytological evidence of cancer, either a solid tumor or a 
lymphoma, which is advanced unresectable or metastatic.

For Part A dose confirmation:  All patients must have histological 
evidence of advanced unresectable or metastatic soft tissue sarcoma or 
breast cancer.  Breast cancer patients must have prescreened mutations, 
amplification, or gene/protein expression alterations related to Notch 
pathway (Attachment 8).

For Part B dose confirmation:  All patients must have histological evidence of 
unresectable advanced or metastatic colon cancer or soft tissue sarcoma. Colon 
cancer patients must have prescreened mutations, amplification, or gene/protein 
expression alterations related to Notch pathway (Attachment 8).  

For Part C dose confirmation:  All patients must have histological 
evidence of unresectable advanced or metastatic breast cancer and 
prescreened mutations, amplification, or gene/protein expression 
alterations related to Notch pathway (Attachment 8).  

For Part D dose confirmation:  All patients must have histological 
evidence of cholangiocarcinoma and prescreened mutations, 
amplification, or gene/protein expression alterations related to Notch 
pathway (Attachment 8).  Patients must not have received >1 line of prior 
systemic therapy for metastatic or resectable disease (that is, patients may 
have received adjuvant gemcitabine and then later gemcitabine/cisplatin 
for recurrent metastatic disease).

For Part E dose confirmation:  All patients must have histological 
evidence of locally advanced unresectable or metastatic TNBC and 
prescreened mutations, amplification, or gene/protein expression 
alterations related to Notch pathway (Attachment 8).  Patients must not 
have received >2 lines of systemic treatment for advanced unresectable or 
metastatic TNBC.
…
[5]
Have adequate organ function, including:

Hematologic:  Absolute neutrophil count (ANC) 1.5 x 109/L, platelets 
100 x 109/L, and hemoglobin 8 g/dL or >5 mmol/L.  Patients may 
receive erythrocyte transfusions to achieve this hemoglobin level at the 
discretion of the investigator; however, initial study drug treatment must 
not begin earlier than the day after the erythrocyte transfusion.

Hepatic:  Bilirubin 1.5 times upper limit of normal (ULN), ALT and 
aspartate aminotransferase (AST) 2.5 times ULN.  If the liver has tumor 
involvement, AST and ALT equaling 5 times ULN are acceptable.

Renal:  calculated creatinine clearance >60 mL/min (Attachment 7).

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
For Part B only:  have fasting glucose ≤140 mg/dL and glycosylated hemoglobin
(HbA1c) ≤7 g/dL.
…
6.1.2.
Exclusion Criteria
…
[19] Part B only:  Have insulin-dependent diabetes mellitus or a history of 
gestational diabetes mellitus.  Patients with a type 2 diabetes mellitus are 
eligible if adequate control of blood glucose level is obtained by oral 
antidiabetics as documented by glycosylated hemoglobin (HbA1c) < ≤7%.  
6.2.
Summary of Study Design
…
The planned duration of treatment is not fixed; patients will remain on study drug therapy until 
they fulfill 1 of the criteria for treatment discontinuation.  The treatment period will be defined as 
the time from treatment start until discontinuation from treatment for any reason (Section 6.3.2).  
The postdiscontinuation follow-up period begins the day after the patient and the investigator 
agree that the patient will no longer continue study treatment and is defined by the following 
periods:
•
The short term follow-up period begins 1 day after discontinuation of study 
treatment the patient and investigator agree that the patient will no longer 
continue treatment and lasts approximately 30 days (Visit 801).  
•
The long-term follow-up period begins 1 day after the short-term follow-up 
period (Visit 801) is completed and continues until death or study closure to 
collect PFS data (Visit 802-80X).
•
After discontinuation, tumor measurements will be performed as indicated in 
Section 8.3.  Other study procedures will be performed as outlined in 
Attachment 1.
This study will be considered closed once it is deemed that sufficient data are obtained to assess 
the primary and the secondary objectives, estimated to be approximately 12 months from the 
date that the last patient was enrolled.  This will ensure that the primary objective and the 
secondary objectives are met for the purpose of the clinical study report.  For PFS, in the event 
that the data are not mature enough to characterize the entire survival curve, a landmark analysis 
at 12 months will be done for the purpose of the clinical study report.  Patients who are 
benefitting from treatment may continue to receive study drug for long-term durations, even after 
the study has closed and final database lock has occurred, in the extension continued access
period.
…

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6.2.2.
Extension Continued Access Period
All patients remaining on study treatment without disease progression following the final 
analysis will be able to enter the extension continued access period of the study.  The extension
continued access period begins after study completion and ends at the end of trial.  During the 
extension continued access period, patients on study treatment who continue to experience 
clinical benefit may continue to receive study treatment until disease progression, death, 
unacceptable toxicity, or start of new anticancer treatment.  The extension continued access
period includes a follow-up visit.  The follow-up visit begins 1 day after the patient and the 
investigator agree that the patient will no longer continue treatment in the extension continued 
access period and lasts approximately 30 days.  If it is deemed to be in the best interest of the 
patient to start a new anticancer treatment prior to the scheduled end of the follow-up visit, the 
follow-up visit duration may be shortened.  In this case, the follow-up assessments should be 
completed prior to the initiation of the new therapy.
Patients must sign a new ICF before entering the extension period.  Eli Lilly and Company 
(Lilly) will notify investigators when the extension period begins. 
During the extension continued access period, all AEs, SAEs, study drug dosing, and dose 
reduction of treatment will be collected on the case report form/electronic case report form 
(CRF/eCRF).
SAEs will also be reported to Lilly Global Patient Safety and collected in the Lilly Safety System 
(LSS).  In the event that an SAE occurs, additional information (such as local laboratory results, 
concomitant medications, and hospitalizations) may be requested by Lilly in order to evaluate the 
reported SAE.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.
7.1.
Materials and Supplies
…
LY3023414 will be supplied as 25-mg, 100-mg, or 200-mg capsules or 50 , 100-mg, 150-mg, or 
200-mg tablets for oral consumption.  LY3023414 should be stored within the temperature range 
stated on the label.  Investigators should instruct patients to store the capsules/tablets at home in 
the original container and to keep out of the reach of children.  Capsules should not be opened, 
crushed, or dissolved.
7.2.1.5.
LY3039478 in Combination with Gemcitabine and Carboplatin 
(Part E)
…
The site is responsible to consult the local laboratory to determine what method of serum 
creatinine measurement is used by that laboratory.
Calvert Formula

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Total Dose (mg) = (target AUC) (GFR + 25) 
Maximum carboplatin dose (mg) = target AUC 6 (mg•min/mL) (125 + 25) = 6 150 mL/min 
= 900 mg
...
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated 
Dose Definition
A DLT is defined as an AE during Cycle 1 that is related to LY3039478, taladegib, LY3023414, 
or abemaciclib and fulfills any 1 of the following criterion using the NCI CTCAE v 4.0:

CTCAE Grade 3 nonhematological toxicity.  Exceptions will be made for:
o
Grade 3 nausea, vomiting, or constipation that lasts ≤72 hours and that can be 
controlled with treatment or Grade 4 vomiting or constipation that lasts ≤24 hours 
and that can be controlled with treatment
o
nausea, vomiting, or constipation that lasts <72 hours and that can be controlled 
with treatment
o
Grade 3 electrolyte disturbance that can be controlled with treatment. Grade 4 
electrolyte disturbance lasting more than 24 hours will be considered a DLT

Electrolyte disturbance that can be controlled with treatment
o
Diarrhea CTCAE Grade 3 for 4 days or less and that can be controlled with 
standard treatment
o
Transient (<7 days) Grade 3 elevations of ALT and/or AST that are not 
accompanied by a Grade 2 bilirubin increase are considered an exception to the 
DLT criteria, unless there is a clear alternative cause for example, worsening 
biliary obstruction) if agreed by the study investigator and Lilly CRP/clinical 
research scientist (CRS)

CTCAE Grade 4 anemia

CTCAE Grade 4 anemia, neutropenia or leukopenia of >5-days duration 

Any febrile neutropenia

Grade 3 thrombocytopenia with clinically significant bleeding or Grade 4 
thrombocytopenia

Inability to start Cycle 2 within 3 weeks of the expected date because of persistent 
toxicity related to LY3039478, taladegib, LY3023414, or abemaciclib

Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting (for example, any toxicity that is possibly related 
to the study medication that requires the withdrawal of the patient from the study during 
Cycle 1)

Exceptions to the DLT criteria for Part B include:
o
Grade 3 fasting hyperglycemia that resolves to ≤Grade 2 within 7 days
o
Grade 4 hyperglycemia lasting <24 hours Grade 4 hyperglycemia of any duration 
that results in intensive care unit admission will be considered a DLT

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o
Grade 3 mucositis that resolves to ≤Grade 2 within 7 days.  Grade 4 mucositis of 
any duration will be considered a DLT.
o
Grade 3 fatigue that resolves to ≤Grade 2 within 5 days
o
Grade 3 hypertriglyceridemia or hyperlipidemia without optimal treatment
Investigators, together with the Lilly CRP, can declare a DLT if a patient is experiencing 
increasing toxicity during treatment, and it becomes clear that it is not going to be possible to 
complete the treatment without exposing the patient to excessive risk.
A DLET is defined as an AE occurring between Day 1 and Day 21/28 of any cycle (other than 
Cycle 1) for a patient enrolled in the dose-escalation phase of Parts A, B, and C or in any cycle 
(including Cycle 1) for a patient enrolled in the dose-confirmation phase of Parts A, B, and C 
that would have met the criteria for DLT if it had occurred during Cycle 1 for a patient enrolled 
in the dose-escalation phase of Parts A, B, and C.
For the purpose of this study, the MTD is defined as the highest tested dose that has 
<33% probability of causing a DLT during Cycle 1 in a cohort of at least 6 patients.
Determination of the recommended dose will take into account toxicities beyond Cycle 1, PK, 
and dose modifications of standard chemotherapy.
7.2.4.1.2.
Dose Adjustments between Cycles
…
Hematologic toxicity must resolve to a level that, in the opinion of the investigator, is reasonable 
to allow for continuation of treatment CTCAE Grade 0, 1, or baseline level before resuming 
treatment.
…
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 
the investigational site and the Lilly clinical research personnel to confirm that each patient 
meets all enrollment criteria.  Upon confirmation of eligibility, the sponsor will confirm the dose 
and identification number assignment, study part, and cohort for each patient.  No dose 
escalations (that is, to the next cohort) can occur without prior discussion and agreement with the 
responsible Lilly CRP or CRS.
…

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Table JJCD.8.1.
Adverse Events and Serious Adverse Reporting Guidelines for 
Study JJCD
Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of informed 
consent and ends just before the 
first dose of study drug)
Preexisting conditions
All AEs
All SAEs regardless of relatedness 
X
X
X
X
On therapy
(Starts at first dose of study drug[s]
and ends when the patient and the 
investigator agree that the patient 
will no longer continue any study 
treatment)
All AEs
All SAEs regardless of relatedness
X
X
X
Follow-up visit (Visit 801)
(Starts the day after the patient and 
the investigator agree that the 
patient will no longer continue any 
study treatment and ends when end 
of study safety assessments are 
completed in 30 days OR the 
planned end of the cycle)
All AEs
All SAEs regardless of relatedness
X
X
X
Extension Continued access period
All AEs 
All SAEs regardless of relatedness
X
X
X
Extension Continued access period 
follow-up
All AEs 
All SAEs regardless of relatedness
X
X
X
Subsequent follow-up visits, if 
necessary for patient monitoring 
Ongoing AEs possibly related to study 
drug(s), or protocol procedures
All SAEs related to protocol procedures 
or study drug
X
X
X
Patient no longer on study
All SAEs related to protocol procedures 
or study drug of which the investigator 
becomes aware
X
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
8.1.3.1
Electrocardiograms
…
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine read 
measurements or to meet regulatory requirements.  

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The machine read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless an overread of the ECGs is conducted prior to completion of the final study 
report (in which case the overread data would be used).
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will then conduct a full overread on 1 of the replicate ECGs 
(including all intervals).  A report based on data from this overread will be issued to the 
investigative site.  For each set of replicates, the RR and QT intervals and heart rate will be 
determined on the ECGs that were not fully overread.  These data are not routinely reported back 
to the investigative site.
All data from the overreads will be placed in the Lilly database for analytical and study report 
purposes.  Any clinically significant finding that was not present on the fully overread ECG but 
was present on the partially overread ECG (where only RR, QT, and heart rate is assessed)will 
be reported to the investigator and to Lilly.  If 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 subject 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 his/her review of 1 of the replicate ECGs 
printed at the time of collection, the final overread ECG report issued by the central ECG 
laboratory, and any alert reports.
…

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Attachment 1.
JJCD Study Schedule
During and Poststudy Assessments - Parts A, B, and C
Cycle 1
3-Day 
Lead-In
Week 1
Week 2
Week 3
Week 4
Study Procedures
Single dose 
Taladegib,
LY3023414, or
Abemaciclib
on Day 1a
First Day of the 
Week 1
Day 1 of 
LY3039478
Combination
First Day of the 
Week 2
Day 8 of 
LY3039478
Combination
First Day of the 
Week 3
Day 15 of 
LY3039478
Combination
First Day of 
the Week 4
Day 22 of 
LY3039478
Combination
Physical examination
X
X
X
X
X
Vital signs and weight (temperature, pulse rate, blood 
pressure, respiratory rate)
X
X
X
X
X
ECOG performance status
X
X
X
X
X
CTCAE version 4.0 grading
X
X
X
X
Concomitant medications
X
X
X
X
X
Central ECGb
X
X
PET scanc
X
Hematologyd
X
X
X
X
X
Serum chemistryd
X
X
X
X
X
Cystatin C (for Part C only)
X
X
X
X
X
HbA1c (for Part B only)
X
ECG chemistryb,d
X
X
Coagulation (PT/INR, aPTT, fibrinogen)d
X
X
X
X
Tumor markerd
X
X
Pharmacogenetics sample (predose)
X
Blood PK samplingb
X
X
X
X
Tumor biopsy, recommendede
X
Skin biopsyb,f
X
Blood PD biomarkers (Aβ[1-x]) during dose escalation 
only)b,g
X
X
Blood exploratory circulating biomarkers predose 
X
Urine (8-hour collection)b,g
X
X
…

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Attachment 2.
Protocol JJCD Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya,b
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Total bilirubin
Neutrophils 
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Gamma-glutamyl transpeptidase (GGT)
Basophils
Blood urea nitrogen (BUN) 
Platelets
Creatinine
Lipase
Coagulationb
Lactate dehydrogenase (LDH)
aPTT
Uric acid
PT/INR
Calcium
Fibrinogen
Phosphorus
Glucose, random (fasted for Part B)
Urinalysisa
Albumin
Specific gravity
Total protein
pH
Creatinine clearance
Protein
Serum or urine pregnancy test (females only)a
Glucose
Ketones
ECG Chemistryb
Blood
Urine leukocyte esterase
Thyroid-stimulating hormone (TSH)
Free Ttri-iodothyronine (T3)
HbA1c (for Part B only)
Free Tthyroxine (T4)
Calciumc
Cystatin C (for Part C only)
Sodiumc
Potassiumc
Tumor Markersa
Phosphorus
Magnesium
Biomarkersb

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Attachment 4.
Protocol JJCD Pharmacokinetic, Pharmacodynamic, and Electrocardiogram with Electrocardiogram 
Chemistry Sampling Schedule
Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part A Dose Escalation – LY3039478 + Taladegib
PK 
Sample 
Numbe
r
Cycle
Day of 
LY3039478
Combination
Sampling 
Time (hr) for 
LY3039478
Sampling 
Time (hr) for 
Taladegib/
LSN3185556
Sampling 
Time (hr) 
for Aβ
Sampling 
Time for 
Plasma 
Cortisol
Sampling 
Time for 
Urine
PD Sampling 
Time for Skin 
Biopsies
ECG with
ECG
Chemistry
1
Lead in
-3 1
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
screening
predose
2
Lead in
-3 1
0.5 
3
Lead in
-3 1
1
4
Lead in
-3 1
2
5
Lead in
-3 1
4
6
Lead in
-3 1
6
7
Lead in
-3 1
8
8
Lead in
-2 2
24-30
9
1
1
predose
predose
10
1
22
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
predose
11
1
22
0.5
0.5 
0.5
12
1
22
1
1
1
13
1
22
2
2
2
2 hr
14
1
22
4
4
4
15
1
22
6
6
6
6-8 hr
(±1 hr)
16
1
22
8
8
8
17
1
22 23
same time as 
taladegib 
predose 
sample
predose 
same time as 
taladegib 
predose 
sample
same time as 
taladegib 
predose 
sample
same time as 
taladegib 
predose sample
18
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.
…

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
Page 122
LY3039478
Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part B Dose Escalation – LY3039478 + LY3023414
PK 
Sample 
Number
Cycle
Day of 
LY3039478 
Combination
Sampling 
Time (hr) 
for 
LY3039478
Sampling 
Time (hr) 
for 
LY3023414
Sampling 
Time (hr) 
for Aβ
Sampling 
Time for 
Plasma 
Cortisol 
Sampling 
Time for 
Urine 
PD 
Sampling 
Time for 
Skin 
Biopsies
ECG with 
ECG
Chemistry
1
Lead in
-3 1
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
screening
predose
2
Lead in
-3 1
0.5 
3
Lead in
-3 1
1
4
Lead in
-3 1
2
5
Lead in
-3 1
4
6
Lead in
-3 1
6
7
Lead in
-3 1
8
8
Lead in
-2 2
24-30
9
1
1
predose
predose
10
1
22
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
predose
11
1
22
0.5
0.5 
0.5
12
1
22
1
1
1
13
1
22
2
2
2
2 hr
14
1
22
4
4
4
15
1
22
6
6
6
6-8 hr
(±1 hr)
16
1
22
8
8
8
17
1
22 23
24-30
24-30
24-30 hr
24-30 hr
18
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr= hour; PD = pharmacodynamic; PK = pharmacokinetic.
…

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
Page 123
LY3039478
Pharmacokinetic and Pharmacodynamic Sampling Schedule:  Part C Dose Escalation – LY3039478 + Abemaciclib
PK Sample 
Number
Cycle
Day of 
LY3039478 
Combination
Sampling 
Time (hr) 
for 
LY3039478
Sampling 
Time (hr) for 
Abemaciclib,
LSN3106726,
LSN2839567
Sampling 
Time (hr) 
for Aβ
Sampling 
Time for 
Plasma 
Cortisol 
Sampling 
Time for 
Urine 
PD 
Sampling 
Time for 
Skin 
Biopsies
ECG with 
ECG 
Chemistry
1
Lead in
-3 1
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
screening
predose
2
Lead in
-3 1
0.5 
3
Lead in
-3 1
1
4
Lead in
-3 1
2
5
Lead in
-3 1
4
6
Lead in
-3 1
6
7
Lead in
-3 1
8
8
Lead in
-2 2
24-30
9
1
1
predose
predose
10
1
22
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 8 hr PK 
sample). 
Record total 
volume
predose
11
1
22
0.5
0.5 
0.5
12
1
22
1
1
1
13
1
22
2
2
2
2 hr
14
1
22
4
4
4
15
1
22
6
6
6
6-8 hr
(±1 hr)
16
1
22
8
8
8
17
1
22 23
24-30
24-30
24-30 hr
24-30 hr
18
2
1
predose
predose
Predose
Abbreviations: ECG = electrocardiogram; hr= hour; PD = pharmacodynamic; PK = pharmacokinetic.
…

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
Page 124
LY3039478
Pharmacokinetic and Pharmacodynamic Sampling Schedule (hours):  Part D Dose Escalation –
LY3039478 + Cisplatin/Gemcitabine
PK 
Sample 
Number
Cycle
Day
Sampling 
Time for 
LY3039478
Sampling 
Time for 
Cisplatin
(Relative to 
Start of 
Infusion)
Sampling 
Time for
Gemcitabine 
(Relative to 
Start of 
Infusion)
Sampling 
Time for Aβ
(Relative to 
LY3039478)
Sampling 
Time for 
Plasma 
Cortisol 
(Relative to 
LY3039478)
Sampling 
Time for 
Urine
(Relative to 
LY3039478)
PD Sampling 
Time for 
Skin 
Biopsies 
(Relative to 
LY3039478)
ECG with 
ECG 
Chemistry 
(Relative to 
LY3039478)
1
screening
predose
predose
2
1
1
predose
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
3
1
1
0.5
0.5 (end of 
infusion)
4
1
1
1
1.5 (end of 
infusion)
1
5
1
1
2
2
2
6
1
1
4
4
4
4
7
1
1
6-8
6
6
6-8
8
1
12
24-30
9
1
15
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
10
1
15
0.5
0.5
11
1
15
1
1
12
1
15
2
2
13
1
15
4
4
14
1
15
6-8
6-8
15
1
15
24-30
24-30
16
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; hr = hour; PD = pharmacodynamic; PK = pharmacokinetic.
…

I6F-MC-JJCD(a) Phase 1 Oncology Protocol
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LY3039478
Pharmacokinetic and Pharmacodynamic Sampling Schedule (hours):  Part E Dose Escalation –
LY3039478 + Gemcitabine/Carboplatin
PK 
Sample 
Number
Cycle
Day
PK Sampling 
Time for 
LY3039478
Sampling 
Time for 
Gemcitabine
(Relative to 
Start of 
Infusion)
Sampling 
Time for 
Carboplatin
(Relative to 
Start of 
Infusion)
Sampling 
Time for Aβ 
(Relative to 
LY3039478)
Sampling 
Time for 
Plasma 
Cortisol 
(Relative to 
LY3039478)
Sampling 
Time for 
Urine
(Relative to 
LY3039478)
PD Sampling 
Time for 
Skin Biopsies 
(Relative to 
LY3039478)
ECG with 
ECG 
Chemistry 
(Relative to 
LY3039478)
1
-
-
screening
predose
predose
2
1
1
predose
predose
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
3
1
1
0.5
0.5 (end of 
infusion)
0.5 (end of 
infusion)
4
1
1
1
1
1
5
1
1
2
2
2
2
6
1
1
4
4
4
7
1
1
6-8
6
6
6-8
8
1
12
24-30
9
1
15
predose
predose
predose
0-8 hr pooled 
sample (end 
time to match 
with 6-8 hr
PK sample). 
Record total 
volume
10
1
15
0.5
0.5
11
1
15
1
1
12
1
15
2
2
13
1
15
4
4
14
1
15
6-8
6-8
15
1
15
24-30
24-30
16
2
1
predose
predose
predose
Abbreviations: ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic.
…

Leo Document ID = b58b3c78-4d75-4511-9f06-84bf9f4966a1
Approver: 
Approval Date & Time: 15-Mar-2016 14:01:30 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 15-Mar-2016 15:05:06 GMT
Signature meaning: Approved
PPD
PPD