Clinical trial NCT02377752
Conditions: Neoplasm
Sponsor: Eli Lilly and Company
Start date: 2015-03-23; Completion date: 2020-01-14
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of 2 parts (Part A and Part B). The main purpose of Part A is to evaluate safety and side effects of olaratumab in combination with doxorubicin in Japanese participants with a group of rare cancers (advanced solid tumors, especially advanced soft tissue sarcoma \[STS\].) The main purpose of Part B is to evaluate how much olaratumab gets into the blood stream of Japanese participants with advanced solid tumors and how long it takes the body to get rid of it.

Detailed description:

Arms: arm 1: 15 milligram per kilogram (mg/kg) of olaratumab administered intravenously (IV) on Day 1 and Day 8, and 25 milligram per square meter (mg/m2) of doxorubicin administered IV on Day 1, Day 2, and Day 3 every 21-day cycle for up to 6 cycles or until the cumulative dose of doxorubicin reached 500 mg/m2, whichever came later, followed by 15 mg/kg of olaratumab IV monotherapy on Day 1 and Day 8 in subsequent cycles. Participants may continue to receive treatment until discontinuation criteria are met

. arm 2: 15 mg/kg of olaratumab administered IV on Day 1 and Day 8, and 75 mg/m2 of doxorubicin administered IV on Day 1 every 21 day-cycle for up to 6 cycles or until the cumulative dose of doxorubicin reached 500 mg/m2, whichever came later, followed by 15 mg/kg of olaratumab IV monotherapy on Day 1 and Day 8 in subsequent cycles. Participants may continue to receive treatment until discontinuation criteria are met. arm 3: 20 mg/kg loading dose of olaratumab administered IV on Day 1 and Day 8 in Cycle 1, followed by 15 mg/kg IV on Day 1 and Day 8 in subsequent cycles, and 75 mg/m2 of doxorubicin administered IV on Day 1 of every 21 day-cycle up to 6 cycles or until the cumulative dose of doxorubicin reached 500 mg/m2, whichever came later, followed by 15 mg/kg of olaratumab IV monotherapy on Day 1 and Day 8 in subsequent cycles. Participants may continue to receive treatment until discontinuation criteria are met. arm 4: 15 mg/kg olaratumab administered IV on Day 1 and Day 8 of every 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Interventions: intervention 1: Olaratumab intervention 2: Doxorubicin
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol I5B-JE-JGDK (b) 
 
 
A Phase 1 Study of Olaratumab in Japanese Patients with Advanced Soft Tissue Sarcoma or 
Advanced Solid Tumors 
 
NCT02377752 
 
Approval Date: 28-Sep-2018 
 
 


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1.
Protocol I5B-JE-JGDK (b)
A Phase 1 Study of Olaratumab in Japanese Patients with 
Advanced Soft Tissue Sarcoma or 
Advanced Solid Tumors
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
olaratumab (LY3012207), 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.  
Note to Regulatory Authorities:  this document may contain protected personal data and/or 
commercially confidential information exempt from public disclosure. Eli Lilly and Company 
requests consultation regarding release/redaction prior to any public release.
Olaratumab (LY3012207)
This Phase 1 study is a multicenter, nonrandomized, open–label study to evaluate 
intravenous olaratumab in combination with doxorubicin in Japanese patients with 
advanced soft tissue sarcoma or advanced solid tumors (Part A), and intravenous 
olaratumab alone in Japanese patients with advanced solid tumors (Part B).
Eli Lilly Japan KK
Kobe, Hyogo, Japan
Protocol Approved by Lilly: 09 Dec 2014
Amendment (a) Protocol Electronically Signed and Approved by Lilly on 26 Jun 2015
Amendment (b) Protocol Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 28-Sep-2018 GMT


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2.
Synopsis
Name of Investigational Product:  Olaratumab
Title of Study: A Phase 1 Study of Olaratumab in Japanese Patients with Advanced Soft Tissue Sarcoma or 
Advanced Solid Tumors
Number of Planned Patients/Subjects:
   Enrolled:  24
Phase of Development:  1
Length of Study:  
First patient enrolled (assigned to therapy): March 2015           Estimated last patient visit:  March 2019
Objectives:  
The primary objective of Part A is to evaluate the safety and tolerability of olaratumab in combination with 
doxorubicin in Japanese patients with advanced solid tumors, especially advanced soft tissue sarcoma.  
The primary objective of Part B is to evaluate the pharmacokinetics (PK) profile of olaratumab in Japanese patients 
with advanced solid tumors.
The secondary objectives of Part A are:

To evaluate the PK of olaratumab and doxorubicin

To evaluate the immunogenicity of olaratumab

To document any antitumor activity of olaratumab in combination with doxorubicin
The secondary objectives of Part B are:

To evaluate the safety and tolerability of olaratumab

To evaluate the immunogenicity of olaratumab

To document any antitumor activity of olaratumab
The exploratory objective of Part A and Part B is to evaluate potentially relevant biomarkers related to the 
mechanism of olaratumab, the platelet-derived growth factor (PDGF) signaling pathway, and the pathobiology of 
cancer.  
othersomeIStudy Design:
This study is a multicenter, non-randomized, open-label Phase 1 study consisting of 2 parts (Part A and Part B).  
Part A and Part B will be conducted in parallel.
Part A is designed to evaluate the safety and tolerability of olaratumab in combination with doxorubicin in 
Japanese patients with advanced solid tumors, especially advanced soft tissue sarcoma.  This part consists of 3
cohorts.  After the first 3 patients from Cohort 1 are enrolled, Cohort 2 can be opened based on safety assessment 
and after discussion between the investigator, the sponsor, and the Safety Assessment Committee.  Cohort 3 can be 
opened after confirmation of tolerability in Cohort 2.
At least 6 patients will be assigned to each cohort and will receive the combination therapy of olaratumab and 
doxorubicin.  One cycle is defined as 21 days, and the combination therapy will continue up to 6 cycles or until the
cumulative dose of doxorubicin reaches 500 mg/m2, whichever comes later.
Patients may continue to receive treatment until progressive disease, the development of unacceptable toxicity, 
noncompliance or withdrawal of consent by the patient, or investigator decision. If doxorubicin is discontinued, 
olaratumab monotherapy can be continued in the absence of progressive disease or other discontinuation criteria. 
For patients who discontinue olaratumab therapy during the first 6 cycles, doxorubicin may be continued (for up to 
6 cycles or until the cumulative dose of doxorubicin reaches 500 mg/m2, whichever comes later), provided no 
discontinuation criteria are met.


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Part B is designed to evaluate the PK profile of olaratumab monotherapy in Japanese patients with advanced solid 
tumors.  This part consists of 1 dose level.  At least 6 patients will be assigned and receive the treatment of 
olaratumab.  One cycle is defined as 21 days, and the treatment will continue until progressive disease or meeting 
other discontinuation criteria.  
Diagnosis and Main Criteria for Inclusion and Exclusion:  
Part A
Japanese patients with advanced solid tumors, especially advanced soft tissue sarcoma which are not amenable to 
surgery and radiotherapy, and who are appropriate candidates for combination therapy of olaratumab and 
doxorubicin.
Part B
Japanese patients with advanced solid tumors who are appropriate candidates for olaratumab monotherapy after 
available standard therapies have failed to provide clinical benefit for their disease.
Investigational Product, Dosage, and Mode of Administration or Intervention:
Part A

Cohort 1: 15 mg/kg of olaratumab on Day 1 and Day 8, and 25 mg/m2 of doxorubicin on Day 1, Day 2,
and Day 3 of every 21-day cycle.

Cohort 2: 15 mg/kg of olaratumab on Day 1 and Day 8, and 75 mg/m2 of doxorubicin on Day 1 of every 
21-day cycle.

Cohort 3: 20 mg/kg loading dose of olaratumab on Day 1 and Day 8 in Cycle 1, followed by 15 mg/kg on 
Day 1 and Day 8 in subsequent cycles, and 75 mg/m2 of doxorubicin on Day 1 of every 21day-cycle.
Part B
This part consists of 1 dose level:  15 mg/kg of olaratumab on Day 1 and Day 8 of every 21-day cycle.
Planned Duration of Treatment:
Patients will be on treatment until one of the discontinuation criteria is met.
Treatment period:  21 days/cycle 
Follow-up Period:  28 days
Criteria for Evaluation:  
Safety:  Dose-limiting toxicities, treatment-emergent adverse events (TEAEs) using Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 and the Medical Dictionary for Regulatory Activities 
(MedDRA), laboratory evaluations, vital signs, electrocardiograms and cardiac function as measured by 
echocardiogram.
Bioanalytical:  Serum concentrations of olaratumab (Part A and B) and plasma concentrations of doxorubicin
(Part A).
Pharmacokinetics:  The primary parameters for analysis will be maximum observed concentration (Cmax) and area 
under the concentration-time curve (AUC) from time 0 to the last time point with a measurable concentration, and 
AUC from time 0 to infinity of olaratumab and doxorubicin.  Other noncompartmental parameters, such as half-
life, clearance, and volume of distribution, may be reported.
Efficacy:  Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1.  
Biomarkers:  Biomarkers related to the mechanism of olaratumab, the PDGF signaling pathway, and the 
pathobiology of cancer.


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Statistical Methods:  
Safety:  Dose-limiting toxicities will be listed and summarized by frequency.  Adverse events (AEs), including 
TEAEs, will be listed and summarized in frequency tables using MedDRA.  Severity of AEs will be classified 
using CTCAE version 4.03.  Other safety data, such as laboratory tests, echocardiography, and vital signs, will be 
listed and summarized, if appropriate.
Efficacy:  Efficacy data will be listed.  Also, efficacy data will be summarized using frequency table or summary 
statistics, depending on the characteristics of the data.
Pharmacokinetics:  The PK parameters of olaratumab and doxorubicin will be computed by standard
noncompartmental methods of analysis using Phoenix WinNonlin.
Biomarkers: Descriptive statistics for biomarkers will be provided.


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3.
Table of Contents
A Phase 1 Study of Olaratumab in Japanese Patients with 
Advanced Soft Tissue Sarcoma or Advanced Solid Tumors
Section
Page
1.
Protocol I5B-JE-JGDK (b)  A Phase 1 Study of Olaratumab in 
Japanese Patients with Advanced Soft Tissue Sarcoma or  Advanced 
Solid Tumors ......................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................5
4.
Abbreviations and Definitions...........................................................................................11
5.
Introduction ......................................................................................................................16
5.1.
Rationale and Justification for the Study ......................................................................16
5.2.
Rationale for Amendments...........................................................................................18
5.2.1.
Rationale for Amendment (a)...............................................................................18
5.2.2.
Rationale for Amendment (b)...............................................................................18
5.3.
Objectives ....................................................................................................................18
5.3.1.
Primary Objective ................................................................................................18
5.3.2.
Secondary Objectives...........................................................................................19
5.3.3.
Exploratory Objective ..........................................................................................19
5.4.
General Introduction to Olaratumab .............................................................................19
5.4.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................20
5.4.2.
Nonclinical Pharmacokinetics ..............................................................................20
5.4.3.
Nonclinical Toxicology........................................................................................20
5.4.4.
Olaratumab Pharmacokinetics..............................................................................21
5.5.
Rationale for Selection of Dose....................................................................................22
6.
Investigational Plan...........................................................................................................24
6.1.
Study Population..........................................................................................................24
6.1.1.
Inclusion Criteria .................................................................................................24
6.1.2.
Exclusion Criteria ................................................................................................25
6.2.
Summary of Study Design............................................................................................27
6.3.
Discontinuations ..........................................................................................................29
6.3.1.
Discontinuation of Patients...................................................................................29
6.3.2.
Discontinuation of Study Sites .............................................................................30
6.3.3.
Discontinuation of the Study................................................................................30
7.
Treatment..........................................................................................................................31
7.1.
Materials and Supplies .................................................................................................31


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7.2.
Study Drug Administration ..........................................................................................31
7.2.1.
Dosing Schedule ..................................................................................................31
7.2.1.1.
Olaratumab.....................................................................................................32
7.2.1.2.
Doxorubicin ...................................................................................................32
7.2.1.3.
Dose-Limiting Toxicity Determination (Part A)..............................................33
7.2.1.4.
Initiation of Cohort 2 and 3 in Part A..............................................................33
7.2.1.5.
Tolerability Confirmation (Part A)..................................................................34
7.2.2.
Dose Adjustments and Delays..............................................................................34
7.2.2.1.
Delays and Omission......................................................................................34
7.2.2.2.
Dose Reductions.............................................................................................35
7.2.2.3.
Guidelines for Olaratumab Dose Reduction....................................................36
7.2.2.3.1.
Hematologic Toxicity ...............................................................................36
7.2.2.3.2.
Nonhematologic Toxicity..........................................................................36
7.2.2.4.
Guidelines for Doxorubicin Dose Reduction (Part A) .....................................37
7.2.2.4.1.
Hematologic Toxicity ...............................................................................37
7.2.2.4.2.
Nonhematologic Toxicity..........................................................................37
7.2.2.4.3.
Cardiovascular..........................................................................................38
7.3.
Method of Assignment to Treatment ............................................................................38
7.4.
Blinding .......................................................................................................................38
7.5.
Concomitant Therapy...................................................................................................38
7.6.
Treatment Compliance .................................................................................................39
8.
Safety, Pharmacokinetic, and Efficacy Data Collection .....................................................40
8.1.
Safety Evaluations........................................................................................................40
8.1.1.
Safety Data Collection and Review ......................................................................40
8.1.2.
Adverse Events ....................................................................................................40
8.1.2.1.
Serious Adverse Events ..................................................................................42
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................43
8.1.2.2.1.
Prior to Administration of Study Drug(s) ..................................................43
8.1.2.2.2.
On Therapy...............................................................................................43
8.1.2.2.3.
Follow-Up Visit........................................................................................43
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................44
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................44
8.1.3.
Other Safety Measures .........................................................................................44
8.1.3.1.
Vital Signs......................................................................................................44
8.1.3.2.
Electrocardiograms.........................................................................................45
8.1.3.3.
Echocardiograms............................................................................................46
8.1.3.4.
Infusion-Related Reactions.............................................................................46
8.1.4.
Safety Monitoring ................................................................................................47


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8.1.5.
Complaint Handling.............................................................................................47
8.2.
Sample Collection and Testing.....................................................................................48
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................48
8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................48
8.2.2.1.
Pharmacokinetic Samples...............................................................................48
8.2.3.
Samples for Immunogenicity Research.................................................................49
8.2.4.
Samples for Translational Research......................................................................49
8.2.4.1.
Blood Sample for Plasma Collection...............................................................50
8.2.4.2.
Optional Tumor Tissue Samples .....................................................................50
8.3.
Efficacy Evaluations ....................................................................................................50
8.4.
Procedure/Sampling Compliance..................................................................................51
9.
Data Management Methods...............................................................................................52
9.1.
Data Quality Assurance................................................................................................52
9.2.
Data Capture Systems ..................................................................................................52
9.2.1.
Case Report Form ................................................................................................52
9.2.2.
Ancillary Data......................................................................................................52
10.
Data Analyses ...................................................................................................................54
10.1. General Considerations ................................................................................................54
10.2. Patient Disposition .......................................................................................................54
10.3. Patient Characteristics ..................................................................................................55
10.4. Safety Analyses............................................................................................................55
10.5. Pharmacokinetic Analyses............................................................................................55
10.6. Efficacy........................................................................................................................56
10.7. Biomarker Analyses.....................................................................................................56
10.8. Interim Analyses ..........................................................................................................56
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................57
11.1. Informed Consent.........................................................................................................57
11.2. Ethical Review.............................................................................................................57
11.3. Regulatory Considerations ...........................................................................................57
11.3.1.
Investigator Information.......................................................................................58
11.3.2.
Protocol Signatures ..............................................................................................58
11.3.3.
Final Report Signature .........................................................................................58
12.
References ........................................................................................................................59


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List of Tables
Table
Page
Table JGDK.7.1. Dosing Regimens (21-day cycles)..................................................................32
Table JGDK.7.2. General Guidelines for Dose Modification Due to Nonhematologic 
Toxicities Related to Olaratumab...................................................................37
Table JGDK.7.3. General Guidelines for Doxorubicin Dose Reduction Due to 
Neutropenia...................................................................................................37
Table JGDK.7.4. General Guidelines for Doxorubicin Dose Reduction Due to 
Hyperbilirubinemia and Elevated AST...........................................................38
Table JGDK.8.1. Adverse Event and Serious Adverse Reporting Guidelines for Study 
JGDK ............................................................................................................44


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List of Figures
Figure
Page
Figure JGDK.6.1.
Illustration of study design for Protocol I5B-JE-JGDK. ............................27
Figure JGDK.6.2.
Illustration of study schedule in Part A......................................................28
Figure JGDK.6.3.
Illustration of study schedule in Part B......................................................29


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List of Attachments
Attachment
Page
Attachment 1.
Protocol I5B-JE-JGDK Study Schedule.........................................................62
Attachment 2.
Protocol I5B-JE-JGDK Clinical Laboratory Tests..........................................71
Attachment 3.
Protocol I5B-JE-JGDK Hepatic Monitoring Tests for Treatment-
Emergent Abnormality ..................................................................................72
Attachment 4.
Protocol I5B-JE-JGDK Pharmacokinetic Sampling, ECG, and 
Immunogenicity Sampling Schedule..............................................................73
Attachment 5.
Protocol I5B-JE-JGDK Olaratumab and Doxorubicin Dosing Scenarios 
for Dose Delay and Omission ........................................................................82
Attachment 6.
Protocol I5B-JE-JGDK Recommendations for Reporting 
Serious Adverse Events .................................................................................88
Attachment 7.
Protocol I5B-JE-JGDK Creatinine Clearance Formula...................................89
Attachment 8.
Protocol I5B-JE-JGDK NCI-CTCAE (v4.03) Infusion-Related 
Reactions.......................................................................................................90
Attachment 9.
Protocol I5B-JE-JGDK (b) Amendment Summary
A Phase 1 Study of Olaratumab in Japanese Patients with Advanced 
Soft Tissue Sarcoma or Advanced Solid Tumors ...........................................91


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4.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibodies
AE
Adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
Akt
protein kinase B
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC[0-96hr]
area under the concentration-time curve from time zero to hour 96
AUC[0-168hr]
area under the concentration-time curve from time zero to hour 168
AUC(0-tlast)
area under the concentration-time curve from time zero to the last time point with a 
measurable 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).
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed concentration
Cmax,ss
maximum observed concentration at steady state
Cmin
minimum observed concentration
Cmin,ss
minimum observed concentration at steady state
CL
clearance
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.


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complaint
Any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, purity, durability, reliability, safety, effectiveness, or performance of a 
drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results are 
accurate.  Confirmation will either occur immediately after initial testing or will require 
that samples be held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results.
CR
complete response
CRF/eCRF
case report form/electronic case report form:  Sometimes referred to as clinical report 
form, a printed or electronic form for recording study participants’ data during a clinical 
study, as required by the protocol.
CRP
clinical research physician
CRS
clinical research scientist
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
Patients who are enrolled in the trial are those who were confirmed to be eligible and 
have been assigned to a treatment.  
enter
Patients who are entered in the trial are those who have signed the informed consent 
form directly or through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board:  /A board or committee (institutional, 
regional, or national) composed of medical and nonmedical members whose 
responsibility is to verify that the safety, welfare, and human rights of the patients 
participating in a clinical study are protected.
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factors
HBV
hepatitis B virus


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HCV
hepatitis C virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IgG1
immunoglobulin G subclass 1
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.
INR
international normalized ratio
interim analysis
An analysis of clinical study data that is conducted before the final reporting database is 
authorized for data lock.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
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.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LVEF
left ventricular ejection fraction
MAPK
mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities
monitor
A person responsible for ensuring the investigator site complies with the monitoring 
plan, applicable local SOPs (if any), and global Medical SOPs.  Monitors are trained on 
the investigational product(s), the protocol, informed consent document, any other 
written information provided to subjects, relevant SOPs, International Conference on 
Harmonisation Good Clinical Practice guidelines (ICH-GCP), and all applicable laws 
(for example, privacy and data protection) and regulations.  
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NOAEL
no-observable-adverse-effects levels


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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.
PDGF
platelet-derived growth factor
PDGFRα
platelet-derived growth factor receptor α
PDGFRβ
platelet-derived growth factor receptor β
PK
pharmacokinetic(s)
PR
partial response
PS
performance status
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
SAC
Safety Assessment Committee
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical trial.  
screen failure
A patient who does not meet one or more criteria required for participation in a trial
SD
Stable disease
sponsor
The party who takes responsibility for the initiation, management and/or financing of a 
clinical study.
STS
soft tissue sarcoma
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TEAE
treatment-emergent adverse event
TK
toxicokinetic(s)
TPO
third-party organization
ULN
upper limit of normal
V
volume of distribution
VEGF
vascular endothelial growth factor


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VEGFR
vascular endothelial growth factor receptor


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A Phase 1 Study of Olaratumab in Japanese Patients with 
Advanced Soft Tissue Sarcoma or Advanced Solid Tumors
5.
Introduction
5.1.
Rationale and Justification for the Study
The term soft tissue sarcoma (STS) refers to a group of histologically distinct subtypes of cancer 
originating in the connective tissue. Soft tissue sarcoma is part of a rare and heterogeneous 
group of tumors that accounts for less than 1% of all adult cancers, and encompasses over 
50 different subtypes.  In Japan, the annual incidence rate is approximately 3 per 100,000
(Nakamura 2011). The most common types of STS in adults in Japan are malignant fibrous 
histiocytoma (26%), liposarcoma (23%), synovial sarcoma (9.7%), rhabdomyosarcoma (6.9%), 
and malignant peripheral nerve sheath tumor (6.8%) (JOA 2002). These tumors exhibit a wide 
range of differing behaviors and underlying molecular pathologies, and can arise anywhere in the 
body.  The most common sites are lower limbs (26%), retroperitoneal and intraperitoneal (25%), 
internal organs including gastrointestinal stromal tumor (25%), upper limbs (11%), thorax (8%), 
and head and neck (5%) (JOA 2012).  
Surgical resection, sometimes in combination with adjuvant radiotherapy is critical to the 
management of locoregional disease. In the locally advanced or metastatic disease settings, 
chemotherapy in this setting is essentially palliative in intent; doxorubicin is the standard of care 
for the majority of such patients, with an associated response rate of 10%-30% (D'adamo et al.
2005).  Some trials have investigated a variety of combination chemotherapeutic regimens 
(variously employing ifosfamide, doxorubicin, vincristine, cisplatin, and dacarbazine, among 
others), which in some cases have yielded improvements in response rate, but have had little 
impact on survival.  In Japan, doxorubicin monotherapy is preferred over combination use for 
unresectable or metastatic disease based on the result of meta-analysis (Bramwell et al. 2000),
and the addition of ifosfamide to doxorubicin is used as neo-adjuvant/adjuvant settings (Iwamoto 
and Tanaka 2012).  However, these treatments have reached a therapeutic plateau and new 
therapies able to improve treatment outcome are required.
Platelet-derived growth factor receptor α (PDGFRα) is a receptor tyrosine kinase that can be 
activated by platelet-derived growth factor (PDGF)-AA, -AB, -BB, and -CC (Heldin et al. 1998; 
Li et al. 2000).  These growth factors are dimeric molecules composed of disulfide-linked 
polypeptide chains that bind to 2 receptors simultaneously and induce receptor dimerization, 
autophosphorylation, and intracellular signaling.  A number of observations suggest that the 
PDGFRα plays an important role in tumorigenesis and tumor progression.  Many cancer types 
have been shown to consistently express PDGFRα on tumor tissues, including osteosarcoma,
chondrosarcoma, prostate cancer, breast cancer, ovarian cancer, glioma, melanoma, bone cancers 
and others.  In malignant disease, the PDGF/PDGFRα axis is effective in promoting tumor 
growth and proliferation through both autocrine and paracrine mechanisms.  PDGFRα is 
expressed on stromal cells, as well as on the cancer cells themselves, within certain tumors.  
Furthermore, studies have shown that PDGF/PDGFRα signaling affects tumor vasculature 


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through paracrine mediation of vascular endothelial growth factor (VEGF) production (de Jong 
et al. 1998; Ostman et al. 2001; Zhang et al. 2003; Shah et al. 2010). In addition to being 
present, PDGFRα has been shown to be highly phosphorylated in a subset of lung cancer cell 
lines and tumors of patients (Rikova et al. 2007).  Due to its potential broad role in 
transformation, metastasis, and progression, PDGFRα could be an important therapeutic target 
for cancer treatment.  Neutralizing antibodies to PDGFRα which have been already reported
(LaRochelle et al. 1993; Lokker et al. 1997) inhibited the growth in vitro of PDGFRα-positive 
cells induced to overexpress PDGF (LaRochelle et al. 1993).  
Olaratumab (LY3012207) is a recombinant human monoclonal antibody of the immunoglobulin 
G subclass 1 (IgG1), which specifically targets the human PDGFRα.  The antibody possesses 
high-affinity binding for PDGFRα and blocks PDGF-AA, -BB, and -CC ligands from binding to 
the receptor.  As a result, olaratumab inhibits ligand-induced receptor autophosphorylation and 
phosphorylation of the downstream signaling molecules protein kinase B (Akt) and mitogen-
activated protein kinase (MAPK).  Olaratumab monotherapy inhibits tumor cell growth response 
to PDGF signaling and survival in multiple tumor types both in vivo and in vitro.  Furthermore, 
in human tumor xenograft models including soft tissue sarcoma (leiomyosarcoma), olaratumab
demonstrates antitumor activity as a single agent and in combination with doxorubicin (Loizos et 
al. 2005; data on file).  Based on this antitumor cell activity in tumor cell models, olaratumab has 
been advanced into human clinical studies.
A multicenter, open-label, dose escalation Phase 1 study (Study CP15-0601; I5B-IE-JGDC
[JGDC]) of olaratumab, which has been conducted in patients with advanced solid tumors and 
lymphomas who no longer respond to standard therapy or for whom no standard therapy is 
available, has shown a favorable short- and long-term toxicity profile.  No dose-limiting 
toxicities (DLTs) were observed in 4, 8, or 16 mg/kg weekly or in 15 or 20 mg/kg every other 
week.  The most common adverse events (AEs), regardless of severity, experienced by ≥20% of 
patients were fatigue (42.1%), constipation (36.8%), diarrhea (26.3%), nausea (26.3%), and 
pyrexia (26.3%) (Chiorean et al. 2014).  Grade 3 AEs were few and no Grade 4 or 5 events were 
reported.  
A Phase 1 study for solid tumors in Japanese patients (Study CP15-0907; I5B-IE-JGDF [JGDF]) 
also demonstrated a well-tolerated safety profile in olaratumab monotherapy administered every 
2 weeks (20 mg/kg) or on Days 1 and 8 every 3 weeks (10 or 15 mg/kg) without any DLTs (Doi
et al. 2014).  
A Phase 1b/2 randomized study evaluating the efficacy of doxorubicin with or without 
olaratumab in the treatment of advanced STS (Study CP15-0806; I5B-IE-JGDG [JGDG]) is 
currently ongoing. A preplanned efficacy interim analysis has demonstrated prolonged 
progression-free survival and overall survival when olaratumab (15 mg/kg on Days 1 and 8 of 
each 21-day cycle) was given with doxorubicin (75 mg/m2 on Day 1 of each cycle).  The toxicity 
profile of olaratumab combined with doxorubicin was acceptable.  
In the olaratumab plus doxorubicin treatment arm, there was a slight increase in known 
doxorubicin-related toxicities events such as nausea, vomiting, and neutropenia.  No difference


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in febrile neutropenia or major gastrointestinal toxicities was observed and the overall incidence 
of life-threatening toxicities was similar between the treatment and control arms. Also, increased 
cardiotoxicity (14.1% in the olaratumab plus doxorubicin arm vs. 9.2% in the doxorubicin arm) 
was observed. However, this was in line with what could be expected given the higher median 
number of cycles of doxorubicin received by patients in the treatment arm.  
Finally, the scientific justification of investigating olaratumab combined with doxorubicin in 
advanced STS is compelling based on the role of PDGFRα in tumor cell survival and 
proliferation and the evidence of antitumor effects in tumor xenograft models. The recent 
(Studies JGDC and JGDF) and ongoing (Study JGDG) clinical trials have shown a well-tolerated
safety profile in olaratumab monotherapy and in combination with doxorubicin.  Furthermore, 
the preliminarily observed prolongation of progression-free survival and overall survival in 
Study JGDG provides additional justification to conduct this study (Study I5B-JE-JGDK
[JGDK]).  Part A of Study JGDK is designed to evaluate the safety and tolerability of olaratumab
when administered in combination with doxorubicin to Japanese patients with advanced solid 
tumors, especially advanced STS.  This safety information will allow Japanese patients to 
participate in the following global Phase 3 study.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.
5.2.
Rationale for Amendments
5.2.1. Rationale for Amendment (a)
The study was amended to add Cohort 3 in Part A to confirm the safety and tolerability of 
20 mg/kg of olaratumab as the loading dose (Cycle 1), followed by 15 mg/kg in subsequent 
cycles, and 75 mg/m2 of doxorubicin in every cycle.
5.2.2. Rationale for Amendment (b)
The study was amended to reduce unnecessary interventions and physical or non-physical burden 
for the patients after enough data was obtained to assess the primary objective and the secondary 
objectives.
5.3.
Objectives
5.3.1. Primary Objective
The study is divided into 2 parts:
The primary objective of Part A is to evaluate the safety and tolerability of olaratumab in 
combination with doxorubicin in Japanese patients with advanced solid tumors, especially STS.
The primary objective of Part B is to evaluate the pharmacokinetics (PK) profile of olaratumab
in Japanese patients with advanced solid tumors.


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5.3.2. Secondary Objectives
The secondary objectives of Part A are:  

To evaluate the PK of olaratumab and doxorubicin

To evaluate the immunogenicity of olaratumab

To document any antitumor activity of olaratumab in combination with doxorubicin
The secondary objectives of Part B are:  

To evaluate the safety and tolerability of olaratumab

To evaluate the immunogenicity of olaratumab

To document any antitumor activity of olaratumab
5.3.3. Exploratory Objective
The exploratory objective of Part A and Part B is to evaluate potentially relevant biomarkers 
related to the mechanism of olaratumab, the PDGF signaling pathway, and the pathobiology of
cancer.
5.4.
General Introduction to Olaratumab
Olaratumab is a fully humanized monoclonal IgG1 antibody and inhibits PDGF ligands binding 
to the extracellular domain of PDGFR, resulting in inhibition of phosphorylation of the 
downstream signaling molecules such as Akt and MAPK, and has demonstrated activity in vitro 
and in vivo systems on cancer models known to be driven by a PDGF-PDGFRα autocrine loop 
(Gerber et al. 2012).  
As of 31 March 2014, olaratumab has been administered to 461 patients in 8 clinical studies:  
4 studies in monotherapy setting and 4 studies in combination with other anticancer agents.  The 
primary tumor types in the clinical studies include solid tumors (2), ovarian cancer (1), non-
small-cell-lung cancer (1), castration refractory prostate cancer (1), STS (1), glioblastoma
multiforme (1), and gastrointestinal stromal tumors (1).  As of 31 March 2014, a total of 129 
patients with advanced STS have been treated in Study JGDG and interim safety data is 
available.  The 129 patients in Study JGDG are comprised of 64 patients in Arm A (olaratumab 
plus doxorubicin) and 65 patients in Arm B (doxorubicin monotherapy).  Overall, the frequency 
of any AEs was similar across the 2 arms (Arm A:  98.4%; Arm B:  98.5%).  The cardiotoxicity 
increased, but was in line with what could be expected with the higher cumulative dose of 
doxorubicin in Arm A.
More information about the known and expected benefits, risks, and reasonably anticipated 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 adverse events (SAEs) expected in the study population 
independent of drug exposure and that will be assessed by the sponsor in aggregate, periodically 
during the course of the study, may be found in Section 6 of the IB.


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5.4.1. Mechanism of Action and In Vitro/In Vivo Activity
Unlike some tyrosine-kinase inhibitors which are anticancer agents that target PDGF/PDGFR 
signaling simultaneously with other targets such as c-kit, vascular endothelial growth factor 
(VEGF), and VEGF receptor (VEGFR), olaratumab is specific to PDGFRα and binds with high 
affinity (Kd:  0.04nM).  Preclinical studies conducted with olaratumab as a single agent or in 
combination with cytotoxic chemotherapeutic agents have demonstrated antimitogenic activity in 
cell lines and antitumor growth activity in human xenografts models.  Olaratumab blockade of 
PDGFRα function also inhibited skeletal metastases by human prostate cancer cells in a mouse 
model.  Olaratumab does not cross-react with PDGFRβ or with murine PDGFRα.  Therefore, in 
vivo experiments in mice bearing human tumor xenografts treated with olaratumab may 
underestimate the potential anticancer activity of olaratumab, because olaratumab cannot react 
with mouse stroma or regulate cancer-associated vasculature.  In humans, olaratumab is expected 
to target and inhibit PDGFRα expressed in both tumor and stroma, thereby potentially inhibiting 
tumor, stroma, and vasculature (Shah et al. 2010).  
5.4.2. Nonclinical Pharmacokinetics
The PK profile of olaratumab was characterized in mice, and the PK and toxicokinetics (TK) 
were determined as part of the monkey toxicology studies.  The PK and TK of olaratumab in 
mice and monkeys were generally consistent with that expected for a monoclonal antibody, 
characterized by a moderate elimination half-life (t1/2) and clearance (CL), and a volume of 
distribution (V) approximately equal to the vascular space.  Increases in exposure were generally 
proportional to or greater than proportional to the increase in dose.  Accumulation of olaratumab 
was evident after repeated dosing in monkeys.  
The formation of antidrug antibodies (ADA) was assessed in all monkey studies.  Attempts to 
evaluate the formation of ADA were often confounded by high circulating concentrations of 
olaratumab; however, ADA were measurable in several individual animals following repeated 
dosing in the toxicology studies, particularly in the low- and mid-dose groups.  The predictive 
value of this nonclinical finding relative to the potential occurrence of immunogenicity in 
humans is unclear.
The nonclinical distribution of olaratumab has not been assessed because monoclonal antibodies 
are largely confined to the extracellular space.  Similarly, metabolism studies of olaratumab have 
not been conducted since the catabolism of antibodies by mammalian systems is well 
understood.  
5.4.3. Nonclinical Toxicology
A standard nonclinical toxicology program was conducted to assess the safety of olaratumab.  
The key studies using cynomolgus monkeys assessed the toxicity, TK, and development of 
antibodies to olaratumab and their potential impact on TK after administration by intravenous
infusion over 5 weeks (4 doses), or 13 and 39 weeks with weekly dosing, followed by recovery 
periods of 7 or 8 weeks.  Cardiovascular safety parameters (blood pressure, heart rate, and 


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electrocardiogram [ECG]) and neurological effects based on clinical observations were evaluated 
in the toxicity studies.  
No clear olaratumab treatment-related adverse effects were noted in the toxicity studies.  A 
single female treated for 39 weeks with 75 mg/kg was noted with mildly to moderately increased 
alanine aminotransferase (ALT), minimal individual cell necrosis, and moderate infiltrates in the 
liver, but this effect was not considered adverse or clearly attributable to treatment.  Therefore, 
the no-observable-adverse-effects levels (NOAEL) were established as the highest test doses, 
50 mg/kg in the 5-week study and 75 mg/kg in the 13- and 39-week studies.  Antidrug antibodies
were measurable in several animals following repeated dosing in the studies, mainly at the low-
and mid-dose levels.
Development and reproductive toxicity studies of olaratumab in animals have not yet been 
conducted.  For a monoclonal antibody, genotoxicity studies are not relevant, and were therefore 
not conducted for olaratumab.
In summary, weekly administration of olaratumab by intravenous infusion for up to 39 weeks was 
well tolerated and not associated with the development of any adverse effects.  The monkey 
serum minimum observed concentration (Cmin) (1164 μg/mL) at the NOAEL (75 mg/kg) in the 
39-week study was approximately 4.5-fold greater than the threshold Cmin (260 μg/mL) believed 
to be needed for antitumor activity based on tumor xenograft models.  The area under the 
concentration-time curve from time zero to hour 168 (AUC[0-168hr]) (284976 hr•μg/mL)
following the last infusion of 75 mg/kg in the 39-week study was approximately 16.5-fold greater 
than exposures of olaratumab that are anticipated to be needed for antitumor activity in humans 
based on animal tumor models (area under the concentration-time curve from time zero to 
hour 96; AUC[0-96hr] = 17184 hr•μg/mL).  Therefore, the cynomolgus monkey study adequately 
evaluated the safety of olaratumab at exposures that appreciably exceed those anticipated to be 
evaluated and effective in humans with advanced cancer.
5.4.4. Olaratumab Pharmacokinetics
Olaratumab serum concentration data are currently available from 2 Phase 1 studies, JGDC and 
JGDF, as well as from 5 Phase 2 studies, I5B-IE JGDA (JGDA), I5B-IE-JGDB (JGDB), I5B-IE-
JGDE (JGDE), JGDG and I5B-IE-JGDH (JGDH).  The serum concentration data available for 
Studies JGDA, JGDC, and JGDF were, however, generated using an enzyme-linked 
immunosorbent assay that was not fully validated.  The quantitative PK results derived from the 
aforementioned 3 studies can therefore only be used as supporting evidence and will only be 
discussed briefly in the interest of completeness.  The human serum assay has been subsequently 
optimized and validated and is being used to support all ongoing and future studies, including 
Study JGDK.  Pharmacokinetic data were obtained using this validated serum assay from 4 
Phase 2 studies, including Study JGDG.
In Study JGDG, olaratumab was tested at the dose of 15 mg/kg administered as a 60-minute 
infusion on Day 1 and 8 of a 21-day cycle and was tested in combination with doxorubicin in 
patients with STS.  Steady state seemed to be reached during Cycle 3, and maximum observed 
concentration at steady state (Cmax,ss) and minimum observed concentration at steady state 


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(Cmin,ss) ranged from 341 to 411 g/mL and from 113 to 121 g/mL, respectively, across Cycle 
3 to 6.  A mean t1/2 estimate of 6.7 days was obtained from 7 subjects after the second dose of 
Cycle 1.  Individual t1/2 estimates of 14.4 and 6.7 days were obtained after the second dose of 
Cycle 3.  It should be pointed out that the t1/2 estimates reported here are likely to be dependent 
on the duration of the sampling time, which never exceeds 168 and 336 hours after the first and 
second dose of each cycle, respectively.
Pharmacokinetic data in other Phase 2 studies may be found in Section 6 of the IB. 
The PK of olaratumab in serum had been previously studied in patients with advanced solid 
tumors in the Phase 1 studies: JGDC (US patients) and JGDF (Japanese patients).  Olaratumab 
was tested at various doses ranging from 4 to 20 mg/kg administered as 1-hour intravenous 
infusions once a week, once every 2 weeks, or on Day 1 and Day 8 of a 21-day cycle.  The 
concentration-time profile of olaratumab in serum following a single infusion and multiple 
infusions administered either once a week or once every 2 weeks in Studies JGDC and JGDF 
suggest that the PK of olaratumab is similar between US and Japanese patients.  As discussed 
previously, PK data in Studies JGDC and JGDF were obtained with an assay that was not fully 
validated and should be interpreted with caution.
5.5.
Rationale for Selection of Dose
Olaratumab 15 mg/kg administered intravenously on Days 1 and 8 of a 21-day cycle was 
selected as the dosage for this study (except for Cohort 3 in Part A) based on interim efficacy and 
safety data from Study JGDG, an open-label Phase 2 study, where a combination of 15 mg/kg 
olaratumab administered intravenously on Days 1 and 8 and 75 mg/m2 doxorubicin administered 
intravenously on Day 1 of a 21-day cycle was tested versus doxorubicin alone at a dose of 
75 mg/m2 in patients with metastatic or locally advanced STS that was not amenable to treatment 
with surgery or curative radiotherapy.  
Interim survival data from Study JGDG show the combination of olaratumab 15 mg/kg with
doxorubicin 75 mg/m2 provides a significant benefit compared to single-agent doxorubicin in
patients with advanced or metastatic STS without an increase in serious toxicity. A matched
case-control analysis was performed per exposure quartiles based on the trough olaratumab 
serum concentration at the end of Cycle 1.  The bottom quartile (Cmin,1 < 61 μg/mL, N=15) tend 
to experience disease progression within the first 2 cycles of treatment, and unlike the other 
quartiles, did not show PFS or OS improvement. Interim results from a population PK (PopPK) 
model performed on PK data from 4 studies (JGDB, JGDE, JGDG, and JGDH) indicate that 
steady-state olaratumab serum levels are not achieved until Cycle 3. Together, these findings 
suggest that clinical outcome for the lowest exposure quartile could be improved if patients were 
able to achieve therapeutic steady-state serum concentration levels (Cmin,1 ≥ 61 μg/mL) of 
olaratumab earlier in treatment, before disease progression.  
Simulations performed with the current PK model indicate that loading doses of 20 mg/kg
administered on Day 1 and Day 8 of Cycle 1 would allow steady-state olaratumab serum levels
to be achieved with the first administration and would minimize the number of patients whose
Cmin,1 falls below 61 μg/mL during the first 2 cycles. Additionally, a dose of 20 mg/kg


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olaratumab administered on Day 1 and Day 8 during the first cycle, followed by 15 mg/kg
administered on Day 1 and Day 8 of all the subsequent cycles, is predicted to yield maximum
serum concentrations within the overall range observed in Study JGDG. Therefore, olaratumab
safety risks related to high serum concentrations or exposure using this loading dose approach
are expected to be similar to those in Study JGDG.
The dosing strategy adopted for Cohort 3 of Part A of this study therefore consists of a loading 
cycle wherein a dose of 20 mg/kg will be administered on Day 1 and Day 8, followed by 15 
mg/kg administered on Day 1 and Day 8 of every subsequent cycle. 
Doxorubicin 25 mg/m2 administered on Day 1, Day 2, and Day 3 of a 21-day cycle (3
intravenous administrations/cycle) was selected for Cohort 1 in Part A based on the approved 
dose in Japan.  In addition, doxorubicin 75 mg/m2 administered on Day 1 (single intravenous 
administration/cycle) of a 21 day-cycle was selected for Cohort 2 and 3 in Part A based on the 
interim efficacy data of Study JGDG and will be used in the upcoming Phase 3 study.
In Japan, doxorubicin monotherapy is most commonly used as first-line treatment for 
unresectable or metastatic STS patients. Doxorubicin treatment for STS was approved by Public 
Knowledge-Based Submission in Japan in February 2005.  The label dosage of doxorubicin is 
20-30 mg/m2 for 3 consecutive days with a maximum cumulative dose of 500 mg/m2 due to risk 
of myocardial damage. The globally approved dose, except in Japan, of doxorubicin is 
75 mg/m2 (single intravenous administration/cycle); however, the single intravenous 
administration/cycle of doxorubicin is used for patients in Japan clinical practices.
Interim data from Study JGDG, where olaratumab at the dose of 15 mg/kg administered on Days 
1 and 8 of a 21-day cycle was evaluated in combination with doxorubicin at a dose of 75 mg/m2
on Day 1 (single intravenous administration/cycle), indicated efficacy in patients with metastatic 
or locally advanced STS that is not amenable to treatment with surgery or curative radiotherapy.
Given the favorable safety and clinical activity data observed so far in Study JGDG and 
simulations performed with the current PK model, the doses of 15 or 20 mg/kg olaratumab and 
25 mg/m2 on Day 1, 2, and 3 or 75 mg/m2 on Day 1 of a 21-day cycle doxorubicin were selected 
for Study JGDK.


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6.
Investigational Plan
6.1.
Study Population
All patients meeting the eligibility requirements will be considered for enrollment.  The 
investigators or the sponsor will not grant exceptions to eligibility criteria.  Individuals who do 
not meet the criteria for participation in this study (screen failure) may not be rescreened; 
however, in case that the sponsor and the investigators judge it appropriate (ie, borderline screen 
failure), retest may be allowed.  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]
Part A
Have histological or cytological evidence of a diagnosis of advanced or metastatic 
solid tumor, especially STS (other than Kaposi’s sarcoma and gastrointestinal 
stromal tumors), which is not amenable to treatment with surgery or radiotherapy. 
The patient must be, in the judgment of the investigator, an appropriate candidate 
for olaratumab and doxorubicin therapy. Patients other than STS patients must be 
an appropriate candidate for olaratumab therapy in combination with doxorubicin
after available standard therapies have failed to provide clinical benefit for their 
disease.
Part B
Have histological or cytological evidence of a diagnosis of solid tumor that is 
advanced or metastatic. The patient must be, in the judgment of the investigator, 
an appropriate candidate for olaratumab monotherapy after available standard 
therapies have failed to provide clinical benefit for their disease.
[2]
Have the presence of measurable or nonmeasurable disease as defined by the 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 
2009). 
[3]
Are ≥20 years of age.
[4]
Have given written informed consent prior to any study-specific procedures.
[5]
Have adequate organ and coagulation function, including:
a.
Hematologic:  Absolute neutrophil count (ANC) ≥1.5 × 109/L, platelets 
≥100 × 109/L, and hemoglobin ≥9 g/dL.  
b. Hepatic:  Bilirubin 1.5 times the upper limit of normal (ULN) and ALT and 
aspartate aminotransferase (AST) 3.0 ×ULN. 
c.
Renal:  Serum creatinine 1.5 ×ULN.  If creatinine is above the ULN, creatinine 
clearance is ≥45 mL/min (Attachment 7).
d. Coagulation:  international normalized ratio (INR) ≤1.5 and prothrombin time 
≤1.5 ×ULN, if not receiving anticoagulation therapy.  Patients on full dose 
anticoagulation must be on a stable dose of oral anticoagulant or low molecular 


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weight heparin, and if on warfarin must have therapeutic INR and have no active 
bleeding (defined as within 14 days prior to first dose of study medication) or 
pathological condition that carries a high risk of bleeding (eg, tumor involving 
major vessels or known varices)
[6]
Have an ECOG PS of ≤1.
[7]
Have discontinued previous treatments for cancer and recovered from the acute 
effects of therapy.
[8]
(Part A only)
Have a prestudy echocardiogram with an actual left ventricular ejection fraction 
(LVEF) ≥50%, within 21 days prior to first dose of study medication.
[9]
All patients agree to use a reliable method of birth control and to not donate sperm 
during the study and for at least 3 months following last dose of study drug.
Acceptable methods of birth control include vasectomy (pipe cut), tubal ligation,
barrier method (eg, condoms or pessary) with spermicide, an intrauterine device
which has been in place for at least 3 months before first dose of study drug, or the 
oral contraceptive pill taken for at least 3 months before first dose of study drug.
[10]
Female patients must either be women not of child-bearing potential due to surgical 
sterilization (at least 6 weeks postsurgical bilateral oophorectomy with or without 
hysterectomy or tubal ligation) confirmed by medical history, or menopause.
or
women of child-bearing potential who test negative for pregnancy within 7 days 
before the first dose of study drug based on serum or urine pregnancy test and agree 
not to breast feed during the study and for 3 months following the last dose of the 
study drug(s)
Menopausal women include women with either
a.
spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa, and not taking medications during the 
amenorrhea that induced the amenorrhea (eg, oral contraceptives, hormones, 
gonadotropin releasing hormone, antiestrogens, selective estrogen receptor 
modulators, or chemotherapy).
or
b. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone 
level greater than 40 mIU/mL.
[11]
Have an estimated life expectancy of ≥3 months in the judgment of the investigator.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[12]
Have received treatment within 21 days of the initial dose of study drug with an 
investigational product or non-approved use of a drug or device (other than the study 
drug/device used in this study) for non-cancer indications or are concurrently enrolled 


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in any other type of medical research judged not to be scientifically or medically 
compatible with this study.
[13]
(Part A only)
Have received prior treatment with doxorubicin, daunorubicin, idarubicin, and/or 
other anthracyclines and anthracenediones (ie, mitoxantrone).
[14]
(Part A only)
Have received prior radiation therapy to the mediastinal/pericardial area.
[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.
[16]
Have an elective or a planned major surgery to be performed during the course of the 
study.
[17]
Have an uncontrolled intercurrent illness including, but not limited to, symptomatic 
congestive heart failure > class II of the New York Heart Association guideline, 
severe myocardial insufficiency, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
[18]
Have unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction 
6 months prior to study entry.
[19]
Have a known allergy to any of the treatment components.
[20]
Have a history of allergic reactions attributed to compounds of chemical or biologic 
composition similar to that of olaratumab.
[21]
Have a known active fungal, bacterial, and/or known viral infection, including:  
a.
human immunodeficiency virus (screening is not required);
b. hepatitis A virus (screening is not required);
c.
hepatitis B virus (HBV) or hepatitis C virus (HCV) (screening is required – a 
documentation of a negative test result within 6 months prior to enrollment must be 
available for HBV [see the details below*] and HCV [antibodies or ribonucleic 
acid according to local standard]).
* have evidence of, or test positive for, HBV.  A positive test for HBV is defined 
as:
positive for hepatitis B surface antigen
or 
positive for anti-hepatitis B core antibody and positive for HBV deoxyribonucleic 
acid (DNA) 
or
positive for anti-hepatitis B surface antibody and positive HBV DNA.
[22]
Have a corrected QT interval of >470 msec on screening ECG
[23]
Have a second primary malignancy that, in the judgment of the investigator and 
sponsor, may affect the interpretation of results.


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6.2.
Summary of Study Design
This is a multicenter, nonrandomized, open-label, Phase 1 study. The study is divided into 2 
parts, Part A and Part B.  Part A and Part B will be conducted in parallel. The DLT evaluation of 
Cohort 1, 2 and 3 in Part A will be performed independently.  The study design is summarized in
Figure JGDK.6.1.
Refer to Attachment 1 for the Study Schedule.
Abbreviations:  ECOG = Eastern Cooperative Oncology Group; PS = performance score; D= day; N = number 
of patients; LVEF = left ventricular ejection fraction
a
For patients whose cumulative dose of doxorubicin does not reach 500 mg/m2 during the first 6 cycles due 
to dose reductions or omissions, doxorubicin can be administrated up to 500 mg/m2 on Cycle 7 and beyond, 
at the discretion of the investigator.
b
Refer to Section 7.2.1.4 for the timing to open Cohort 2 and 3. 
Figure JGDK.6.1.
Illustration of study design for Protocol I5B-JE-JGDK.


I5B-JE-JGDK(b) Phase 1 Oncology Protocol
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Part A is designed to evaluate the safety and tolerability of olaratumab in combination with 
doxorubicin in Japanese patients with advanced solid tumors, especially advanced STS.
Part A consists of 3 cohorts (Figure JGDK.6.1).  At least 6 patients will be assigned to Cohort 1.  
Similarly, at least 6 patients will be assigned to Cohort 2 and 3: 

Cohort 1:  15 mg/kg of olaratumab on Day 1 and Day 8, and 25 mg/m2 of doxorubicin on 
Day 1, Day 2, and Day 3 up to 6 cycles or until when cumulative dose of doxorubicin 
reaches 500 mg/m2, whichever comes later, every 21 day-cycle.

Cohort 2:  15 mg/kg of olaratumab on Day 1 and Day 8, and 75 mg/m2 of doxorubicin on 
Day 1 up to 6 cycles or a cumulative dose of doxorubicin reaches 500 mg/m2, whichever 
comes later, every 21 day-cycle.

Cohort 3: 20 mg/kg loading dose of olaratumab on Day 1 and Day 8 in Cycle 1, followed 
by 15 mg/kg on Day 1 and Day 8 in subsequent cycles, and 75 mg/m2 of doxorubicin on 
Day 1 up to 6 cycles or a cumulative dose of doxorubicin reaches 500 mg/m2, whichever 
comes later, every 21 day-cycle.
An overview of the study design for Part A is shown in Figure JGDK.6.2.
Abbreviations:  DLT = dose-limiting toxicity; IC = informed consent; n = number; N = no; Y = yes.
Figure JGDK.6.2.
Illustration of study schedule in Part A.
Part B is designed to evaluate the PK profile of olaratumab monotherapy in Japanese patients 
with advanced solid tumors. This part consists of 1 dose regimen (Figure JGDK.6.1). At least 6 
patients will be assigned to receive olaratumab monotherapy treatment:  15 mg/kg of olaratumab
on Day 1 and Day 8 every 21 day-cycle.
An overview of the study design for Part B is shown in Figure JGDK.6.3.




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
Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
the investigator/physician decides that the patient should be discontinued from the 
study or study drug(s)
o
if the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for 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 
GCP

The patient has evidence of objective progressive disease by radiological assessments 
(RECIST version 1.1) or deteriorating clinical symptoms of progressive disease.  
(Patients with objective progressive disease can be treated continuously based on the 
clinical symptoms at the discretion of the investigator.)

The patient experiences unacceptable toxicity.

The patient is significant noncompliant with study procedures and/or treatment 
(Section 7.6).

The patient becomes pregnant.  

Both doxorubicin and olaratumab in Part A or olaratumab in Part B are discontinued
(Section 7.2.2.1).
The reason 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 case 
report form (CRF).  Patients who discontinue will have follow-up procedures performed as 
shown in the Study Schedule (Attachment 1).
6.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review 
board/institutional review board (ERB/IRB) of the study site judges it necessary for any 
scientific, medical, safety, regulatory, ethical, or other reasons consistent with applicable laws, 
regulations, and GCP.
6.3.3. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges it necessary for any scientific, medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.


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7.
Treatment
7.1.
Materials and Supplies
Olaratumab will be supplied as a sterile preservative-free solution for intravenous infusion in 
single-use vials containing 500 mg/50 mL of olaratumab (10 mg/mL).  Olaratumab is formulated 
in 10 mM histidine, 100 mM glycine, 50 mM sodium chloride, 75 mM mannitol, and 0.02% 
polysorbate-20, pH 5.5.  All excipients used in the formulation of olaratumab drug product are of 
pharmacopeia grade.  Each single-use vial of olaratumab is packaged in a 50-mL nominal 
volume United States Pharmacopeia type I glass vial, stoppered with a FluroTec® coated latex-
free stopper, and sealed with an aluminum seal and a flip-off cap.
Olaratumab must be stored under refrigeration at 2°C to 8°C with protection from light.  The 
detailed information is described in a separate procedural manual. 
For doxorubicin, investigators should consult the separate procedural manual that will be 
provided by sponsor or its representative/delegate for complete packaging and labeling 
information.  Doxorubicin hydrochloride will be supplied as one of clinical study materials by 
Lilly. 
Clinical study materials will be labeled according to the regulatory requirements. 
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 site personnel,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensation and collection, and

returning all unused medication to Lilly or its designee at the end of the study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
7.2.1. Dosing Schedule
The dosing schedule and mode of administration are summarized in Table JGDK.7.1.




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doxorubicin are administered, doxorubicin will be administered approximately 1 hour after the 
completion of the olaratumab infusion.
If a patient completes 6 cycles, olaratumab monotherapy can be continued in the absence of 
disease progression or other discontinuation criteria.  
If doxorubicin is discontinued (eg, for reasons of toxicity), olaratumab monotherapy can be 
continued.  For patients who discontinue olaratumab during the first 6 cycles of treatment, 
doxorubicin may be continued (for up to 6 cycles or up to 500 mg/m2 at the discretion of the 
investigator).  
The dose of doxorubicin will be calculated using body surface area and is dependent upon the 
patient’s baseline height in centimeters.  A change of weight ≥10% from baseline will result in 
re-calculation of doxorubicin dose to be administered based on body surface area. 
7.2.1.3.
Dose-Limiting Toxicity Determination (Part A)
Dose-limiting toxicity is defined as an AE during Cycle 1 (first 21 days from Day 1 in Cycle 1) 
that is possibly related to the study drug(s) (olaratumab and/or doxorubicin) and fulfills any one 
of the following criteria using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) (v4.03):

CTCAE Grade 3 or above nonhematologic toxicity.  Exceptions will be made for:
o
Nausea, vomiting, diarrhea, constipation, or electrolyte abnormality that can be 
controlled with treatment.
o
Fatigue and anorexia.
o
Transient (ie, ≤1 week) Grade 3 elevations of ALT and/or AST without evidence of 
other hepatic injury.

Febrile neutropenia.

Grade 4 anemia.

Grade 4 neutropenia lasting >1 week.

Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia requiring platelet transfusion.

Toxicities which require dose reduction or omission of study drug(s) (olaratumab and/or 
doxorubicin) during Cycle 1.

Any other significant toxicity deemed by the primary investigator and Lilly CRP/clinical 
research scientist (CRS) to be dose limiting (eg, any toxicity that is possibly related to the 
study medication that requires the discontinuation of the patient from the study during 
Cycle 1).
In the event of a Grade 3 or 4 infusion-related reaction, the patient will be replaced; however, the 
event will not be considered a DLT. An evaluable patient for DLT is defined as a patient who 
takes 100% of planned dose in Cycle 1 or a patient who experiences DLT in Cycle 1.  If a patient 
is judged to be non-evaluable for DLT, the patient will be replaced by a new patient.
7.2.1.4.
Initiation of Cohort 2 and 3 in Part A
After first 3 patients from Cohort 1 are enrolled, Cohort 2 can be opened based on safety 
assessment and after discussion between the investigator and the sponsor. In addition, the 


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sponsor should consult with Safety Assessment Committee (SAC) about the appropriateness for 
the timing.  Cohort 3 can be opened after confirmation of tolerability in Cohort 2.
7.2.1.5.
Tolerability Confirmation (Part A)
Tolerability confirmation will be judged if frequency of DLT is confirmed less than 33% 
each of cohort.  At least 6 patients will be enrolled in each cohort and evaluated for DLT 
during Cycle 1 (first 21 days from Day 1 in Cycle 1). 

If 0 or 1 out of 6 evaluable patients experience DLTs, it will be judged that the dose is 
tolerable for Japanese patients.  

If 2 patients experience DLTs at any given dose, the sponsor will examine the safety data 
and consult with the SAC as needed.  The sponsor and the investigators will decide if the 
dose is intolerable or if additional patients will be enrolled to the same dose level for 
further investigation.  

If ≥3 patients experience DLTs at any given dose, it will be judged that the dose is not 
tolerable for Japanese patients.
7.2.2. Dose Adjustments and Delays
7.2.2.1.
Delays and Omission
In the case that olaratumab or doxorubicin cannot be administered due to any reason including 
toxicity, the administration can be delayed beyond the time window within the cycle. If the 
planned administration cannot be conducted within the cycle, the dose is defined as an omission.  
For olaratumab-related toxicity ≥Grade 3 not adequately controlled with appropriate supportive 
care, olaratumab should not be administered until the toxicity becomes ≤Grade 2 or returns to 
pretreatment baseline.
Part A
Illustrative examples of dose adjustments are shown in Attachment 5.
In general, discontinuation of 1 study drug (olaratumab or doxorubicin) will not necessitate 
discontinuation of the other study drug. Dose omission, delays, or discontinuation of olaratumab
due to an olaratumab-related toxicity will not alter those of doxorubicin.  Similarly, olaratumab
therapy should not be altered for doxorubicin-related toxicity. 
Day 1 of Cycles 2 through 7 (the first cycle of olaratumab monotherapy for the patients who 
receive doxorubicin on Cycle 7 or later, by reason that cumulative dose of doxorubicin does not 
reach 500 mg/m2 during the first 6 cycles) is defined as the 21st day after the first doxorubicin 
administration in the previous cycle.  Day 1 of Cycle 8 (the second cycle of olaratumab 
monotherapy for the patients who receive doxorubicin on Cycle 7 or later, by reason that 
cumulative dose of doxorubicin does not reach 500 mg/m2 during the first 6 cycles) or any of the
following cycles is defined as the 21st day after the first olaratumab administration in the 
previous cycle. In the case that olaratumab is delayed or omitted for any reason (including AEs), 
administration of doxorubicin will continue according to the original schedule.  Dose delay of 
olaratumab on Day 8 is allowed until 7 days before Day 1 of the following cycle.  Upon 


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resolution of the event(s) causing the delay and omission in olaratumab administration, 
olaratumab treatment will resume according to a Day 1/Day 8 schedule.  In this study, every 
effort will be made to synchronize administration of olaratumab and doxorubicin according to 
the original dosing schedule; therefore, olaratumab may be administered for up to 4 weeks in a 
row.  
If olaratumab is not administered for more than 21 days from Day 1 of the following scheduled 
cycle due to an olaratumab related-toxicity that does not resolve, or if more than 2 toxicity-
related olaratumab dose reductions are required, treatment with olaratumab will be permanently 
discontinued. 
In the case that doxorubicin is delayed or omitted for any reason (including AEs), administration 
of olaratumab will continue according to the original schedule.  If doxorubicin is not 
administered for more than 21 days from Day 1 of the following scheduled cycle due to a 
doxorubicin-related toxicity that does not resolve, treatment with doxorubicin will be 
permanently discontinued.
If both doxorubicin and olaratumab are discontinued, the patient will be discontinued from the 
study.
Part B
Day 1 of each cycle (Cycle 2 and beyond) is defined as the 21st day after the first olaratumab 
administration in the previous cycle. 
When olaratumab is not administered on the scheduled day, study therapy will resume provided 
resolution of the event(s) causing the delay.  Dose delay of olaratumab on Day 8 is allowed until 
7 days before Day 1 of the following cycle.  If olaratumab is discontinued, the patient will be 
discontinued from the study.
7.2.2.2.
Dose Reductions
Olaratumab
Olaratumab dose can be reduced to a lower dose to either 12 or 10 mg/kg (15 mg/kg if the 
toxicity occurs during Cycle 1 of Cohort 3 in Part A), in accordance with the general guidelines 
shown in Section 7.2.2.3. Once the dose of olaratumab is reduced, re-escalation to the prior dose 
level is not permitted.
Doxorubicin (Part A)
Dose reduction between cycles in Cohort 1, 2 and 3
Doxorubicin dose can be reduced to a lower dose in accordance with the general guidelines 
shown in Section 7.2.2.4.  Once the dose of doxorubicin is reduced, re-escalation to the prior 
dose level is not permitted.
Dose reduction within a cycle in Cohort 1


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In principle, doxorubicin must be administered on Day 1/2/3 consecutively. No breaks between 
these administration days are allowed; that is, dose reduction within a cycle is not 
permitted. The dose must remain constant over these 3 days. In the case that doxorubicin on 
Day 2/3 or Day 3 cannot be administered due to doxorubicin-related toxicity (or any other 
reasons), those administrations should be omitted.  If a patient recovers from the toxicity 
sufficiently, and then doxorubicin administration can be resumed, a lower dose than the prior 
dose level must be selected in accordance with the general guidelines shown in Section 7.2.2.4.
However, if the investigators judge that the dose reduction is unnecessary, the dose does not to 
be reduced in the case that the investigators and the sponsor agree.
7.2.2.3.
Guidelines for Olaratumab Dose Reduction
7.2.2.3.1. Hematologic Toxicity
For Grade ≤2 hematologic toxicity, no dose modification is required.  For Grade 3 toxicity not 
adequately controlled with appropriate supportive care (including hematopoietic growth factors, 
if indicated), olaratumab should not be administered until toxicity ≤Grade 2, or has returned to 
pretreatment baseline; at this time, dose should be reduced to 12 mg/kg and treatment resumed.  
In the case of Grade 4 hematologic toxicity associated with olaratumab, olaratumab should not 
be administered until toxicity is ≤Grade 2, then dose should be reduced to 10 mg/kg and 
treatment should resume.
7.2.2.3.2. Nonhematologic Toxicity
Specific guidelines for dose reduction in patients who experience infusion-related reactions 
while receiving treatment with olaratumab are found in Section 8.1.3.4.
General guidelines for dose modification for other nonhematologic toxicities related to 
olaratumab are shown in Table JGDK.7.2.


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Table JGDK.7.2.
General Guidelines for Dose Modification Due to Nonhematologic
Toxicities Related to Olaratumab
Reaction Grade
Required Dose Modification
Grade 1
No dose modification is required.
Grade 2
At the investigator’s discretion, the patient may continue to receive olaratumab per protocol, 
provided that the event does not pose a serious health risk or is easily treated.  If necessary,
the patient may be dose reduced up to 2 dose reductions (to 12 mg/kg and subsequently to 
10 mg/kg) during the study.
Grade 3
For a Grade 3 toxicity not adequately controlled with appropriate supportive care, the dosing
must not be administered until toxicity is ≤Grade 1 or has returned to pretreatment baseline; 
treatment may then resume at a reduced dose of 12 mg/kg (15 mg/kg if the toxicity occurs 
during Cycle 1 of Cohort 3 in Part A).  If toxicity recurs after therapy resumes, a second 
dose reduction (to 10 mg/kg) is permitted.  If more than 2 toxicity-related olaratumab dose 
reductions are required, treatment with this agent will be permanently discontinued.
Grade 4
The dose must not be administered until dose toxicity is ≤Grade 1 or has returned to 
baseline.  Treatment may then resume with the dose reduced to 10 mg/kg (15 mg/kg if the 
toxicity occurs during Cycle 1 of Cohort 3 in Part A).  If toxicity recurs after therapy 
resumes, olaratumab treatment will be discontinued.
7.2.2.4.
Guidelines for Doxorubicin Dose Reduction (Part A)
7.2.2.4.1. Hematologic Toxicity
Doxorubicin will not be administered if the patient’s ANC is <1000 cells/mm3 or if the platelet 
count is <100,000 cells/mm3.  When necessary, the next treatment cycle should be delayed until 
the ANC is ≥1000 cells/mm3 and the platelet count is ≥100,000 cells/mm3. See Table JGDK.7.3
for doxorubicin dose reduction for neutropenia.
Table JGDK.7.3.
General Guidelines for Doxorubicin Dose Reduction Due to 
Neutropenia
Required Dose Modification
Toxicity
Cohort 1
(25 mg/m2 on Day1/2/3)
Cohort 2 and 3
(75 mg/m2 on Day1)
≥Grade 3 neutropenic fever/infection
Approximately 60 mg/m2
(20 mg/m2 on Day 1/2/3)
Approximately 60 mg/m
2
Grade 4 neutropenia lasting longer than 
7 days
Approximately 60 mg/m2
(20 mg/m2 on Day 1/2/3)
Approximately 60 mg/m
2
Second incidence of either:  
1) ≥Grade 3 neutropenic fever/infection 
2) Grade 4 neutropenia lasting longer than 
7 days
Second level of dose reduction 
to 45 mg/m
2 (15 mg/m2 on Day
1/2/3)
Second level of dose reduction 
to 45 mg/m
2
7.2.2.4.2. Nonhematologic Toxicity
In the case of hyperbilirubinemia and elevated AST, dose reduction of doxorubicin should be 
considered. See Table JGDK.7.4 for doxorubicin dose reduction for hyperbilirubinemia and 
elevated AST.


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Table JGDK.7.4.
General Guidelines for Doxorubicin Dose Reduction Due to 
Hyperbilirubinemia and Elevated AST
Serum bilirubin
concentration (mg/dL)
AST (IU/L)
Required Dose Reduction
(Cohort 1, 2 and 3)
1.5 to 3.0
or, 60 to 180
50%
3.1 to 5.0
or, >180
75%
>5.0
-
Discontinuation
Abbreviation:  AST = aspartate aminotransferase.
7.2.2.4.3. Cardiovascular
Electrocardiogram changes, arrhythmias, tachycardia, and/or chest pain should be managed 
based on the specific findings.  
Patients will undergo baseline LVEF determination by echocardiogram.  This evaluation may be 
repeated at any time during the study if clinically indicated.  If an echocardiogram conducted on 
study indicates a resting LVEF is <50%, then the echocardiogram should be repeated for 
monitoring.  If there is an absolute decrease in LVEF of >20% from the previous evaluation, or if
the actual LVEF decreases to ≤40%, then doxorubicin should be discontinued.  Doxorubicin 
should also be discontinued if the patient develops Grade 3 or 4 left ventricular systolic 
dysfunction (symptomatic congestive heart failure).  
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive olaratumab in 
combination with doxorubicin (Cohort 1, 2 or 3 in Part A) or olaratumab monotherapy (Part B), 
at the investigator’s discretion.  Before each patient’s enrollment into the study, an eligibility 
check must be conducted at the investigational site to confirm that each patient meets all 
enrollment criteria.  Upon confirmation of eligibility, the sponsor or designee will confirm the 
dose and identification number assignment for each patient.  For initiation of Cohort 2 and 3,
refer to Section 7.2.1.4.
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
No other chemotherapy, immunotherapy, radiation therapy, hormonal cancer therapy, surgery for
cancer, or experimental medications will be permitted while patients are participating in this
study.
Patients must receive full supportive care therapies concomitantly during the study, including
antiemetic treatment as per institutional guidelines.  Granulocyte colony stimulating factors
(G-CSF) may be used in accordance with American Society of Clinical Oncology (ASCO)
guidelines (Smith et al. 2006), and if they adhere to the dosage and administration described in 
the Japan Package Insert. Granulocyte colony stimulating factor treatment as the primary 
prophylaxis is not permitted and pegfilgrastim are not permitted.  Granulocyte colony 


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stimulating factors must be discontinued at least 24 hours before beginning the next cycle of 
treatment.
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications (eg, medications such as sedatives, antibiotics, analgesics, antihistamines, 
corticosteroids, erythropoietin; procedures such as paracentesis, thoracentesis; blood products 
such as blood cells, platelets, fresh frozen plasma transfusions) must be captured on the 
electronic case report form (eCRF).  Erythropoietin/blood product use and platelet transfusions 
may be used in accordance with ASCO guidelines (Schiffer et al. 2001; Rizzo et al. 2010).
7.6.
Treatment Compliance
Olaratumab and doxorubicin (Part A) or olaratumab (Part B) will be administered at the 
investigational sites, 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.  


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8.
Safety, Pharmacokinetic, and Efficacy Data Collection
8.1.
Safety Evaluations
The safety and tolerability of olaratumab have been assessed in nonclinical toxicology studies 
and the results from these studies are detailed in the IB.  This Phase 1 study contains detailed 
safety monitoring that will permit initial characterization of the safety profile of olaratumab in 
combination with doxorubicin 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 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 
JGDK.8.1 presents a summary of AE and SAE reporting guidelines.  Table JGDK.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 labs, 
vital sign measurements, and so on, that occur should also be reported to Lilly or its designee as 
an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect.


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The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE (v4.03).
The NCI-CTCAE (v4.03) will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms. All AEs observed 
will be graded using CTCAE (v4.03).  Any minor version of CTCAE (v4.03) may be used for 
this study.  Minor CTCAE (v4.03) updates from the NCI will not necessitate a protocol 
amendment.  For AEs without matching terminology within the NCI-CTCAE (v4.03) criteria, 
the investigator will be responsible for selecting the appropriate System Organ Class and 
assessing severity grade based on the intensity of the event.  Note that both CTCAE term (actual 
or coded) and severity grade must be selected by study site personnel and collected on the 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 eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment. 
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure or study drug via eCRF.
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.


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
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 treatment.
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.
Preplanned 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 (eg, for the administration of study therapy or other protocol-required procedure) 
should not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug administration)

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor, and the SAEs will be entered in the
Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  


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8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the informed consent form (ICF).  For patients who do not 
enroll in the trial (ie, have not received at least 1 dose of olaratumab), 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 
to when he/she receives the last dose of study drug.
8.1.2.2.3. Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
during the follow-up visit must be reported to Lilly or its designee.  The follow-up visit starts on 
the day after the patient and the investigator agree to discontinue the study treatment and extends 
28 days (±5 days) from the last dose of study drug (olaratumab or doxorubicin).  For patients 
who discontinue from the study treatment after a treatment delay, the follow-up visit can be 
performed after the allowed time window if it is difficult to perform the follow-up procedures 
within this time period.  In such a situation, the follow-up visit should be performed as early as 
possible.  At the end of the follow-up visit, the patient will be required to have specific safety 
assessments (Attachment 1).  
Following the safety assessments, which mark the end of the follow-up visit, 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 monitored in subsequent follow-up visits 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.
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, AEs are not required to be reported unless the investigator feels the 
AEs were related to either study drug, drug delivery system, or a protocol procedure. If an 
investigator becomes aware of SAEs believed to be related to protocol procedures or study drug, 
the investigator should report the SAE to the sponsor, and the SAE will be entered in the Lilly 
Safety System.


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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.  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 JGDK.8.1 and in Attachment 6.
Table JGDK.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study JGDK
Timing
Types of AEs/SAEs Reported 
Collection 
Database
Lilly 
Safety 
System
Pretreatment (baseline assessments)
(Starts at the signing of informed consent 
and ends just before the first dose of study 
drug)
Preexisting conditions
All AEs regardless of relatedness
All SAEs regardless of relatedness 
X
X
X
X
On therapy
(Starts at first dose of study drug[s] and ends 
at last dose of study drug[s])
All AEs regardless of relatedness
All SAEs regardless of relatedness
X
X
X
Follow-up
(Starts on the day after the patient and the 
investigator agree to discontinue the study 
treatment and extends 28 days [±5 days]
from the last dose of study drug [olaratumab 
or doxorubicin]). 
All AEs regardless of relatedness
All SAEs regardless of relatedness
X
X
X
Subsequent follow-up visits (prior to patient 
discontinuation from the study), if necessary
Ongoing AEs possibly related to 
study drug(s), or protocol procedures
Ongoing SAEs possibly related to 
protocol procedures or study drug
X
X
X
Patient no longer on study
All SAEs possibly related to protocol 
procedures or study drug that the 
investigator becomes aware of
X
Abbreviations:  AE = adverse event; SAE = serious adverse event.
8.1.3. Other Safety Measures
8.1.3.1.
Vital Signs
Pulse rate, respiration rate, temperature, and supine blood pressure will be measured as specified 
in the Study Schedule and as clinically indicated (Attachment 1).  Vital signs will be collected 
before any blood samples are collected at the specified time.


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8.1.3.2.
Electrocardiograms
Serial 12-lead digital ECGs will be collected during the study. Electrocardiograms should be 
collected prior to any blood draws scheduled at the same time point
For each patient, ECGs will be collected according to the Study Schedule (Attachment 1) and the 
Pharmacokinetic Sampling, ECG, and Immunogenicity Sampling Schedule (Attachment 4).  
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  
Single local ECGs will be obtained at screening (within 21 days prior to the first administration 
of study drug).  Consecutive triplicate ECGs will be obtained at approximately 1-minute 
intervals.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs (more replicates) than expected at a particular time point is allowed to 
ensure high quality records. 
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (eg, palpitations, near syncope, 
syncope) to determine whether the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation from at least 1 of 
the replicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will 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 sites.  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.


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The investigator (or qualified designee) must document his/her review of one 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.
When enough data for the analysis of the primary and the secondary endpoints has been
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, 12-lead digital ECGs will be performed annually (±2 weeks) except for the 
ECG scheduled to be performed at the follow-up visit; each assessment will be conducted locally 
according to the procedure at the respective site.  Investigators will still be responsible for patient 
safety management, however centralized review will no longer be mandatory.  If clinically 
indicated, 12-lead digital ECGs can be performed more frequently.
8.1.3.3.
Echocardiograms
Echocardiogram scans will be performed locally at the time points according to the Study 
Schedule (Attachment 1).  The scans must be performed within 3 days prior to any treatment 
administration in these respective cycles.
8.1.3.4.
Infusion-Related Reactions
The NCI-CTCAE definition of infusion-related reactions is provided in Attachment 8.
Symptoms occurring during or following infusion of olaratumab may also be defined according 
to AE categories such as allergic reaction, anaphylaxis, or cytokine release syndrome.  In the 
setting of symptoms occurring during or following infusion of olaratumab, investigators are 
encouraged to use the AE term “infusion-related reaction” and any additional terms (including 
those not listed here) that best describe the event.
Consistent with usual medical practice, selected parenteral medications may be utilized for 
Grade 2 allergic/hypersensitivity reaction as detailed below.  The Lilly CRP or CRS should be 
contacted immediately if questions arise concerning the grade of the reaction.
The following are treatment guidelines for olaratumab infusion-related reactions:
In general, if a patient experiences a Grade 1 or 2 infusion-related reaction, the infusion should 
stop and the patient should be treated with an antihistamine (for example diphenhydramine 
hydrochloride), steroids (for example dexamethasone), acetaminophen, and oxygen (as 
appropriate), according to standard medical practices.  After recovery, the infusion rate should be 
decreased 50% for the duration of the infusion. After a Grade 1 or 2 infusion reaction, patients 
should be premedicated with antihistamines, steroids, acetaminophen, etc., as appropriate for 
subsequent infusions.
A Grade 3 or 4 infusion-related reaction will require immediate treatment, including the use of 
epinephrine, bronchodilators, and/or glucocorticoids for symptomatic bronchospasm, IV fluids 
and/or pressors for hypotension, and immediate and permanent discontinuation of olaratumab 
with appropriate supportive care.
A patient has to be carefully observed for potential infusion-related reactions for approximately 
60 minutes after olaratumab administration, especially after the first 2 administrations. If a 


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patient should have an infusion-related reaction to olaratumab, all attempts should be made to 
obtain an anti-olaratumab antibody blood sample as close to the onset of the event as possible, at 
the resolution of the event, and 28 days following the event.  In addition, these samples may be 
assessed for levels of olaratumab (PK assay).
8.1.4. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study. 
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical research scientist, and periodically review:

Trends in safety data.

Laboratory analyses.

Adverse events.

If a study patient experiences elevated ALT >5 × ULN and elevated total bilirubin 
>2 × ULN, clinical and laboratory monitoring should be initiated by the investigator.
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 (Attachment 3).
For interstitial lung disease and suspected interstitial lung disease cases diagnosed after starting 
the study drug (Day 1 in Cycle 1), external specialists may evaluate its related examination 
results such as image data.  The investigator should provide the test results, including imaging 
examination and pathological examination, upon request by Lilly.
8.1.5. Complaint Handling
Lilly collects complaints on study drugs (olaratumab and doxorubicin) used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and facilitate process and 
product improvements.
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.


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8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.  
Attachment 4 lists the schedule for PK and immunogenicity sample collections and ECG
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 
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 the Pharmacokinetic Sampling, ECG, 
and Immunogenicity Sampling Schedule (Attachment 4). 
8.2.2.1.
Pharmacokinetic Samples
At the visits and times specified in the Pharmacokinetic Sampling, ECG and Immunogenicity 
Sampling Schedule (Attachment 4), blood samples of approximately 3 mL each will be collected 
to determine the serum concentrations of olaratumab.  In Part A, blood samples of approximately 
3 mL each will also be collected to determine the plasma concentrations of doxorubicin.  A 
maximum of 5 samples may be collected at additional time points during the study if warranted 
and agreed upon between both the investigator and Lilly. Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling will be recorded.
These samples will be analyzed at a laboratory designated by the sponsor.  Serum concentrations 
of olaratumab will be assayed using a validated enzyme-linked immunosorbent assay method.
Plasma concentrations of doxorubicin will be assayed using a validated liquid chromatography 
with tandem mass spectrometry method.
The PK samples will be stored at a facility designated by the sponsor.
The remaining plasma/serum from the samples collected for PK may be pooled and used for 
exploratory metabolism work as deemed appropriate.


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Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 years following last patient visit for the study.
When enough data for the analysis of the primary and the secondary endpoints has been 
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, PK samples will no longer be collected except for sampling required for the 
follow-up visit (Attachment 4).
8.2.3. Samples for Immunogenicity Research
Blood samples of approximately 4 mL for immunogenicity testing will be collected to determine 
antibody production against olaratumab.  A schedule for immunogenicity sample collection is 
provided in Attachment 4.  In addition to the scheduled immunogenicity sampling, in the event 
of an infusion-related reaction samples are to be collected as close to the onset of the event as 
possible, at the resolution of the event, and 28 days following the event.  An immunogenicity 
sample should also be collected approximately 28 days after the discontinuation of treatment 
(ie, 28-day follow-up visit).
Immunogenicity will be assessed by a validated assay designed to detect ADA in the presence of 
olaratumab.  Antibodies may be further characterized and/or evaluated for their ability to 
neutralize the activity of olaratumab.
Detailed instructions for collecting, processing, storing, and shipping the samples will be 
provided by the sponsor in a separate procedural manual.  
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to olaratumab.  
The duration allows the sponsor to respond to regulatory requests related to olaratumab.
When enough data for the analysis of the primary and the secondary endpoints has been
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, immunogenicity samples will no longer be collected except for sampling 
required for the follow-up visit or in the event of an infusion-related reaction (Attachment 4).
8.2.4. Samples for Translational Research
Exploratory analyses will assess the potentially relevant biomarkers obtained from blood 
samples. Tumor tissue submission is optional and tumor specimens might be used if available.

Blood samples and tumor tissues (if available) will be used for the analysis of potential
biomarkers related to the mechanism of olaratumab, the PDGF signaling pathway, and 
the pathobiology of cancer.  
Gene expression profiling and/or genetic analyses will not be conducted in any samples collected 
in this study.
Required samples for biomarker to be collected from all patients in this study are the following:

plasma samples from whole blood (see Section 8.2.4.1)


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Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following:

archived tumor tissue (see Section 8.2.4.2)
Samples will be collected at the times specified in Attachment 1.
The translational research samples will be coded with the patient number and stored for up to a 
maximum 15 years after the last patient visit for the study at a facility selected by the sponsor or 
designee.  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 treatment.
Patients will not receive results of these investigations except where required by local law.  
Samples will be destroyed according to a process consistent with local regulation.  
Supplies required for the collection and shipment of the patients’ stored samples will be supplied 
by the central laboratory vendor.  Sample handling and shipment to the central laboratory will 
occur per instructions provided to the study site.
8.2.4.1.
Blood Sample for Plasma Collection 
Circulating markers may include, but are not limited to, markers relevant to the mechanism of 
olaratumab, the PDGF signaling pathway, and the pathobiology of cancer.
8.2.4.2.
Optional Tumor Tissue Samples
Collection of tumor tissue samples (blocks or slides) is optional for participation in this study.  If 
provided, due diligence should be used to make sure that tumor specimen (not a normal adjacent 
or a tumor margin sample) is provided.  Pathology notes accompanying archival tissue may also 
be requested.  If paraffin-embedded whole blocks will be submitted, the whole blocks will be 
sectioned.  After testing has been completed, the paraffin-embedded whole blocks will be 
returned to the site.  Whole blocks can be returned sooner, if requested by the sites.  Partial 
blocks and slides will not be returned.
Immunohistochemistry may be performed on these tissue samples to assess potential associations 
with biomarkers relevant to pathways associated with the mechanism of olaratumab, the PDGF 
signaling pathway, and the pathobiology of cancer and cancer-related conditions, and may also 
be used for related research methods and clinical outcomes.  Additional exploratory markers 
studied may include, but are not limited to, markers relevant to the PDGF pathway.
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 scan

Magnetic resonance imaging


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Each patient’s full extent of disease will also be assessed with:  

Tumor measurement by RECIST version 1.1 (Eisenhauer et al. 2009)

Evaluation of PS
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.  If a patient is discontinued from the 
study, repeat radiology assessments may be omitted if clear clinical signs of progressive disease 
are present.
8.4.
Procedure/Sampling Compliance
Every attempt will be made to enroll patients who have the ability to understand and comply 
with instructions.  Noncompliant patients may be discontinued from the study.
The collection times of safety assessments, PK samples, and efficacy measurements are given as 
targets, to be achieved within reasonable limits.  The scheduled time points may be subject to 
minor alterations; however, the actual collection time must be correctly recorded on the CRF or 
lab requisition form.  
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.


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


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Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system and/or the TPO system.
Electrocardiogram data will be stored electronically in the central database system of Lilly’s 
central review organization.  Data will subsequently be transferred from the central review 
organization system to the Lilly generic labs system and/or the TPO system.
When enough data for the analysis of the primary and the secondary endpoints has been
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, electrocardiogram data will no longer be stored electronically in the central 
vendor’s system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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10. Data Analyses
10.1. General Considerations
The study design requires 6 patients at each cohort in Part A for assessing the DLTs observed.  
This sample size was not based on a statistical power calculation.
In Part B, 6 patients are needed to evaluate PK and safety profile of olaratumab monotherapy.  
This sample size was estimated empirically based on other Phase 1 oncology studies. The 
estimation precision of PK parameters in this study is expected to be similar to that in previous 
studies (Study JGDC and Study JGDF), although there are no inter-subject variability data on a 
new assay.
Statistical analysis of this study will be the responsibility of the sponsor.
The interpretation of the study results will be the responsibility of the investigator with the 
sponsor’s CRP, pharmacokineticist, and statistician.  The CRP 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.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
Detailed information regarding the planned statistical analyses will be described in the Statistical 
Analysis Plan.
10.2. Patient Disposition
The analysis populations are defined as follows:  

Enrolled Population:  Anyone who signed the informed consent and who was confirmed 
to be eligible and have been assigned to a treatment will be included in this population.

FAS Population:  All enrolled patients who received any amount of study drugs (either 
olaratumab or doxorubicin) will be included in the FAS Population.  The FAS Population 
is based on the intent-to-treat principle and will be used for the analysis of baseline 
characteristics, efficacy data, safety data, and biomarkers.  

DLT Population:  All enrolled patients who will complete Cycle 1 (initial 21-day
treatment period), or who will discontinue due to DLT during Cycle 1, will be included in 
the DLT Population.  Patients who will discontinue during Cycle 1 due to other reasons 
than DLT will be excluded from the DLT Population.  The DLT Population will be used 
for summarizing a proportion of patients with DLT.
Number (percent) of patients in the Enrolled Population, the FAS Population, or the DLT 
Population (Part A only) will be summarized by part and cohort. 


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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 patient discontinuation will be given.
Number (percent) of patients who discontinued will also be summarized by part and reason for 
discontinuation and by part and cohort.
10.3. Patient Characteristics
Demographic and baseline characteristics (ie, age [years], age categories [<65 years vs. ≥65 
years], gender, height [cm], weight [kg], and ECOG PS), pre-treatment disease characteristics (ie,
cancer type, TNM staging at the time of diagnosis, sites of metastatic disease, and duration of 
disease [months from first confirmation of cancer to first dose]), prior anticancer treatments or 
surgery (ie, type of therapy, regimen, and prior surgery), and medical history will be summarized 
by part and cohort for the FAS Population.
10.4. Safety Analyses
All safety evaluations will be based on the FAS Population (except a DLT summary).  Safety 
variables listed below will be summarized by part and cohort (and by study visit/time point, if 
applicable).
•
Study drug exposure of olaratumab or doxorubicin:  number of cycles, number of infusions, 
duration of treatment (weeks), cumulative dose (mg/kg or mg/m2), dose intensity 
(mg/kg/week or mg/m2/week), relative dose intensity (%), treatment delays, treatment
omissions, treatment reductions, and treatment interruptions.
•
TEAEs:  MedDRA will be used for categorizing to System Organ Class and Preferred Term.  
National Cancer Institute-Common Terminology Criteria for Adverse Events will be used 
for identifying grade and/or relevant event term.  In addition to TEAEs, all AEs, SAEs, 
study drug-related AEs and SAEs, AEs leading to treatment discontinuation (olaratumab or
doxorubicin in Part A and olaratumab in Part B), and AEs leading to treatment 
delay/omission/reduction/interruption (olaratumab or doxorubicin in Part A and olaratumab
in Part B) will be summarized. 
•
DLT:  In Part A, the number of patients who experienced any DLTs during Cycle 1 will be 
summarized by cohort using the DLT Population.
•
Deaths, SAEs, other significant AEs:  these findings will be listed by patients.
•
PS, physical exams, vital signs, laboratory tests and ECG:  actual measurements, as well as
categorized values of laboratory tests, vital signs, and ECG parameters, will be summarized 
by part, cohort, and study visit/time point. 
10.5. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of the 
study drug and have had samples collected.  
Pharmacokinetic parameter estimates for olaratumab and doxorubicin will be calculated by 
standard noncompartmental methods of analysis.


I5B-JE-JGDK(b) Phase 1 Oncology Protocol
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The primary parameters for analysis will be maximum observed concentration (Cmax) and AUC 
from time 0 to the last time point with a measurable concentration (AUC[0-tlast]), and AUC from 
time 0 to infinity (AUC0-∞) of olaratumab and doxorubicin.  Other noncompartmental 
parameters such as t1/2, CL, and V may be reported.  Additional exploratory analyses may be 
performed if warranted by data and other validated PK software programs (eg, NONMEM) may 
be used if appropriate and approved by global PK management.  The version of any software 
used for the analysis will be documented and the program will meet the Lilly requirements of 
software validation.
10.6. Efficacy
Efficacy data will be summarized by part and cohort using the FAS population.  Efficacy data 
includes the objective response rate with confirmed partial response (PR) or complete response 
(CR), and the disease control rate with confirmed PR, CR, or stable disease (SD) as best overall 
response according to RECIST version 1.1.  Progression-free survival and duration of response 
will also be included in efficacy data.
10.7. Biomarker Analyses
Descriptive statistics and visual plots of time course (if applicable) for biomarkers will be 
provided.
10.8. Interim Analyses
Safety data evaluation for Part A will be performed after 3 patients in Cohort 1 are enrolled.
The SAC is authorized to review available safety data.  The SAC may consist of members 
external to Lilly.
Safety and/or PK data will be reviewed during the study, if needed, for doxorubicin dosing 
schedule change, modifications to the doxorubicin dosing schedule strategy or to the amount of 
olaratumab dosage, or other design elements.
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, biomarker, and PK.  
All data defined in the protocol will continue to be collected from patients on treatment after the 
data cutoff date unless otherwise specified.  These data may be reported separately and the 
analyses on all patients, including these data, may not be performed.
In addition, the sponsor may consider interim analyses for regulatory communication purposes
and/or scientific disclosures. In this case, collected data may be summarized.


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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 given by patients.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the ICH guideline on GCP.  
Documentation of ERB/IRB 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)/IRB(s) will review the 
protocol as required.
The study site’s ERB(s)/IRB(s) should be provided with the following:

the current IB or Patient Information Leaflet, Package Insert, Protocol or Summary of
Product Characteristics and updates during the course of the study

ICF

relevant curricula vitae
11.3. Regulatory Considerations
This study will be conducted in accordance with:
1) Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 
2) The ICH GCP Guideline [E6]
3) Applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).


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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 chosen by the sponsor or designee will serve as the clinical study 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
Bramwell VH, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative 
treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-
analysis and clinical practice guideline. Sarcoma. 2000;4(3):103-112.
Chiorean EG, Sweeney C, Youssoufian H, Qin A, Dontabhaktuni A, Loizos N, Nippgen J, 
Amato R. A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha 
(PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother 
Pharmacol. 2014;73(3):595-604.
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
D'Adamo DR, Anderson SE, Albritton K, Yamada J, Riedel E, Scheu K, Schwartz GK, Chen H, 
Maki RG. Phase II study of doxorubicin and bevacizumab for patients with metastatic 
soft-tissue sarcomas. J Clin Oncol. 2005;23(28):7135-7142.
de Jong JS, van Diest PJ, van der Valk P, Baak JP. Expression of growth factors, growth 
inhibiting factors, and their receptors in invasive breast cancer. I: An inventory in search of 
autocrine and paracrine loops. J Pathol. 1998;184(1):44-52.
Doi T, Ma Y, Dontabhaktuni A, Nippgen C, Nippgen J, Ohtsu A. Phase I study of olaratumab in 
Japanese patients with advanced solid tumors. Cancer Sci. 2014;105(7):862-869.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
Gerber DE, Gupta P, Dellinger MT, Toombs JE, Peyton M, Duignan I, Malaby J, Bailey T, 
Burns C, Brekken RA, Loizos N. Stromal platelet-derived growth factor receptor α (PDGFRα) 
provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer 
xenografts. Mol Cancer Ther. 2012;11(11):2473-2482.
Heldin CH, Ostman A, Ronnstrand L. Signal transduction via platelet-derived growth factor 
receptors. Biochem Biophys Acta. 1998;1378(1):F79-F113.
Iwamoto Y, Tanaka K. The activity of the Bone and Soft Tissue Tumor Study Group of the 
Japan Clinical Oncology Group. Jpn J Clin Oncol. 2012;42(6):467-470.
[JOA] Japanese Orthopaedic Association. General rules for clinical and pathological studies on 
malignant soft tissue tumors. 3rd ed. Tokyo: Kanehara-shuppan Co., LTD,; 2002.
[JOA] Japanese Orthopaedic Association. Clinical practice guideline on the diagnosis and 
treatment of soft tissue tumors. Tokyo; Nankodo Co., LTD.; 2012.
LaRochelle WJ, Jensen RA, Heidaran MA, May-Siroff M, Wang LM, Aaronson SA, Pierce JH. 
Inhibition of platelet-derived growth factor autocrine growth stimulation by a monoclonal 
antibody to the human alpha platelet-derived growth factor receptor. Cell Growth Differ. 
1993;4(7):547-553.


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Li X, Ponten A, Aase K, Karlsson L, Abramsson A, Uutela M, Backstrom G, Hellstrom M, 
Bostrom H, Li H, Soriano P, Betsholtz C, Heldin CH, Alitalo K, Ostman A, Eriksson U.
PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol.
2000;2(5):302-309.
Loizos N, Xu Y, Huber J, Liu M, Lu D, Finnerty B, Rolser R, Malikzay A, Persaud A, Corcoran 
E, Deevi DS, Balderes P, Bassi R, Jimenez X, Joynes CJ, Mangalampalli VR, Steiner P, Tonra 
JR, Wu Y, Pereira DS, Zhu Z, Ludwig DL, Hicklin DJ, Bohlen P, Witte L, Kussie P. Targeting 
the platelet-derived growth factor receptor alpha with a neutralizing human monoclonal 
antibody inhibits the growth of tumor xenografts: implications as a potential therapeutic target. 
Mol Cancer Ther. 2005;4(3):369-379.
Lokker NA, O'Hare JP, Barsoumian A, Tomlinson JE, Ramakrishnan V, Fretto LJ, Giese NA. 
Functional importance of platelet-derived growth factor (PDGF) receptor extracellular 
immunoglobulin-like domains. Identification of PDGF binding site and neutralizing 
monoclonal antibodies. J Biol Chem. 1997;272(52):33037-33044.
Nakamura K, ed. “Passage” series for specialists of clinical orthopaedics (6). Practical guide for 
soft tissue tumors. Tokyo: Nakayama Shoten Co., Ltd,; 2011.
Ostman A, Heldin CH. Involvement of platelet-derived growth factor in disease: development of 
specific antagonists. Adv Cancer Res. 2001;80:1-38.
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu 
Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski 
CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush 
J, Comb MJ. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung 
cancer. Cell. 2007;131(6):1190-1203.
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, 
Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR; American Society of 
Clinical Oncology; American Society of Hematology. American Society of Clinical
Oncology/American Society of Hematology clinical practice guideline update on the use of 
epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996-5010.
Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, Goldstein M, 
Hume H, McCullough JJ, McIntyre RE, Powell BL, Rainey JM, Rowley SD, Rebulla P, 
Troner MB, Wagnon AH; American Society of Clinical Oncology. Platelet transfusion for 
patients with cancer: clinical practice guidelines of the American Society of Clinical
Oncology. J Clin Oncol. 2001;19(5):1519-38.
Shah GD, Loizos N, Youssoufian H, Schwartz JD, Rowinsky EK. Rationale for the development 
of IMC-3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the 
platelet-derived growth factor receptor alpha. Cancer. 2010;116(4 suppl):1018-1026.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor 
SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, 
Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. 2006 update 
of recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J Clin Oncol. 2006;24(19):3187-3205.


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Zhang P, Gao WY, Turner S, Ducatman BS. Gleevec (STI-571) inhibits lung cancer cell growth 
(A549) and potentiates the cisplatin effect in vitro. Mol Cancer. 2003;2:1.


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Attachment 1.
Protocol I5B-JE-JGDK Study Schedule


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Study Schedule for Protocol I5B-JE-JGDK – Part A:  Screening and Cycle 1
Screening
Cycle 1
Relative day within a cycle
21
14
7
1
2
3
8
Comments
Informed consent
X
Informed consent form signed (prior to performance of any protocol-
specific tests/procedures and patients must be ≥20 years of age).
Medical history
X
Includes past and current medical conditions, treatments, and 
alcohol/tobacco use.
Pregnancy test
X
Serum or urine: Pregnancy test is only required for females of child-
bearing potential.
Physical examination
X
Xa
Xa
Includes medical interview, height (at screening only), weight, and body 
surface area.
Vital signs 
X
Xb
Xc
Pulse rate, respiration rate, temperature, and supine blood pressure will 
be measured.
ECOG performance status
X
Xa
NYHA classification
X
ECG
X
See Attachment 4
Screening ECGs will be performed locally.  Obtain ECGs before any 
associated blood draws.  
Echocardiogram
X
Echocardiogram will be performed locally. Data obtained before 
patient’s consent may be used as the screening data if the relevant tests 
are conducted within the allowed time window.
Hematology
X
Xa
Xa
Serum chemistry
X
Xa
Xa
Coagulation
X
Xa
Urinalysis
X
Xa
Hepatitis B and C virus
X
Includes tests for Hepatitis B surface antigen, Hepatitis B surface 
antibody, Hepatitis B core antibody and Hepatitis C antibody.  Test for 
Hepatitis B DNA will be performed as necessary.  
CTCAE v4.03 grading
X
X
Xd
Xd
X
Throughout study as needed.  
Concomitant medications
X
X
Xd
Xd
X
Radiological tumor assessment
X
Data obtained before patient’s consent can be used as screening data if 
the relevant tests are conducted within the allowed time window.
PK sampling 
See Attachment 4
Immunogenicity sampling
See Attachment 4
Blood sampling for translational
research
Xa
Plasma samples will be collected from whole blood.
Tumor tissue submission
X
If available.
Olaratumab administration
Xe
Xe
Doxorubicin administration
X
Xd
Xd


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Study Schedule for Protocol I5B-JE-JGDK – Part A:  Screening and Cycle 1
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; NYHA = New York Heart Association; PK = pharmacokinetic.
a
Predose only.
b
Vital sign measurements will be obtained prior to and at the completion of each olaratumab administration, and prior to each doxorubicin administration.  
c
Vital sign measurements will be obtained prior to and at the completion of olaratumab administration, and approximately one hour following the completion 
of olaratumab administration.
d
Cohort 1 only.
e
15 mg/kg in Cohort1 and 2, and 20 mg/kg as loading dose in Cohort 3.


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Study Schedule for Protocol I5B-JE-JGDK – Part A:  Cycle 2 and beyond
Cycle 2-6 
Cycle 7-n
Follow-
Relative day within a cycle 
1a
2
3
8
1b
8
Upc
Allowance (days)
+3
±3d
+3
±3
±5
Comments
Informed consent
X
Informed consent form signed (prior to beginning of Cycle 2).
Pregnancy test
Xe
Xe
X
Should be performed approximately every 6 weeks (i.e., at the 
beginning of Cycle 3 and every other cycle thereafter) during the 
study.
Physical examination
Xe
Xe
X
Includes medical interview, weight, and body surface area.
Vital signs 
Xf
Xf
Xf
Xf
X
Pulse rate, respiration rate, temperature, and supine blood 
pressure will be measured.  
ECOG performance status
Xe
Xe
X
ECG
See Attachment 4
Obtain ECGs before any associated blood draws.
Echocardiogram
Xe
Xe
X
Should be performed locally at Cycles 5 and 7 (within 3 days 
prior to the treatment on Day 1, but re-measurement is not 
necessary in case of dose delay of Day 1) and follow-up visit.  
Hematology
Xe
Xe
Xe
Xe
X
Serum chemistry
Xe
Xe
Xe
Xe
X
Coagulation
Xe
Xe,h
X
Should be performed approximately every 6 weeks (ie, at the 
beginning of Cycle 3 and every other cycle thereafter).
Urinalysis
Xe
Xe,h
X
CTCAE v4.03 grading
X
Xg
Xg
X
X
X
X
Throughout study as needed.  
Concomitant medications
X
Xg
Xg
X
X
X
X
Radiological tumor assessment
X
X
X
Prior to Cycles 3 and 5 (no more than 14 days prior to Day 1 
Cycle 3 and 5), then every 2-4 cycles as clinically indicated.
PK sampling 
See Attachment 4
Immunogenicity plasma sampling
See Attachment 4
Olaratumab administration
X
X
X
X
Doxorubicin administration
X
Xg
Xg


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Study Schedule for Protocol I5B-JE-JGDK – Part A:  Cycle 2 and beyond
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
PK = pharmacokinetic.
a
If neither olaratumab nor doxorubicin are administered on this date, Day 1 will be the next following day when either olaratumab or doxorubicin is actually 
administered.
b
If olaratumab is not administered on this date, Day 1 will be the next following day when olaratumab is actually administered.
c
The follow-up period starts on the day after the patient and the investigator agree to discontinue study treatment and extends 28 days (±5 days) from the last 
dose of study drug (olaratumab or doxorubicin).  Note (exception):  For patients who discontinue from study treatment after a treatment delay, the follow-up 
visit can be performed after the allowed time window, if it is difficult to perform the follow-up procedures within this time period.  In such a situation, the 
follow-up visit should be performed as early as possible.  
d
No time window is allowed for Day 8 in Cycle 3.
e
Predose only.
f
Vital sign measurements will be obtained prior to each olaratumab administration.
g
Cohort 1 only.
h
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the sponsor and the patient has continued 
the study treatment for more than 3 years, coagulation test and urinalysis will no longer be mandatory.


I5B-JE-JGDK(b) Phase 1 Oncology Protocol
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Study Schedule for Protocol I5B-JE-JGDK – Part B:  Screening and Cycle 1
Screening
Cycle 1
Relative day within a cycle
21
14
7
1
8
Comments
Informed consent
X
Informed consent form signed (prior to performance of  any protocol-
specific tests/procedures and  patients must be ≥20 years of age).
Medical history
X
Includes past and current medical conditions, treatments, and 
alcohol/tobacco use.
Pregnancy test
X
Physical examination
X
Xa
Xa
Includes medical interview height (at screening only) and weight.
Vital Signs 
X
Xb
Xb
Pulse rate, respiration rate, temperature, and supine blood pressure will be 
measured.
ECOG performance status
X
Xa
NYHA classification
X
ECG
X
See Attachment 4
Screening ECGs will be performed locally.  Obtain ECGs before any 
associated blood draws.  
Hematology
X
Xa
Xa
Serum chemistry
X
Xa
Xa
Coagulation
X
Xa
Urinalysis
X
Xa
Hepatitis B and C virus
X
Includes tests for Hepatitis B surface antigen, Hepatitis B surface antibody, 
Hepatitis B core antibody and Hepatitis C antibody.  Test for Hepatitis B 
DNA will be performed as necessary.  
CTCAE v4.03 grading
X
X
X
Throughout study as needed.  
Concomitant medications
X
X
X
Radiological tumor assessment
X
Data obtained before patient’s consent can be used as screening data if the 
relevant tests are conducted within the allowed time window.
PK Sampling 
See Attachment 4
Immunogenicity sampling
See Attachment 4
Blood sampling for translational 
research
Xa
Plasma samples will be collected from whole blood.
Tumor tissue submission
X
If available.
Olaratumab administration
X
X


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Study Schedule for Protocol I5B-JE-JGDK – Part B:  Screening and Cycle 1
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; NYHA = New York Heart Association; PK = pharmacokinetic.
a
Predose only.
b
Vital sign measurements will be obtained prior to and at the completion of olaratumab administration, and approximately one hour following the completion 
of olaratumab administration.


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Study Schedule for Protocol I5B-JE-JGDK – Part B:  Cycle 2 and beyond
Cycle 2-n
Follow-
Upb 
Relative Day Within a Cycle
1a
8
Comments
Allowance (days)
+3
±3c
±5
Pregnancy test
Xd
X
Should be performed approximately every 6 weeks (ie, at the beginning of Cycle 3 
and every other cycle thereafter) during the study.
Physical examinations
Xd
X
Includes medical interview and weight.
Vital signs 
Xe
Xe
X
Pulse rate, respiration rate, temperature, and supine blood pressure will be measured
ECOG performance status
Xd
X
ECG
See Attachment 4
Obtain ECGs before any associated blood draws.  
Hematology
Xd
Xd
X
Serum chemistry
Xd
Xd
X
Coagulation
Xd,f
X
Should be performed approximately every 6 weeks (ie, at the beginning of Cycle 3 
and every other cycle thereafter).
Urinalysis
Xd,f
X
CTCAE v4.03 grading
X
X
X
Throughout study as needed.  
Concomitant medications
X
X
X
Radiological tumor assessment
X
X
Prior to Cycles 3 and 5 (no more than 14 days prior to Day 1 Cycle 3 and 5), then 
every 2-4 cycles as clinically indicated.
PK sampling 
See Attachment 4
Immunogenicity sampling
See Attachment 4
Olaratumab administration
X
X
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
PK = pharmacokinetic.
a
If olaratumab is not administered on this date, Day 1 will be the next following day when olaratumab is actually administered.
b
The follow-up period starts on the day after the patient and the investigator agree to discontinue the study treatment and extends 28 days (±5 days) from the 
last dose of olaratumab.  Note (exception):  For patients who discontinue from the study treatment after a treatment delay, the follow-up visit can be 
performed after the allowed time window, if it is difficult to perform the follow-up procedures within this time period.  In such a situation, the follow-up visit 
should be performed as early as possible.
c
No time window is allowed for Day 8 in Cycle 3.
d
Predose only.
e
Vital sign measurements will be obtained prior to each olaratumab administration.


I5B-JE-JGDK(b) Phase 1 Oncology Protocol
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f
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the sponsor and the patient has continued 
the study treatment for more than 3 years, coagulation test and urinalysis will no longer be mandatory.


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Attachment 2.
Protocol I5B-JE-JGDK Clinical Laboratory 
Tests
Clinical Laboratory Testsa
Hematology:
Clinical Chemistry:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Chloride
Mean cell hemoglobin concentration
Calcium
Leukocytes (WBC)
Albumin
Neutrophils
Total protein
Lymphocytes
Blood urea nitrogen
Monocytes
Creatinine
Eosinophils
Alkaline phosphatase
Basophils
Alanine aminotransferase 
Platelets
Aspartate aminotransferase
Total bilirubin
Urinalysisf
Lactate dehydrogenase
Specific gravity
Magnesium
pH
Phosphorus
Protein
Glucose
Glucose
Ketones
Pregnancy test (serum or urine)
Blood
Human chorionic gonadotropinc
Follicle-stimulating hormoneb,d
Viral serologyb, e
Coagulationf
Hepatitis B surface antigen
Prothrombin time
Hepatitis B surface antibody
International normalized ratio
Hepatitis B core antibody
Activated partial thromboplastin time
Hepatitis B DNA
Hepatitis C antibody
Abbreviations:  DNA = deoxyribonucleic acid; RBC = red blood cells; WBC = white blood cells.
a
Local- or investigator-designated laboratory.
b
Performed only at screening.
c
To be done for women of child-bearing potential
d
To be done for women only when needed to confirm postmenopausal status.
e
Each of these tests will be completed unless results have been obtained from the patients within the last 6 
months.
f
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined 
by the sponsor and the patient has continued the study treatment for more than 3 years, coagulation test and 
urinalysis will no longer be mandatory.


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Attachment 3.
Protocol I5B-JE-JGDK 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
Erythrocyte count (RBC)
Prothrombin time
Leukocytes (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
Alanine aminotransferase
Anti-nuclear antibodya
Aspartate aminotransferase
Gamma glutamyl transferase
Anti-smooth muscle antibodya
Creatine phosphokinase
Abbreviations:  Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cells; WBC = white 
blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 4.
Protocol I5B-JE-JGDK Pharmacokinetic 
Sampling, ECG, and Immunogenicity Sampling Schedule






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m
When only olaratumab is discontinued before Cycle 6 (doxorubicin continues for up to 6 cycles or until when a cumulative 
dose reaches), this PK and immunogenicity sampling and ECG will be taken at the nearest planned visit to 28 days after the 
last dose of olaratumab.
n
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the 
sponsor and the patient has continued the study treatment for more than 3 years, PK samples and immunogenicity samples 
will no longer be collected.
o
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the 
sponsor and the patient has continued the study treatment for more than 3 years, 12-lead digital ECGs will be performed 
annually (±2 weeks) except at the follow-up visit; each assessment will be conducted locally according to the procedure at the 
respective site.  Investigators will still be responsible for patient safety management, but centralized review will not be 
mandatory.  If clinically indicated, 12-lead digital ECGs can be performed more frequently.






I5B-JE-JGDK(b) Phase 1 Oncology Protocol
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k
If the first olaratumab administration in the cycle is delayed, the specified olaratumab PK and immunogenicity sampling and 
ECG will be conducted based on the day of the first olaratumab administration in the cycle.
l
If doxorubicin administration is delayed, the specified doxorubicin PK sampling and ECG will be conducted based on the 
day of the doxorubicin administration.
m
When only olaratumab is discontinued before Cycle 6 (doxorubicin continues for up to 6 cycles or until when a cumulative 
dose reaches), this PK and immunogenicity sampling and ECG will be taken at the nearest planned visit to 28 days after the 
last dose of olaratumab.
n
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the 
sponsor and the patient has continued the study treatment for more than 3 years, PK samples and immunogenicity samples 
will no longer be collected.
o
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the 
sponsor and the patient has continued the study treatment for more than 3 years, 12-lead digital ECGs will be performed 
annually (±2 weeks) except at the follow-up visit; each assessment will be conducted locally according to the procedure at the 
respective site.  Investigators will still be responsible for patient safety management, but centralized review will not be 
mandatory.  If clinically indicated, 12-lead digital ECGs can be performed more frequently.


















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Attachment 6.
Protocol I5B-JE-JGDK Recommendations 
for Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events (SAEs)
When contacting Lilly to report a SAE, please have the following information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalization), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug & 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 7.
Protocol I5B-JE-JGDK 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.
Reference:  Cockcroft and Gault 1976.


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Attachment 8.
Protocol I5B-JE-JGDK NCI-CTCAE (v4.03)
Infusion-Related Reactions
Adverse 
Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Infusion-
related 
reaction
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤ 24 hrs
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition:  A disorder characterized by an adverse reaction to the infusion of pharmacological or biological substances.
Allergic 
reaction
Transient 
flushing or rash, 
drug fever 
<38°C 
(<100.4°F); 
intervention not 
indicated
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics); 
prophylactic medications 
indicated for ≤24 hrs
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition:  A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-
related 
edema/angioedema; 
hypotension
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition:  A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and 
histamine-like substances from mast cells, causing a hypersensitivity immune response.  Clinically, it presents with 
breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness, and may lead to death.
Cytokine 
release 
syndrome
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
pressor or 
ventilator support 
indicated
Death
Definition:  A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is 
caused by the release of cytokines from the cells.
Abbreviations:  hr = hour; I.V. = intravenous; NSAID = nonsteroidal anti-inflammatory drug.


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Attachment 9.
Protocol I5B-JE-JGDK (b) Amendment 
Summary
A Phase 1 Study of Olaratumab in Japanese Patients with 
Advanced Soft Tissue Sarcoma or Advanced Solid 
Tumors
Overview
Protocol I5B-JE-JGDK [A Phase 1 Study of Olaratumab in Japanese Patients with Advanced 
Soft Tissue Sarcoma or Advanced Solid Tumors] has been amended to reduce unnecessary 
interventions and physical or non-physical burden for the patients after enough data was obtained 
to assess the primary objective and the secondary objectives. The new protocol is indicated by 
Amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Section 8.1.3.2, Section 9.2.2 and Attachment 4:
The central review of ECGs will not be mandatory, and the frequency of ECGs was 
reduced for any patient under treatment over 3 years.

Section 8.2.2.1 and Section 8.2.3:
PK samples/immunogenicity samples will not be collected except for 
sampling required for the follow-up visit or the event of an infusion-related 
reaction for any patient under treatment over 3 years..

Attachment 1 and Attachment 2:
Coagulation test and urinalysis will not be mandatory for any patient under
treatment over 3 years.

Minor editorial changes were made for accuracy, consistency and clarity.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2.
Synopsis
Length of Study:  
Estimated first patient visit:  February 2015First patient enrolled (assigned to therapy): March 
2015           Estimated last patient visit:  July 2016 March 2019
5.2.
Rationale for Amendments
5.2.1. Rationale for Amendment (a)
The study was amended to add Cohort 3 in Part A to confirm the safety and tolerability of 
20 mg/kg of olaratumab as the loading dose (Cycle 1), followed by 15 mg/kg in subsequent 
cycles, and 75 mg/m2 of doxorubicin in every cycle.
5.2.2. Rationale for Amendment (b)
The study was amended to reduce unnecessary interventions and physical or non-physical burden 
for the patients after enough data was obtained to assess the primary objective and the secondary 
objectives.
8.1.3.2.
Electrocardiograms
When enough data for the analysis of the primary and the secondary endpoints has been 
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, 12-lead digital ECGs will be performed annually (±2 weeks) except for the 
ECG scheduled to be performed at the follow-up visit; each assessment will be conducted locally 
according to the procedure at the respective site.  Investigators will still be responsible for patient 
safety management, however centralized review will no longer be mandatory. If clinically 
indicated, 12-lead digital ECGs can be performed more frequently.
8.2.2.1.
Pharmacokinetic Samples
When enough data for the analysis of the primary and the secondary endpoints has been 
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, PK samples will no longer be collected except for sampling required for the 
follow-up visit (Attachment 4).


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8.2.3. Samples for Immunogenicity Research
When enough data for the analysis of the primary and the secondary endpoints has been 
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, immunogenicity samples will no longer be collected except for sampling 
required for the follow-up visit or in the event of an infusion-related reaction (Attachment 4).
9.2.2. Ancillary Data
When enough data for the analysis of the primary and the secondary endpoints has been 
collected as determined by the sponsor and the patient has continued the study treatment for 
more than 3 years, electrocardiogram data will no longer be stored electronically in the central 
vendor’s system.
10.8.
Interim Analyses
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, biomarker, and PK.  
All data defined in the protocol will continue to be collected from patients on treatment after the 
data cutoff date unless otherwise specified.  These data may be reported separately and the 
analyses on all patients, including these data, may not be performed.


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Attachment 1.
Protocol I5B-JE-JGDK Study Schedule
Study Schedule for Protocol I5B-JE-JGDK – Part A:  Screening and Cycle 1
b
Vital sign measurements will be obtained prior to and at the completion of each olaratumab administraition, and prior to each doxorubicin administration.  
Study Schedule for Protocol I5B-JE-JGDK – Part A:  Cycle 2 and beyond
Cycle 2-6 
Cycle 7-n
Follow-
Relative day within a cycle 
1a
2
3
8
1b
8
Upc
Allowance (days)
+3
±3d
+3
±3
±5
Comments
Coagulation
Xe
Xe,h
X
Should be performed approximately every 6 weeks (ie, at the 
beginning of Cycle 3 and every other cycle thereafter).
Urinalysis
Xe
Xe,h
X
h
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the sponsor and the patient has continued 
the study treatment for more than 3 years, coagulation test and urinalysis will no longer be mandatory.
Study Schedule for Protocol I5B-JE-JGDK – Part B:  Cycle 2 and beyond
Cycle 2-n
Follow-
Upb 
Relative Day Within a Cycle
1a
8
Comments
Allowance (days)
+3
±3c
±5
Coagulation
Xd,f
X
Should be performed approximately every 6 weeks (ie, at the beginning of Cycle 3 
and every other cycle thereafter).
Urinalysis
Xd,f
X
f
When enough data for the analysis of the primary and the secondary endpoints has been collected as determined by the sponsor and the patient has continued 
the study treatment for more than 3 years, coagulation test and urinalysis will no longer be mandatory.






Leo Document ID = 80fabefa-a076-4330-bd78-5b41c2f53553
Approver: 
Approval Date & Time: 28-Sep-2018 03:48:50 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 28-Sep-2018 07:49:57 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I5B-JE-JGDK Version 1 
 
 
A Phase 1 Study of Olaratumab in Japanese Patients with Advanced Soft Tissue Sarcoma or 
Advanced Solid Tumors 
 
NCT02377752 
 
Approval Date: 4-Mar-2015 
 
 
 
 
 


I5B-JE-JGDK Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan:  
I5B-JE-JGDK:  A Phase 1 Study of Olaratumab in 
Japanese Patients with Advanced Soft Tissue Sarcoma or 
Advanced Solid Tumors
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
Olaratumab (LY3012207)
This Phase 1 study is a multicenter, nonrandomized, open–label study to evaluate 
intravenous olaratumab in combination with doxorubicin in Japanese patients with 
advanced soft tissue sarcoma or advanced solid tumors (Part A), and intravenous 
olaratumab alone in Japanese patients with advanced solid tumors (Part B).
Eli Lilly Japan K.K.
Kobe, Hyogo Japan
Protocol I5B-JE-JGDK
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 04-Mar-2015 GMT


I5B-JE-JGDK Statistical Analysis Plan Version 1
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I5B-JE-JGDK:  A Phase 1 Study of 
Olaratumab in Japanese Patients with Advanced Soft Tissue Sarcoma 
or Advanced Solid Tumors..................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
4.3.
Exploratory Objectives...................................................................................................7
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ......................................................................................10
5.3.
Method of Assignment to Treatment ............................................................................10
6.
A Priori Statistical Methods ..............................................................................................11
6.1.
General Considerations ................................................................................................11
6.1.1.
Analysis Populations............................................................................................11
6.1.2.
Data Analyses ......................................................................................................11
6.2.
Adjustments for Covariates ..........................................................................................12
6.3.
Handling of Dropouts or Missing Data.........................................................................12
6.4.
Multiple Comparisons/Multiplicity...............................................................................12
6.5.
Use of an “Efficacy Subset” of Patients........................................................................12
6.6.
Patient Disposition .......................................................................................................12
6.7.
Patient Characteristics ..................................................................................................12
6.8.
Treatment Compliance .................................................................................................13
6.9.
Concomitant Therapy...................................................................................................13
6.10. Efficacy Analyses ........................................................................................................13
6.10.1.
Primary Outcomes and Methodology ...................................................................13
6.10.2.
Other Secondary Efficacy Analyses .....................................................................14
6.10.2.1.
Tumor assessment including tumor size evaluation.........................................14
6.10.2.2.
Other efficacy outcomes .................................................................................14
6.10.2.2.1.
Overall Survival........................................................................................14
6.10.2.2.2.
Progression-free Survival..........................................................................14
6.10.2.2.3.
Duration of Resonse..................................................................................15
6.11. Safety Analyses............................................................................................................16
6.11.1.
Extent of Exposure...............................................................................................16


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6.11.2.
Dose-limiting toxicity ..........................................................................................17
6.11.3.
Adverse Events ....................................................................................................17
6.11.4.
Deaths, Serious Adverse Events, and Other Significant 
Adverse Events ....................................................................................................17
6.11.5.
Clinical Laboratory Evaluation.............................................................................18
6.11.6.
Vital Signs and Other Physical Findings...............................................................18
6.11.7.
Electrocardiograms and Echocardiography...........................................................18
6.11.7.1.
PK matched ECG Data...................................................................................19
6.11.7.2.
Echocardiography...........................................................................................19
6.12. Biomarker Analyses.....................................................................................................19
6.13. Subgroup Analyses.......................................................................................................19
6.14. Protocol Deviations......................................................................................................19
6.15. Interim Analyses and Data Monitoring.........................................................................19
6.16. Annual Report Analyses...............................................................................................20
6.17. Clinical Trial Registry Analyses...................................................................................20
7.
References ........................................................................................................................22


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Table of Contents
Table
Page
Table JGDK.6.1. Censoring rules..............................................................................................14


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Table of Contents
Figure
Page
Figure JGDK.5.1.
Illustration of study design for Protocol I5B-JE-JGDK. ..............................8
Figure JGDK.5.2.
Illustration of study schedule in Part A........................................................9
Figure JGDK.5.3.
Illustration of study schedule in Part B......................................................10


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3.
Revision History
SAP Version 1 was approved prior to the first patient visit. This version of SAP was based on 
the protocol approved on December 9, 2014.


I5B-JE-JGDK Statistical Analysis Plan Version 1
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4.
Study Objectives
4.1.
Primary Objective
The study is divided into two parts:
The primary objective of Part A is to evaluate the safety and tolerability of olaratumab in 
combination with doxorubicin in Japanese patients with advanced solid tumors, especially soft 
tissue sarcoma (STS).
The primary objective of Part B is to evaluate the pharmacokinetics (PK) profile of olaratumab
in Japanese patients with advanced solid tumors.
4.2.
Secondary Objectives
The secondary objectives of Part A are: 
•
To evaluate the PK of olaratumab and doxorubicin
•
To evaluate the immunogenicity of olaratumab
•
To document any antitumor activity of olaratumab in combination with doxorubicin
The secondary objectives of Part B are:
•
To evaluate the safety and tolerability of olaratumab
•
To evaluate the immunogenicity of olaratumab
•
To document any antitumor activity of olaratumab
4.3.
Exploratory Objectives
The exploratory objective of Part A and Part B is to evaluate potentially relevant biomarkers 
related to the mechanism of olaratumab, the PDGF signaling pathway, and the pathobiology of 
cancer.


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5.
Study Design
5.1.
Summary of Study Design
This is a multicenter, nonrandomized, open-label, Phase 1 study. The study is divided into 2 
parts, Part A and Part B.  Part A and Part B will be conducted in parallel.  The DLT evaluation of 
Cohort 1 and Cohort 2 in Part A will be performed independently.  The study design is 
summarized in Figure JGDK.5.1.
•
Solid tumor, especially 
soft tissue sarcoma
•
ECOG PS = 0,1
•
LVEF ≥50%
Cohort 2b (N=6)
• Combination therapy (21 days/cycle): Up to 6 cycles or 
until when cumulative dose of doxorubicin reaches 
500 mg/m2, whichever comes later.

Olaratumab 15 mg/kg on D1 and D8

Doxorubicin 75 mg/m2 on D1
• Monotherapy (21 days/cycle): Cycle 7 and beyonda

Olaratumab 15 mg/kg on D1 and D8
Cohort 1 (N=6)
• Combination therapy (21 days/cycle): Up to 6 cycles or until 
when cumulative dose of doxorubicin reaches 500 mg/m2, 
whichever comes later. 

Olaratumab 15 mg/kg on D1 and D8

Doxorubicin 25 mg/m2 on D1, D2 and D3
• Monotherapy (21 days/cycle): Cycle 7 and beyonda

Olaratumab 15 mg/kg on D1 and D8
Part A
•
Solid tumor
•
ECOG PS = 0,1
(N=6)
Monotherapy (21 days/cycle)

Olaratumab 15 mg/kg on D1 and D8
Part B
Abbreviations:  ECOG = Eastern Cooperative Oncology Group; PS = performance score; 
D= day; N = number of patients; LVEF = left ventricular ejection fraction
a
For patients whose cumulative dose of doxorubicin does not reach 500 mg/m2 during 
the first 6 cycles due to dose reductions or omissions, doxorubicin can be administrated 
up to 500 mg/m2 on Cycle 7 and beyond, at the discretion of the investigator.
b
Refer to Section 7.2.1.4 in the protocol for the timing to open Cohort 2. 
Figure JGDK.5.1.
Illustration of study design for Protocol I5B-JE-JGDK.
Part A is designed to evaluate the safety and tolerability of olaratumab in combination with 
doxorubicin in Japanese patients with advanced solid tumors, especially advanced STS.






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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly Japan K.K.
Pharmacokinetic analyses will be planned separately from this SAP.
6.1.1. Analysis Populations
The Analysis populations are defined as follows: 
•
Enrolled Population:  Anyone who signed the informed consent and who was confirmed to 
be eligible and have been assigned to a treatment will be included in this population.
•
FAS Population:  All enrolled patients who received any amount of study drugs (either 
olaratumab or doxorubicin) will be included in the FAS Population. The FAS Population is 
based on the intent-to-treat principle and will be used for the analysis of baseline 
characteristics, efficacy data, safety data, and biomarkers. 
•
DLT Population:  All enrolled patients who will complete Cycle 1 (initial 21-day treatment 
period), or who will discontinue due to DLT during Cycle 1, will be included in the DLT 
Population.  Patients who will discontinue during Cycle 1 due to other reasons than DLT will 
be excluded from the DLT Population.  The DLT Population will be used for summarizing a 
proportion of patients with DLT.
6.1.2. Data Analyses
All summary tables, figures and data listings will be produced by using the statistical packages
SAS version 9.2 (or a more recent version).
Data will be summarized by part and cohort.
Baseline is defined as the last non-missing observation prior to the time of the first infusion of 
the study drug, unless otherwise stated.  Observations on the same day of the first infusion of the 
study drug for which the time (hours and/or minutes) is missing and, according to the study
schedule, to be collected prior to treatment, will also be considered baseline.
Descriptive statistics will include counts and percentages for categorical variables, and number
of observations, mean, standard deviation, median, minimum and maximum for continuous 
variables unless otherwise stated.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
The following data handling conventions will be applied in the analyses.
Study Day: Study day indicates the number of days the patient has been receiving study 
treatment.  It is calculated as (assessment date)-(date of the first infusion of the study drug)+1
days if the assessment is done on or after the first infusion day of the study drug.  If the 
assessment is done prior to the first infusion day of the study drug, study day will be calculated 
as (assessment date)-(date of the first infusion of the study drug). Date of the first infusion of the 
study drug is defined as study day 1.


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6.2.
Adjustments for Covariates
Adjustments for covariates will not be performed in any analysis of this study.
6.3.
Handling of Dropouts or Missing Data
The birth date will be imputed by assigning month and day with July 1st to calculate age.
The following rules will be used for the imputation of incomplete initial pathological diagnosis 
date for the purpose of deriving duration of disease:
•
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day.
•
If both the day and the month are missing, July 1st will be used to replace the missing 
information.
Patient data listings will show partial dates without applying the above imputation rules.
In other measurement for efficacy and safety variables, the imputation for missing values will 
not be performed.
6.4.
Multiple Comparisons/Multiplicity
No adjustments for multiplicity will be made in this study.
6.5.
Use of an “Efficacy Subset” of Patients
No particular efficacy subsets will bedefined in this study.
6.6.
Patient Disposition
Frequency distributions of patients in the Enrolled population, the FAS population or the DLT
population (Part A only), will be summarized by part and cohort. 
Summary of the screen failure and reason will be provided.
For the Enrolled population, frequency distributions of patients with a specific value for 
disposition (i.e. completion or discontinuation) will be summarized by part and cohort. Also, 
frequency distributions of patients who discontinued will also be summarized by part, cohort and 
reason for discontinuation.
Listing of patient disposition and of primary reason for discontinuation will be provided for the 
Enrolled population.
6.7.
Patient Characteristics
For the FAS population, demographic and baseline disease characteristics will be summarized by 
part and cohort.
Demographic characteristics are as follows:
age (years), age categories (<65 years vs. ≥65 years), gender, race, height (cm), weight (kg), 
body surface area (m2) and Body Mass Index (kg/m2),


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where body surface area is calculated using DuBois method; 0.007184 weight0.425 height
0.725 and Body Mass Index = weight / (height / 100)2.
Baseline disease characteristics are as follows:
Alcohol use, Tobacco use, Eastern Cooperative Oncology Group (ECOG) performance status, 
initial pathological diagnosis (or cancer type), disease stage at diagnosis, TNM at diagnosis, sites 
of Metastatic Disease, and duration of disease (months from the first confirmation of cancer to 
the first infusion)
In addition, prior anticancer treatments or surgery (radiotherapy, surgical procedure and systemic 
therapy), historical conditions and pre-existing conditions will be summarized by part and cohort.
Listings of demographic and baseline disease characteristics, of historical conditions and of pre-
existing conditions also will be provided for the FAS population.
6.8.
Treatment Compliance
Details are described in Section 6.11.1.
6.9.
Concomitant Therapy
Concomitant therapies will be categorized using World Health Organization Drug dictionary.
Granulocyte colony stimulating factors (G-CSF) and other concomitant therapies will be 
summarized by part and cohort for the FAS population, respectively. Listings of G-CSF, other 
concomitant therapies and transfusion will be provided.
6.10. Efficacy Analyses
6.10.1. Primary Outcomes and Methodology
The objective response rate (ORR) and the disease control rate (DCR) will be primarily 
evaluated.
The ORR will be calculated as the number of patients who achieve a best overall response 
(BOR) of complete response (CR) or partial response (PR) using the investigator response 
assessments, divided by the total number of patients.
The DCR will be similarly calculated as the number of patients who achieve a BOR of CR, PR
or stable disease (SD) using the investigator response assessments, divided by the total number 
of patients.
Patients who do not have a tumor response assessment for any reason are considered as not 
evaluable (NE) and are included in the denominator when calculating these response rates. 
It should be noted that the BOR is determined from the sequence of cycle responses (i.e. 
responses obtained from the start of the study treatment until the study discontinuation). CR or 
PR will be claimed only if the criteria for each are met at a subsequent time point (at least 4 


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weeks). In the case of SD, measurements must have met the SD criteria at least once, at least 6 
weeks after the first infusion of the study drug.
For the FAS population, the ORR, DCR and BOR will be summarized by part and cohort with 
95% CI using the Wilson formula (Altman et al. 2000; Wilson 1927).
6.10.2. Other Secondary Efficacy Analyses
6.10.2.1. Tumor assessment including tumor size evaluation
For the FAS population, the waterfall plot of the best percentage change in tumor size will be 
provided. Also, line plot of percent change from baseline in tumor size may also be provided. 
Percent change from baseline in tumor size is calculated as follows and the smaller means better:
•
Percent change from baseline = (SUMPostbaseline – SUMBaseline) × 100 / SUMBaseline,
•
SUM = Longest diameter for extranodal lesions + short axis diameter for nodal lesions ,
where SUM is calculated only when all target/measurable lesions observed at baseline are
measured.
Listings will be prepared presenting relevant information on response (response on target lesions
including the percentage changes, response on non-target lesions, new lesions and overall 
response for each tumor assessment) for the FAS population.
6.10.2.2. Other efficacy outcomes
The overall survival (OS), the progression-free survival (PFS) and the duration of response
(DOR) will be evaluated using the Kaplan-Meier method as described bellow.
For the FAS population, a listing of efficacy outcomes (i.e. BOR, OS, PFS and DOR) will be 
provided.
6.10.2.2.1.Overall Survival
The OS is defined as the time from the date of the first infusion of the study drug to the date of 
death from any cause. If a patient is not known to have died on or before the date of data cut-off, 
the OS will be censored on the last date (on or before the cut-off date) the patient was known to 
be alive.
For the FAS population, the number of events and the OS will be summarized by part and cohort.
6.10.2.2.2.Progression-free Survival
The PFS is defined as the time from the date of the first infusion of the study drug to the date of
objectively determined PD or death from any cause, whichever is first. Censoring rules are
described in Table JGDK.6.1.
Table JGDK.6.1.
Censoring rules
Situation
Date of Progression or Censoring
Outcome


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Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessments
Date of the first infusion of the study drug
Censored
Progression documented 
between scheduled visits
Earliest of the following dates:
• Date of radiological assessment showing new lesion 
(if progression is based on new lesion)
• Date of last radiological assessment of measured 
lesions (if progression is based on increase in sum of 
measured lesions)
Progressed
No progression
Date of last radiological assessment of measured 
lesions
Censored
discontinuation for
undocumented progression
Date of last radiological assessment of measured 
lesions
Censored
Treatment discontinuation for 
toxicity or other reason
Date of last radiological assessment of measured 
lesions
Censored
New anticancer treatment started
Date of last radiological assessment of measured 
lesions
Censored
Death before first PD 
assessment
Date of death
Progressed
Death between adequate 
assessment visits
Date of death
Progressed
Death or progression after more 
than one missed visit
Date of last radiological assessment of measured 
lesions
Censored
For the FAS population, the number of events and the PFS will be summarized by part and 
cohort.
6.10.2.2.3.Duration of Response
The DOR is derived from data of patients who achieved response (CR or PR) and is defined as 
the time from the date of response achievement (the first observation of response before 
confirmation) to the date of objectively determined PD.
For the responders in the FAS population, the number of events and the DOR will be 
summarized by part and cohort.


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6.11. Safety Analyses
6.11.1. Extent of Exposure
The exposure data of the study drug (i.e. number of cycles, number of infusions, duration of 
treatment, cumulative dose, dose intensity and relative dose intensity) will be listed for the FAS 
population.
These data are defined as follows:
•
Number of cycles = Maximum cycle given per patient
•
Number of infusions for olaratumab = Total number of infusions
•
Duration of treatment for olaratumab (weeks) = (Date of Day 1 of last cycle + 21 – Date of 
Cycle 1 Day 1) / 7
•
Cumulative dose for olaratumab (mg/kg) = Sum of (total doses administered [mg] / baseline 
weight [kg] or available weight [kg] prior to each infusion in case of more than 10% change 
from baseline)
•
Dose intensity for olaratumab (mg/kg/week) = (Cumulative dose for olaratumab) / (Duration 
of treatment for olaratumab)
•
Relative dose intensity for olaratumab (%) = (Dose intensity) / (Planned weekly dose 
intensity) 100,
where planned weekly dose intensity (mg/kg/week) = 15 mg/kg 2 intravenous 
administrations / 3 weeks = 10 mg/kg/week.
[Part A only]
•
Number of infusions for doxorubicin = Total number of infusions
•
Duration of treatment for doxorubicin (weeks) = (Date of Day 1 of last cycle + 21 – Date of 
Cycle 1 Day 1) / 7
•
Cumulative dose for doxorubicin (mg/m2) = Sum of (total doses administered [mg] / 
baseline body surface area [m2] or available body surface area [m2] prior to each infusion in 
case of more than 10% change from baseline)
•
Dose intensity for doxorubicin (mg/m2/week)
•
Relative dose intensity for doxorubicin (%), where planned weekly dose intensity is 25 mg/
m2/week.
A listing of study drug exposures will be provided. Also, details of treatment delays, treatment 
omissions, treatment reductions, and treatment interruptions will be listed.


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6.11.2. Dose-limiting toxicity
In Part A, frequency distributions of patients who experienced any DLTs during Cycle 1 will be 
summarized by cohort using the DLT population. A listing of DLTs will be produced.
6.11.3. Adverse Events
The available latest version of Medical Dictionary for Regulatory Activities (MedDRA) will be 
utilized for categorizing to System Organ Class (SOC) and Preferred Term (PT). National 
Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.03 will be referred for identifying grade and/or relevant event term.
Treatment-emergent adverse events (TEAEs) are defined as events that first occurred or 
worsened in severity after/on the first infusion of the study drug.
Adverse events will be summarized by CTCAE term and MedDRA term. 
The summary by MedDRA term would be primary for the study report. For the FAS population, 
the following summaries will be provided by part and cohort:
•
An overview of AEs
•
Summary of TEAEs by SOC and PT
•
Summary of TEAEs by PT
•
Summary of TEAEs by SOC, PT and Maximum Grade
These analyses will be repeated for AEs related to study drug. Also, a listing of AEs will be 
prepared.
Using CTCAE term, TEAEs by CTCAE SOC, CTCAE Term and Maximum Grade will be 
summarized.
6.11.4. Deaths, Serious Adverse Events, and Other Significant 
Adverse Events
All deaths that occur after the first infusion of the study drug together with primary cause of 
death will be listed based on the FAS population.
The following items for AEs leading to death will be provided:
•
Summary of AEs leading to death by PT
•
Summary of AEs leading to death related to study drug by PT
•
Listing of AEs leading to death
For the FAS population, the following items for treatment emergent SAEs will be generated:
•
Summary of SAEs by PT
•
Summary of SAEs related to study drug by PT


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•
Listing of SAEs
As other significant AEs, the following items will be provided:
•
Summary of AEs leading to olaratumab discontinuation by PT
•
Summary of AEs leading to doxorubicin discontinuation by PT in Part A
•
Summary of AEs leading to olaratumab delay/omission/reduction/interruption by PT
•
Summary of AEs leading to doxorubicin delay/omission/reduction/interruption by PT in Part 
A
The above four items will be repeated for AEs related to study drug. Also, a listing of AEs 
leading to study drug discontinuation (olaratumab or doxorubicin in Part A and olaratumab in 
Part B) will be prepared.
6.11.5. Clinical Laboratory Evaluation
Laboratory results will be graded according to NCI-CTCAE Version 4.03, when applicable.
Grading will be purely based on the numeric results and no investigator’s assessment will be
considered. Laboratory values will be converted to standard units. The laboratory results not 
corresponding to terms in NCI-CTCAE Version 4.03 will not be graded.
For the FAS population, shift tables of graded laboratory parameters from baseline to the worst 
value on the study will be generated by part and cohort.
For the FAS population, the laboratory results will be presented in a listing with a flag for values 
outside of the laboratory normal range. Laboratory reference ranges will be listed. Also, a line 
plot of the laboratory results will also be provided.
6.11.6. Vital Signs and Other Physical Findings
Listings of vital signs, physical examinations, and Eastern Cooperative Oncology Group 
performance status will be provided for the FAS population.
6.11.7. Electrocardiograms and Echocardiography
Three replicate electrocardiograms (ECGs) will be obtained at each time point. All parameters 
will be fully read at the first measurement and only RR interval, QT interval and heart rate will 
be read at the second and third measurements. The average of them will be used for analysis, if 
applicable. If missing values exist, the average will be derived without the missing values.
QT analyses will be performed with Bazett and Fridericia correction (QTcB and QTcF),
respectively. QTcB and QTcF based on each read are calculated as follows:
•
QTcB = QT / RR1/2
•
QTcF = QT / RR1/3


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6.11.7.1. PK matched ECG Data
The change will be calculated using the time-matched baseline for Cycle 1. Frequency 
distributions of patients who fulfill the following criteria will be summarized by part and cohort 
for the FAS population.
•
QTc values: >450, >480, and >500 msec
•
The change from baseline in QTc: >30 and >60 msec
Line plot of QTc values and their time-matched changes from baseline will be provided based on 
the FAS population.
Also, the time-matched changes will be plotted against the blood concentration of olaratumab by 
part and cohort for the FAS population. A linear regression model will be used to investigate the 
relationship between the QTc changes and the concentration of olaratumab and the fitted model 
and the 90% confidential interval will also be shown in the plot. It should be noted that, in 
Cohort 2 of Part A, ECG data at the sampling time of  ‘0.5 h ± 5 min Postinfusion of 
doxorubicin’ in both Cycle 1 and Cycle 3 will be excluded to avoid the effect of doxorubicin.
Especially when olaratumab and doxorubicin will be administered on Day 8 in Cycle 3, 
additional sampling times (‘1 h ± 10 min Postinfusion of olaratumab’, ‘48 ± 6 h Postinfusion of 
olaratumab’, ‘72 ± 6 h Postinfusion of olaratumab’ and ‘168 ± 8 h Postinfusion of olaratumab’) 
will be excluded.
ECG data including QTc values and their time-matched changes from baseline will be listed. A 
listing of blood concentration of olaratumab will be provided.
6.11.7.2. Echocardiography
Normal/Abnormal results of echocardiography will be listed.
6.12. Biomarker Analyses
For the FAS population, descriptive statistics for biomarkers obtained from blood samples will 
be provided by part and cohort. Also, listings of all biomarkers will be prepared.
6.13. Subgroup Analyses
Subgroup analyses are not preplanned, but some subgroup analyses may be conducted, if needed. 
6.14. Protocol Deviations
Important protocol deviations will be described in a separate document and the information will 
be provided by the Clinical Trial Manager to the Statistician in an Excel file.  The Statistician 
will convert the Excel file to a SAS dataset, and store both of them in SAS Drug Development 
(SDD) for the use of analysis.
A listing of protocol deviations will be provided with the Enrolled population.
6.15. Interim Analyses and Data Monitoring
Interim access to safety data will be performed during the study for safety review.


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In this study, preplanned interim analysis will be conducted after completing Cycle 1 and the 
DLT evaluation in Cohort 2 of Part A. Interim safety analyses will be conducted for the decision 
of joining future global phase 3 studies. Deatils of the safety analyses will refer to Section 6.11.
Additional interim analyses may be conducted, if needed.
6.16. Annual Report Analyses
The datasets including the following tables and listings will be generated for the Development 
Safety Update Report (DSUR) reports based on the resource document ‘Statistical Guidance and 
Mock Tables for the Development Safety Update Report (DSUR) and Periodic Safety Update 
Report (PSUR) / Periodic Benefit Risk Evaluation Report (PBRER)’:
•
Summary of patients demographics by age and gender
•
Summary of patients demographics by racial groups
•
Summary of cumulative patient exposure information
•
Listing of patients who died
•
Listing of patients who discontinued study rugs or study due to AEs
Investigator’s Brochure (IB) related analyses may be conducted at the same time as the DSUR 
analyses if applicable.
6.17. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by part and 
cohort, by MedDRA term.
•
An adverse event is considered ‘Serious’ whether or not it is a TEAE.
•
An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term, part and cohort, the
following are provided:
•
the number of participants at risk of an event
•
the number of participants who experienced each event term
•
the number of events experienced.
•
Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients in every part and cohort may not be included if a 5% threshold is
chosen (5% is the minimum threshold).


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•
AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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7.
References
Altman DG, Bryant TN, Gardner MJ, Machin, D. (Eds) Statistics with Confidence: confidence
intervals and statistical guidelines, 2nd ed. London: British Medical Journal; 2000.
Wilson EB. Probable inference, the law of succession, and statistical inference. J Am Stat 
Assoc.1927;22:209-212.


Leo Document ID = 870f9863-ede5-4375-8016-4d6980923dfb
Approver: 
Approval Date & Time: 04-Mar-2015 03:02:30 GMT
Signature meaning: Approved
PPD