Clinical trial NCT02783599
Conditions: Soft Tissue Sarcoma
Sponsor: Eli Lilly and Company
Start date: 2016-10-11; Completion date: 2018-07-05
Enrollment: 51 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate potential biomarkers and method of action, efficacy and safety of olaratumab in participants with soft tissue sarcoma (STS).

Detailed description:

Arms: arm 1: Cycle 1: Olaratumab 20 milligram per kilogram (mg/kg) given intravenously (IV) on Day 1 and Day 8 (21 day cycle).

Cycle 2: Olaratumab 20 mg/kg given IV on Day 1 and Day 8 plus doxorubicin 75 mg/m2 given IV on Day 1 (21 day cycle).

Cycle 3 through Cycle 7: Olaratumab 15 mg/kg given IV on Day 1 and Day 8 plus doxorubicin 75 mg/m2 given IV on Day 1 (21 day cycles). arm 2: Olaratumab given IV on Day 1 and Day 8 (21 day cycle) concurrently with radiotherapy.

Radiotherapy addendum was not implemented.
Interventions: intervention 1: Olaratumab intervention 2: Doxorubicin intervention 3: External Beam Radiotherapy
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV intervention 3: None

Protocol documents:
Prot_000.pdf: 
Protocol I5B-MC-JGDM(c) 
 
Title: A Phase 1b Trial to Assess the Modulation of Biological Markers in Patients with Potentially 
Resectable Soft Tissue Sarcoma Treated with Olaratumab Monotherapy Followed by Olaratumab plus 
Doxorubicin Combination Therapy 
 
NCT02783599 
 
Approval Date: 08-May-2017 


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Approval Date: 
1. Protocol I5B-MC-JGDM(c)
A Phase 1b Trial to Assess the Modulation of Biological 
Markers in Patients with Potentially Resectable Soft Tissue
Sarcoma Treated with Olaratumab Monotherapy Followed 
by Olaratumab plus Doxorubicin Combination Therapy
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.
Olaratumab (LY3012207)
Study I5B-MC-JGDM is an open-label, single-arm, multicenter, multicountry Phase 1b 
study to enumerate whole blood circulating tumor cells and to characterize platelet-derived 
growth factor receptor alpha, platelet-derived growth factor receptor beta and canonical 
ligands (PDGF-A, B, C, and D) expression changes pre- and post-olaratumab monotherapy 
in tumor tissue in patients with potentially resectable soft tissue sarcoma.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 02 March 2016
Amendment (a) Electronically Signed and Approved by Lilly: 25 May 2016
Amendment (b) Electronically Signed and Approved by Lilly:  26 Jul 2016
Amendment (c) Electronically Signed and Approved by Lilly
on approval date provided below:
Approval Date: 08-May-2017 GMT


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2. Synopsis
This Phase 1b study is an open-label, single-arm, multicenter, multicountry study to enumerate 
whole blood circulating tumor cells and to characterize platelet-derived growth factor receptor
alpha, platelet-derived growth factor receptor beta, and canonical ligands (PDGF-A, B, C, and D)
expression changes pre- and post-olaratumab monotherapy in tumor tissue in patients with 
potentially resectable soft tissue sarcoma.


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3. Table of Contents
A Phase 1b Trial to Assess the Modulation of Biological 
Markers in Patients with Potentially Resectable Soft Tissue 
Sarcoma Treated with Olaratumab Monotherapy Followed by 
Olaratumab plus Doxorubicin Combination Therapy
Section
Page
1.
Protocol I5B-MC-JGDM(c)  A Phase 1b Trial to Assess the 
Modulation of Biological Markers in Patients with Potentially 
Resectable Soft Tissue Sarcoma Treated with Olaratumab 
Monotherapy Followed by Olaratumab plus Doxorubicin 
Combination Therapy..........................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................3
4.
Abbreviations and Definitions...........................................................................................10
5.
Introduction ......................................................................................................................16
5.1.
Rationale and Justification for the Study ......................................................................16
5.2.
Objectives ....................................................................................................................17
5.2.1.
Primary Objectives...............................................................................................17
5.2.2.
Secondary Objectives...........................................................................................18
5.2.3.
Exploratory Objectives.........................................................................................18
5.3.
General Introduction to Olaratumab .............................................................................18
5.4.
Rationale for Selection of Dose....................................................................................19
6.
Investigational Plan...........................................................................................................21
6.1.
Study Population..........................................................................................................21
6.1.1.
Inclusion Criteria .................................................................................................21
6.1.2.
Exclusion Criteria ................................................................................................23
6.2.
Summary of Study Design............................................................................................24
6.2.1.
Study Completion and End of Trial......................................................................27
6.3.
Discontinuations ..........................................................................................................27
6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................28
6.3.2.
Discontinuation of Patients from Study or Study Drug .........................................28
6.3.3.
Patients Lost to Follow-Up...................................................................................29
6.3.4.
Discontinuation of Study Sites .............................................................................29
6.3.5.
Discontinuation of the Study................................................................................29
7.
Treatment..........................................................................................................................30
7.1.
Materials and Supplies .................................................................................................30


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7.1.1.
Packaging and Labelling ......................................................................................30
7.1.2.
Olaratumab ..........................................................................................................30
7.1.3.
Doxorubicin.........................................................................................................31
7.2.
Study Drug Administration ..........................................................................................31
7.2.1.
Treatments Administered .....................................................................................31
7.2.2.
Premedication ......................................................................................................32
7.2.3.
Dose Modifications..............................................................................................33
7.2.3.1.
Dose Delays, Modifications, and Discontinuations .........................................33
7.2.3.1.1.
Olaratumab...............................................................................................35
7.2.3.1.1.1.
Infusion-Related Reactions .................................................................35
7.2.3.1.1.2.
Hematologic Toxicity..........................................................................36
7.2.3.1.1.3.
Nonhematologic Toxicity....................................................................37
7.2.3.1.2.
Doxorubicin..............................................................................................37
7.2.3.1.2.1.
Hematologic Toxicity..........................................................................37
7.2.3.1.2.2.
Cardiovascular Toxicity......................................................................38
7.2.3.1.2.3.
Hepatic Impairment.............................................................................38
7.2.3.1.2.4.
Nonhematologic Toxicity....................................................................39
7.3.
Method of Assignment to Treatment ............................................................................39
7.3.1.
Selection and Timing of Doses.............................................................................39
7.4.
Blinding .......................................................................................................................39
7.5.
Concomitant Therapy...................................................................................................39
7.5.1.
Supportive Care ...................................................................................................40
7.5.1.1.
Dexrazoxane...................................................................................................40
7.5.1.2.
Granulocyte-Colony Stimulating Factors and Erythroid 
Growth Factors...............................................................................................40
7.5.1.3.
Transfusion of Blood Products........................................................................41
7.5.1.4.
Anti-emetic Therapy.......................................................................................41
7.5.2.
Prohibited Therapies ............................................................................................41
7.5.2.1.
Effect of CYP3A4, CYP2D6, and P-gp Inhibitors and 
Inducers on Doxorubicin ................................................................................41
7.6.
Treatment Compliance .................................................................................................41
7.6.1.
Evaluable Patients................................................................................................41
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................43
8.1.
Safety Evaluations........................................................................................................43
8.1.1.
Safety Data Collection and Review ......................................................................43
8.1.2.
Adverse Events ....................................................................................................43
8.1.2.1.
Serious Adverse Events ..................................................................................44
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................45


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8.1.2.2.1.
Prior to Administration of Study Drugs.....................................................45
8.1.2.2.2.
On Study Treatment..................................................................................45
8.1.2.2.3.
Follow-Up Visit........................................................................................46
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................46
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................46
8.1.3.
Other Safety Measures .........................................................................................47
8.1.3.1.
Electrocardiograms.........................................................................................47
8.1.3.2.
Echocardiograms/MUGA Scans .....................................................................48
8.1.4.
Safety Monitoring ................................................................................................48
8.1.4.1.
Adverse Events of Special Interest..................................................................49
8.1.5.
Complaint Handling.............................................................................................49
8.2.
Sample Collection and Testing.....................................................................................50
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................50
8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................50
8.2.2.1.
Pharmacokinetic Samples...............................................................................50
8.2.3.
Samples for Biomarkers .......................................................................................51
8.2.3.1.
Blood Samples................................................................................................52
8.2.3.2.
Tumor Tissue .................................................................................................52
8.2.3.3.
Imaging Studies..............................................................................................54
8.2.4.
Samples for Pharmacogenetics .............................................................................54
8.2.5.
Samples for Immunogenicity Research.................................................................54
8.3.
Efficacy Evaluations ....................................................................................................54
8.4.
Procedure/Sampling Compliance..................................................................................55
9.
Data Management Methods...............................................................................................56
9.1.
Data Quality Assurance................................................................................................56
9.2.
Data Capture Systems ..................................................................................................56
9.2.1.
Case Report Form ................................................................................................56
9.2.2.
Ancillary Data......................................................................................................57
10.
Data Analyses...................................................................................................................58
10.1. General Considerations ................................................................................................58
10.1.1.
Determination of Sample Size..............................................................................58
10.1.2.
Analysis Populations............................................................................................59
10.2. Patient Disposition .......................................................................................................59
10.3. Patient Characteristics ..................................................................................................59
10.4. Safety Analyses............................................................................................................59
10.5. Biomarker Analyses.....................................................................................................60
10.6. Efficacy........................................................................................................................60


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10.7. Pharmacokinetic Analyses............................................................................................61
10.8. Interim Analyses ..........................................................................................................61
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................62
11.1. Informed Consent.........................................................................................................62
11.2. Ethical Review.............................................................................................................62
11.3. Regulatory Considerations ...........................................................................................62
11.3.1.
Investigator Information.......................................................................................63
11.3.2.
Protocol Signatures ..............................................................................................63
11.3.3.
Final Report Signature .........................................................................................63
12.
References ........................................................................................................................64


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List of Tables
Table
Page
Table JGDM.1.
Treatment Regimens......................................................................................32
Table JGDM.2.
General Guidelines for Olaratumab Dose Modification Due to 
Hematologic Toxicity Deemed Related to Olaratumab...................................36
Table JGDM.3.
General Guidelines for Olaratumab Dose Modification Due to 
Nonhematologic Toxicity Deemed Related to Olaratumab.............................37
Table JGDM.4.
General Guidelines for Doxorubicin Dose Modification Due to 
Neutropenia...................................................................................................38
Table JGDM.5.
Adverse Event and Serious Adverse Event Reporting Guidelines...................47
Table JGDM.6.
Bazett’s QT Heart Rate Correction Formula ..................................................48
Table JGDM.8.3 Fridericia’s QT Correction Formula...............................................................48


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List of Figures
Figure
Page
Figure JGDM.1. Illustration of study design.............................................................................26


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List of Attachments
Attachment
Page
Attachment 1.
Protocol JGDM Study Schedule.....................................................................66
Attachment 2.
Protocol JGDM Clinical Laboratory Tests .....................................................75
Attachment 3.
Protocol JGDM Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................77
Attachment 4.
Protocol JGDM Biomarker, Pharmacokinetic, and Immunogenicity 
Blood Sampling Schedule..............................................................................78
Attachment 5.
Protocol JGDM Recommendations for Reporting 
Serious Adverse Events .................................................................................81
Attachment 6.
Protocol JGDM ECOG Performance Status...................................................82
Attachment 7.
Protocol JGDM Creatinine Clearance Formula ..............................................83
Attachment 8.
Protocol JGDM RECIST Criteria...................................................................84
Attachment 9.
Protocol JGDM CYP3A4, CYP2D6, and P-gp Inhibitors and Inducers 
of Doxorubicin ..............................................................................................91
Attachment 10.
Protocol JGDM Protocol Amendment I5B-MC-JGDM(c) Summary:  A 
Phase 1b Trial to Assess the Modulation of Biological Markers in 
Patients with Potentially Resectable Soft Tissue Sarcoma Treated with 
Olaratumab Monotherapy Followed by Olaratumab plus Doxorubicin 
Combination Therapy ....................................................................................93


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4. Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to the last 
measurable plasma concentration
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
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).
BE1
biomarker evaluable 1
BE2
biomarker evaluable 2
C1D1
Cycle 1 Day 1
C1D8
Cycle 1 Day 8
C2D1
Cycle 2 Day 1
C2D8
Cycle 2 Day 8
C3D1
Cycle 3 Day 1
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
clearance


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CLRM
clinical laboratory results modernization
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.
complaint
Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
CR
complete response
CRu
complete response unconfirmed
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
CTC
circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DCSI
Development Core Safety Information
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
ethylenediaminetetraacetic


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EMT
epithelial-mesenchymal transition
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last 
patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least 1 dose of study treatment.
enter
Patients who are entered in the trial are those who have signed the informed 
consent form directly or through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board:  /A board or committee 
(institutional, regional, or national) composed of medical and nonmedical 
members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical study are protected.
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factor
GIST
gastrointestinal stromal tumors
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IG
immunogenicity
IgG1
immunoglobulin G, subclass 1
IHC
immunohistochemistry
informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the 
trial that are relevant to the patient’s decision to participate.  Informed consent 
is documented by means of a written, signed and dated informed consent form.
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for datalock.
IRR
infusion-related reaction


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investigational 
product (IP)
A pharmaceutical form of an active substance or placebo being tested or used as 
a reference in a clinical trial.  Investigational product includes a product with a 
marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from 
the authorized form
2.
used for an unauthorized indication or
3.
used to gain further information about the authorized form
investigator
A person responsible for the conduct of the clinical study at a study site.  If a 
study is conducted by a team of individuals at a study site, the investigator is the 
responsible leader of the team and may be called the principal investigator.
ITT
intent-to-treat
IV
intravenous(ly)
IWRS
Interactive Web Response System
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.
LMS
leiomyosarcoma
LVEF
left ventricular ejection fraction
MAPK
mitogen-activated protein kinase 
MedDRA
Medical Dictionary for Regulatory Activities
MOA
mechanism of action
monitor
A person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local standard operating procedures (if any), and 
global Medical standard operating procedures.  Monitors are trained on the 
investigational product(s), the protocol, informed consent document, any other 
written information provided to subjects, relevant standard operating 
procedures, International Conference on Harmonisation Good Clinical Practice 
guidelines, and all applicable laws (for example, privacy and data protection) 
and regulations. 
mOS
median overall survival
MRI
magnetic resonance imaging
MUGA
multi-gated acquisition
NCCN
National Comprehensive Cancer Network


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NCI
National Cancer Institute
open-label
A study in which there are no restrictions on knowledge of treatment allocation; 
therefore, the investigator and the study participants are aware of the drug 
therapy received during the study.
ORR
objective response rate
patient
A subject with a defined disease.
PD
progressive disease 
PDGF
platelet-derived growth factor
PDGFRα
platelet-derived growth factor receptor alpha
PDGFRβ
platelet-derived growth factor receptor beta
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PR
partial response
PS
performance status
QTc
corrected QT interval
QTcF
Fridericia’s QT corrected interval
RECIST
Response Evaluation Criteria in Solid Tumors
Resectability
Evaluation of the resectability of a tumor is determined by the surgeon in 
consultation with the multi-disciplinary team, and depends on the tumor stage 
and the patient’s co-morbidity.  The primary aim of surgery is to completely 
excise the tumor with a margin of normal tissue.
reporting database
A point-in-time copy of the collection database.  The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data.
re-screen
to screen a patient who was previously declared a screen failure for the same 
study
SAE
serious adverse event


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screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.  In this 
study, screening involves invasive or diagnostic procedures and/or tests (for 
example, diagnostic psychological tests, x-rays, blood draws).  For this type of 
screening, informed consent for these screening procedures and/or tests shall be 
obtained; this consent may be separate from obtaining consent for the study.
screen failure
A patient who does not meet one or more criteria required for participation in a 
trial
SD
stable disease
sponsor
The party who takes responsibility for the initiation, management and/or 
financing of a clinical study.
STS
soft tissue sarcoma
study completion
This study will be considered complete once Lilly determines that the 
evaluations of the primary objective and safety are sufficient and complete.
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TPO
third-party organization
ULN
upper limit of normal
Vd
volume of distribution


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A Phase 1b Trial to Assess the Modulation of Biological 
Markers in Patients with Potentially Resectable Soft Tissue 
Sarcoma Treated with Olaratumab Monotherapy Followed by 
Olaratumab plus Doxorubicin Combination Therapy
5. Introduction
5.1.
Rationale and Justification for the Study
Soft tissue sarcoma (STS) is a heterogeneous group of tumors that arise mainly from embryonic 
mesoderm, with some neuroectodermal contribution and differentiation to non-epithelial 
extraskeletal tissue including muscle, fat, and fibrous tissue (D’Angelo et al. 2014).  There are 
approximately 50 tumor subtypes of STS (Sharma et al. 2013) and they can be located anywhere 
in the body.  Soft tissue sarcoma is rare, comprising approximately 1% of adult cancers. The
annual incidence of STS in the United Kingdom and United States is 3300 and 10,000, 
respectively (Jemal et al. 2009; NCIN [WWW]).  Soft tissue sarcoma is best treated by 
multidisciplinary teams specialized in the management of these tumors (Linch et al. 2014). 
When the disease is localized, it is usually treated with curative intent using surgical resection 
with or without radiotherapy and/or chemotherapy.  Unfortunately, STS recurs frequently as 
locally inoperable or metastatic disease, at which time systemic therapy plays a prominent role in 
the multidisciplinary management of this tumor.  Single-agent doxorubicin is still considered the 
standard treatment option for many patients with metastatic STS (NCCN 2011; ESMO 2014; 
Schoffski et al. 2014) and has also been used in the pre-operative setting (NCCN 2016).  
Previously reported data supported the advancement of olaratumab (IMC-3G3, LY3012207) in 
later phase human trials, including Eli Lilly and Company (Lilly)’s Phase 1b/2 randomized Phase 
2 Study I5B-IE-JGDG (JGDG), which evaluated the efficacy and safety of doxorubicin with or 
without olaratumab in advanced STS.  Patients treated with olaratumab and doxorubicin in the 
Phase 2 portion of this study, compared to those treated with single-agent doxorubicin, achieved 
a higher median progression-free survival (PFS; 6.6 vs. 4.1 months, respectively [stratified 
hazard ratio (HR) = 0.672 (95% confidence interval [CI]:  0.442, 1.021); p = 0.0615]), median 
overall survival (mOS; 26.5 vs. 14.7 months, respectively [stratified HR = 0.463 (95% CI:  
0.301, 0.710); p = 0.0003]) and objective response rate (ORR; 18.2% vs. 11.9%, respectively; 
p = 0.3421), with an acceptable and monitorable safety profile. 
The efficacy of olaratumab in this STS patient population provides an important opportunity to 
more fully characterize the mechanism of action (MOA) of olaratumab.
Olaratumab is a recombinant human immunoglobulin G, subclass 1 (IgG1) antagonist of the 
platelet-derived growth factor receptor alpha (PDGFR, which has been demonstrated to play 
an important role in mesenchymal biology, and in modulating the tumor and stromal 
microenvironment.  Preliminary analysis of tumor specimens from Study JGDG indicated that 
tumor expression of PDGFRreceptor by immunohistochemistry (IHC) did not predict 
improvement in mOS. Possible explanations for this finding include the highly variable and 
often lengthy time periods between tumor sampling and study entry, the analysis of primary 


I5B-MC-JGDM(c) Phase 1 Oncology Protocol
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versus metastatic lesions, and incomplete understanding of the level of PDGFRreceptor and 
ligand expression in tumor and stroma needed for efficacy.
For these reasons, this study will enroll patients with potentially resectable STS, to allow pre-
and post-olaratumab dosing tumor sampling of the same primary tumor lesion, while also 
providing the potential opportunity to examine a resected tumor specimen after combination 
treatment with olaratumab and doxorubicin. 
Platelet-derived growth factor receptor alpha activation leads to the activation of several well-
characterized downstream signaling cascades including the Ras/mitogen-activated protein kinase 
(MAPK) pathway, the phosphatidylinositol 3-kinase pathway, and the phospholipase C-ɣ 1 
pathway in sarcomas (Shah et al. 2010).  Increased expression of PDGFRα has been described in 
epithelial malignancies as part of the epithelial-mesenchymal transition (EMT) (Jechlinger et al. 
2006).  The EMT state is associated with increased invasiveness and metastasis (Thiery et al. 
2009).  Autocrine signaling via PDGFRα in association with Ras oncogenic mutation is 
positively correlated with metastasis in a murine breast cancer line (Jechlinger et al. 2006).  Non-
canonical activation of PDGFRαpromotes bone metastasis of prostate cancer cells, and 
inhibition of PDGFRα in prostate cancer suppresses tumor angiogenesis and growth of skeletal 
metastases (Doloff et al. 2007; Russell et al. 2009, 2010; Park et al. 2011). Given this growing 
body of literature, the ability of olaratumab to disrupt sarcoma metastasis will be investigated in 
Study I5B-MC-JGDM (JGDM).
The predilection for sarcomas to spread hematogenously provide rationale for using a whole 
blood “liquid biopsy” approach for enumeration and characterization of circulating sarcoma 
tumor cells pre- and posttreatment with olaratumab to investigate the role of olaratumab in 
disrupting the metastatic potential of sarcomas.  Using serial pre- and posttreatment whole blood 
samples, the proposed study will investigate the effects of olaratumab (as monotherapy and in 
combination with doxorubicin) on circulating tumor cell (CTC) counts.  The whole blood 
samples may also be used for exploratory analyses and further molecular characterization.
The sponsor (Lilly), monitor, and investigators will perform this study in compliance with the 
protocol, good clinical practice (GCP) and International Conference on Harmonisation (ICH) 
guidelines, and applicable regulatory requirements.
5.2.
Objectives
5.2.1. Primary Objectives
The primary objectives of this study are:

to enumerate CTCs changes pre- and post-olaratumab monotherapy in whole 
blood in patients with potentially resectable STS.

to characterize PDGFRand platelet-derived growth factor receptor beta 
(PDGFR) and canonical ligands (PDGF-A, B, C, and D) expression changes 
pre- and post-olaratumab monotherapy in tumor tissue in patients with 
potentially resectable STS.


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5.2.2. Secondary Objectives
The secondary objectives of this study are:

to evaluate any antitumor activity observed with olaratumab:
o
progression-free survival (PFS) and 3-month PFS 
o
ORR (complete response [CR] + partial response [PR])
o
disease control rate (DCR) (CR+ PR + stable disease [SD])
o
rate of resectability.

to evaluate the safety of olaratumab as assessed by reported AEs, clinical 
laboratory tests, vital signs, physical examinations, electrocardiograms
(ECGs), and echocardiograms (ECHOs) or multi-gated acquisition (MUGA) 
scans.

to evaluate the pharmacokinetics (PK) of olaratumab and immunogenicity 
(IG) parameters of olaratumab.
5.2.3. Exploratory Objectives
The exploratory objectives of this study are:

to evaluate blood, CTCs, and tumor tissue pre- and post-therapy for
biomarkers related to pathways associated with STS, the MOA of olaratumab, 
cancer-related conditions, and/or immune cells/immune and tumor 
microenvironment functioning within the disease state and/or cancer-related 
conditions. 

to assess the relationship between biomarker expression at baseline, and 
change from baseline, and clinical outcomes.
5.3.
General Introduction to Olaratumab
Olaratumab is a recombinant human IgG1-type monoclonal antibody that binds to PDGFRα.  
This antibody possesses high affinity binding for PDGFRα and blocks platelet-derived growth 
factor (PDGF)-AA, -BB, and -CC from binding to the receptor.  In addition to blocking ligand-
induced cell mitogenesis and receptor autophosphorylation, olaratumab inhibits ligand-induced 
phosphorylation of the downstream signaling molecules Akt and MAPK (Loizos et al. 2005; 
Study Report IMC-3G3-01).
Platelet-derived growth factor/PDGFRα signaling has been implicated in the pathogenesis of 
multiple cancers, including sarcoma, prostate cancer, breast cancer, ovarian cancer, and others.  
In malignant disease, the PDGF/PDGFRα axis promotes tumor growth and proliferation through 
both autocrine and paracrine mechanisms.  Platelet-derived growth factor receptor alpha can be 
expressed in both the tumor and stromal microenvironment.  Furthermore, studies have shown 
that PDGF/PDGFRα signaling affects tumor vasculature through paracrine mediation of vascular 
endothelial growth factor production (Shah et al. 2010).


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More information on the known and expected benefits, risks, and reasonably anticipated adverse 
events (AEs) of olaratumab may be found in the Investigator’s Brochure (IB).  Information on 
AEs expected to be related to the investigational product (IP) may be found in Section 7 
(Development Core Safety Information [DCSI]) of the IB.  Information on serious adverse 
events (SAEs) expected in the study population independent of drug exposure and that will be 
assessed by the sponsor in aggregate, periodically during the course of the study, may be found 
in Section 6 (Effects in Humans) of the IB.
More information about the known and expected benefits and risks of doxorubicin hydrochloride 
can be found in the approved doxorubicin package insert.
5.4.
Rationale for Selection of Dose
The current olaratumab dose-selection strategy for this study is based on the integrated safety, 
efficacy, and PK data for olaratumab across previous Phase 1 and Phase 2 studies.  
In 2 Phase 1 dose-escalation trials (Studies I5B-IE-JGDC and I5B-IE-JGDF) and in the 2 Phase 
2 monotherapy studies (Studies I5B-IE-JGDE and I5B-IE-JGDH), single-agent olaratumab has 
consistently been well tolerated, with no dose-limiting toxicities observed up to a dose of 20 
mg/kg administered every 2 weeks and up to a dose of 15 mg/kg administered on Days 1 and 8 
of a 21-day cycle.  When used in combination with liposomal doxorubicin in Study I5B-IE-
JGDA (olaratumab dose of 20 mg/kg every 2 weeks), and with paclitaxel plus carboplatin in 
Study I5B-IE-JGDB (olaratumab dose of 15 mg/kg Days 1 and 8 every 3 weeks), a higher rate of 
toxicities such as neutropenia and infections was observed versus the comparator agents.  In 
Study JGDG, an increase in neutropenia and mucositis, but not in neutropenic sepsis or febrile 
neutropenia, was observed for olaratumab plus doxorubicin compared with single-agent 
doxorubicin.  Overall, these toxicities are consistent with the toxicity profile of the combination 
agents used, and are considered monitorable and acceptable for the patient populations studied.
Based on an exposure-response analysis of data from Study JGDG, an olaratumab loading dose 
of 20 mg/kg on Day 1 and Day 8 of Cycle 1 was incorporated into Study I5B-MC-JGDJ (JGDJ), 
an ongoing randomized Phase 3 trial of doxorubicin plus olaratumab versus doxorubicin plus 
placebo in patients with advanced or metastatic STS. The goal of this dosing refinement was to 
decrease the time patients achieved steady state concentrations of olaratumab.
Study JGDM will consist of an initial cycle of olaratumab monotherapy (Cycle 1) administered 
on Day 1 and Day 8 of a 21-day cycle using a dose of 20 mg/kg.  This dose is consistent with the 
loading dose used in Study JGDJ, and is anticipated to provide olaratumab concentrations 
optimal for testing olaratumab tumor and CTC biomarker effects during Cycle 1.  
Because the patient population for Study JGDM consists of patients who have potentially 
resectable STS, early tumor reduction is an important therapeutic goal.  Therefore, in Cycle 2, 
patients will receive additional 20 mg/kg doses of olaratumab on Day 1 and Day 8, in 
combination with 75 mg/m2 doxorubicin on Day 1 of a 21-day cycle (totaling 2 cycles of 
olaratumab at a 20 mg/kg dose: 1 as monotherapy and 1 in combination with doxorubicin).  This 
dosing schedule is intended to maximize the number of patients reaching potentially therapeutic 


I5B-MC-JGDM(c) Phase 1 Oncology Protocol
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drug concentrations in the first 6 weeks, which is potentially important in this patient population. 
Pharmacokinetic model simulations indicate that this proposed dosing regimen may result in 
exposures slightly (approximately 15%) above previously studied steady-state serum levels of 
olaratumab.  However, given the previously acceptable toxicity profile of olaratumab in 
combination with doxorubicin in Study JGDG, it is not anticipated that this will result in any 
additional safety risk to the patients enrolled in this study.
From Cycle 3 through Cycle 7, patients will receive olaratumab at a dose of 15 mg/kg on Day 1 
and Day 8, in combination with doxorubicin 75 mg/m2 on Day 1 of a 21-day cycle, the same 
doses studied in Study JGDG.


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6. Investigational Plan
6.1.
Study Population
The duration of the screening period is 14 days for the majority of procedures (Attachment 1); 
certain noted procedures may be performed within 28 days of enrollment. Individuals who do 
not meet the criteria for participation in this study within the 28-day screening period (screen 
failure) may be re-screened.  Note that repeating laboratory tests during the 28-day screening 
period does not constitute re-screening.  Screening laboratory tests may not be repeated more 
than once to meet eligibility during the 28-day screening period.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
[1]
Have a histologically confirmed diagnosis of STS for which olaratumab and 
doxorubicin would be appropriate therapy.  Patients with a diagnosis of 
Grade 1 liposarcoma are eligible if there is histological or radiographic 
evidence of evolution to more aggressive disease.  Patients with Kaposi’s 
sarcoma and gastrointestinal stromal tumors (GIST) will be excluded.  
Patients must have potentially resectable disease (as assessed by the study 
investigator) and have a primary tumor lesion deemed amenable to serial 
biopsy.
[2]
Have consented to undergo mandatory serial peripheral whole blood and 
tumor tissue sampling for pathology review and translational research.  Refer 
to Sections 8.2.3.1 and 8.2.3.2 for details of biopsy and whole blood sample 
collection.  
[3]
Have signed an informed consent form (ICF) and authorization for release of 
health information for research prior to any study-specific procedures being 
performed.
[4]
Are age 18 years at time of consent.
[5]
Have measurable or nonmeasurable but evaluable disease as defined by the 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1, Eisenhauer et 
al. 2009). Tumors within a previously irradiated field will be designated as 
“nontarget” lesions unless progression is documented or a biopsy is obtained 
to confirm persistence at least 90 days following completion of radiotherapy.
[6]
Have a performance status (PS) of 0 to 1 on the Eastern Cooperative 
Oncology Group (ECOG) scale (Oken et al. 1982).  Attachment 6 provides the 
ECOG PS scale.


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[7]
Have had 2 prior systemic cytotoxic therapies for potentially resectable
disease.  All previous anticancer treatments must have been completed 
≥3 weeks (21 days) prior to enrollment.
[8]
Have had resolution of AEs and of all clinically significant toxic effects of 
prior locoregional therapy, surgery, radiotherapy, or systemic anticancer 
therapy to Grade ≤1, by National Cancer Institute (NCI)-Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
[9]
Have adequate hematologic, organ, coagulation, and cardiac function within 
2 weeks (14 days) prior to enrollment:
•
Absolute neutrophil count (ANC) ≥1.5 x 109/L.  Granulocyte colony-
stimulating factor (G-CSF) cannot be administered within 2 weeks 
(14 days) prior to enrollment.
•
Platelet count ≥100 x 109/L.
•
Hemoglobin ≥9.0 g/dL.  No transfusions are allowed within 2 weeks 
(14 days) prior to enrollment.
•
Creatinine clearance ≥45 mL/min (refer to Attachment 7 for the 
Cockcroft-Gault formula).
•
Proteinuria ≤1000 mg in 24 hours (if routine urinalysis indicates 
≥2+ proteinuria).
•
Total bilirubin below upper limit of normal (ULN) (except for patients 
with Gilbert’s Syndrome, who must have a total bilirubin <3 mg/dL).
•
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
≤3.0 × ULN; if the liver has tumor involvement, AST and ALT ≤5.0 × 
ULN are acceptable.

An adequate coagulation function as defined by International 
Normalized Ratio ≤1.5 x ULN or prothrombin time ≤1.5 x ULN, and 
partial thromboplastin time or activated partial thromboplastin time
≤1.5 x ULN if not receiving anticoagulation therapy.  For patients 
receiving anticoagulants, exceptions to these coagulation parameters 
are allowed if they are within the intended or expected range for their 
therapeutic use. Patients must have no history of active bleeding 
(defined as within 14 days of first dose of study drug) or pathological 
condition that carries a high risk of bleeding (for example, tumor 
involving major vessels or known esophageal varices).
[10] Have left ventricular ejection fraction (LVEF) ≥50% assessed within 28 days 
prior to enrollment.
[11] Females of child-bearing potential must have a negative serum or urine 
pregnancy test within 7 days prior to enrollment.


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•
Exceptions:  females not of child-bearing potential due to surgical 
sterilization (at least 6 weeks following surgical bilateral oophorectomy 
with or without hysterectomy or tubal ligation) confirmed by medical 
history or menopause.
A “postmenopausal woman” is a woman meeting either of the following 
criteria:
•
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 (for example, oral 
contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, 
selective estrogen receptor modulators, or chemotherapy)
•
spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone level >40 mIU/mL
[12] Females of child-bearing potential must agree to use highly effective 
contraceptive precautions and men must agree to use effective contraceptive 
methods (for example, condom with spermicide) during the trial and up to 6
months following the last dose of study drug.  A highly effective method of birth 
control is defined as one that results in a low failure rate (that is, <1% per year) 
when used consistently and correctly, such as implants, injectables, combined 
oral contraceptives, some intrauterine contraceptive devices, a vasectomized 
partner, or sexual abstinence that is in line with the preferred and usual lifestyle 
of the subject (periodic abstinence [for example, calendar, ovulation, 
symptothermal, post-ovulation methods], declaration of abstinence for the 
duration of a trial, and withdrawal are not acceptable methods of contraception).
[13] Have, in the opinion of the investigator, a life expectancy of at least 3 months.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.  
[14] Have a diagnosis of GIST or Kaposi sarcoma.
[15] Have active central nervous system (CNS) or leptomeningeal metastasis (brain 
metastasis) at the time of enrollment.  Patients with a history of a CNS 
metastasis previously treated with curative intent (for example, stereotactic 
radiation or surgery) that have not progressed on follow-up imaging, have been 
asymptomatic for at least 60 days, and are not receiving systemic corticosteroids 
and or/anticonvulsants are eligible. Patients with signs or symptoms of 
neurological compromise should have appropriate radiographic imaging 
performed before enrollment to rule out brain metastasis.
[16] Have received prior treatment with doxorubicin, epirubicin, idarubicin, and/or 
other anthracyclines or anthracenediones; has received treatment with 
olaratumab or has participated in a prior olaratumab trial.


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[17] Have a history of another primary cancer, with the exception of a) curatively 
treated non-melanomatous skin cancer; b) curatively treated cervical carcinoma 
in situ; c) other primary non-hematologic malignancies or solid tumor treated 
with curative intent; no known active disease; and no treatment administered 
during the last 3 years prior to enrollment.
[18] Have unstable angina pectoris, angioplasty, cardiac stenting, or myocardial 
infarction within 6 months of enrollment. 
[19] Have a Bazett’s corrected QT interval of >450 msec for males and >470 msec
for females on screening ECG utilizing Bazett’s correction. For bundle branch 
block patients, have a QTcF interval of >450 msec for males and >470 ms for 
females on screening ECG utilizing Fridericia’s correction.
[20] Are females who are pregnant or breastfeeding.
[21] Are enrolled in, or discontinued study treatment from, another trial involving an 
investigational agent or use of non-approved drug or device within 28 days of 
being enrolled/randomized in this trial, or concurrent enrollment in any other 
type of medical research judged scientifically or medically incompatible with 
this trial.  Patients participating in surveys or observational studies are eligible 
to participate in this study.
[22] Have serious pre-existing medical conditions that, in the opinion of the 
investigator, would exclude the patient as a candidate for this study.
[23] Have a known allergy to any of the treatment components including a history of 
allergic reactions attributed to compounds of chemical or biological composition 
similar to olaratumab.
6.2.
Summary of Study Design
Study JGDM is an open-label, single-arm, multicenter, multicountry Phase 1b study to 
enumerate whole blood CTCs and to characterize PDGFRand PDGFRand canonical ligands
(PDGF-A, B, C and D) expression changes pre- and post-olaratumab monotherapy in tumor 
tissue in patients with potentially resectable STS.
Patients are to be treated with 20 mg/kg of olaratumab on Day 1 and Day 8 of Cycle 1, followed 
by up to 6 cycles (Cycle 2 – Cycle 7) of combination therapy with olaratumab plus doxorubicin.  
For Cycle 2, olaratumab is to be dosed at 20 mg/kg on Day 1 and Day 8 and doxorubicin is to be 
dosed at 75 mg/m2 on Day 1.  For Cycle 3 – Cycle 7, olaratumab is to be dosed at 15 mg/kg on
Day 1 and Day 8 and doxorubicin is to be dosed at 75 mg/m2 on Day 1.  Each cycle of treatment 
is defined as an interval of 21 days.  Approximately 35 patients are to be enrolled.  
Starting with the first cycle of combination therapy (Cycle 2), the use of dexrazoxane (in a 10:1 
ratio vs. doxorubicin dose) to mitigate cardiotoxicity during treatment with doxorubicin is 
allowed at the investigator’s discretion and is recommended for all patients receiving 5 or more 
cycles of doxorubicin.


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Tissue biopsies are required pre- and posttreatment with olaratumab monotherapy.  The 
pretreatment tissue biopsy is to be performed within the screening period.  The posttreatment 
tissue biopsy is to be performed after completion of the lead-in cycle of olaratumab monotherapy
and prior to the initiation of combination therapy in Cycle 2. An optional third tissue biopsy (or 
tissue from a posttherapy surgical resection specimen) may be performed at the end of the 
patient’s study treatment.  If clinically feasible, the tissue biopsies should be taken from the same 
primary tumor lesion.  If the patient has an additional surgical resection, tissue from this 
procedure is requested.  Refer to Section 8.2.3.2 for details on tissue biopsies. 
Whole blood samples for CTC analyses are to be collected predose at Cycle 1 Day 1 (C1D1), at 
Cycle 1 Day 8 (C1D8), at Cycle 2 Day 1 (C2D1), at Cycle 2 Day 8 (C2D8), at Cycle 3 Day 1 
(C3D1), and at the end of the patient’s study treatment or at the time of surgical resection.  Refer 
to Section 8.2.3.1 for details on blood samples.
After 1 cycle of monotherapy, patients will receive combination therapy for up to 6 cycles or 
until evidence of progressive disease (PD), unacceptable toxicity, surgical resection, death, or 
other withdrawal criteria are met.  Patients who discontinue study treatment for reasons other 
than progression or surgical resection will be followed every 6 weeks (±7 days) until PD.
Refer to Attachment 1 for the Study Schedule.
Figure JGDM.1 illustrates the study design.


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Abbreviations:  C1D1 = Cycle 1 Day 1; C2D1 = Cycle 2 Day 1; C3D1 = Cycle 3 Day 
1; CTC = circulating tumor cell; D = day(s); ECOG PS = Eastern Cooperative 
Oncology Group performance status; STS = soft tissue sarcoma, tx = treatment.
a The pre- and post-olaratumab monotherapy tissue biopsies and the whole blood 
sample collections pre-dose at C1D1, C1D8, C2D1, and C2D8 for CTC analyses are 
mandatory. The pre-olaratumab monotherapy biopsy is to be collected within the 
screening period.  The post-olaratumab monotherapy biopsy is to be collected after 
completion of Cycle 1 and prior to initiation of Cycle 2 combination therapy. If 
clinically feasible, the biopsies should be taken from the same primary tumor lesion.
b An optional third tumor tissue biopsy is to be collected at the end of the patient’s 
study treatment or when the patient undergoes a surgical resection through which a 
posttherapy tissue specimen can be collected.  If clinically feasible, the biopsies should 
be taken from the same primary tumor lesion.  Additionally, a whole blood sample for 
CTC analysis is to be collected at C3D1 and at the end of the patient’s study treatment 
or at the time of surgical resection. 
c See text in Section 6.2, Summary of Study Design.
Note:  Each cycle of treatment is defined as an interval of 21 days.
Figure JGDM.1.
Illustration of study design.
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the ICF is signed (study entry) and ends at the first study 
treatment (or at discontinuation, if no treatment is given).

Study Period:  begins at the first study treatment and ends at study completion.
o
Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue study 


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treatment.  The date of this agreement is to be reported on the electronic case 
report form (eCRF) as the Date of Discontinuation from study treatment.

Olaratumab Monotherapy Treatment Period: begins at the first 
administration of olaratumab 20 mg/kg on Day 1 of Cycle 1 and ends on 
Day 21 of Cycle 1.

Combination Olaratumab plus Doxorubicin Therapy Treatment 
Period:  begins after the post Cycle 1 treatment biopsy is obtained, with 
the first administration of olaratumab 20 mg/kg and doxorubicin 75 mg/m2
on Day 1 of Cycle 2, followed by the administration of olaratumab 
20 mg/kg on Day 8 of Cycle 2.  This treatment period continues from 
Cycle 3 through Cycle 7 with the administration of olaratumab at a dose of 
15 mg/kg on Days 1 and 8 and doxorubicin 75 mg/m2 on Day 1 of each 
21-day cycle. Upon completion of the combination therapy treatment 
period, the patient will no longer receive study treatment.
o
Post-discontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.

Short-term follow-up: begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment 
and lasts approximately 30 days (±7 days).  The short-term follow-up visit 
occurs at or near the end of the short-term follow-up period (±7 days).
Follow-up for safety - Patients who undergo surgical resection will 
be followed for safety for approximately 30 days (±7 days) after 
surgery.

Long-term follow-up: begins the day after short-term follow-up is 
completed.
Follow-up for progression - Patients who discontinue study 
treatment, or have completed 6 cycles of combination therapy, and 
have not progressed and have not initiated a new systemic 
treatment for their disease will be assessed for progression by 
imaging studies every 6 weeks (<7 days) until PD.  Patients who 
have had surgical resection will not be followed for subsequent 
progression by imaging studies.
6.2.1. Study Completion and End of Trial
The study will be considered complete after all patients have progressed or undergone surgical 
resection and completed the follow-up period. The end of trial occurs after study completion and 
after the last patient has discontinued study treatment and completed the 30-day follow-up 
period. 
6.3.
Discontinuations
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
The date of discontinuation from study treatment for any of the reasons specified in Section 6.3.2


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is to be reported on the eCRF.  Patients who discontinue will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
6.3.1. Discontinuation of Patients Inadvertently Enrolled
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified. A discussion must occur between 
the sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without IP.  Inadvertently enrolled patients may be 
maintained in the study and on IP when the Lilly CRP agrees with the investigator that it is 
medically appropriate for that patient. The patient may not continue in the study with or without 
IP if the Lilly CRP does not agree with the investigator’s determination that it is medically 
appropriate for the patient to continue. The investigator must obtain documented approval from 
the Lilly CRP to allow the inadvertently enrolled patient to continue in the study with or without 
IP.
6.3.2. Discontinuation of Patients from Study or Study Drug
The date of and the reason for discontinuation from study treatment will be collected for all 
patients; the date of discontinuation from study treatment (for any of the reasons listed below) is 
to be reported on the eCRF.  Patients who discontinue study treatment will have follow-up 
procedures performed as shown in the Study Schedule (Attachment 1).
In addition, patients will be discontinued from the study drug and/or from the study in the 
following circumstances:

enrollment in any other clinical trial involving an IP 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
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


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o
the patient or the patient’s designee (for example, parents or legal guardian) 
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

evidence of PD

unacceptable toxicity

pregnancy

surgical resection

significant noncompliance with study procedures and/or treatment.
6.3.3. Patients Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit, or with whom the site 
is otherwise unable to follow-up.
6.3.4. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for any 
scientific, medical, safety, regulatory, ethical, or other reasons consistent with applicable laws, 
regulations, and GCP.
6.3.5. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges discontinuation of the study necessary for any scientific, medical, safety, 
regulatory, ethical, or other reasons consistent with applicable laws, regulations, and GCP.


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7. Treatment
7.1.
Materials and Supplies
7.1.1. Packaging and Labelling
Olaratumab will be provided by Lilly.  
Olaratumab will be supplied as a sterile preservative-free solution for IV 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 pharmacopeial grade.
Where commercially available, doxorubicin hydrochloride will be purchased by the sites.  In the 
event that there are regional restrictions or supply limitations, doxorubicin may be provided to 
the sites by Lilly.
Where commercially available, dexrazoxane will be purchased by the sites.  In the event that 
there are regional restrictions or supply limitations, dexrazoxane may be provided to the sites by 
Lilly.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.1.2. Olaratumab
Olaratumab Drug Product:  The drug product must be stored under refrigeration at 2°C-8°C 
(36°F-46°F) with protection from direct light.  Do not freeze and/or shake olaratumab drug 
product.  Stability studies have demonstrated that the drug product can withstand transient 
excursion to room temperature without adverse effect; however, storage at this temperature is not 
recommended.
Please refer to the Pharmacy Manual for information on preparing the olaratumab dosing 
solution for infusion.
CAUTION:  Infusion-related reactions may occur during or following olaratumab administration 
(see Section 7.2.3.1.1.1 for a definition of Grade 3 and 4 IRRs).  During the administration of 
olaratumab, patients should be in an area with resuscitation equipment and treatments necessary 
for advanced life support and cardiopulmonary resuscitation, such as bronchodilators, 
vasopressor agents (for example, epinephrine), oxygen, glucocorticoids, antihistamines, and IV 
fluids.  A 1-hour Observation Period is required after the administration of the first and second 
cycles of olaratumab.  If no evidence of an IRR manifests during the initial 2 cycles of 
olaratumab, then no observation period is required for subsequent treatment cycles.  In the event 
that a Grade 1 or 2 IRR occurs after Cycle 2, the 1-hour observation period will be reinstituted
for a minimum of 2 cycles.  The reinstituted observation period may be suspended after 2 cycles 
if the patient shows no further signs or symptoms of an IRR. 


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7.1.3. Doxorubicin
Investigators should consult the approved doxorubicin hydrochloride package insert for complete 
prescribing information (including warnings, precautions, contraindications, adverse reactions, 
and dose modifications) and follow institutional procedures for the administration of 
doxorubicin.  If a patient should have an IRR to doxorubicin, the investigator should follow the 
manufacturer’s recommendations and clinical guidelines in the management of the patient.  
Doxorubicin 75 mg/m2 is administered IV.  The dose of doxorubicin should be reconstituted in 
100 mL of normal saline.  Administer doxorubicin as an IV injection or as an infusion in less 
than 60 minutes.  Decrease the rate of doxorubicin administration if erythematous streaking 
along the vein proximal to the site of infusion or facial flushing occurs.
Doxorubicin must be reconstituted prior to infusion.  The reconstituted solution is stable for 
7 days at room temperature and under normal room light and 15 days under refrigeration (2ºC-
8ºC [36ºF-46ºF]).  It should be protected from exposure to sunlight.
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit.
Clinical study materials will be labeled according to the country’s regulatory requirements. 
See Section 7.5.1.1 for dexrazoxane administration.  Dexrazoxane should be started within 
30 minutes prior to the doxorubicin infusion.
7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient/study site personnel/legal representative

verifying that instructions are followed properly 

maintaining accurate records of study drug dispensation, and collection, and 
returning or destroying all unused medication to Lilly or its designee at the end of 
the study
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
7.2.1. Treatments Administered
Table JGDM.1 shows the treatment regimens to be administered in this study.


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Table JGDM.1.
Treatment Regimens
Treatment
Cycle
Length
(Days)
Study Drug
Dose
Timing
Route 
Monotherapy 
Cycle 1
21
Olaratumaba
20 mg/kg
approximately 1 hour 
infusion D1, D8 
IV
1-hour (+5 minutes) 
Observation Periodb
Combination Therapy
Cycle 2
21
Olaratumaba
20 mg/kg
approximately 1 hour 
infusion D1, D8 
IV
1-hour (+5 minutes) 
Observation Periodb
followed by
Doxorubicinc
75 mg/m2
IV injection on D1
IV
Combination Therapy
Cycle 3 – Cycle 7
21
Olaratumaba
15 mg/kg
approximately 1 hour 
infusion D1, D8 
IV
Doxorubicinc
75 mg/m2
IV injection on D1
IV
Abbreviations:  D = day; eCRF = electronic case report form; IRR = infusion-related reaction; IV = intravenous; 
PO = orally.
a
Premedicate all patients with the following (or equivalent) medications:  a histamine H1 antagonist (for example, 
diphenhydramine) and dexamethasone intravenously 30–60 minutes prior to the olaratumab doses on Days 1 and 
8 of Cycle 1.  For subsequent cycles, premedicate all patients with a histamine H1 antagonist (for example, 
diphenhydramine) intravenously 30-60 minutes prior to each dose of olaratumab.  Additional premedication may 
be provided at the investigator’s discretion.  Premedication must be provided in the setting of a prior Grade 1-2 
IRR, as detailed in Section 7.2.2 and Section 7.2.3.1.1.1.  All premedication administered must be adequately 
documented in the eCRF.
b
A 1-hour (+5 minutes) Observation Period is required after the administration of the initial 2 cycles of 
olaratumab.  During the Observation Period, collect vital signs 3 times:  1) within 15 minutes (+5 minutes) prior 
to olaratumab infusion, 2) within 1 hour (+5 minutes) after completion of the olaratumab infusion, and 3) within 
1 hour (+5 minutes) after completion of the doxorubicin infusion.  If no evidence of an IRR manifests during the 
initial 2 cycles of olaratumab, then no observation period is required for subsequent treatment cycles.  In the 
event an IRR occurs thereafter, then the 1-hour Observation Period should be reinstituted; see Section 7.1.2.  
Thereafter (Cycles 3+), obtain vital signs 2 times:  1) within 15 minutes (+5 minutes) prior to olaratumab 
infusion and 2) within 1 hour (+5 minutes) after completion of the doxorubicin infusion.
c
Administer doxorubicin according to institutional guidelines and/or clinical practice as an IV injection or as an 
infusion within 60 minutes.  Decrease the rate of doxorubicin administration if erythematous streaking along the 
vein proximal to the site of infusion or facial flushing occurs.  Infusion or injection start and end times will need 
to be recorded.  Starting with Cycle 2, dexrazoxane may be administered at a 10:1 ratio 
(dexrazoxane:doxorubicin) at the investigator’s discretion according to instructions provided in the pharmacy 
manual for this study, beginning within 30 minutes prior to the doxorubicin infusion for prevention of 
cardiotoxicity.  It is recommended that all patients receiving 5 or more cycles of doxorubicin receive 
dexrazoxane.
7.2.2. Premedication
Infusion-related reactions, including Grade 3-5 IRR events, have been observed with 
olaratumab. To date, Grade 3-5 IRR events have primarily occurred during the first cycle of 
olaratumab treatment.  Therefore, premedicate all patients with the following (or equivalent) 


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medications:  a histamine H1 antagonist (for example, diphenhydramine) and dexamethasone 
intravenously 30–60 minutes prior to the olaratumab doses on Days 1 and 8 of Cycle 1.  
For subsequent cycles, premedicate all patients with a histamine H1 antagonist (for example, 
diphenhydramine) intravenously 30-60 minutes prior to each dose of olaratumab.  
Premedication must be provided in the setting of a prior Grade 1 or 2 IRR, as detailed in Section 
7.2.3.1.1.1. All premedication administered must be adequately documented in the eCRF.
Given the emetogenic potential of doxorubicin, premedication with anti-emetics per institutional 
guidelines is recommended.  Additional premedication may be provided at investigator 
discretion.
If doxorubicin premedication is required prior to the doxorubicin infusion, this must be done 
after completion of the olaratumab infusion, not before the olaratumab infusion. This 
premedication may be administered immediately following the end of the observation period (if 
applicable) or after completion of the olaratumab infusion.
Starting with Cycle 2, dexrazoxane may be administered IV at a 10:1 ratio 
(dexrazoxane:doxorubicin) at the investigator’s discretion according to instructions provided in 
the pharmacy manual for this study, beginning no later than 30 minutes prior to each doxorubicin 
infusion for the prevention of cardiotoxicity. It is recommended that all patients receiving 5 or 
more cycles of doxorubicin receive dexrazoxane.
7.2.3. Dose Modifications
7.2.3.1.
Dose Delays, Modifications, and Discontinuations 
After treatment has been initiated, in order to start the next cycle, the following criteria must be
fulfilled:

ANC ≥1.0 × 103/L (1000/L; ≥1.0 × 109/L)
Note that in order to administer single-agent olaratumab on Day 8, ANC must 
be 750/L; 0.75 × 109/L.  If the ANC is 750/L, the Day 8 administration 
of olaratumab may be delayed for a maximum of 7 days.  If the ANC level has 
not increased to 750/L within 7 days, then the Day 8 olaratumab dose in 
that cycle should be skipped and dosing resumed on Day 1 of the following 
cycle if criteria for dosing are met.  If all dosing criteria are met, a delay or 
omission of the Day 8 olaratumab dose should not result in a delay of the 
Day 1 olaratumab dose of the following cycle. 

Platelets ≥100 × 103/L (100,000/L; ≥100 × 109/L)

Hemoglobin ≥8 g/dL

Creatinine clearance ≥45 mL/min (refer to Attachment 7 for the 
Cockcroft-Gault formula)

Proteinuria ≤1000 mg in 24 hours (if routine urinalysis indicates 
≥2+ proteinuria) (to be performed every other cycle)


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
Total bilirubin below ULN

AST and ALT ≤3.0 x ULN, or ≤5 x ULN if the transaminase elevation is due 
to liver metastases

Olaratumab-related AEs that are NCI-CTCAE Version 4.0 Grade <2 or 
equivalent severity to baseline
Delays:
In general, dose delays of 1 study drug (olaratumab or doxorubicin) due to toxicity guidances 
outlined in Sections 7.2.3.1.1 and 7.2.3.1.2 will not necessitate delays of the other study drug.
Treatment may be delayed for up to 21 days (1 equivalent cycle) to allow a patient sufficient 
time for recovery from study drug-related toxicity.  If a patient does not recover from the toxicity 
within 42 days (2 equivalent cycles) from Day 1 of the previous treatment cycle, then the patient 
must be discontinued from study therapy.
Any procedure or sample collection whose timing is related to olaratumab dosing is to be 
completed according to when the olaratumab dose was actually administered, not when that dose 
was expected to occur.  Samples whose adjusted timing would fall outside of the treatment cycle 
duration due to dose delay may be omitted.
Dose Modifications:
Any patient who requires a dose reduction will continue to receive the reduced dose for the 
remainder of the study.  Any patient who has had 2 dose reductions and who experiences a 
toxicity that would cause a third dose reduction must be discontinued from study drug.
In the event of an alteration in olaratumab dose due to an olaratumab-related toxicity, 
doxorubicin need not be altered, and the planned doxorubicin schedule should be maintained.
Similarly, olaratumab therapy need not be altered for doxorubicin-related toxicity.  An alteration 
in doxorubicin dose will always necessitate a corresponding change to dexrazoxane, if 
administered, in order to maintain a dosage ratio of 10:1 (dexrazoxane:doxorubicin).
Discontinuations:
In general, discontinuation of olaratumab will not necessitate discontinuation of doxorubicin.  In 
the event of discontinuation of olaratumab therapy due to an olaratumab-related toxicity or 
Grade 3 or 4 IRR, doxorubicin need not be altered, and the planned doxorubicin schedule may be 
maintained at the discretion of the investigator.  Discontinuation of doxorubicin will necessitate 
discontinuation of olaratumab.
Any changes in treatments being added to or removed from patient care will be recorded on the 
eCRF.
The following information (in this section and the following subsections) pertains to dose 
modifications and delays for and management of AEs of concern, which may or may not be 
associated with olaratumab therapy, including the following:


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
IRR (see Section 7.2.3.1.1.1)

Hematologic toxicity (see Section 7.2.3.1.1.2)

Nonhematologic toxicity (see Section 7.2.3.1.1.3)
The following information (in this section and the following subsections) pertains to dose 
modifications and delays for and management of AEs of concern, which may or may not be 
associated with doxorubicin therapy, including the following:

Hematologic toxicity (see Section 7.2.3.1.2.1)

Cardiovascular toxicity (see Section 7.2.3.1.2.2)

Hepatic impairment (see Section 7.2.3.1.2.3)

Nonhematologic toxicity (Section 7.2.3.1.2.4)
7.2.3.1.1. Olaratumab
7.2.3.1.1.1.
Infusion-Related Reactions
As with other therapeutic protein products, hypersensitivity reactions may occur during or 
following olaratumab administration.
For the initial 2 cycles of olaratumab treatment, it is mandatory that patients be closely 
monitored by the medical staff for signs and symptoms indicative of an IRR from the start of the 
infusion until at least 1 hour after the end of the infusion (see Table JGDM.1) in an area where 
emergency medical resuscitation equipment and other agents (such as epinephrine or
prednisolone equivalents) are available.  If no evidence of an IRR manifests during the initial 
2 cycles of olaratumab, then no observation period is required for subsequent treatment cycles.  
In the event an IRR occurs thereafter, then the 1-hour observation period should be reinstituted
(see Section 7.1.2).  
Olaratumab IRRs will be defined according to the NCI-CTCAE Version 4.0 definition of IRRs.
Symptoms occurring during or following infusion of investigational therapy may also be defined 
according to AE terms such as allergic reaction, anaphylaxis, or cytokine release syndrome 
(NCI-CTCAE Version 4.0 section “Immune system disorders”).  In the setting of symptoms 
occurring during or following infusion of investigational therapy, investigators are encouraged to 
use the AE term “IRR” and any additional terms (including those not listed here) that best 
describe the event.
For patients who experience a Grade 1 or 2 IRR, the infusion should be stopped and the patient
treated with the following (or equivalent) medications:  a histamine H1 antagonist (for example, 
diphenhydramine) and glucocorticoid (for example, dexamethasone) IV, acetaminophen, and 
oxygen (as indicated), according to standard medical practices.  After recovery, the infusion rate 
should be decreased by 50% for the duration of the infusion.  After a Grade 1 or 2 IRR, patients 
should be premedicated with the following (or equivalent) medications:  a histamine H1 
antagonist (for example, diphenhydramine) and glucocorticoid (for example, dexamethasone) IV, 
and acetaminophen, as appropriate, approximately 30-60 minutes prior to all subsequent 
olaratumab infusions.


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A Grade 3 or 4 IRR 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.
If a patient experiences an IRR 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 30 days (±3 days) following the event.  In addition, these same 
samples may be assessed for levels of olaratumab and for pharmacodynamic markers to provide 
information on the nature of the IRR.  The procedure for sample collection and handling is 
described in a separate procedural manual.
Section 7.1.3 provides information on doxorubicin and IRRs.
7.2.3.1.1.2.
Hematologic Toxicity
Table JGDM.2 summarizes the olaratumab dose modifications required in case of hematological 
toxicities.
Table JGDM.2.
General Guidelines for Olaratumab Dose Modification Due to 
Hematologic Toxicity Deemed Related to Olaratumab
Toxicity
Required Dose Modification
Neutropenia
  ANC Grade 1-3
No dose modification required.
  ANC <500 cells/L (Grade ≥4)
No treatment administered; treatment cycle delayed.
  At retreatment:
  If  Grade ≥3 neutropenic fever/infection has 
occurred
Withhold dose until ANC is 1000 cells/L or higher; 
reduce dose to 12 mg/kg (15 mg/kg if toxicity occurs 
during Cycle 1 or Cycle 2).
  If Grade 4 neutropenia lasting longer than 1 week 
has occurred
Withhold dose until ANC is 1000 cells/L or higher; 
reduce dose to 12 mg/kg (15 mg/kg if toxicity occurs 
during Cycle 1 or Cycle 2).
  Grade 4 ANC without fever/infection
Retreatment with olaratumab at full dose at investigator’s 
discretion with recommended use of prophylactic G-CSFs.
  Second incidence of either:  
  1) Grade ≥3 neutropenic fever/infection
  2) Grade 4 neutropenia lasting longer than 1 week
Second dose reduction to 10 mg/kg.
Thrombocytopenia
  Platelets <75,000 cells/L (Grade 1)
No treatment administered; treatment delayed until 
resolved to ≥100,000 cells/L.
Anemia
  Hemoglobin <9 gm/dL (Grade 2)
No treatment administered; treatment delayed until 
resolved to ≤Grade 1.


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Abbreviations:  ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor.
7.2.3.1.1.3.
Nonhematologic Toxicity
Specific guidelines for dose adjustments in patients who experience olaratumab IRRs may be 
found in Section 7.2.3.1.1.1.
Table JGDM.3 provides general guidelines for dose modification for other nonhematologic 
toxicities related to olaratumab.  If more than 2 toxicity-related olaratumab dose reductions are 
required, treatment with this agent will be permanently discontinued.
Table JGDM.3.
General Guidelines for Olaratumab Dose Modification Due to 
Nonhematologic Toxicity Deemed 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.
Grade 3 
For a Grade 3 toxicity not adequately controlled with appropriate supportive care, the dose 
must be withheld until toxicity is Grade ≤1 or has returned to pretreatment baseline; then 
treatment may resume at a reduced dose of 12 mg/kg (15 mg/kg if the toxicity occurs during 
Cycle 1 or Cycle 2).  If toxicity recurs after therapy resumes, a second dose reduction (to 
10 mg/kg) is permitted.
Grade 4
The dose must be withheld until dose toxicity is ≤Grade 1 or has returned to baseline.  
Permanent discontinuation should be considered for any patient experiencing Grade 4 
nonhematological toxicity assessed as related to olaratumab.  However, if resumption of 
dosing is deemed appropriate by the investigator, treatment may resume only after 
consultation with the Lilly study physician, with the dose reduced to 10 mg/kg (15 mg/kg if 
the toxicity occurs during Cycle 1 or Cycle 2).  If Grade 4 toxicity recurs after therapy 
resumes, olaratumab treatment will be discontinued.
7.2.3.1.2. Doxorubicin
7.2.3.1.2.1.
Hematologic Toxicity
Doxorubicin will not be administered after the initial dose if the patient’s ANC is <1000 cells/L 
or if the platelet count is <100,000 cells/L.  When necessary, the next treatment cycle should be 
delayed until the ANC is ≥1000 cells/L and the platelet count is ≥100,000 cells/L and 
nonhematologic toxicities have resolved.  For patients who experience ≥Grade 3 neutropenic 
fever or infection or Grade 4 neutropenia without fever lasting more than 1 week, doxorubicin 
should be reduced to 75% of the starting dose (that is, to approximately 60 mg/m2).  If a patient 
experiences a second incidence of neutropenic fever/infection or has another episode of Grade 4 
neutropenia lasting >1 week, then a second dose reduction to 45 mg/m2 will be necessary.  
Therapeutic and prophylactic use of pegfilgrastim (Neulasta®) or other G-CSFs will be allowed 
per current American Society of Clinical Oncology (ASCO; Smith et al. 2006) and National 
Comprehensive Cancer Network (NCCN) guidelines (NCCN 2014).  For patients with Grade 4 
ANC without fever/infection lasting less than 1 week, retreatment will be allowed at the 
investigator’s discretion with the full dose of doxorubicin (75 mg/m2) with recommended use of 


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G-CSFs per current ASCO guidelines (Smith et al. 2006).  See Table JGDM.4 for doxorubicin 
dose modification for neutropenia.
Table JGDM.4.
General Guidelines for Doxorubicin Dose Modification Due to 
Neutropenia
Toxicity
Required Dose Modification
ANC <1000 cells/L
No doxorubicin administered; treatment cycle delayed.
At pretreatment:
If  Grade ≥3 neutropenic fever/infection has occurred
Approximately 60 mg/m2 doxorubicin.
If Grade 4 neutropenia lasting longer than 1 week 
has occurred 
Approximately 60 mg/m2 doxorubicin.
Grade 4 ANC without fever/infection
Retreatment with doxorubicin at full dose at 
investigator’s discretion with recommended use of 
prophylactic G-CSFs.
Second incidence of either:  
1) Grade ≥3 neutropenic fever/infection
2) Grade 4 neutropenia lasting longer than 1 week
Second dose reduction to 45 mg/m2.
Abbreviations:  ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor.
7.2.3.1.2.2.
Cardiovascular Toxicity
Cardiotoxicity is a recognized risk of doxorubicin that increases with higher cumulative drug 
exposure.  Cardiac monitoring is conducted by a combination of monitoring of clinical 
parameters, ECG, and ECHO/MUGA scans.
Electrocardiogram changes, arrhythmias, tachycardia, and/or chest pain should be managed 
according to clinical practice based on the specific findings.
Patients will undergo baseline LVEF determination by ECHO or MUGA scan.  This evaluation 
may be repeated at any time during the study if clinically indicated.  If there is a decrease in 
LVEF of 10% and below the lower limit of normal, if there is an absolute decrease of 20%, or 
if the absolute LVEF decreases to or below 40%, then doxorubicin will be discontinued.  
Doxorubicin should also be discontinued if the patient develops Grade 3 or 4 left ventricular 
systolic dysfunction (symptomatic congestive heart failure).  All such changes should be 
reported as AEs.  If doxorubicin is discontinued for the above changes in LVEF, then olaratumab 
must be discontinued as well (see Section 7.2.3.1).  
The diagnostic method used at baseline for cardiovascular assessments (for example, ECHO or 
MUGA scans) should be the same method used throughout the study, unless there is clinical or 
instrumental evidence that further investigations are needed.
7.2.3.1.2.3.
Hepatic Impairment
Doxorubicin is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C 
or total serum bilirubin >5.0 mg/dL).  Refer to Section 7.2.3.1 for additional information.  


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7.2.3.1.2.4.
Nonhematologic Toxicity
Permanent discontinuation of doxorubicin should be considered for any patient experiencing 
Grade 4 nonhematologic toxicity assessed as related to doxorubicin.  If the investigator feels re-
dosing of doxorubicin is appropriate (except for Grade 4 cardiotoxicities and Grade 4 bilirubin 
increase which require mandatory discontinuation [see Section 7.2.3.1.2.2 and 
Section 7.2.3.1.2.3]), treatment may only resume after consultation with the Lilly study 
physician, with the dose reduced to 60 mg/m² (or less if agreed by the investigator and Lilly 
physician). If Grade 4 toxicity recurs after therapy resumes, doxorubicin treatment will be 
permanently discontinued.
For appropriate management of cardiac toxicities and hepatic impairment, refer to Section 
7.2.3.1.2.2 and Section 7.2.3.1.2.3. 
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive treatment.  After the 
patient signs the ICF, the site will register the patient in the Interactive Web Response System 
(IWRS), which is web-based and accessible 24 hours a day.  The IWRS registration consists of 
assigning the patient a unique study identification number.  Once the patient is registered through 
the IWRS, he/she is considered to be enrolled in the study.  
7.3.1. Selection and Timing of Doses
A cycle is defined as an interval of 21 days (a cycle may be delayed up to 3 days due to holidays, 
weekends, bad weather, or other unforeseen circumstances without being counted as a protocol 
deviation). 
The dose of olaratumab to be administered will be determined by measuring the patient’s weight 
in kilograms on Day 1 and Day 8 of each cycle.  The dose of doxorubicin to be administered will 
be determined by calculating the patient's body surface area at the beginning of each cycle.  If the 
patient’s weight does not fluctuate by 10% (increase or decrease) from the weight used to 
calculate the prior dose, the olaratumab dose will not need to be recalculated.  A 5% variance in 
the calculated total dose will be allowed for ease of dose administration.
A patient may continue to receive study treatment until he or she has received a maximum of 
6 cycles of olaratumab in combination with doxorubicin, or until he or she meets 1 or more of 
the specified reasons for discontinuation (as described in Section 6.3.2).
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
Concomitant medications and supportive care therapies must also be documented at the time of 
discontinuation and at the 30-day short-term follow-up visit.


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With the exceptions listed in the sections below, no other chemotherapy, investigational 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation
therapy, surgery for cancer, or investigational medications will be permitted while patients are on 
study treatment.
Bisphosphonate osteoclast inhibitors (for example, zoledronic acid or pamidronate) for treatment 
of bone metastases will be permitted while patients are on study treatment.  However, the 
osteoclast inhibitor denosumab is a monoclonal antibody and could confound safety analysis in 
the study if the patient experiences a hypersensitivity reaction to denosumab. Therefore, 
concomitant use of denosumab will not be permitted.
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications (for example, medications such as sedatives, antibiotics, analgesics, antihistamines, 
corticosteroids, or erythropoietin; procedures such as paracentesis, or thoracentesis; or blood 
products such as blood cells, platelets, or fresh frozen plasma transfusions) must be captured on 
the eCRF.
If doxorubicin premedication is required prior to the doxorubicin infusion, this must be done 
after the completion of olaratumab infusion, not before the olaratumab infusion.
7.5.1. Supportive Care
Patients should receive full supportive care, if necessary.  Patients will receive supportive care as 
judged by their treating physician.  If it is unclear whether a therapy should be regarded as 
supportive care, the investigator should consult with the Lilly CRP.  Use of any supportive care 
therapy must be captured on the eCRFs.
7.5.1.1.
Dexrazoxane
Starting with the first cycle of combination therapy (that is, Cycle 2), dexrazoxane may be 
administered IV at the investigator’s discretion according to instructions provided in the 
pharmacy manual for this study, beginning within 30 minutes prior to each doxorubicin infusion 
for the prevention of cardiotoxicity.  It is recommended that all patients receiving 5 or more 
cycles of doxorubicin receive dexrazoxane.  Investigators should consult the dexrazoxane 
information provided in the pharmacy manual for this study for administration information 
(including warnings, precautions, contraindications, adverse reactions, and dose modifications).
As the dose of dexrazoxane administered is dependent on the dose of doxorubicin administered, 
any dose modifications to doxorubicin will require a corresponding dose modification to 
dexrazoxane in order to maintain a dosage ratio of 10:1 (dexrazoxane:doxorubicin).
7.5.1.2.
Granulocyte-Colony Stimulating Factors and Erythroid Growth Factors
Following the first dose of doxorubicin treatment, the use of G-CSFs such as pegfilgrastim and 
erythroid stimulating factors (for example, erythropoietin) are permitted, including prophylactic 
use, during investigational therapy at the discretion of the investigator, according to ASCO 
guidelines (Smith et al. 2006) and NCCN guidelines (NCCN 2014).


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7.5.1.3.
Transfusion of Blood Products
Transfusions of red blood cells, platelets, or other blood products are permitted at the 
investigator’s discretion, but may not be used to meet hematologic criteria for inclusion in the 
study (refer to Section 6.1.1, inclusion criterion #9).
7.5.1.4.
Anti-emetic Therapy
Both prophylactic and symptom-directed anti-emetic therapy are recommended and should be 
used in accordance with institutional guidelines (when existent) and/or at investigator’s 
discretion.
7.5.2. Prohibited Therapies
Additional concurrent chemotherapy, radiation therapy, biologic response modifiers, or other 
investigational or approved anticancer agents may not be administered to patients on this study.  
Palliative radiation to symptomatic sites of disease will not be permitted while on study.
7.5.2.1.
Effect of CYP3A4, CYP2D6, and P-gp Inhibitors and Inducers on 
Doxorubicin
Doxorubicin is a major substrate of cytochrome P450 (CYP)3A4 and CYP2D6, and P-
glycoprotein (P-gp).  Clinically significant interactions have been reported with inhibitors of 
CYP3A4, CYP2D6, and/or P-gp (for example, verapamil), resulting in increased concentration 
and clinical effect of doxorubicin.  Inducers of CYP3A4 (for example, phenobarbital, phenytoin, 
St. John’s Wort) and P-gp inducers may decrease the concentration of doxorubicin.  Avoid 
concurrent use of doxorubicin with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp.  
Attachment 9 provides a list of these inhibitors and inducers. 
7.6.
Treatment Compliance
The study medication will be administered only at the investigational sites by the authorized 
study site personnel.  As a result, treatment compliance is ensured.  Treatment compliance will 
be monitored by drug accountability records, and treatment administration data are recorded in 
the patient’s medical record and eCRF.  An investigator is required to prepare, maintain, and 
record all observations and other data pertinent to the investigation on each individual treated in 
this clinical trial.  All data reported on the eCRF must be derived from source documents and be 
consistent with the source documents.
7.6.1. Evaluable Patients
Evaluable patients are those with adequate biomarker samples who have a baseline (pre-
monotherapy) and at least 1 postbaseline measurement. Patients who withdraw from the study 
before receiving study drug will be replaced and will not be included in the safety or primary 
objective assessments.  Safety analyses will be conducted on all patients who have received at 
least 1 dose of study drug.
If the patient is noncompliant during olaratumab monotherapy (Cycle 1) and does not undergo 
the post-olaratumab monotherapy biopsy or the C1D1 pre-dose and C2D1 predose whole blood 
sample collection due to reasons other than drug-related toxicity, he or she will be considered 
nonevaluable for the primary objective.  These patients may be replaced to ensure that 35


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patients complete the pre-treatment tissue biopsy, the C1D1 pre-dose whole blood sample 
collection, 1 cycle of olaratumab monotherapy, and the post-olaratumab monotherapy biopsy,
and the associated C2D1 predose whole blood sample collection.


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8. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
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).  Section 
8.1.2.4 presents a summary of AE and SAE reporting guidelines.  Table JGDM.5 shows the 
database or system 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.
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
(Attachment 1).  The NCI-CTCAE Version 4.0 will serve as the reference document for 
choosing appropriate terminology for, and grading the severity of, all AEs and other symptoms.  
All AEs observed will be graded using CTCAE Version 4.0. For AEs without matching 
terminology within the NCI-CTCAE Version 4.0 criteria, the investigator will be responsible for 
selecting the appropriate System Organ Class and assessing severity grade based on the intensity 
of the event.  Note that both CTCAE term (actual or coded) and severity grade must be selected 


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by study site personnel and collected on the case report form (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 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 drugs 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 will be 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 and/or study drug via eCRF.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
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.
An SAE is any AE during this study that results in one of the following outcomes:

death


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
initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
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.  Attachment 5 provides recommendations for reporting SAEs.
When a condition related to study treatment necessitates medical or surgical intervention to 
preclude either permanent impairment of a body function or permanent damage to a body 
structure, the serious outcome of “required intervention” will be assigned.
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.  
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 in 
the Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drugs
Although all AEs after signing the ICF are recorded in the CRF, SAE reporting begins after the 
patient has signed the ICF and has received study treatment. However, if an SAE occurs after 
signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedure.
8.1.2.2.2. On Study Treatment
All AEs and SAEs, regardless of relatedness to study drugs or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 


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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 drugs or protocol procedures, occurring 
during the follow-up visit (Visit 801) must be reported to Lilly or its designee. The follow-up 
visit begins the day after the patient and the investigator agree that the patient will no longer 
continue study treatment.  At the end of the follow-up visit, the patient will be required to have 
specific safety assessments (Attachment 1).  The timing of these safety assessments is 30 ± 7
days after the last dose of study drug.
Following the safety assessments, which mark the end of the follow-up visit (Visit 801), the 
patient will continue into long-term follow-up until disease progression.  Any ongoing AE or 
SAE considered possibly related to study drug should be followed during the long-term follow-
up.  In this instance, the patient should be followed in subsequent follow-up visits (Visit 802, 
Visit 8XX) until the event is resolved, or is no longer considered to be drug-related, or becomes 
stable, or returns to baseline, a new treatment is initiated for the patient, or the patient dies or is 
lost to follow-up.
If it is deemed to be in the best interest of the patient to start a new anticancer treatment prior to 
the scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this 
case, the follow-up assessments should be completed prior to the initiation of the new therapy.
After the follow-up visit (Visit 801), AEs are not required to be reported unless the investigator 
feels the AEs were related to either study drug, drug delivery system, or a protocol procedure. If 
an investigator becomes aware of any 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.
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the
DCSI and that the investigator identifies as related to study drug or procedure.  The United States 
21 CFR 312.32, the European Union Clinical Trial Directive 2001/20/EC, and the associated 
detailed guidances or national regulatory requirements in participating countries require the 
reporting of SUSARs.  Lilly has procedures that will be followed for the recording and expedited 
reporting of SUSARs that are consistent with global regulatory regulations and the associated 
detailed guidances.
8.1.2.4.
Summary of AE/SAE Reporting Guidelines
Table JGDM.5 summarizes the AE and SAE reporting guidelines.


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Table JGDM.5.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study treatment
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment and 
no longer in long-term 
postdiscontinuation follow-up)
All SAEs related to protocol procedures 
or study treatment 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.
Electrocardiograms
For each patient, 12-lead ECGs will be collected according to the Study Schedule (Attachment 
1).  Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed 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 and for immediate 
patient management, should any clinically relevant findings be identified.  Section 9.2.2 provides 
additional information on ECG collection and storage. 
After enrollment, if a clinically significant increase in the QT/corrected QT interval (QTc) from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if 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.


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Table JGDM.6 provides Bazett’s QT heart rate correction formula.  Table JGDM.8.7 provides 
Fridericia’s QT correction formula for patients with bundle branch block.
Table JGDM.6.
Bazett’s QT Heart Rate Correction Formula
Formula
Bazett’s QTc=QT (HR/60)1/2=QT (RR)–1/2
Type of formula
Nonlinear
Use
Most commonly used in clinical practice
Unique limitations
Over-corrects QT at fast HRs
Under-corrects QT at low HRs (the risk of TdP which 
frequently occurs at low HRs, may not be evident)
Abbreviations:  QTc = corrected QT interval; HR = heart rate; RR = duration of ventricular cardiac cycle; 
TdP = torsade de pointes (a polymorphic ventricular tachycardia). 
Table JGDM.8.3 
Fridericia’s QT Correction Formula
Formula
QTcF=QT/(RR)1/3
Abbreviations:  QT = ECG interval measured from the onset of the QRS complex to the offset of the T wave; 
QTcF = QT interval corrected for heart rate using Fridericia’s formula; RR = time between corresponding points 
on 2 consecutive R waves on ECG.
8.1.3.2.
Echocardiograms/MUGA Scans
An ECHO or MUGA scan is required within 28 days prior to enrollment for all patients.  
Thereafter, ECHO or MUGA scans, whichever technique was used initially (as described in 
Section 7.2.3.1.2.2), must be performed at the end of Cycles 5 and 7, and when clinically
indicated.  For patients with LVEF <50% or other cardiac dysfunction, perform more frequently, 
if clinically indicated. After Cycle 7 (for patients with resting LVEF ≥50%), an ECHO or 
MUGA scan should be obtained at the 30-day follow-up visit (refer to the Study Schedule
[Attachment 1]).  
Patients who stop doxorubicin prior to Cycle 7 will undergo cardiac monitoring assessment at the 
30-day follow-up visit (refer to the Study Schedule [Attachment 1]) with whichever technique 
(ECHO or MUGA scan) was used initially (as described in Section 7.2.3.1.2.2).
8.1.4. Safety Monitoring
The Lilly CRP/clinical research scientist (CRS) will monitor safety data throughout the course of 
the study, including a safety review conducted after the first 5 patients have completed Cycle 2 
of treatment. 


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Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP 
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review:

trends in safety data

laboratory analytes

AEs, including cardiac events such as:
o
myocardial failure or dysfunction
o
myocardial ischemia or infarction
o
arrhythmias
o
cardiovascular insufficiency

adverse events of special interest (AESIs; as defined in Section 8.1.4.1)

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 (see Attachment 3).  
8.1.4.1.
Adverse Events of Special Interest
Adverse events of special interest are events that have been identified as safety signals during 
preclinical or early clinical trials or based on class effects of similar drugs.  These events will be 
monitored prospectively in the clinical developmental program.  Each event is defined by a 
careful assessment and grouping of individual related MedDRA preferred terms. 
AESI for olaratumab
IRRs
AESI for combination of olaratumab and doxorubicin
Cardiac arrhythmias and cardiac dysfunction
Refer to Section 7.2.3 for special treatment considerations for dose delay, modifications, and 
discontinuations from olaratumab and/or doxorubicin, including AEs of concern or AESIs.
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
Complaints related to doxorubicin and/or dexrazoxane or concomitant drugs are reported directly 
to the manufacturers of those drugs in accordance with the package insert.


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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 product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.  
Attachment 2 lists the specific tests that will be performed for this study.  
Attachment 4 provides details on and timing for the collection of biomarker, PK, and 
immunogenicity blood samples.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood, urine, and tissue 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.
Section 8.2.3.1 specifies blood sample requirements for study qualification.  
Section 8.2.3.2 specifies tumor tissue sample requirements for study qualification. 
8.2.2. Samples for Drug Concentration Measurements 
Pharmacokinetics
Pharmacokinetic samples will be collected as specified in the Biomarker, PK, and 
Immunogenicity Blood Sampling Schedule (Attachment 4). 
8.2.2.1.
Pharmacokinetic Samples
At the visits and times specified in the Study Schedule (Attachment 1) and in the Biomarker, PK, 
and Immunogenicity Blood Sampling Schedule (Attachment 4), samples of approximately 3 mL 
of whole blood will be drawn into tubes to perform olaratumab serum PK measurements.  A 
maximum of 3 samples per drug may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and Lilly.  Instructions for the 


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collection and handling of blood samples will be provided by Lilly.  The actual date and time 
(24-hour clock time) of each sampling will be recorded.
These samples will be analyzed at laboratories designated by the sponsor.  Serum concentrations 
of olaratumab will be assayed using a validated enzyme-linked immunosorbent assay method.  
Bioanalytical samples collected to measure IP concentration will be retained for a maximum of 
1 year following last patient visit for the study and will be stored at facilities designated by Lilly.
8.2.3. Samples for Biomarkers
As part of Lilly’s ongoing efforts to understand the relationship between cancer, genetics, and
response to therapy, this study will analyze biomarkers relevant to drug targets, disease process, 
pathways associated with STS and/or cancer-related conditions, immune cells/immune and 
tumor microenvironment functioning within the disease state and MOA of olaratumab or 
doxorubicin. 
The primary objectives of this study are to enumerate whole blood CTCs and to characterize 
PDGFRα, PDGFRβ, and canonical ligands (PDGF-A, B, C, and D) expression changes pre- and 
post-olaratumab monotherapy in tumor tissue in patients with potentially resectable STS.  
There will be mandatory collection of tumor tissue samples pre- and post-olaratumab 
monotherapy and an optional collection of tumor tissue at the end of the patient’s study 
treatment, or when the patient undergoes a surgical resection, for study objectives relating to 
PDGFRexpression and related pathways, and to the biomarkers in the primary objective and 
clinical outcomes.  The study may be used for related research methods or validation of 
diagnostic tools or assays.
Collection of samples for biomarker research is a mandatory part of this study.  Blood and tissue
samples will be collected.  
Required samples for biomarker research to be collected from all patients in this study are the 
following:

blood (see Section 8.2.3.1 and Section 8.2.4)

tumor tissue (see Section 8.2.3.2)
Sample collection including blood and tumor tissue will occur at specified time points as 
indicated in the Study Schedule (Attachment 1). These samples are also described in the 
following sections.
It is possible that biomarker data has already been generated from samples that were collected 
and analyzed prior to enrolling in this trial.  This may include data generated from genetic 
analyses.  If available, this data may be requested from medical records for use in the research 
described in the following sections.
Samples may be stored for a maximum of 15 years following last patient visit for the study.


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8.2.3.1.
Blood Samples
Whole blood samples are required for all patients in order to participate in this study for 
biomarker research:

newly obtained peripheral whole blood specimens will be collected 
specifically to enumerate CTCs.  These specimens will be collected at C1D1 
(predose), C1D8 (predose), C2D1 (predose), C2D8 (predose), C3D1 
(predose), and at the end of the patient’s study treatment or at the time of 
surgical resection.  Refer to Attachment 4 for details. 

blood (ethylenediaminetetraacetic [EDTA] plasma, serum) samples for 
nonpharmacogenetic biomarker research will be collected.  Refer to 
Attachment 4 for details.
Newly obtained peripheral whole blood specimens are to be collected specifically to enumerate 
CTCs.  Sequentially collected blood specimens will be used for CTC detection and enumeration.  
The primary analysis of these samples will be focused on the relationship between pre-
olaratumab monotherapy and on-treatment (post-olaratumab monotherapy treatment) CTC 
counts. These samples may be used for other exploratory analyses and further molecular 
characterization.
Additional blood (EDTA plasma, serum) samples for nonpharmacogenetic biomarker research 
will be collected.  These samples will be examined for biomarkers related to STS, immune 
cells/immune and tumor microenvironment functioning within the disease state and/or cancer-
related conditions, variable response to olaratumab and/or doxorubicin, and the MOA of 
olaratumab or doxorubicin.  Potential pharmacodynamics and/or circulating markers may 
include, but are not limited to, PDGF receptors, canonical ligands (PDGF-A, B, C, and D), and 
downstream signaling pathways.  Biomarker assays may be performed on these samples to 
evaluate systemic immune modulation and changes in immune cell infiltration, activation, 
modulation, microenvironment, and changes in stromal and tumor biology in response to study 
treatment.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  Samples will be retained for a 
maximum of 15 years after the last patient visit for the study at a facility selected by the sponsor.  
This retention period enables use of new technologies, response to questions from regulatory 
agencies, and investigation of variable response that may not be observed until later in the drug 
development or when the drug is commercially available for a shorter period if local regulations 
and/or ERBs impose shorter time limits.
8.2.3.2.
Tumor Tissue 
Collection of the following tumor tissue samples is mandatory for all patients:

newly obtained biopsy specimens taken from the primary tumor lesion pre- and post-
olaratumab monotherapy treatment will be collected.  The pretreatment tissue biopsy is to 
be performed within the screening period.  The posttreatment tissue biopsy is to be 
performed after completion of the lead-in cycle of olaratumab monotherapy and prior to 


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the initiation of combination therapy (Cycle 2).  Refer to Attachment 1 for additional 
details.  If clinically feasible, the biopsies should be taken from the same primary tumor 
lesion. 
Collection of the following tumor tissue samples is optional for all patients:

biopsy specimen collected at the end of the patient’s study treatment.  Refer to
Attachment 1 for additional details.  If clinically feasible, this biopsy should be taken 
from the same primary tumor lesion.

tumor tissue from any post-therapy surgical resection may also be collected and provided.
While this specimen is optional, it is expected this sample will be sent for analysis.
Sites should examine samples to determine adequacy of tumor tissue using their local laboratory 
procedures prior to the first dose of olaratumab monotherapy and again prior to the first dose of 
combination therapy.  If additional tumor biopsies are collected as part of clinical care, they 
should be submitted, along with local pathology reports, for further analysis. 
Details for the handling and shipping of the tumor tissue will be provided by Lilly in a separate 
document.  The tissue samples will be obtained using appropriate method.  Tumor tissue should 
be submitted as a newly acquired excisional or core needle (minimum 18 gauge) biopsy in 
formalin (10% neutral buffered).  Cytological or fine-needle aspiration specimens are not 
acceptable.  Due diligence should be used to make sure that tumor sample (not a normal adjacent 
or a tumor margin sample) is provided.  Pathology reports accompanying tissue may also be 
requested.  The reports must be coded with the patient number.  Personal identifiers, including 
the patient’s name and initials, must be removed from the institutional pathology notes prior to 
submission.  
Collected tumor samples will be used for research on the drug targets, disease process, pathways 
associated with STS and/or cancer-related conditions, immune cells/immune and tumor 
microenvironment functioning within the disease state and/or cancer-related conditions, MOA of 
olaratumab or doxorubicin, and/or research methods or in validating diagnostic tools or assay(s) 
related to cancer.  The primary analysis of these tumor tissue samples will be focused on the 
assessment of expression level change of PDGFRα, PDGFRβ, and canonical ligands (PDGF A, 
B, C, and D) pre- and post-olaratumab monotherapy treatment. The relationship of baseline 
expression and expression level changes from baseline of these markers will also be evaluated. 
In addition, as a part of exploratory analysis mutation profiling, gene expression, sequencing 
and/or IHC may be performed on these tissue samples to evaluate changes in immune cell 
infiltration, activation, modulation, microenvironment and changes in stromal and tumor biology 
in response to study treatment.  This may include evaluation of biomarkers related to, but not 
limited to, PD1 ligand and tumor infiltrating lymphocytes on tumor and stroma cells.
The 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.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.  


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Samples will be destroyed according to a process consistent with local regulation.
8.2.3.3.
Imaging Studies
A pre- and post-olaratumab monotherapy positron emission tomography (PET) scan will be 
collected for exploratory analyses at times specified in Attachment 1.  Positron emission 
tomography scan analyses measure tumor metabolic activity.  Associations between PET scan 
findings, tissue biomarkers, and CTCs will be investigated in this study.  
8.2.4. Samples for Pharmacogenetics
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis
(Attachment 1).  
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to olaratumab and/or doxorubicin.  These investigations may be 
limited to a focused candidate gene study or, if appropriate, genome-wide analysis may be 
performed to identify regions of the genome associated with the variability observed in drug 
response.  The pharmacogenetic biomarker samples will only be used for investigations related 
to disease and drug or class of drugs under study in the context of this clinical program.  They 
will not be used for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
8.2.5. Samples for Immunogenicity Research
Blood samples for IG testing will be collected to determine antibody production against 
olaratumab. Refer to Attachment 4 for details. Immunogenicity will be assessed by a validated 
assay designed to detect anti-drug antibodies in the presence of olaratumab.  Antibodies may be 
further characterized and/or evaluated for their ability to neutralize the activity of olaratumab.
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.
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.  


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Tumor assessments will be performed for each patient at the times shown in Attachment 1 until 
documented progression for patients with CR, PR, or SD, and/or for patients who have 
discontinued study treatment due to toxicity or reasons other than PD.  Imaging requirements 
include computed tomography (CT) scan or magnetic resonance imaging (MRI) of chest, 
abdomen, and pelvis and other areas, as clinically indicated.  
Computed tomography scans, including spiral CT, are the preferred methods of measurement.
The exploratory PET Scan performed pre and post Cycle 1 will not be used to determine 
efficacy.
The CT portion of a PET-CT scan may be used as a method of response assessment if the site 
can document that the CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast).  A PET scan alone or as part of a PET-CT may be performed for additional analyses,
but cannot be used to assess response according to RECIST.
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Patients will be evaluated for response according to RECIST v1.1 guidelines (Eisenhauer 
et al. 2009), as outlined in Attachment 8.
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 eCRF.
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/
institutional review boards (IRBs) with direct access to the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.
For data handled by a data management third-party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to the Lilly data 
warehouse, using standard Lilly file transfer processes.
For data handled by the sponsor internally, CRF data and some or all data that are related will be 
managed by the sponsor and stored electronically in the sponsor’s system.


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9.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly
clinical laboratory results modernization (CLRM) system.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly CLRM system.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) and will then store the ECGs in a database.  At a future time, the 
stored ECG data may be overread at the central ECG laboratory for further evaluation of 
machine-read measurements or to meet regulatory requirements.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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10.
Data Analyses
10.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
The analyses for this study will mostly be descriptive. For continuous variables, summary 
statistics will include the number of patients, mean, median, standard deviation, minimum and 
maximum.  Categorical endpoints will be summarized using the number of patients, frequency,
and percentages. For time-to-event endpoints, the Kaplan-Meier curves (Kaplan and Meier 
1958) will be estimated, and quartiles and rates at various time points together with the 95% CI 
will be provided. Missing data will not be imputed.
The interpretation of the study results will be the responsibility of the investigator with the Lilly
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.
This study will have 2 database locks. The first database lock will occur when the pre- and 
post-olaratumab monotherapy tissue biopsies and the predose C1D1 and predose C2D1 whole 
blood samples have been collected for all 35 evaluable patients. The main purpose of this 
database lock is to assess biomarker expression level changes pre- and post-olaratumab 
monotherapy. The safety of olaratumab will also be evaluated at this database lock. The second 
database lock will occur at the end of the study when all patients have either completed or 
discontinued from the study and the 30-day short-term follow-up period has been completed.  In 
the second database lock, all of the study objectives will be evaluated.  There will be an interim 
analysis to look at the biomarker data once approximately half of the evaluable patients complete 
the second biopsy and the predose C2D1 whole blood draw.
10.1.1. Determination of Sample Size
To investigate the primary objective, approximately 35 evaluable patients have to have 
completed the pre-treatment tissue biopsy, the predose C1D1 whole blood draw, 1 cycle of 
olaratumab monotherapy, the post-olaratumab monotherapy biopsy, and the predose C2D1 
whole blood draw.
If the patient is noncompliant during olaratumab monotherapy (Cycle 1) and does not undergo 
the pre-treatment tissue biopsy, the post-olaratumab monotherapy biopsy, or the predose C1D1 
and predose C2D1 whole blood draw, he or she will be considered nonevaluable and may be 
replaced.
It is hypothesized that 49% (17 out of 35) or more patients will have a reduction of at least 30% 
in PDGFRα level change in tissue from baseline to post-olaratumab monotherapy. The sample 
size of 35 patients provides a 95% CI that the hit rate (proportion of patients with at least 30% 
reduction in PDGFRα level change from baseline) will be between 31% and 66%, which 
excludes a 30% or lower hit rate.  


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10.1.2. Analysis Populations
Efficacy analysis: the efficacy analysis will be performed on the intent-to-treat (ITT) population,
which includes all enrolled patients. The ITT population will be included in overall patient 
listings, in summary tables of patient demographics and disease characteristics, in the list of 
treatment discontinuation after enrollment, and in the analysis of efficacy.
Safety analysis:  all enrolled patients who receive any quantity of IP, regardless of their 
eligibility for the study, will be included in the safety analysis.  Safety evaluation will be 
performed based on the actual therapy a patient has received.
Biomarker analysis: the biomarker evaluable 1 (BE1) population will include all ITT patients 
with evaluable samples at both baseline and post-olaratumab monotherapy.  The BE1 population 
will be used in the biomarker analyses for the primary objective and exploratory objectives. The 
biomarker evaluable 2 (BE2) population will include all ITT population with evaluable samples 
at both baseline and post-combination (olaratumab plus doxorubicin) therapy, and will be used in 
the biomarker analyses for the exploratory objectives.
10.2. Patient Disposition
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
10.3. Patient Characteristics
Patient characteristics will include a summary of the following:

Patient demographics including age, sex, screening height and weight, and screening 
body mass index will be reported

Baseline disease characteristics

Historical diagnoses

Pre-existing conditions

Prior disease-related therapies 

Concomitant medications

Tissue histology grouped as leiomyosarcoma (LMS) or non-LMS.
Other patient characteristics will be summarized as deemed appropriate.
10.4. Safety Analyses
All patients who receive at least 1 dose of study drug will be evaluated for safety and toxicity.
The safety and tolerability of study drug is determined by reported AEs, physical examinations, 
laboratory tests, ECGs, dose adjustments, and results from ECHO/MUGA scans. 
All patients will be assessed regularly for potential occurrence of AEs from the time that the 
patient provides informed consent until 30 days after the last dose of study therapy.  Adverse 
events will be summarized by MedDRA System Organ Class and preferred term, classified from 
verbatim terms.  The incidence and percentage of patients with at least 1 occurrence of a 


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preferred term will be included, according to the most severe NCI-CTCAE Version 4.0 grade.  
The number of AEs reported per MedDRA preferred term will also be summarized.  Causality 
(relationship to study drug) will be summarized separately.  Duration of AE will be determined 
and included in listings along with action taken and outcome.
Laboratory results will be classified according to NCI-CTCAE Version 4.0.  Incidence of 
laboratory abnormalities will be summarized; laboratory results not corresponding to an NCI-
CTCAE Version 4.0 term will not be graded.  Laboratory toxicity shifts from baseline to worst 
grade will also be provided.
The results from physical examination and vital sign measurement will be tabulated.  Descriptive 
statistics will be provided as appropriate.  Electrocardiogram and ECHO/MUGA evaluation will 
be listed.
10.5. Biomarker Analyses
Primary analysis:  
All patients in the BE1 population will be evaluated for:

CTC enumeration in whole blood  

PDGFRα, PDGFRβ, and canonical ligand (PDGF-A, B, C, and D) expression 
in tumor tissue.  
The percent change from baseline for post-olaratumab monotherapy in biomarker expressions 
will be provided for each patient and summarized for all qualified patients.  Summary of number 
and frequency of patients with at least 30% reduction in change from baseline PDGFRα 
expression will also be provided.  For patients with an observed value of 0 for baseline 
expression or both baseline and post-olaratumab monotherapy expressions, a value of 0.1 will 
be used. 
10.6. Efficacy
The following secondary efficacy endpoints will be measured:
Progression-free survival (PFS): is defined as the time from enrollment until the first 
radiographic documentation of objective progression as defined by RECIST (v1.1) (Attachment 
8), or death from any cause. Patients who die without a reported prior progression will be 
considered to have progressed on the day of their death. Patients who did not progress or who 
are lost to follow-up will be censored at the day of their last radiographic tumor assessment.  If 
no baseline or postbaseline radiologic assessment is available, the patient will be censored at the 
date of enrollment.  If death or PD occurs after 2 or more consecutive missing radiographic 
visits, censoring will occur at the date of the last radiographic visit prior to the missed visits. The 
use of a new anticancer therapy or the performance of a surgical resection prior to the occurrence 
of PD will result in censoring at the date of last radiographic assessment prior to initiation of new 
therapy or surgical resection.


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3-month PFS:  estimated as the total number of patients who did not progress 3 months after 
enrollment divided by the total number of patients.
Overall response rate (ORR): estimated as the total number of CRs, complete responses 
unconfirmed (CRus), and PRs divided by the total number of patients.  
Disease control rate (DCR): is computed as the total number of patients with the best overall 
response of CR, CRu, PR, or SD divided by the total number of patients.  
Rate of Resectability:  is defined as the total number of patients who are resectable (see 
definition of resectability in Section 4) divided by the total number of patients.
10.7. Pharmacokinetic Analyses
Pharmacokinetic parameter estimates for olaratumab will be calculated by standard 
noncompartmental methods of analysis in patients who have received at least 1 dose of 
olaratumab and have had samples collected.  The primary parameters for analysis will be 
maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), area under the 
plasma concentration-time curve from time zero to the last measurable plasma concentration 
(AUC[0-tlast]), and area under the plasma concentration-time curve from time zero to infinity
(AUC[0-∞]) of olaratumab, where appropriate.  Other noncompartmental parameters, such as
half-life (t1/2), clearance (CL), and volume of distribution (Vd), may be reported.
Additional exploratory analyses may be performed if warranted by data and other validated PK 
software programs (for example, NONMEM) may be used if appropriate and approved by Lilly 
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.
10.8. Interim Analyses
An interim analysis will be done to look at the biomarker data once approximately half of the 
evaluable patients complete the second tumor tissue biopsy and C2D1 whole blood draw.  The 
purpose of this interim analysis is to review the biomarker and safety data.  If this interim look at 
the biomarker data warrants any changes in the study conduct, it will be implemented in an 
appropriate manner (that is, protocol amendment). Section 10.1 describes the 2 database locks 
and the interim analysis that will occur in this study.


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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 or their legal 
representatives.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the ICH guideline on GCP.  
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
The study site’s ERBs should be provided with the following:
1. the current IB and updates during the course of the study
2. ICF
3. 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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Some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data.
11.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
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 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
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
D’Angelo SP, Tap WD, Schwartz GK, Carvajal RD. Sarcoma immunotherapy: past approaches 
and future directions [published correction appears in Sarcoma. 2015;2015:259817]. Sarcoma. 
2014;2014:391967.
Dolloff NG, Russell MR, Loizos N, Fatatis A. Human bone marrow activates the Akt pathway in 
metastatic prostate cells through transactivation of the alpha-platelet-derived growth factor 
receptor. Cancer Res. 2007;67(2):555-562.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
[ESMO] European Society for Medical Oncology/European Sarcoma Network Working Group. 
Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up [published correction appears in Ann Oncol. 2015;26(suppl 5):v174-v177]. Ann 
Oncol. 2014;25(suppl 3):iii102–iii112.
Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-
Cardo C, Beug H, Grunert S. Autocrine PDGFR signaling promotes mammary cancer 
metastasis. J Clin Invest. 2006;116(6):1561-1570.
Jemal A, Center MM, Ward E, Thun MJ. Cancer occurrence. Methods Mol Biol. 2009;471:3-29.
Linch M, Miah AB, Thway K, Judson IR, Benson C. Systemic treatment of soft-tissue sarcoma -
gold standard and novel therapies. Nat Rev Clin Oncol. 2014;11(4):187-202.
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.
[NCIN] National Cancer Intelligence Network. Bone and soft tissue sarcomas UK incidence and 
survival: 1996 to 2010. Available at: http://www.ncin.org.uk/view?rid=2353. Published 
November 2013. Accessed February 22, 2015.
[NCCN 2011] National Comprehensive Cancer Network. Clinical Practice Guidelines in 
Oncology. Soft Tissue Sarcoma. V1.2011. Available at: http://www.nccn.org. Accessed 
February 19, 2016.
[NCCN 2014] National Comprehensive Cancer Network. Clinical Practice Guidelines in 
Oncology. Myeloid Growth Factors. V2.2014. Available at: 
http://williams.medicine.wisc.edu/myeloid_growth.pdf. Accessed February 19, 2016.


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[NCCN 2016] National Comprehensive Cancer Network. Clinical Practice Guidelines in 
Oncology. Soft Tissue Sarcoma. V1.2016. Available at: http://www.nccn.org. Accessed 
February 19, 2016.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 
1982;5(6):649-655.
Park YH, Seo SY, Ha M, Ku JH, Kim HH, Kwak C. Inhibition of prostate cancer using RNA 
interference-directed knockdown of platelet-derived growth factor receptor. 
Urology. 2011;77(6):1509.e9-1509.e15. 
Russell MR, Jamieson WL, Dolloff NG, Fatatis A. The α-receptor for platelet-derived growth 
factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer 
cells. Oncogene. 2009;28(3):412-421.
Russell MR, Liu Q, Lei H, Kazlauskas A, Fatatis A. The α-receptor for platelet-derived growth 
factor confers bone-metastatic potential to prostate cancer cells by ligand- and dimerization-
independent mechanisms. Cancer Res. 2010;70(10):4195-4203.
Schoffski P, Cornillie J, Wozniak A, Lia H, Hompes D. Soft tissue sarcoma: an update on 
systemic treatment options for patients with advanced disease. Oncol Res Treat.
2014;37(6):355-362.
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(suppl 4):1018-1026.
Sharma S, Takyar S, Manson SC, Powell S, Penel N. Efficacy and safety of pharmacological 
interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: a 
systemic review. BMC Cancer. 2013;13:385.
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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Attachment 1.Protocol JGDM Study Schedule
Perform procedures as indicated in the following tables for the baseline, treatment, and 
posttreatment periods, respectively.  
All screening/baseline evaluations are performed within 14 days prior to enrollment, unless 
otherwise specified.  Patients who meet all criteria for enrollment will be assigned to receive 
treatment.  After the patient signs the informed consent form, the site will register the patient in 
the Interactive Web Response System, which is web-based and accessible 24 hours a day.  


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Baseline Schedule of Activities 
 
 
Study Period 
Baseline 
 
 
 
Cycle 
BL 
 
 
 
Visit 
0 
 
 
 
Duration 
Up to 14 days 
(except where noted) 
 
 
 
Relative Day from Enrollment 
≤14 
≤7 
 
Procedure 
Category 
Protocol 
Sections 
Procedure 
 
Comments 
Study Entry/ 
Enrollment 
11.1 
Informed Consent 
X (within 28 days 
of enrollment) 
Written informed consent must be obtained prior to any study-specific screening 
evaluations.  For screening purposes, required assessments performed prior to the 
date of consent may be used provided they are noted exceptions.  
6.1  
7.2.3.1.2.4 
Inclusion/Exclusion Evaluation and IWRS 
 
X 
Patients who meet all criteria for enrollment will be assigned to receive treatment.  
After the patient signs the ICF, the site will register the patient in the IWRS.  
After enrollment, patients should receive their first dose of treatment within 72 
hours (3 days) whenever possible. 
Medical 
History 
8.1.2 
Medical History 
X 
Any preexisting and pretreatment toxicity (treatment- or disease-related) should 
be documented and recorded as part of the pretreatment medical history.  Disease 
characteristics at initial diagnosis and at study entry will be collected. 
All adverse events must be recorded after signing the informed consent. 
6.1 
Demography 
X 
Year of birth, sex, and race/ethnicity will be collected at baseline. 
6.1 
Prior Treatment Therapies of Underlying Disease 
X 
Prior treatment includes any treatment for underlying disease, including 
maintenance therapy.  Start and stop dates should be documented as well. 
Physical 
Examination 
6.1 
Physical Examination  
 
X 
Physical examination at baseline includes height, weight, and BSA measurement.  
6.1 
Attachment 6 
ECOG Performance Status 
 
X 
Refer to Attachment 6 for details. 
6.1 
Vital Signs 
 
X 
Vital signs include blood pressure, pulse, and temperature. 
Concomitant 
Medications 
7.5 
Concomitant Medications 
X  
Concomitant medications will be recorded, including any taken within 30 days 
prior to start of study treatment (C1D1). 
 
 
 
Lab/ 
Diagnostic 
Tests 
 
 
 
 
 
 
 
6.1.1 
Attachment 2 
Hematology 
X 
Screening evaluations done within 7 days prior to enrollment do not have to be 
repeated.  Testing will be performed locally for patient management and centrally 
for analysis purposes. 
6.1.1 
Attachment 2 
Serum Chemistry  
X 
Screening evaluations done within 7 days prior to enrollment do not have to be 
repeated.  Testing will be performed locally for patient management and centrally 
for analysis purposes. 
6.1.1 
Attachment 2 
Coagulation Profile  
X 
Screening evaluations done within 7 days prior to enrollment do not have to be 
repeated.  Testing will be performed locally only. 
Attachment 2 
Urinalysis  
X 
Screening evaluations done within 7 days prior to enrollment do not have to be 
repeated.  Includes a routine UA, and if clinically indicated a microscopic 
analysis.  If routine analysis indicates > 2+ proteinuria, then a 24-hour urine must 
be collected and must demonstrate ≤ 1000 mg of protein in 24 hours.  Testing will 
be performed locally only. 


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Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 14 days
(except where noted)
Relative Day from Enrollment
≤14
≤7
Procedure 
Category
Protocol 
Sections
Procedure
Comments
Lab/
Diagnostic 
Tests
6.1.1
Attachment 2
Pregnancy Test 
X
Serum β-HCG or urine pregnancy test (women of child-bearing potential only) 
within 7 days prior to enrollment.  If the pregnancy test performed for inclusion 
purposes is positive, confirm by repeating a serum or urine pregnancy test.  The 
results of this test will not be collected on the eCRF.  Testing will be performed 
locally only.
6.1.1
Attachment 2
FSH 
X
Performed only at screening in menopausal women that have experienced 
spontaneous amenorrhea for 6 to 12 months.  To be done for women only when 
needed to confirm postmenopausal status.  Testing will be performed locally only.
8.2.3
Tumor Tissue Biopsy
X (within 28 days
of enrollment)
When submitting a tissue biopsy, sites should examine samples to determine 
adequacy of tumor tissue using their local laboratory procedures prior to first dose 
of olaratumab monotherapy.  If additional tumor biopsies are collected as part of 
clinical care, they should be submitted, along with local pathology reports for 
further analysis (refer to Section 8.2.3 for details).
8.1.3.1
9.2.2
ECG 
X (within 28 days
of enrollment)
A single 12-lead ECG is to be obtained within 28 days prior to enrollment (refer 
to Section 8.1.3.1 and Section 9.2.2 for details). ECGs will be read locally and 
measurements will be electronically submitted to a central vendor.
8.1.3.2
Echocardiogram or MUGA Scan
X (within 28 days
of enrollment)
Within 28 days prior to enrollment (refer to Section 8.1.3.2 for details).
8.2.3.3
PET Scan
X (within 28 days
of enrollment)
Within 28 days prior to enrollment.  PET scans will be read locally by the 
investigator and sent to a central vendor where the images will be stored.
Efficacy
Assessment
Attachment 8
Imaging Studies (CT/MRI)
Tumor Assessments (according to RECIST v1.1)
X (within 28 days
of enrollment)
Within 28 days prior to enrollment (refer to Attachment 8 for details).  CT/MRI 
scans will be read locally and a scan will also be sent for storage at a central 
vendor.
Patient Disposition
X
At the time that the patient is discontinued from study participation, information 
regarding the patient status will be collected.
Abbreviations:  β-HCG = beta human chorionic gonadotropin; BL = baseline; BSA = body surface area; C = cycle; CT= computed tomography; D = day; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; FSH = follicle-stimulating hormone; ICF = informed consent 
form; IWRS = Interactive Web Response System; MRI = magnetic resonance imaging; MUGA = multi-gated acquisition; PET = positron emission tomography; RECIST = 
Response Evaluation Criteria in Solid Tumors; UA = urinalysis.


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On-Study-Treatment Schedule of Activities
Study Period
Treatment Period
Olaratumab
Monotherapy
Combination Therapy
Olaratumab + Doxorubicin
Cycle (21-day cycle 
±3 days)
1
2-7
Relative Day within 
Cycle 
(±3 days)
1a,b
8a
1a,b
8a
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination
6.1
Physical Examination
X
X
X
X
Physical examination during treatment period includes weight and BSA 
measurement.  Patients should be weighed on D1 and D8 of each cycle and BSA 
calculated.
6.1
Attachment 6
ECOG Performance 
Status
X
X
Complete prior to treatment infusion.  Refer to Attachment 6 for details.
6.1
Vital Signs
X
X
X
X
Vital signs include blood pressure, pulse, and temperature.
During the Observation Period (initial 2 cycles of olaratumab therapy), collect vital 
signs 3 times:

within 15 minutes (+5 minutes) prior to olaratumab infusion

within 1 hour (+5 minutes) after completion of the olaratumab infusion

within 1 hour (+5 minutes) after completion of the doxorubicin infusion.  
Thereafter (Cycles 3+), obtain vital signs 2 times:  
within 15 minutes (+5 minutes) prior to olaratumab infusion 
within 1 hour (+5 minutes) after completion of the doxorubicin infusion.
Lab/
Diagnostic 
Tests
Attachment 2
Hematology 
X
X
X
X
Laboratory assessments may be done within 7 days prior to D1 and D8 of each 
cycle.  See Attachment 2 for details. Testing will be performed locally for patient 
management and centrally for analysis purposes.
Attachment 2
Serum Chemistry 
X
X
Laboratory assessments may be done within 7 days prior to D1 of each cycle.  See 
Attachment 2 for details. Testing will be performed locally for patient management 
and centrally for analysis purposes.
Attachment 2
Coagulation Profile 
X
X
Perform on D1 every other cycle or as clinically indicated.  See Attachment 2 for 
details. Testing will be performed locally only.
Attachment 2
Urinalysis
X
X
Laboratory assessments may be done within 7 days prior to D1 of every other cycle 
or as clinically indicated.  Includes a routine UA, and, if clinically indicated, a 
microscopic analysis.  If routine analysis indicates >2+ proteinuria, then a 24-hour 
urine must be collected and must demonstrate ≤1000 mg of protein in 24 hours.
Testing will be performed locally only.
Attachment 2
Pregnancy Test 
X
X
Serum β-HCG or urine pregnancy test on D1 of every cycle or per local practice 
(whichever is of shorter duration).  If a pregnancy test performed on D1 of the cycle 
is positive, confirm with a serum or urine pregnancy test (pregnancy test results are 
not recorded on the eCRF).  If results are positive, the investigator is to consult with 
the Lilly CRP. Testing will be performed locally only.
8.2.2
Attachment 4
PK Samples
See Attachment 4 for specific time points
Whole blood samples collected for olaratumab serum PK measurements.


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Study Period
Treatment Period
Olaratumab
Monotherapy
Combination Therapy
Olaratumab + Doxorubicin
Cycle (21-day cycle 
±3 days)
1
2-7
Relative Day within 
Cycle 
(±3 days)
1a,b
8a
1a,b
8a
Procedure 
Category
Protocol 
Section
Procedure
Comments
8.2.5
Attachment 4
Immunogenicity 
Samples
See Attachment 4 for specific time points
Whole blood samples collected.  If a patient experiences an IRR to olaratumab, 
blood samples for immunogenicity and PK analysis will be taken at the following 
time points:  (1) as soon as possible after the onset of the IRR, (2) at the resolution 
of the IRR, and (3) 30 (± 3 days) days after onset of the IRR event.
Lab/
Diagnostic 
Tests
8.2.4
Pharmacogenetic Whole 
Blood Sample for DNA 
storage
X
Whole blood sample collected.  It is highly recommended to draw the whole blood 
sample prior to the first dose (C1D1 at predose); however, it can be collected later 
during the study if necessary.
8.2.3
Attachment 4
Plasma sample for 
exploratory biomarkers
X
See Attachment 4 for specific time 
points
Plasma sample collected.  C1D1 at predose, C2D1 (combination therapy pre-dose) 
and at the end of the patient’s study treatment.  See Section 8.2.3.1 and Attachment 
4 for details and specific time points.
8.2.3
Attachment 4
Serum sample for 
exploratory biomarkers
X
See Attachment 4 for specific time 
points
Serum sample collected.  C1D1 at predose, C2D1 (combination therapy pre-dose) 
and at the end of the patient’s study treatment.  See Section 8.2.3.1 and Attachment 
4 for details and specific time points.
8.2.3
Attachment 4
Mandatory Whole Blood 
Collection for 
Circulating Tumor Cells
X
See Attachment 4 for specific time 
points
Collect mandatory peripheral whole blood samples predose at C1D1, C1D8, C2D1, 
C2D8, and C3D1, and at end of the patient’s study treatment or at the time of 
surgical resection.  See Section 8.2.3.1 and Attachment 4 for details.
8.2.3
Mandatory Tumor Tissue
X
Mandatory tumor tissue must be collected up to 3 days prior to the first dose of 
C2D1. When submitting a specimen from a tumor resection after or during 
combination therapy, sites should examine samples to determine adequacy of tumor 
tissue using their local laboratory procedures.  If additional tumor biopsies are 
collected as part of clinical care, they should be submitted, along with pathology 
reports, for further analysis.  See Section 8.2.3.2 for details.
8.1.3.1
ECG 
X
X
Twelve-lead ECGs are to be collected on Day 1 of monotherapy Cycle 1 and on Day 
1 of combination therapy Cycles 2-7.  Patients who stop doxorubicin prior to Cycle 
7 will undergo the same cardiac monitoring assessment. ECGs will be read locally 
and measurements will be electronically submitted to a central vendor.
8.1.3.2
Echocardiogram or 
MUGA
X
Echocardiograms or MUGA scans must be performed at the end of combination 
therapy Cycles 5 and 7 and when clinically indicated.  After Cycle 7, (resting LVEF 
≥50%), perform echocardiograms or MUGA at the 30-day follow-up visit.  Patients 
who stop doxorubicin prior to Cycle 7 will undergo the same cardiac monitoring 
assessment. For patients with LVEF <50% or other cardiac dysfunction, perform 
more frequently, if clinically indicated.
8.2.3.3
PET Scan
X
Mandatory PET scan must be collected up to 3 days prior to the first dose of C2D1.  
PET scans will be read locally by the investigator and sent to a central vendor where 
the images will be stored.


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Study Period
Treatment Period
Olaratumab
Monotherapy
Combination Therapy
Olaratumab + Doxorubicin
Cycle (21-day cycle 
±3 days)
1
2-7
Relative Day within 
Cycle 
(± 3 days)
1ab
8a
1a
8ab
Procedure 
Category
Protocol 
Section
Procedure
Comments
Efficacy
Assessment
Attachment 8
Imaging Studies 
(CT/MRI)
Tumor Assessments 
(according to RECIST 
v1.1)
X
Imaging studies and tumor assessments are to be obtained every 6 weeks (up to 
7 days before), irrespective of treatment cycles as calculated from enrollment, until 
documented progression for patients with CR, PR, or SD, and/or for patients who 
have discontinued study treatment due to toxicity or reasons other than PD.  Refer 
to Attachment 8 for details. CT/MRI scans will be read locally and a scan will 
also be sent for storage at a central vendor.
Adverse Events 
Collection/
CTCAE 
Grading
8.1.2
Toxicity Assessment
X
X
X
X
All AEs considered at least possibly related to study treatment will be followed 
until resolution, stabilization, or return to baseline, or until deemed irreversible.
Concomitant 
Therapy
7.5
Concomitant 
Medications
X
X
X
X
Concomitant medications will be recorded throughout the treatment period, 
including those taken during the 30 days after the last dose of all study treatment.
Premedication
7.2.2
Administer 
premedication prior to 
olaratumab treatment  
X
X
X
X
Premedicate all patients with the following medications (or equivalent):  a 
histamine H1 antagonist (eg, diphenhydramine) and dexamethasone intravenously 
30–60 minutes prior to the olaratumab doses on Days 1 and 8 of Cycle 1.  For 
subsequent cycles, premedicate all patients with a histamine H1 antagonist (eg, 
diphenhydramine) intravenously 30-60 minutes prior to each dose of olaratumab. 
7.2.2
Administer dexrazoxane 
prior to doxorubicin
X
Dexrazoxane is recommended for all patients receiving 5 or more cycles of 
doxorubicin.
Study 
Treatment
7.1.2
Administer olaratumab 
X
X
X
X
Administer through completion of Cycle 7 or until PD, surgical resection, 
unacceptable toxicity, death, or other withdrawal criteria are met.  
7.1.3
Administer doxorubicin
X
Administered to all patients during combination therapy for up to a maximum of 6 
cycles (Cycles 2-7) (unless previous unacceptable toxicity).
Patient Disposition
X
X
At the time that the patient is discontinued from any component of the study 
treatment or study participation, information regarding the patient status will be 
collected.


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Abbreviations:  β-HCG = beta human chorionic gonadotropin; AE = adverse event; BSA = body surface area; C = cycle; CR = complete response; CRP = clinical research 
physician; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; IRR = infusion-related reaction; LVEF = left ventricular ejection fraction; MRI = 
magnetic resonance imaging; MUGA = multi-gated acquisition; PD = progressive disease; PET = positron emission tomography; PK = pharmacokinetic; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; UA = urinalysis.
a
Study procedures will be performed prior to study drug administration, except where noted (such as vital signs).  In case of dose interruption, these evaluations will also be 
done at minimum frequency every 21 days (±3 days).
b
Relative day within each cycle (≤3 days). Procedure allowed up to 3 days before D1.


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Posttreatment Discontinuation Follow-Up Schedule of Activities
Study Period
Posttreatment Discontinuation Follow-Up
Short-Term Follow-Up
Long-Term Follow-Up
Visit
801
802-8XX
Duration
30 ± 7 days
See footnote for duration
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination 
6.1
Physical examination
X
Physical examination will include weight.
6.1
Attachment 6
ECOG performance 
status
X
Refer to Attachment 6 for details.
6.1
Vital signs
X
Includes blood pressure, pulse, and temperature.
Lab/
Diagnostic 
Tests
Attachment 2
Hematology 
X
See Attachment 2 for details. Testing will be performed locally for patient 
management and centrally for analysis purposes.
Attachment 2
Serum chemistry 
X
See Attachment 2 for details.  Testing will be performed locally for patient 
management and centrally for analysis purposes.
Attachment 2
Coagulation profile
X
See Attachment 2 for details. Testing will be performed locally only.
Attachment 2
Urinalysis
X
Includes a routine UA and, if clinically indicated, a microscopic analysis.  If 
urine dipstick or routine analysis indicates proteinuria ≥2+, a 24-hour urine 
collection (to assess protein) must be obtained. Testing will be performed 
locally only.
Attachment 2
Pregnancy test
X
Serum or urine pregnancy test.  If the pregnancy test is positive, confirm with 
a serum or urine pregnancy test (pregnancy test results are not recorded on the 
eCRF).  Additional pregnancy tests may be done after short-term follow-up if 
required by local regulation.  If results are positive, the investigator is to 
consult with the Lilly CRP. Testing will be performed locally only.
8.1.3.1
ECG
X
Twelve-lead ECGs are to be collected for all patients at the short-term 
follow-up visit. ECGs will be read locally and measurements will be 
electronically submitted to a central vendor.
8.1.3.2
Echocardiogram or 
MUGA
X
Echocardiogram or MUGA scans are to be collected for all patients at the 
short-term follow-up visit. 
Attachment 4
PK sample
X
See Attachment 4.
Attachment 4
Immunogenicity sample
X
See Attachment 4.  In addition, if a patient experiences an IRR to olaratumab, 
blood samples for immunogenicity and PK analysis will be taken at the short-
term follow-up after the IRR.
8.2.3
Attachment 4
Plasma sample for 
exploratory biomarkers
X
Plasma sample collected at 30-day follow-up visit.  See Section 8.2.3.1 for 
details.
8.2.3
Attachment 4
Serum sample for 
exploratory biomarkers
X
Serum sample collected at 30-day follow-up visit.  See Section 8.2.3.1 for 
details.
Efficacy 
Assessments
Attachment 8
Imaging Studies 
(CT/MRI)
Tumor Assessments 
(according to RECIST 
v1.1)
X (if applicable)
X
For patients who discontinue study treatment, or complete 6 cycles of 
combination therapy, and have not progressed, imaging studies and tumor 
assessments are to be obtained every 6 weeks (±7 days) until PD, irrespective 
of treatment cycles, until documented progression as calculated from baseline 
scan.  Patients who have had surgical resection will not be followed for 
subsequent progression by imaging studies. CT/MRI scans will be read 
locally and a scan will also be sent for storage at a central vendor.


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Study Period
Posttreatment Discontinuation Follow-Up
Short-Term Follow-Up
Long-Term Follow-Up
Visit
801
802-8XX
Duration
30 ± 7 days
See footnote for duration
Procedure 
Category
Protocol 
Section
Procedure
Comments
Adverse 
Events 
Collection/
CTCAE 
Grading
8.1.2
Toxicity assessment
X
Xa
All AEs considered at least possibly related to study treatment will be 
followed until resolution, stabilization, or return to baseline, or until deemed 
irreversible.  After the 30-day short-term follow-up visit, only new and 
ongoing SAEs deemed related to study treatment will be collected.
Concomitant 
Medication 
Notation
7.5
Concomitant 
medications
X
Patient Disposition
X
X
At the time that the patient is discontinued from study participation, 
information regarding the patient status will be collected.
Abbreviations:  AE = adverse event; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; eCRF = electronic case report form; IRR = infusion-related reaction; MRI = magnetic resonance imaging; MUGA = multi-gated acquisition; PD 
= progressive disease; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; UA = urinalysis.
Short-term follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts approximately 30 days (±7 days).  
The short-term follow-up visit occurs at or near the end of the short-term follow-up period (±7 days).
a
Follow up for safety:  Patients who undergo surgical resection will be followed for safety for approximately 30 days (±7 days) after surgery.
Long-term follow-up begins the day after short-term follow up is completed. 


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Attachment 2.Protocol JGDM Clinical Laboratory Tests
All laboratory screening evaluations are to be performed within 14 days prior to enrollment, 
unless otherwise specified.  Eligibility for inclusion in this clinical trial will be based on local 
clinical laboratory results (not transcribed onto electronic case report forms); duplicate samples 
will be submitted to the central laboratory.  Treatment decisions may be based upon results of 
tests performed locally.  Discrepancies between local and central laboratory that may have an 
impact on eligibility or treatment decisions will not be considered protocol deviations.  On-study 
clinical laboratory tests assayed for patient safety (such as hematology, serum chemistry, 
coagulation, and pregnancy tests) are to be collected prior to study treatment.


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Clinical Laboratory Tests
Hematologya,b
Clinical Chemistrya,b
Hemoglobin
Serum Concentrations of the following:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Alkaline phosphatase
Leukocytes (WBC)
Alanine aminotransferase (ALT)
Neutrophils
Aspartate aminotransferase (AST)
Lymphocytes
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose, random
Coagulation Testa
Albumin
Prothrombin time (PT)
Total protein
Partial Thromboplastin Time (PTT) 
Chloride
International normalized ratio (INR)
Thyroid-stimulating hormone
Direct bilirubin
Urinalysisa,c
Specific gravity
pH
Pregnancy testa,e
Protein
Glucose
Follicle-stimulating hormone (FSH)a,f
Ketones
Blood
Urine leukocyte esterase
Otherd
Immunogenicity samples
PK samples
Biomarker samples
Abbreviations:  CRP = clinical research physician; D = Day; PK = pharmacokinetics; RBC = red blood cells; WBC 
= white blood cells
a
Assayed by local or investigator-designated laboratory.
b
Duplicate samples will also be assayed by a sponsor-designated laboratory.
c
If urinary protein is ≥2+ at evaluations, a 24-hour urine collection (to assess protein) must be collected and must 
be ≤1000 mg of protein in 24 hours (up to 3 business days is allowed if the weekend).
d
Assayed by a sponsor-designated (central) laboratory.  
e
Serum pregnancy test will be performed at screening in females of child-bearing potential only.  If the baseline 
serum test is positive, a repeat serum or urine pregnancy test will be done.  While on-study, a serum or urine 
pregnancy test will be performed in females of child-bearing potential only on D1 of every cycle or per local 
practice (whichever is of shorter duration) and at the short-term follow-up visit.  If the pregnancy test performed 
on D1 of each cycle is positive, confirm with a serum or urine pregnancy test.  If results are positive, the 
investigator is to consult with the Lilly CRP.
f
Performed only at screening in menopausal women that have experienced spontaneous amenorrhea for 6 to 12 
months.  To be done for women only when needed to confirm postmenopausal status.


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Attachment 3.Protocol JGDM 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 (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time (PT)
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
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 (ALT)
Recommended Autoimmune Serology:
Aspartate aminotransferase (AST)
Anti-nuclear antibodya
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibodya
Creatine phosphokinase (CPK) 
Abbreviations:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 4.Protocol JGDM Biomarker, Pharmacokinetic,
and Immunogenicity Blood Sampling Schedule


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Cycle
Day
Dosing
Sampling Time (hour)a
Olara PKb
IGc,d
Whole Blood for 
CTC Analyses
Plasma
Serum
Doxorubicin
Olaratumab
1
1
Prior to olaratumab infusionf
X
X
X
X
X
X
Within 5 min post olaratumab infusion
X
8
Prior to olaratumab infusionf
X
X
X
X
Within 5 min post olaratumab infusion
X
2
1
Prior to infusionf
X
X
X
X
X
X
X
Within 5 min post doxorubicin injection
X
2
24 hours ± 3 hours
X
5
96 hours ± 3 hours
X
8
Prior to olaratumab infusionf
X
X
X
Within 5 min post olaratumab infusion
X
9
24 hours ± 3 hours
X
10
48 hours ± 3 hours
X
12
96 hours ± 3 hours
X
18
240 hours ± 3 hours
X
3
1
Prior to olaratumab infusionf
X
X
X
X
X
Within 5 min post doxorubicin infusion
X
8
Prior to olaratumab infusionf
X
X
Within 5 min post olaratumab infusion
X
5, 7
1
Prior to olaratumab infusionf
X
X
30-day follow-up
Anytime
X
X
Xe
X
X


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Abbreviations:  CTC = circulating tumor cells; IG = immunogenicity; min = minutes; olara = olaratumab; PK = pharmacokinetic.
a
Time 0 is defined as end of infusion.
b
Samples of approximately 3 mL of whole blood will be drawn into tubes.  For the olaratumab samples, olaratumab serum PK measurements will be performed.
c
Samples of approximately 4 mL will be collected.
d
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 30 days following the event.
e
At end of the patient’s study treatment.
f
Pretreatment PK samples may be collected up to 60 minutes prior to the olaratumab infusion and must be collected prior to administering any premedication.


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Attachment 5.Protocol JGDM 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, and weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalization), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug & Protocol Procedures
Concomitant Drug Therapy

indication, total daily dose, duration of treatment, start date, action taken
In Case of Death

cause, autopsy finding (if available), date, relationship to study drug and protocol 
procedures.


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


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Attachment 7.Protocol JGDM 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 JGDM RECIST Criteria
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).  
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis,  inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:  

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.


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


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


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


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


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


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


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Attachment 9.Protocol JGDM CYP3A4, CYP2D6, and P-gp 
Inhibitors and Inducers of Doxorubicin
CYP3A4 Inducers
Strong CYP3A4 Inhibitors
Moderate CYP3A4 Inhibitors
Aminoglutethimide
Clarithromycin 
Amiodarone
Bosentan
Chloramphenicol
Amprenavir
Carbamazepine
Cobicistat 
Aprepitanta
Efavirenz (in liver only)
Conivaptan
Atazanavir
Fosphenytoin 
Cremophor EL
Cimetidine
Nafcillin
Cyclosporine 
Ciprofloxacin
Nevirapine
Delavirdine
Clotrimazole
Oxcarbazepine
Diclofenac
Darunavir
Pentobarbital
Diltiazem 
Darunavir and ritonavir
Phenobarbital
Elvitegravir and ritonavir
Desipramine
Phenytoin
Enoxacin
Doxycycline
Primidone
Fosamprenavir
Dronedarone
Rifabutin
Grapefruit juice, starfruit, and Seville oranges
Efavirenz
Rifampin
Indinavir
Erythromycin
Rifapentine
Indinavir and ritonavir
FK1706
St. John's wort
Itraconazole 
Fluconazole 
Ketoconazole 
Fluvoxamine
Lopinavir and ritonavir
Haloperidol
Mibefradil
Imatinib
Miconazole
Metronidazole
Nefazodone  
Norfloxacin
Nelfinavir 
Protease inhibitors
Nicardipine
Quinidine
Posaconazole 
Schisandra sphenanthera extract
Quinidine
Sertraline
Ritonavir 
Tetracycline
Saquinavir 
Tofisopam
Telithromycin
Verapamil
Theophylline 
Troleandomycin 
Voriconazole 


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CYP2D6 Inducers
CYP2D6 Inhibitors
P-glycoprotein 1 (P-gp) Inhibitors
Rifampin
Amiodarone
Amiodarone
Celecoxib
Azithromycin
Chloroquine
Captopril
Chlorpromazine
Clarithromycin
Cimetidine
Cyclosporine
Citalopram
Piperine
Clomipramine
Quercetin
Codeine
Quinidine
Deiavirdine
Quinine
Desipramine
Reserpine
Dextropropoxyphene
Ritonavir
Diltiazem
Tariquidar
Doxorubicin
Verapamil
Entacapone (high dose)
Fluoxetine
Fluphenazine
Fluvoxamine
Haloperidol
Labetalol
Lobeline
Lomustine
Methadone
Mibefradil
Moclobemide
Nortuloxeline
Paroxetine
Perphenazine
Propafenone
Quinacrine
Quinidine
Ranitidine (ranitidine, Zantac)
Risperidone (weak)
Ritonavir
Serindole
Sertraline (weak)
Thioridazine
Valproic acid
Venlafaxine (weak)
Vinblastine
Vincristine
Vinorelbine
Yohimbine
Abbreviation: CYP = cytochrome P450.
a
Aprepitant is allowed when given according to local practice and institutional guidelines and if no alternative 
anti-emetic is recommended.


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Attachment 10.
Protocol JGDM Protocol Amendment I5B-
MC-JGDM(c) Summary: A Phase 1b Trial to Assess the 
Modulation of Biological Markers in Patients with 
Potentially Resectable Soft Tissue Sarcoma Treated with 
Olaratumab Monotherapy Followed by Olaratumab plus 
Doxorubicin Combination Therapy
Overview
Protocol I5B-MC-JGDM, A Phase 1b Trial to Assess the Modulation of Biological Markers in 
Patients with Potentially Resectable Soft Tissue Sarcoma Treated with Olaratumab Monotherapy 
Followed by Olaratumab plus Doxorubicin Combination Therapy, has been amended.  The new 
protocol is indicated by Amendment (c) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The term QTcF was defined in the abbreviations and definition section.

Fridericia’s QT correction formula was added for patients with bundle branch block.

Exclusion criteria 22 was updated by removing language related to the patient’s 
ability to adhere to the protocol and to indicate the exclusion criteria refers to a 
concomitant systemic disorder the patient is currently experiencing.

Exclusion criteria 23 was corrected.

Section 7.1.2. was updated to reference the Pharmacy Manual rather than text from 
the manual. 

A clarification was made in Section 7.2.3.1 for dose delays that collection of PK 
samples should be derived from time the actual olaratumab dose was given vs when 
dose was originally expected.

Section 8.2.3.2. was corrected for tumor tissue from any posttherapy surgical 
resection to be optional rather than required.

Section 10.1. and 10.1.1. was clarified to add the C1D1 predose blood draw to the 
definition of an evaluable patient.

A clarification was made in the schedule of events to both treatment and baseline PET 
scan to move them to the appropriate place in the schedule.

A change was made in the timing of pre-Dose PK sample in order to allow for 
samples to be collected before pre-medications are administered. 


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Where existing language is underlined, additions have been identified by the use 
of double underscore.
4. Abbreviations and Definitions
QTcF
Fridericia’s QT corrected interval
6.1.2. Exclusion Criteria
[9]
Have adequate hematologic, organ, coagulation, and cardiac function within 
2 weeks (14 days) prior to enrollment:
•
Absolute neutrophil count (ANC) ≥1.5 x 109/L.  Granulocyte colony-
stimulating factor (G-CSF) cannot be administered within 2 weeks 
(14 days) prior to enrollment.
•
Platelet count ≥100 x 109/L.
•
Hemoglobin ≥9.0 g/dL.  No transfusions are allowed within 2 weeks 
(14 days) prior to enrollment.
•
Creatinine clearance ≥45 mL/min (refer to Attachment 7 for the 
Cockcroft-Gault formula).
•
Proteinuria ≤1000 mg in 24 hours (if routine urinalysis indicates 
≥2+ proteinuria).
•
Total bilirubin below upper limit of normal (ULN) (except for patients 
with Gilbert’s Syndrome, who must have a total bilirubin <3 mg/dL).
•
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
≤3.0 × ULN; if the liver has tumor involvement, AST and ALT ≤5.0 × 
ULN are acceptable.

An adequate coagulation function as defined by International 
Normalized Ratio ≤1.5 x ULN or prothrombin time ≤1.5 x ULN, and 
partial thromboplastin time or activated partial thromboplastin time 
≤1.5 x ULN if not receiving anticoagulation therapy.  For patients 
receiving anticoagulants, exceptions to these coagulation parameters 
are allowed if they are within the intended or expected range for their 
therapeutic use.  Patients must have no history of active bleeding 
(defined as within 14 days of first dose of study drug) or pathological 
condition that carries a high risk of bleeding (for example, tumor 
involving major vessels or known esophageal varices).


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[19] Have a Bazett’s corrected QT interval of >450 msec for males and >470 msec 
for females on screening ECG utilizing Bazett’s correction. For bundle branch 
block patients, have a QTcF interval of >450 msec for males and >470 msec for 
females on screening electrocardiogram (ECG) utilizing Fridericia’s correction.
[22] Have a serious pre-existing medical conditions that in the opinion of the 
investigator would exclude the patient as a candidate for this study.concomitant 
systemic disorder (for example, active infection including human 
immunodeficiency virus, or cardiac disease) that , in the opinion of the 
investigator, would compromise the patient’s ability to adhere to the 
protocol.[23]Have a known allergy to any of the treatment components 
including a history of allergic reactions attributed to compounds of chemical or 
biological composition similar to olaratumab intravenous (IV) injection on Day 
1. 
6.2 Summary of Study Design

Long-term follow-up:  begins the day after short-term follow-up is 
completed.
Follow-up for progression - Patients who discontinue study 
treatment, or have completed 6 cycles of combination therapy, and 
have not progressed and have not initiated a new systemic 
treatment for their disease will be assessed for progression by 
imaging studies every 6 weeks (±<7 days) until PD.  Patients who 
have had surgical resection will not be followed for subsequent 
progression by imaging studies.
7.1.2. Olaratumab
Please refer to the Pharmacy Manual for information on preparing the olaratumab dosing 
solution for infusion.
Prepared Olaratumab Dosing Solution for Infusion:  Chemical and physical in-use stability for 
the prepared olaratumab dosing solution has been demonstrated for up to 24 hours below 25ºC 
(77ºF) in the concentration range of 1.2 mg/mL to 6.4 mg/mL.  It is recommended that the 
prepared dosing solution be used immediately to minimize the risk of microbial contamination.  
If not used immediately, the prepared olaratumab dosing solution must be stored under 
refrigeration at 2ºC-8ºC (36ºF-46ºF) for a duration not to exceed 24 hours.  If the prepared 
solution is held at room temperature (below 25ºC [77ºF]), it must be used within 4 hours.  Do not 
freeze and/or shake prepared olaratumab dosing solution for infusion.
Aseptic technique is to be used when preparing and handling olaratumab.  Patients are to receive 
a loading dose of 20 mg/kg on Days 1 and 8 in the monotherapy lead-in cycle, and again on Days 
1 and 8 in the first cycle of combination therapy (Cycle 2), followed by 15 mg/kg of olaratumab 
on Days 1 and 8 of each subsequent 21-day treatment cycle (Cycle 3-Cycle 7), administered as 
an IV infusion.  On the days that both olaratumab and doxorubicin are administered, olaratumab 


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will be administered prior to doxorubicin.  The dose of olaratumab is dependent upon the 
patient’s body weight (Section 7.3.1).  Actual body weight will be used for dose calculation.  
Subsequent doses of olaratumab must be recalculated if there is a ≥10% change (increase or 
decrease) in body weight; subsequent doses may be recalculated if there is a <10% change in 
body weight from prior dose and considered clinically relevant by the treating investigator.
Olaratumab is compatible with commonly used infusion containers.  Refer to the IB or pharmacy 
manual for detailed information.  Olaratumab concentration of below 1.2 mg/ml in prepared dose 
should be avoided due to dilution of excipients, which are important in maintaining stability.
The dose of olaratumab will be aseptically withdrawn from the vial and transferred to a sterile 
infusion bag or an evacuated glass container.  To prepare the dose, a sufficient quantity of sterile 
normal saline (0.9% weight/volume) solution should be added (or removed in the case of a 
prefilled container such as AVIVA) to make the total volume 250 mL.  The container should be 
gently inverted to ensure adequate mixing.  In some cases, the volume of infusion solution 
required may exceed the 250-mL scenario described here to keep the infusion solution 
concentration within the desired range stated above.  This situation may be more likely with the 
required loading dose of 20 mg/kg given in Cycle 1, but may also apply to any subsequent cycle 
depending on the patient’s body weight.  In case of dose volumes >250 mL, an empty 500-mL 
container of acceptable material of construction can be used without addition of any normal 
saline.  A pre-filled container (filled with 0.9% normal saline) of >250 mL size can be used as 
long as the material of construction is acceptable and the concentration of olaratumab in prepared 
dose remains within 1.2 mg/mL to 6.4 mg/mL.
The dose should be infused over approximately 60 minutes.  The infusion rate should not exceed 
25 mg/min.  Infusion durations longer than 60 minutes are permitted in specific circumstances 
(that is, for patients with higher body weight for whom the upper limit of infusion rate is limited 
or in the setting of prior olaratumab Grade 1-2 infusion-related reaction [IRR]); the infusion 
duration must always be accurately recorded.
The infusion set must be flushed immediately postinfusion of dose with sterile normal saline to 
ensure complete delivery of the calculated dose.
7.2.1. Treatments Administered
Table JGDM 1
Treatment Regimens
Treatment
Cycle
Length
(Days)
Study Drug
Dose
Timing
Route 
Monotherapy 
Cycle 1
21
Olaratumaba
20 mg/kg
approximately 1 hour 
infusion D1, D8 
IV
1-hour (+5 minutes) 
Observation Periodb


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Combination Therapy
Cycle 2
21
Olaratumaba
20 mg/kg
approximately 1 hour 
infusion D1, D8 
IV
1-hour (+5 minutes) 
Observation Periodb
followed by
Doxorubicinc
75 mg/m2
IV injection on D1
IV
Combination Therapy
Cycle 3 – Cycle 7
21
Olaratumaba
15 mg/kg
approximately 1 hour 
infusion D1, D8 
IV
Doxorubicinc
75 mg/m2
IV injection on D1
IV
Abbreviations:  D = day; eCRF = electronic case report form; IRR = infusion-related reaction; IV = intravenous; 
PO = orally.
a
Premedicate all patients with the following (or equivalent) medications:  a histamine H1 antagonist (for example, 
diphenhydramine) and dexamethasone intravenously 30–60 minutes prior to the olaratumab doses on Days 1 and 
8 of Cycle 1.  For subsequent cycles, premedicate all patients with a histamine H1 antagonist (for example, 
diphenhydramine) intravenously 30-60 minutes prior to each dose of olaratumab.  Additional premedication may 
be provided at the investigator’s discretion.  Premedication must be provided in the setting of a prior Grade 1-2 
IRR, as detailed in Section 7.2.2 and Section 7.2.3.1.1.1.  All premedication administered must be adequately 
documented in the eCRF.
b
A 1-hour (+5 minutes) Observation Period is required after the administration of the initial 2 cycles of 
olaratumab.  During the Observation Period, collect vital signs 3 times:  1) within 15 minutes (+5 minutes) prior 
to olaratumab infusion, 2) within 1 hour (+5 minutes) after completion of the olaratumab infusion, and 3) within 
1 hour (+5 minutes) after completion of the doxorubicin infusion.  If no evidence of an IRR manifests during the 
initial 2 cycles of olaratumab, then no observation period is required for subsequent treatment cycles.  In the 
event an IRR occurs thereafter, then the 1-hour Observation Period should be reinstituted; see Section 7.1.2.  
Thereafter (Cycles 3+), obtain vital signs 2 times:  1) within 15 minutes (+5 minutes) prior to olaratumab 
infusion and 2) within 1 hour (+5 minutes) after completion of the doxorubicin infusion.
c
Administer doxorubicin according to institutional guidelines and/or clinical practice as an IV injection or as an 
infusion in less thanwithin 60 minutes.  Decrease the rate of doxorubicin administration if erythematous streaking 
along the vein proximal to the site of infusion or facial flushing occurs.  Infusion or injection start and end times 
will need to be recorded.  Starting with Cycle 2, dexrazoxane may be administered at a 10:1 ratio 
(dexrazoxane:doxorubicin) at the investigator’s discretion according to instructions provided in the pharmacy 
manual for this study, beginning within 30 minutes prior to the doxorubicin infusion for prevention of 
cardiotoxicity.  It is recommended that all patients receiving 5 or more cycles of doxorubicin receive 
dexrazoxane.
7.2.3.1. Dose Delays, Modifications, and Discontinuations
To begin dosing at each cycle, the following criteria must be fulfilled:After treatment has been 
initiated, in order to start the next cycle the following criteria must be fulfilled:

ANC ≥1.0 × 103/L (1000/L; ≥1.0 × 109/L)


I5B-MC-JGDM(c) Phase 1 Oncology Protocol
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Note that in order to administer single-agent olaratumab on Day 8, ANC must 
be 750/L; 0.75 × 109/L.  If the ANC is 750/L, the Day 8 administration 
of olaratumab may be delayed for a maximum of 7 days.  If the ANC level has 
not increased to 750/L within 7 days, then the Day 8 olaratumab dose in 
that cycle should be skipped and dosing resumed on Day 1 of the following 
cycle if criteria for dosing are met.  If all dosing criteria are met, a delay or 
omission of the Day 8 olaratumab dose should not result in a delay of the 
Day 1 olaratumab dose of the following cycle. 

Platelets ≥100 × 103/L (100,000/L; ≥100 × 109/L)

Hemoglobin ≥98 g/dL

Creatinine clearance ≥45 mL/min (refer to Attachment 7 for the 
Cockcroft-Gault formula)

Proteinuria ≤1000 mg in 24 hours (if routine urinalysis indicates 
≥2+ proteinuria) (to be performed every other cycle)

Total bilirubin below ULN

AST and ALT ≤3.0 x ULN, or ≤5 x ULN if the transaminase elevation is due 
to liver metastases

Olaratumab-related AEs that are NCI-CTCAE Version 4.0 Grade <2 or 
equivalent severity to baseline
Delays:
In general, dose delays of 1 study drug (olaratumab or doxorubicin) due to toxicity guidances 
outlined in Sections 7.2.3.1.1 and 7.2.3.1.2 will not necessitate delays of the other study drug.
Treatment may be delayed for up to 21 days (1 equivalent cycle) to allow a patient sufficient 
time for recovery from study drug-related toxicity.  If a patient does not recover from the toxicity 
within 42 days (2 equivalent cycles) from Day 1 of the previous treatment cycle, then the patient 
must be discontinued from study therapy.
Any procedure or sample collection whose timing is related to olaratumab dosing is to be 
completed according to when the olaratumab dose was actually administered, not when that dose 
was expected to occur.   Samples whose adjusted timing would fall outside of the treatment cycle 
duration due to dose delay may be omitted.]
7.5 Concomitant Therapy
Bisophosphonate osteoclast inhibitors (for example, zoledronic acid or pamidronate) for 
treatment of bone metastases will be permitted while patients are on study treatment.  However, 
the osteoclast inhibitor denosumab is a monoclonal antibody and could confound safety analysis 
in the study if the patient experiences a hypersensitivity reaction to denosumab.  Therefore, 
concomitant use of denosumab will not be permitted.
7.6.1. Evaluable Patients


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If the patient is noncompliant during olaratumab monotherapy (Cycle 1) and does not undergo 
the post-olaratumab monotherapy biopsy or the C1D1 pre-dose and C2D1 predose whole blood 
sample collection due to reasons other than drug-related toxicity, he or she will be considered 
nonevaluable for the primary objective.  These patients may be replaced to ensure that 35 
patients complete the pre-treatment tissue biopsy, the C1D1 pre-dose whole blood sample 
collection, 1 cycle of olaratumab monotherapy, and the post-olaratumab monotherapy biopsy, 
and the associated C2D1 predose whole blood sample collection.
8.1.2.2.3. Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drugs or protocol procedures, occurring 
during the follow-up visit (Visit 801) must be reported to Lilly or its designee. The follow-up 
visit begins the day after the patient and the investigator agree that the patient will no longer 
continue study treatment starts following the last dose of study drug.  At the end of the follow-up 
visit, the patient will be required to have specific safety assessments (Attachment 1).  The timing 
of these safety assessments is 30 ± 7 days after the last dose of study drug.
8.1.3.1. Electrocardiograms
Table JGDM.6 provides Bazett’s QT  heart rate correction formula. Table JGDM.8.3 provides 
Fridericia’s QT correction formula for patients with bundle branch block.
Table JGDM.6.
Bazett’s QT Heart Rate Correction Formula
Formula
Bazett QTc = QT (HR/60)1/2 = QT (RR)–1/2
Type of formula
Nonlinear
Use
Most commonly used in clinical practice
Unique limitations
Over-corrects QT at fast HRs
Under-corrects QT at low HRs (the risk of TdP which 
frequently occurs at low HRs, may not be evident)
Abbreviations:  QTc = corrected QT interval; HR = heart rate; RR = duration of ventricular 
cardiac cycle; TdP = torsade de pointes (a polymorphic ventricular 
tachycardia).
Table JGDM 8.3         Fridericia’s QT Correction Formula
Formula
QTcF=QT/(RR)1/3


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Abbreviations:  QT = ECG interval measured from the onset of the QRS complex to the offset
of the T wave; QTcF = QT interval corrected for heart rate using Fridericia’s formula; RR = time between 
corresponding points on 2 consecutive R waves on ECG.
8.1.3.2. Echocardiograms/MUGA Scans
An ECHO or MUGA scan is required within 28 days prior to enrollment for all patients.  
Thereafter, ECHO or MUGA scans, whichever technique was used initially (as described in 
Section 7.2.3.1.2.2), must be performed at the end of Cycles 5 and 7, and when clinically 
indicated.  For patients with LVEF <50% or other cardiac dysfunction, perform more frequently, 
if clinically indicated.  After Cycle 7 (for patients with resting LVEF >≥50%), an ECHO or 
MUGA scan should be obtained at the 30-day follow-up visit (refer to the Study Schedule 
[Attachment 1]).  
Patients who stop doxorubicin prior to Cycle 7 (with resting LVEF >≥50%) will undergo cardiac 
monitoring assessment at the 30-day follow-up visit (refer to the Study Schedule [Attachment 1]) 
with whichever technique (ECHO or MUGA scan) was used initially (as described in Section
7.2.3.1.2.2).
8.2.3.2. Tumor Tissue
Collection of the following tumor tissue samples is mandatory for all patients:

newly obtained biopsy specimens taken from the primary tumor lesion pre- and post-
olaratumab monotherapy treatment will be collected.  The pretreatment tissue biopsy is to 
be performed within the screening period.  The posttreatment tissue biopsy is to be 
performed after completion of the lead-in cycle of olaratumab monotherapy and prior to 
the initiation of combination therapy (Cycle 2).  Refer to Attachment 1 for additional 
details.  If clinically feasible, the biopsies should be taken from the same primary tumor 
lesion. 

tumor tissue from any posttherapy surgical resection should also be collected and 
provided.
Collection of the following tumor tissue samples is optional for all patients:

biopsy specimen collected at the end of the patient’s study treatment.  Refer to 
Attachment 1 for additional details.  If clinically feasible, this biopsy should be taken 
from the same primary tumor lesion.

tumor  tissue from any posttherapy surgical resection may also be collected and provided.  
While this specimen is optional, it is expected this sample will be sent for analysis.
8.3 Efficacy Evaluations
Computed tomography scans, including spiral CT, are the preferred methods of measurement.
The exploratory PET Scan performed pre and post cycle 1 will not be used to determine efficacy.
10.1 General Considerations


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This study will have 2 database locks.  The first database lock will occur when the pre- and post-
olaratumab monotherapy tissue biopsies and the pre-dose C1D1 and the predose C2D1 whole 
blood sample have been collected for all 35 evaluable patients.  The main purpose of this 
database lock is to assess biomarker expression level changes pre- and post-olaratumab 
monotherapy.  The safety of olaratumab will also be evaluated at this database lock.  The second 
database lock will occur at the end of the study when all patients have either completed or 
discontinued from the study and the 30-day short-term follow-up period has been completed.  In 
the second database lock, all of the study objectives will be evaluated.  There will be an interim 
analysis to look at the biomarker data once approximately half of the evaluable patients complete 
the second biopsy and the predose C2D1 whole blood draw.
10.1.1. Determination of Sample Size
To investigate the primary objective, approximately 35 evaluable patients have to have 
completed the pre-treatment tissue biopsy, the predose C1D1 whole blood draw, 1 cycle of 
olaratumab monotherapy, the post-olaratumab monotherapy biopsy, and the predose C2D1 
whole blood draw. 
If the patient is noncompliant during olaratumab monotherapy (Cycle 1) and does not undergo 
the pre-treatment tissue biopsy, the post-olaratumab monotherapy biopsy, or the pre-dose C1D1 
and predose C2D1 whole blood draw, he or she will be considered nonevaluable and may be 
replaced.
10.8. Interim Analyses
An interim analysis will be done to look at the biomarker data once approximately half of the 
evaluable patients complete the second tumor tissue biopsy and C2D1 whole blood draw.  The 
purpose of this interim analysis is to review the biomarker and safety data.  If this interim look at 
the biomarker data warrants any changes in the study conduct, it will be implemented in an 
appropriate manner (that is, protocol amendment).  Section 10.1 describes the 2 database locks 
and the interim analysis that will occur in this study.


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Attachment 1. Protocol JGDM Study Schedule
Baseline Schedule of Activities
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 14 days
(except where noted)
Relative Day from Enrollment
≤14
≤7
Procedure 
Category
Protocol 
Sections
Procedure
Comments
Medical 
History
6.1
Prior Treatment Therapies of Underlying Disease
X
Prior treatment includes any treatment for underlying disease, including 
maintenance therapy.  Start and stop dates should be documented as well. Previous 
therapy must be completed ≥4 weeks (28 days) prior to enrollment.
Lab/
Diagnostic 
Tests
8.2.3.3
PET Scan
X (within 28 days
of enrollment)
Within 28 days prior to enrollment.  PET scans will be read locally by the 
investigator and sent to a central vendor where the images will be stored.
Efficacy
Assessment
8.2.3.3
PET Scan
X (within 28 days
of enrollment)
Within 28 days prior to enrollment.  PET scans will be read locally by the 
investigator and sent to a central vendor where the images will be stored.
On-Study-Treatment Schedule of Activities
Study Period
Treatment Period
Olaratumab
Monotherapy
Combination Therapy
Olaratumab + 
Doxorubicin
Cycle (21-day cycle 
± 3 days)
1
2-7
Relative Day within 
Cycle 
(± 3 days)
1ab
8a
1ab
8a
Procedure 
Category
Protocol 
Section
Procedure
Comments
Lab/
Diagnostic 
Tests
8.2.3.3
PET Scan
X
Mandatory PET scan must be collected up to 3 days prior to the first dose of C2D1.  
PET scans will be read locally by the investigator and sent to a central vendor where 
the images will be stored.
8.1.3.2
Echocardiogram or 
MUGA
X
Echocardiograms or MUGA scans must be performed at the end of combination 
therapy Cycles 5 and 7 and when clinically indicated.  After Cycle 7, (resting LVEF 
≥>50%), perform echocardiograms or MUGA at the 30-day follow-up visit.  Patients 
who stop doxorubicin prior to Cycle 7 (with resting LVEF ≥>50%) will undergo the 
same cardiac monitoring assessment. For patients with LVEF <50% or other cardiac 
dysfunction, perform more frequently, if clinically indicated.


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Study Period
Treatment Period
Olaratumab
Monotherapy
Combination Therapy
Olaratumab + 
Doxorubicin
Cycle (21-day cycle 
± 3 days)
1
2-7
Relative Day within 
Cycle 
(± 3 days)
1ab
8a
1ab
8a
Procedure 
Category
Protocol 
Section
Procedure
Comments
Efficacy 
Assessment
Attachment 8
Imaging Studies (CT/MRI)
Tumor Assessments 
(according to RECIST 
v1.1)
X
Imaging studies and tumor assessments are to be obtained every 6 weeks (±up to 7 
days before), irrespective of treatment cycles as calculated from enrollment, until 
documented progression for patients with CR, PR, or SD, and/or for patients who 
have discontinued study treatment due to toxicity or reasons other than PD.  Refer to 
Attachment 8 for details.  CT/MRI scans will be read locally and a scan will also be 
sent for storage at a central vendor.
8.2.3.3
PET Scan
X
Mandatory PET scan must be collected up to 3 days prior to the first dose of C2D1.  
PET scans will be read locally by the investigator and sent to a central vendor where 
the images will be stored.
Abbreviations:  β-HCG = beta human chorionic gonadotropin; AE = adverse event; BSA = body surface area; C = cycle; CR = complete response; CRP = clinical research 
physician; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; IRR = infusion-related reaction; LVEF = left ventricular ejection fraction; MRI = 
magnetic resonance imaging; MUGA = multi-gated acquisition; PD = progressive disease; PET = positron emission tomography; PK = pharmacokinetic; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; UA = urinalysis.
a
Study procedures will be performed prior to study drug administration, except where noted (such as vital signs).  In case of dose interruption, these evaluations will also 
be done at minimum frequency every 21 days (±3 days).
b
Relative day within each cycle (≤3 days). Procedure allowed up to 3 days before D1.
Attachment 2. Protocol JGDM Clinical Laboratory Tests
Clinical Chemistry
Serum Concentrations of the following:
Gammaglutamyl transferase


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Attachment 4. Protocol JGDM Biomarker, Pharmacokinetic, and Immunogenicity Blood Sampling Schedule 


I5B-MC-JGDM(c) Phase 1 Oncology Protocol
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Cycle
Day
Dosing
Sampling Time (hour)a
Olara PKb
IGc,d
Whole Blood for 
CTC Analyses
Plasma
Serum
Doxorubicin
Olaratumab
1
1
Within 15 min beforePrior to olaratumab infusionf
X
X
X
X
X
X
Within 5 min post olaratumab infusion
X
8
Within 15 min beforePrior to olaratumab infusionf
X
X
X
X
Within 5 min post olaratumab infusion
X
2
1
Within 15 min beforePrior to infusionf
X
X
X
X
X
X
X
Within 5 min post doxorubicin injection
X
2
24 hours ± 3 hours
X
5
96 hours ± 3 hours
X
8
Within 15 min beforePrior to olaratumab infusionf
X
X
X
Within 5 min post olaratumab infusion
X
9
24 hours ± 3 hours
X
10
48 hours ± 3 hours
X
12
96 hours ± 3 hours
X
18
240 hours ± 3 hours
X
3
1
Within 15 min beforePrior to olaratumab infusionf
X
X
X
X
X
Within 5 min post doxorubicin infusion
X
8
Within 15 min beforePrior to olaratumab infusionf
X
X
Within 5 min post olaratumab infusion
X
5, 7
1
Within 15 min beforePrior to olaratumab infusionf
X
X
30-day follow-up
Anytime
X
X
Xe
X
X


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Abbreviations:  CTC = circulating tumor cells; IG = immunogenicity; min = minutes; olara = olaratumab; PK = pharmacokinetic.
a
Time 0 is defined as end of infusion.
b
Samples of approximately 3 mL of whole blood will be drawn into tubes.  For the olaratumab samples, olaratumab serum PK measurements will be performed.
c
Samples of approximately 4 mL will be collected.
d
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 30 days following the event.
e
At end of the patient’s study treatment.
f
Pretreatment PK samples may be collected up to 60 minutes prior to the olaratumab infusion and must be collected prior to administering any premedication.

SAP_001.pdf: 
Statistical Analysis Plan I5B-MC-JGDM 
 
A Phase 1b Trial to Assess the Modulation of Biological Markers in Patients With Potentially 
Resectable Soft Tissue Sarcoma Treated With Olaratumab Monotherapy Followed by 
Olaratumab Plus Doxorubicin Combination Therapy 
 
NCT02783599 
 
Approval Date: 20-Jul-2018 


I5B-MC-JGDM Statistical Analysis Plan Version 2
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LY3012207
1.
Statistical Analysis Plan for Clinical Studies:  
I5B-MC-JGDM:  A Phase 1b Trial to Assess the 
Modulation of Biological Markers in Patients with 
Potentially Resectable Soft Tissue Sarcoma Treated with 
Olaratumab Monotherapy Followed by Olaratumab plus 
Doxorubicin Combination Therapy
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries..
Olaratumab (LY3012207 ) Soft Tissue Sarcoma
Study I5B-MC-JGDM is an open-label, single-arm, multicenter, multicountry Phase 1b 
study to enumerate whole blood circulating tumor cells and to characterize platelet-derived 
growth factor receptor alpha, platelet-derived growth factor receptor beta and canonical 
ligands (PDGF-A, B, C and D) expression changes pre- and post-olaratumab 
monotherapy..
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I5B-MC-JGDM
Phase 1b
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly on date 
provided below.


I5B-MC-JGDM Statistical Analysis Plan Version 2
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LY3012207
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for Clinical Studies:   I5B-MC-JGDM:  A 
Phase 1b Trial to Assess the Modulation of Biological Markers in 
Patients with Potentially Resectable Soft Tissue Sarcoma Treated 
with Olaratumab Monotherapy Followed by Olaratumab plus 
Doxorubicin Combination Therapy .....................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objective ..........................................................................................................8
4.2.
Secondary Objectives.....................................................................................................8
4.3.
Exploratory Objectives...................................................................................................8
5.
A Priori Statistical Methods ................................................................................................9
5.1.
Study Design and Sample Size Consideration.................................................................9
5.2.
General Considerations ................................................................................................10
5.3.
Definitions of Analysis Variables.................................................................................11
5.3.1.
Circulating Tumor Cells (CTC) enumeration in blood..........................................11
5.3.2.
PDGFRα and PDGFRβ protein expression in tumor tissue ...................................12
5.3.3.
PDGF-A, B, C, and D canonical ligand expression in tumor 
tissue....................................................................................................................12
5.3.4.
Safety Variables...................................................................................................12
5.3.5.
Efficacy Variables................................................................................................13
5.4.
Handling of Dropouts or Missing Data.........................................................................15
5.5.
Study Patients ..............................................................................................................16
5.5.1.
Analysis Population .............................................................................................16
5.5.2.
Patient Disposition...............................................................................................18
5.5.3.
Demographic and Baseline Characteristics...........................................................18
5.6.
Important Protocol Deviations......................................................................................19
5.7.
Concomitant Medications.............................................................................................19
5.8.
Treatment Compliance .................................................................................................19
5.9.
Biomarker Analyses.....................................................................................................19
5.10. Efficacy Analyses ........................................................................................................20
5.11. Safety Analyses............................................................................................................20
5.11.1.
Study Drug Exposure...........................................................................................20
5.11.2.
Adverse Events ....................................................................................................21
5.11.3.
Clinical Laboratory Evaluation.............................................................................22


I5B-MC-JGDM Statistical Analysis Plan Version 2
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LY3012207
5.11.4.
Vital Signs, Physical Findings, and Other Observations 
Related to Safety..................................................................................................23
5.12. Pharmacokinetic Analyses............................................................................................23
5.13. Immunogenicity...........................................................................................................23
5.14. Interim Analysis...........................................................................................................24
5.15. Annual Report Analyses...............................................................................................24
5.15.1.
Clinical Investigator Brochure..............................................................................24
5.15.2.
Development Saftey Update Report .....................................................................24
5.16. Clinical Trial Registry Analyses...................................................................................25
6.
References ........................................................................................................................26
7.
Appendices .......................................................................................................................27


I5B-MC-JGDM Statistical Analysis Plan Version 2
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Table of Contents
Table
Page
Table JGDM.5.1.
Censoring Rule of PFS Primary Analysis..................................................14
Table JGDM.5.2.
Analysis Populations.................................................................................17


I5B-MC-JGDM Statistical Analysis Plan Version 2
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Table of Contents
Figure
Page
Figure JGDM.5.1 Illustration of study design............................................................................10


I5B-MC-JGDM Statistical Analysis Plan Version 2
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Table of Contents
Appendix
Page
Appendix 1.
Flow Chart of PFS Censoring Rules ...............................................................28


I5B-MC-JGDM Statistical Analysis Plan Version 2
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3.
Revision History
Statistical Analysis 
Version
Approval Date
Notes
1
26OCT2016
First version.
2
Administrative and format changes; 
Updated AE and CM imputation rule; 
Clarification of efficacy population. Update 
to include lung disease subgroup analyses.  
Clarification of evaluable population to 
correspond to protocol amendment C.


I5B-MC-JGDM Statistical Analysis Plan Version 2
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4.
Study Objectives
4.1.
Primary Objective
The primary objectives of this study are:

to enumerate circulating tumor cells (CTCs) changes pre- and post-olaratumab 
monotherapy in wholeblood in patients with potentially resectable soft tissure 
sarcoma(STS).

to characterize PDGFRα and platelet-derived growth factor receptor beta
(PDGFRβ) and canonical ligands (PDGF-A, B, C, and D) expression changes
pre- and post-olaratumab monotherapy in tumor tissue in patients with
potentially resectable STS.
4.2.
Secondary Objectives
The secondary objectives of this study are:

to evaluate any antitumor activity observed with olaratumab:
o
progression-free survival (PFS) and 3-month PFS
o
ORR (complete response [CR] + partial response [PR])
o
disease control rate (DCR) (CR+ PR + stable disease [SD])
o
rate of resectability.

to evaluate the safety of olaratumab as assessed by reported AEs, clinical laboratory tests, 
vital signs, physical examinations, electrocardiograms (ECGs), and echocardiograms 
(ECHOs) or multi-gated acquisition (MUGA) scans.

to evaluate the pharmacokinetics (PK) of olaratumab and immunogenicity
(IG) parameters of olaratumab.
4.3.
Exploratory Objectives 
The exploratory objectives of this study are:

to evaluate blood, CTCs, and tumor tissue pre- and post-therapy for biomarkers related 
to pathways associated with STS, the mechanism of action (MOA) of olaratumab, cancer-
related conditions, and/or immune cells/immune and tumor microenvironment 
functioning within the disease state and/or cancer-related conditions.

to assess the relationship between biomarker expression at baseline, and change from 
baseline, and clinical outcomes.


I5B-MC-JGDM Statistical Analysis Plan Version 2
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5.
A Priori Statistical Methods
5.1.
Study Design and Sample Size Consideration
Study JGDM is an open-label, single-arm, multicenter, multicountry Phase 1b study to 
enumerate whole blood CTCs and to characterize PDGFRα and PDGFRβ and canonical ligands 
(PDGF-A, B, C and D) expression changes pre- and post-olaratumab monotherapy in tumor 
tissue in patients with potentially resectable STS. 
Patients are to be treated with 20 mg/kg of olaratumab on Day 1 and Day 8 of Cycle 1, followed 
by up to 6 cycles (Cycle 2 – Cycle 7) of combination therapy with olaratumab plus doxorubicin.  
For Cycle 2, olaratumab is to be dosed at 20 mg/kg on Day 1 and Day 8 and doxorubicin is to be 
dosed at 75 mg/m2 on Day 1. For Cycle 3 – Cycle 7, olaratumab is to be dosed at 15 mg/kg on 
Day 1 and Day 8 and doxorubicin is to be dosed at 75 mg/m2 on Day 1. Each cycle of treatment 
is defined as an interval of 21 days. Approximately 35 patients are to be enrolled.  
Starting with the first cycle of combination therapy (Cycle 2), the use of dexrazoxane (in a 10:1 
ratio vs. doxorubicin dose) to mitigate cardiotoxicity during treatment with doxorubicin is 
allowed at the investigator’s discretion and is recommended for all patients receiving 5 or more 
cycles of doxorubicin. 
Tissue biopsies are required pre- and posttreatment with olaratumab monotherapy. The 
pretreatment tissue biopsy is to be performed within the screening period. The posttreatment 
tissue biopsy is to be performed after completion of the lead-in cycle of olaratumab monotherapy 
and prior to the initiation of combination therapy in Cycle 2. An optional third tissue biopsy (or 
tissue from a posttherapy surgical resection specimen) may be performed at the end of the 
patient’s study treatment. If clinically feasible, the tissue biopsies should be taken from the same 
primary tumor lesion. If the patient has an additional surgical resection, tissue from this 
procedure is requested. Refer to Protocol Section 8.2.3.2 for details on tissue biopsies. 
Whole blood samples for CTC analyses are to be collected predose at Cycle 1 Day 1 (C1D1), at 
Cycle 1 Day 8 (C1D8), at Cycle 2 Day 1 (C2D1), at Cycle 2 Day 8 (C2D8), at Cycle 3 Day 1 
(C3D1), and at the end of the patient’s study treatment or at the time of surgical resection. Refer 
to Protocol Section 8.2.3.1 for details on blood samples.
After 1 cycle of monotherapy, patients will receive combination therapy for up to 6 cycles or
until evidence of progressive disease (PD), unacceptable toxicity, surgical resection, death, or
other withdrawal criteria are met. Patients who discontinue study treatment for reasons other
than progression or surgical resection will be followed every 6 weeks (±7 days) until PD.
Refer to Protocol Attachment 1 for the Study Schedule.
Figure JGDM.1 illustrates the study design.  
To investigate the primary objective, approximately 35 evaluable patients have to have
completed the pre-treatment tissue biopsy, the predose C1D1 whole blood draw, 1 cycle of 
olaratumab monotherapy, the post-olaratumab monotherapy biopsy, and the predose C2D1 
whole blood draw.
If the patient is noncompliant during olaratumab monotherapy (Cycle 1) and does not undergo


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the pre-treatment tissue biopsy, the post-olaratumab monotherapy biopsy, or the predose C2D1
whole blood draw, he or she will be considered nonevaluable and may be replaced.
It is hypothesized that 49% (17 out of 35) or more patients will have a reduction of at least 30%
in PDGFRα level change in tissue from baseline to post-olaratumab monotherapy. The sample
size of 35 patients provides a 95% CI that the hit rate (proportion of patients with at least 30%
reduction in PDGFRα level change from baseline) will be between 31% and 66%, which
excludes a 30% or lower hit rate.
Figure JGDM.5.1 Illustration of study design
Abbreviations: C1D1 = Cycle 1 Day 1; C2D1 = Cycle 2 Day 1; C3D1 = Cycle 3 Day 1; CTC = circulating tumor
cell; D = day(s); ECOG PS = Eastern Cooperative Oncology Group performance status; STS = soft tissue sarcoma,
tx = treatment.
a The pre- and post-olaratumab monotherapy tissue biopsies and the whole blood sample collections pre-dose at 
C1D1, C1D8, C2D1, and C2D8 for CTC analyses are mandatory. The pre-olaratumab monotherapy biopsy is to be 
collected within the screening period. The post-olaratumab monotherapy biopsy is to be collected after completion 
of Cycle 1 and prior to initiation of Cycle 2 combination therapy. If clinically feasible, the biopsies should be taken 
from the same primary tumor lesion.
b An optional third tumor tissue biopsy is to be collected at the end of the patient’s study treatment or when the 
patient undergoes a surgical resection through which a posttherapy tissue specimen can be collected. If clinically 
feasible, the biopsies should be taken from the same primary tumor lesion. Additionally, a whole blood sample for
CTC analysis is to be collected at C3D1 and at the end of the patient’s study treatment  or at the time of surgical 
resection.c See text in protocol Section 6.2, Summary of Study Design.
Note: Each cycle of treatment is defined as an interval of 21 days.
5.2.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly).  The 
analyses for this study will be descriptive, except for possible exploratory analysis as deemed 


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appropriate.  Data analyses will be provided by cycle (cycle 1 versus cycle 2 onward) for 
specified analyses and for all study patients combined wherever appropriate.  For continuous 
variables, summary statistics will include number of patients, mean, median, standard deviation, 
minimum, and maximum.  Categorical endpoints will be summarized using number of patients, 
frequency, and percentages.  Unless otherwise specified, missing data will not be imputed.
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
Clinical Research Physician (CRP)/Clinical Research Scientist (CRS), pharmacokineticist, and 
statistician.  The CRP or CRS and statistician will also be responsible for the appropriate conduct 
of an internal review for both the final study report and any study-related material to be 
authorized by Lilly for publication.
Exploratory analyses of the data not described below will be conducted as deemed appropriate.
5.3.
Definitions of Analysis Variables
Definitions of safety and efficacy analysis variables are listed in Section 5.3.1 and Section 5.3.5, 
respectively.  
The general analysis variables are listed below alphabetically.

Age (years):  (Informed Consent Date - Date of Birth + 1)/365.25.
Note.  Average days in a year = 365.25, reflecting the Julian Year of 3 years with 365 days each 
and 1 leap year of 366 days.  Birth month and day are imputed to be 01 July because only birth 
year is collected through the case report form (CRF).

Baseline measurement:  The last non-missing measurement prior to or on the first dose 
date will serve as the baseline measurement.

Duration is calculated as:
-
Duration (days):  (End Date – Start Date + 1)
-
Duration (weeks):  (End Date – Start Date + 1)/7
-
Duration (months):  (End Date – Start Date + 1)/30.4375
-
Duration (years):  (End Date – Start Date + 1)/365.25

Study Day:  Study day indicates the number of days relative to the date of first dose.  It is 
calculated as assessment date – first dose date + 1 day if the assessment is done on or 
after the first dose day.  If the assessment is done prior to the first dose day, study day 
will be calculated as assessment date – first dose date.  Date of first dose is defined as 
Study Day 1.
5.3.1. Circulating Tumor Cells (CTC) enumeration in blood
For all samples collected for each patient, circulating tumor cells identified by a combination of 
morphology and/or diagnostic staining characteristics will be enumerated as a simple count of 
circulating tumor cells per milliliter of peripheral blood.


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5.3.2.
PDGFRα and PDGFRβ protein expression in tumor tissue
PDGFRand PDGFRprotein expression will be assessed by immunohistochemical staining 
interpreted by a pathologist experienced in interpreting these assays.  Separate assays will be 
used for each receptor.  Results of both assays will be reported as qualitatively positive or 
negative based on analytically validated criteria for interpretation of each assay’s protein 
expression score.  
5.3.3.
PDGF-A, B, C, and D canonical ligand expression in tumor tissue
PDGF-A, B, C and D ligand expression will be assayed by real-time RT-PCR with relative 
quantification to housekeeping genes MRPL19, SF3A1 and PPIA.  Normalized relative 
expression data will be reported using the Ct value of the gene of interest (GOI) and average Ct 
of the reference genes for that sample (RG) transformed with the following formula:  2^(20-
GOI+RG)/1000. Additional approaches for normalizing and reporting relative gene expressions 
may be explored as deemed appropriate.
5.3.4. Safety Variables
Safety measures that will be used in the study include adverse events (AEs), DLT, clinical 
laboratory test results, vital signs, electrocardiograms (ECGs) and ECHO/MUGA scanning.  
Adverse event-related variables are listed below:

Adverse event (AE) is defined as any untoward medical occurrence in a patient 
administered a pharmaceutical product, without regard to the possibility of a causal 
relationship.

AEs of special interest (AESIs) 
AESI for olaratumab:
-
Infusion-related reactions (IRRs)
      AESI for combination of olaratumab and doxorubicin:
-
Cardiac arrhythmias and cardiac dysfunction
Notes:  Categories of AESI may be modified as the understanding of the safety of the 
investigational drug increases.  The final list of categories will be maintained at both 
compound and study level and reported in the clinical study report (CSR).

Consolidated AEs are composite AE terms consisting of synonymous Medical 
Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) to allow 
meaningful interpretation of the AE data.  Consolidated AE categories and PTs will be 
maintained at compound level and reported in the CSR.

Serious adverse event (SAE) is any AE that results in one of the following outcomes:


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-
death
-
a life-threatening experience (that is, immediate risk of dying)
-
persistent or significant disability/incapacity
-
initial or prolonged in-patient hospitalization
-
congenital anomaly/birth defect
-
considered significant by the investigator for any other reason

Treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline and 30 days after the last dose of study treatment and 
related SAEs reported beyond 30 days after the last dose of study treatment, where last 
dose stands for actual dose, that is, 0 dose is not counted as last dose.
Exposure-related variables are listed below:

Dose exposures: As reported in the eCRF

Number of dose level reductions:  Sum of the number of dose level reductions as 
reported in the eCRF

Dose delays:  As reported in the eCRF

Dose withheld/skip (Not Administered):  As reported in the eCRF

Dose interruption:  As reported in the eCRF
5.3.5. Efficacy Variables
The study was not designed to make an efficacy assessment.  However, any tumor response data 
will be tabulated according to assigned treatment.
Circulating tumor cells (CTC) will be assessed at pre-olaratumab and post-olaratumab in whole 
blood.  
Secondary efficacy analysis will be performed to investigate antitumor activity by assigned 
treatment.  Response and disease progression will be evaluated using Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009) for all tumors.  
Overall Response Rate (ORR) is defined as the percentage of patients achieving a best overall 
response of either Complete Response (CR), complete responses unconfirmed (CRus) or Partial 
Response (PR), as determined by RECIST 1.1.  The best overall response is the best response 
from the start of the treatment until PD/recurrence.  
Disease control rate (DCR) is defined as the percentage of patients achieving a best overall 
response of CR, CRu, PR, or SD as determined by RECIST 1.1.  Patients who do not have any 


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postbaseline tumor response assessments for any reason are considered non-responders and are 
included in the denominator when calculating the response rate.
Progression-free survival (PFS) is defined as the time from the date of first study dose to the 
first date of radiologic disease progression or death due to any cause.  Table JGDM.5.1 defines 
the rules of censoring to be applied to PFS.  
3-month Progression-free survival (PFS) is defined as the 3-month PFS rate as estimated using 
Kaplan-Meier methods.  PFS is as defined above.  
Rate of Resection is defined to be the percentage of patients whose tumors are determined to be 
resectable divided by the total number of patients. The evaluation of resectability of a tumor is 
determined by the surgeon in consultation with the multi-disciplinary team, and depends on the 
tumor stage and the patient’s co-morbidity. The primary aim of surgery is to completely excise 
the tumor with a margin of normal tissue.  
Table JGDM.5.1.
Censoring Rule of PFS Primary Analysis
Situation
Event / Censord
Date of Event or Censore
Tumor progressiona or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate radiological assessment or 
date of first study dose 
unless
No baseline radiological tumor assessment 
available
Censored
Date of first study dose
No adequateb postbaseline radiological 
tumor assessment available and death 
reported after 2 scan intervalsc following first 
study dose 
Censored
Date of first study dose 
New anticancer treatment (including 
surgery) started and no tumor progression or 
death within 14 days
Censored
Date of adequate radiological assessment prior 
to (start of new therapy +14 days) or date of 
first study dose (whichever is later)
Tumor progression or death documented
immediately after 2 or more consecutive 
missing scan intervals following last 
adequate radiological tumor assessment or 
first study dose (whichever is later)
Censored
Date of last adequate radiological assessment 
prior to the missing assessment or date of first 
study dose 
Abbreviations:  CR = complete response; PD = progressive disease; PFS = progression free survival; PR = partial 
response; SD = stable disease.
a
Symptomatic deteriorations (that is, symptomatic progressions, which are not radiologically confirmed) will not 
be considered as disease progressions.
b Adequate radiological tumor assessment refers to an assessment with one of the following responses:  CR, PR, 
SD, or PD.
c
The 2-scan interval is counted from the date of last adequate tumor assessment to the date of next 2 scheduled 
tumor assessments plus 14 days (adjusted by tumor assessment window).
d Refer to flow chart in Appendix 1 if a patient meets multiple censoring criteria.
e
If there are multiple dates associated with 1 assessment, the assessment date will be set to the first date when the 
overall response is PD and the last date otherwise.


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5.4.
Handling of Dropouts or Missing Data
Rules for handling dropouts or missing data are listed by type of analysis alphabetically.  Unless 
otherwise specified, observed data will be used and missing data will not be imputed or carried 
forward.
In the event that the date of progression is reported only to the nearest month, the date will be 
imputed for analysis (assumed to have occurred on the 15th day of the reported month).
General rules for imputing dates related to AE or concomitant therapy:

Onset date of an AE or start date of a concomitant therapy:
o
If only the day is missing, the date will be set to:

First day of the month that the event occurred, if the onset yyyy-mm is 
after the yyyy-mm of first study treatment.

The day of the first study treatment, if the onset yyyy-mm is the same as 
yyyy-mm of the first study treatment. 
o
If month is missing, the month should be set to July.

Resolution date of an AE or end date of a concomitant therapy:
o
If only the day is missing, the date will be set to the last day of the month of the 
occurrence, or to the date of death if the patient died in the same month.
o
If month is missing, the month should be set to July.
If an onset date for an AE is missing, then the AE will be considered treatment emergent with 
unknown onset date.  For additional therapies, if the start date is missing then the therapy will be 
assumed concomitant.
General rule for imputing other dates:  If a date variable is needed for an analysis, use the 
following general rule to impute incomplete date:

If only the day is missing, then assign Day 15 to the day.

If month is missing, the month should be set to July.
However, after imputation, check if the imputed date is logically consistent with other relevant 
date variable(s) and make appropriate correction if necessary.  For example, if a visit start date 
was 16 May 2008 and a tumor assessment date was xx May 2008 (missing day) but it was known 
that it occurred on or after that visit, then after imputation, the tumor assessment date became 
16 May 2008.  In this case, the imputed tumor assessment date should be compared to the visit 
start date and then corrected to be the later of the 15th day of the month and the visit start date.
Safety analysis:  The following rule for missing data processing will apply for safety analysis:


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
Missing classifications concerning study medication relationship will be considered as 
related to study medication (both components).

If the AE onset date is missing or partial, the date will be compared as far as possible 
with the date of first dose of study medication when determining whether or not the AE is 
present at baseline.  In this case, the AE will be assumed to be treatment emergent, unless 
there is clear evidence (through comparison of partial dates) to suggest that the AE 
started prior to the first dose of study medication. 
5.5.
Study Patients
5.5.1. Analysis Population
Table JGDM.5.2 lists analysis population definitions and associated data type for analysis.


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Table JGDM.5.2.
Analysis Populations
Population
Definition
Analysis Type / Variable
Note
All Entered 
Patients
All patients who signed Inform 
Consent
Safety 
Population 
All enrolled patients who 
receive any quantity of 
investigationalproduct (IP), 
regardless of their eligibility for 
the study, will be included in 
the safety analysis.
Baseline characteristics, 
concomitant medication, efficacy 
analyses, Safety, e.g. 
dosing/exposure, AE and resource 
utilization.
Safety evaluation 
will be performed 
based on the 
assigned therapy. 
Select analyses 
will be conducted 
by cycle 1 versus 
cycle 2 onward.
Efficacy 
Population
The efficacy analysis will be 
performed on the intent-to-treat 
(ITT) population, which 
includes all enrolled patients
that have received any quantity 
of investigational product (IP), 
regardless of their eligibility for 
the study.
The ITT population will be 
included in overall patient 
listings, in summary tables of 
patient demographics and 
disease characteristics, in the 
list of treatment 
discontinuation after 
enrollment, and in the 
analysis of efficacy.
Biomarkers 
Evaluable 1 
Population 
(BE1)
The biomarker evaluable 1 
(BE1) population will include 
all ITT patients with evaluable 
samples at both baseline and 
post-olaratumab monotherapy. 
If the patient is noncompliant 
during olaratumab monotherapy 
(Cycle 1) and does not undergo
the post-olaratumab 
monotherapy biopsy or the 
C1D1 pre-dose and C2D1 
predose whole blood
sample collection due to 
reasons other than drug-related 
toxicity, he or she will be 
considered
nonevaluable
The BE1 population
will be used in the biomarker 
analyses for the primary 
objective and exploratory 
objectives.
Biomarkers 
Evaluable 2
Population
(BE2)
The biomarker evaluable 2 
(BE2) population will include 
all ITT population with 
evaluable samples
at both baseline and post-
combination (olaratumab plus 
doxorubicin) therapy. If the 
The BE2 population will be 
used in the biomarker 
analyses for the exploratory 
objectives.


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patient is noncompliant during 
olaratumab monotherapy (Cycle 
1) and does not undergo
the post-olaratumab 
monotherapy biopsy or the 
C1D1 pre-dose and C2D1 
predose whole blood
sample collection due to 
reasons other than drug-related 
toxicity, he or she will be 
considered
nonevaluable
\Abbreviations:  AE = adverse event; BE = Biomarker Evaluable; IP = Investigator Product;  ITT = Intent-to-Treat.
5.5.2. Patient Disposition
A detailed description of patient disposition will include:

Summary of the number of patients who entered into the study, and who received at least 
one dose of study treatment, by site, assigned treatment and  overall. 

The summary of the number (and percent) of patients with the primary reasons for 
discontinuation from study treatment and patients still receiving treatment by assigned 
treatment and overall.  The discontinuation reasons collected in CRF (eg.  AE, PD, death, 
and etc) will be presented.

Listing of patient discontinuation.
5.5.3. Demographic and Baseline Characteristics
The following patient demographic and other baseline characteristics will be summarized:

patient demographics:  age (years) and age group, gender, race (White, Black, Asian, All 
Other), ethnicity, height (cm), weight (kg), and BSA (m2), ECOG performance status

baseline disease characteristics:
-
at study entry only:  current disease stage, grade, duration of disease (months), lung 
disease (yes, no)

prior cancer therapies:  type of therapy (surgery, radiotherapy, systemic therapy), type of 
prior surgery, type of prior radiotherapy, and type of prior systemic therapy 

Medical history by MedDRA PT, presented in decreasing frequency 
Note:  Subjects reporting more than 1 condition/diagnosis within a PT will be counted 
only once for that PT.


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Patient listings of demographic data and baseline characteristics will be provided.  Patient 
listings of prior cancer therapies (surgery, radiotherapy, and systemic therapy) will also be 
provided.
Other patient characteristics will be summarized as deemed appropriate.
5.6.
Important Protocol Deviations
Protocol deviations will be identified in Protocol Deviation Plan.  Important protocol deviations 
(e.g. not meeting inclusion/exclusion criteria, noncompliance with protocol procedures, dosing 
errors, use of prohibited medication, continuing after meeting withdrawal criteria) will be listed 
by treatment group and by category of deviations.  
5.7.
Concomitant Medications
The following concomitant medications used during study treatment period or up to the 30-day 
(± 7 days) postdiscontinuation follow-up period will be summarized by numbers and percentages 
by dose cohort, presented in decreasing frequency of the World Health Organisation drug term:

all concomitant medications

premedication for study drug
Patient listing of all concomitant therapies and premedications will be provided.
5.8.
Treatment Compliance
The number of dose omissions, reductions, and delays, and the number of cycles received will be 
summarized by cohort.
A by-patient listing of treatment compliance data will be provided.
5.9.
Biomarker Analyses 
The primary endpoints of the study are 

CTC enumeration changes pre- and post-olaratumab monotherapy in whole blood  

PDGFRα and PDGFRβ and canonical ligands (PDGF-A, B, C, and D) expression 
changes pre- and post-olaratumab monotherapy in tumor tissue  
The percent change from baseline for post-olaratumab monotherapy in biomarker expressions will be 
provided for each patient and summarized for all qualified patients in the BE1 population. For 
patients with an observed value of 0 for baseline expression or both baseline and post-olaratumab 
monotherapy expressions, a value of 0.1 will be used. In particular, summary of number and 
frequency of patients with at least 30% reduction in change from baseline PDGFRα expression will 
be provided.
Exploratory biomarker analyses may be described in a separate biomarker statistical analysis 
plan, if deemed necessary.


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5.10.Efficacy Analyses
A secondary objective of the study is to document any antitumor activity.  The efficacy analysis 
will be conducted on the intent-to-treat (ITT) population.  Tumor response data will be tabulated 
according to assigned treatment.  Best overall response will be also summarized by assigned 
treatment.  A listing will also be provided.  The objective response rate (ORR=CR+Cru+PR) and 
disease control rate (DCR=CR+Cru+PR+SD) along with the 95exact confidence interval (CI) 
will be tabulated.  For patients having CR/CRu/PR, the median duration of response, together 
with a 95% CI will be estimated using Kaplan-Meier method.  The median PFSand OSwill be 
estimated along with 95% CI using Kaplan-Meier method.  
Any deaths observed during the study will be summarized descriptively for each patient 
observed to have died.  See section 5.4 pertaining to missing data for additional details.
Similar efficacy analyses will be conducted for those with lung disease versus not. 
5.11.Safety Analyses
All the safety analyses will be performed based on Safety Population.  Most safety analyses will 
be conducted on entire treatment phase.  However, a selection of safety analyses will be 
conducted on cycle 1 only and cycle 2 onward separately.  See section 5.4 pertaining to missing 
data for additional details.
5.11.1.Study Drug Exposure
Study drug exposure will be summarized based on Safety Population.  The summary will include 
duration of treatment, number of infusions, the number of cycles received per patient, cumulative 
dose, cumulative dose level, weekly dose intensity, relative dose intensity, by assigned treatment.   
Details of study drug administration will be included in patient listings.
Dose modifications, delays and discontinuationswill also be summarized.
The exposure formulas are defined below.
Olaratumab:
Duration of treatment (weeks) = ([Date of last dose −date of first dose] + 21) ÷ 7
Cumulative dose (mg) = Sum of all doses
Calculated dose level administered (mg/kg) = Actual total dose of olaratumab 
(mg) / Closest body weight prior to that administration (kg)Cumulative dose level 
(mg/kg) = Sum ofall calculated infusion doses
Dose intensity (mg/kg/week)=(Cumulative dose level)÷(Duration of treatment )
Planned dose intensity (mg/kg/week) 
- Cycle 1 = 20mg/kg/three weeks
- Cycle 2= 20 mg/kg/three weeks
- Cycle 3-7= 15mg/kg/three weeks


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Relative dose intensity (%) (Based on planned dose)= (Dose intensity) ÷ (Planned dose 
intensity) x 100
Doxorubicin: 
Duration of treatment (weeks) = ([Date of last dose −date of first dose] + 21) ÷ 7
Cumulative dose (mg) = Sum of all doses
Cumulative dose level (mg/m
2) = Sum of (dose administered at each infusion 
[mg] ÷ Last available body surface area [BSA] [m
2] prior to that infusion)
BSA (m2) = 0.007184 * weight (kg) ^0.425 * height (cm) ^0.725
Dose intensity (mg/m2/weeks) =(Cumulative dose level)÷(Duration of treatment 
)
Planned dose intensity (mg/m2/week) = 75mg/m2/ 3 weeks= 25 (Cycle 2-7)
Relative dose intensity (%)=(Dose intensity)÷(Dose intensity) x 100
5.11.2.Adverse Events
Adverse events will be coded using the MedDRA dictionary.  Severity grades will be assigned 
by investigators using the NCI-CTCAE Version 4.0.
The AE analysis variables have been specified in Section 5.3.4. 
Study drug-related AEs are AEs that were considered to be at least possibly related to study 
drug by an investigator.  See section 5.4 pertaining to missing data.
The most current version of MedDRA at time of analysis will be used when reporting AEs by 
MedDRA terms.  Unless otherwise specified, when summarized by PT, AEs will be presented in 
descending frequency of PT across treatment arms; when summarized by system organ class 
(SOC) and PT, AEs will be presented in descending frequency of PT within SOC across 
treatment arms.  If more than one AE is recorded for a patient within any SOC or PT term, the 
patient will only be counted once on the most severe grade and the closest relationship to 
treatment.
An overall summary of AEs will be provided to summarize the following categories using 
frequency counts and percentages by assigned treatment:
patients with at least one treatment-emergent adverse event (TEAE), serious adverse 
event (SAE), or CTCAE Grade 3 or 4 TEAE
patients with AEs that led to death (all, up to 30 days after last dose of study
 drug), or 
discontinuation of study drug regimen
The summary will be provided for regardless of study drug causality, and repeated for events 
deemed by the investigator to be related to study treatment.  
Treatment-emergent adverse events (TEAEs) will be summarized/listed as follows:
treatment-emergent AE by system organ class (SOC) and PT 


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
study drug related TEAE

summary of TEAEs by worst CTCAE grade 

consolidated TEAEs by consolidated category and PT

study drug related consolidated TEAE

summary of TEAEs by PT and descending frequency

listing of TEAE leading to death (on treatment and within 30 days of last dose of study 
drug)

listing of TEAE leading to discontinuation of olaratumab, chemotherapy, or any study 
drug

listing of TEAEs leading to dose modification of any study drug, olaratumab, or 
chemotherapy
A patient listing of all AEs will be provided.
The following treatment-emergent SAE summaries will be provided:

summary of treatment-emergent SAE by SOC and PT

summary of study drug-related treatment-emergent SAE by SOC and PT

summary of consolidated treatment-emergent SAEs

summary of study drug-related consolidated treatment-emergent SAEs
A listing of SAEs will be produced.
The following death reports will be provided:

summary of deaths (all deaths and deaths within 30 days of last dose of study drug) 
The following AE of special interest (AESIs) summary will be provided:

summary of treatment-emergent AESIs by AESI group and PT (regardless of causality 
and study drug-related)

listing of treatment-emergent AESIs 
5.11.3. Clinical Laboratory Evaluation
The severity of laboratory results will be classified according to CTCAE Version 4.0.  The shifts 
in CTCAE toxicity grading from baseline to worst postbaseline (first dose up to 30 days after the 
last dose of study treatment) grade will be produced.
A patient listing of all laboratory data will be provided with a flag for values outside of the 
laboratory normal range.


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5.11.4. Vital Signs, Physical Findings, and Other Observations Related 
to Safety
Actual value and change from baseline for vital sign measurements will be summarized at each 
assessment time point using summary statistics.  Electrocardiogram, 
Echocardiogram(ECHO)/MUGA measurements will also be summarized at each assessment 
time point using summary statistics.  Listings of vital signs, ECG, ECHO/MUGA and data will 
be provided.
5.12. Pharmacokinetic Analyses
Serum concentrations of olaratumab prior to infusion (minimum concentration) and immediately 
after the end of the olaratumab infusion (approximately maximum concentration) will be 
summarized by descriptive statistics or visually presented.  Additionally, PK parameter estimates 
will be computed by standard noncompartmental methods of analysis for olaratumab PK samples 
collected during cycle 2.  The maximum concentration (Cmax), time of Cmax (tmax), area under 
the concentration-time curve (AUC), half life (t1/2), volume of distribution (Vd), clearance (CL), 
and other relevant parameters that can be calculated from the data will be reported from these 
noncompartmental analyses. Additional analyses utilizing the population pharmacokinetic 
approach may also be conducted if deemed appropriate.
5.13. Immunogenicity
The immunogenicity analyses will be conducted on all immunogenicity evaluable patients 
(evaluable population) within the defined safety population.  The frequency and percentage 
(incidence) of evaluable patients with positive, negative, or missing anti-drug antibody (ADA), 
to olaratumab at baseline, and with positive, negative, or inconclusive ADA at post-baseline will 
be summarized by dose cohort and combination treatment arm.  Patients who are TE (treatment-
emergent)-ADA positive (persistent positive or transient positive), TE-ADA persistent positive, 
and TE-ADA transient positive will also be summarized.  Positive neutralizing ADA, negative 
neutralizing ADA and inconclusive neutralizing ADA will also be reported for patients with TE 
positive ADA. Quantitative analysis will be conducted on total IgE and alpha-Gal.  Analyses will 
include change from baseline, mean, median, range and standard deviation.  
The following analyses will also be performed based on evaluable or safety population:

Listing of Treatment-Emergent Adverse Events for evaluable patients with at least 
one sample of ADA positive antibody to olaratumab (evaluable population)

Listing of antibody to olaratumab and drug concentration data for evaluable 
patients who have at least one ADA positive sample (evaluable population)

Listing of anti-olaratumab antibody for patients with IRR (safety population)

Listing of antibody to olaratumab and drug concentration data (safety population)
Listing for alpha-Ga1 and igE (safety population)


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The potential impact of immunogenicity on olaratumab exposure will be evaluated in the 
population PK modeling exercises where immunogenicity will be evaluated as a covariate.  In 
addition, graphical assessments will be conducted, as appropriate, to compare drug exposure 
between TE-ADA-negative and TE-ADA-positive patients at correspondent visits, or before and 
after TE-ADA development for patients who developed TE-ADA.
Additional efficacy or safety analyses may be performed in the subgroup of patients and 
immunogenicity endpoints.  
5.14. Interim Analysis
With limited prior experience with the performance of the biomarker assays (i.e, QC issues, 
dynamic range, data variability), an interim analysis will be done to evaluate the biomarker data 
once approximately half of the evaluable patients complete the second tumor tissue biopsy and 
C2D1 whole blood draw. The purpose of this interim analysis is to review the biomarker data in 
order to identify technical issues that may potentially impact the study’s ability to meet its key 
objectives. If this interim look at the biomarker data warrants any changes in the study conduct, 
it will be implemented in an appropriate manner (that is, protocol amendment). At this interim 
analysis, a review of the safety data will also be conducted. 
This would be in addition to the safety data review that will be conducted after 5 patients have 
completed 2 cycles of treatment.
5.15. Annual Report Analyses
The following reports are needed as requested for annual reporting purposes
5.15.1. Clinical Investigator Brochure
·
Summary of SAE (patients on therapy).
·
Summary of deaths reported (patients on therapy).
·
Summary of Patient disposition.
·
Summary of primary reason for treatment discontinuation.
·
Listing and summary of treatment-emergent adverse events –by CTCAE category and 
term.
5.15.2. Development Saftey Update Report
·
Cumulative Subject Exposure by Age Group and Sex
·
Cumulative Subject Exposure by Racial Group


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·
Estimated Cumulative Subject Exposure
·
Subject Exposure by Gender
·
Listing of Patients Who Discontinued Due to Adverse Event
·
Listing of Deaths
5.16. Clinical Trial Registry Analyses
For the purpose of fulfilling the Clinical Trial Registry requirements, summaries of SAEs 
(whether treatment emergent or not) and ‘Other’ AEs (that is, non-serious TEAEs) by PT and 
treatment group will be performed.  For each PT, the number of patients at risk, patients who 
experienced the event, and events will be presented.  In addition, the summary will be provided 
as a dataset in XML format.


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6.
References
Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., ... & 
Rubinstein, L. (2009). New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). European journal of cancer, 45(2), 228-247.


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7.
Appendices


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Appendix 1.
Flow Chart of PFS Censoring Rules