A Phase 1b Study of Olaratumab, Doxorubicin and Ifosfamide in the Treatment of Patients With Advanced or Metastatic Soft Tissue Sarcoma
Phase: PHASE1
Conditions: Soft Tissue Sarcoma
Sponsor: Eli Lilly and Company

Protocol I5B-MC-JGDR(a)  
  
 
A Phase 1b Study of Olaratumab, Doxorubicin and Ifosfamide in the Treatment of Patients With 
Advanced or Metastatic Soft Tissue Sarcoma  
  
 
NCT03283696     
  
 
Approval Date: 26-Jun-2018 
 

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Protocol I5B-MC-JGDR(a)
A Phase 1b Study of Olaratumab, Doxorubicin and Ifosfamide 
in the Treatment of Patients with Advanced or Metastatic Soft 
Tissue Sarcoma
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. 
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)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 14 March 2017.
Amendment (a) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 26-Jun-2018 GMT

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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................22
3.1.
Background..................................................................................................................22
3.1.1.
Soft Tissue Sarcoma.............................................................................................22
3.1.2.
Olaratumab ..........................................................................................................22
3.2.
Study Rationale............................................................................................................23
3.2.1.
Rationale for Amendment (a)...............................................................................24
3.3.
Benefit-Risk Assessment..............................................................................................24
4.
Objectives and Endpoints..................................................................................................25
5.
Study Design.....................................................................................................................27
5.1.
Overall Design .............................................................................................................27
5.1.1.
Dose-Finding Phase:  Olaratumab 15-mg/kg Dose Level......................................30
5.1.2.
Dose-Finding Phase:  Olaratumab 20 mg/kg Loading Dose 
Cycle Level..........................................................................................................30
5.1.3.
Dose-Finding Phase:  Ifosfamide Dose Reduction Options...................................30
5.1.4.
Dose Confirmation Phase.....................................................................................30
5.2.
Number of Patients.......................................................................................................30
5.3.
Study Completion Definition........................................................................................30
5.4.
Scientific Rationale for Study Design...........................................................................31
5.5.
Justification for Dose ...................................................................................................31
5.5.1.
Olaratumab ..........................................................................................................31
5.5.2.
Doxorubicin, Ifosfamide and Mesna.....................................................................31
6.
Study Population...............................................................................................................32
6.1.
Inclusion Criteria..........................................................................................................32
6.2.
Exclusion Criteria ........................................................................................................34
6.3.
Screen Failures.............................................................................................................36
7.
Treatments........................................................................................................................37
7.1.
Treatment Administered (Dosing Schedule) .................................................................37
7.1.1.
Olaratumab Premedications and Required Monitoring..........................................40
7.1.2.
Doxorubicin Premedications and Dexrazoxane 
Administration .....................................................................................................40
7.1.3.
Ifosfamide Premedications and Mesna Administration .........................................40
7.2.
Method of Treatment Assignment ................................................................................41
7.2.1.
Selection and Timing of Doses.............................................................................41

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7.2.2.
Dose-Finding Phase .............................................................................................41
7.2.2.1.
Dose-Limiting Toxicity Determination ...........................................................41
7.3.
Blinding .......................................................................................................................45
7.4.
Dosage Delays, Discontinuations and Modifications ....................................................45
7.4.1.
Delays..................................................................................................................45
7.4.2.
Discontinuations ..................................................................................................46
7.4.3.
Dose Modifications..............................................................................................46
7.4.3.1.
Olaratumab Dose Modifications .....................................................................46
7.4.3.1.1.
Hematologic Toxicity ...............................................................................47
7.4.3.1.2.
Nonhematologic Toxicity..........................................................................48
7.4.3.2.
Doxorubicin Dose Modifications ....................................................................50
7.4.3.2.1.
Hematologic Toxicity ...............................................................................50
7.4.3.2.2.
Nonhematologic Toxicity..........................................................................51
7.4.3.2.3.
Monitoring for Doxorubicin-Associated 
Cardiotoxicity...........................................................................................51
7.4.3.3.
Ifosfamide Toxicities and Dose Modifications................................................52
7.4.3.3.1.
Ifosfamide-Associated Central Nervous System 
Toxicity....................................................................................................53
7.4.3.3.2.
Ifosfamide-Associated Urotoxic Effects....................................................53
7.4.3.3.3.
Ifosfamide-Associated Proximal Tubular Damage ....................................54
7.5.
Packaging and Labeling ...............................................................................................54
7.5.1.
Olaratumab ..........................................................................................................54
7.5.2.
Doxorubicin, Ifosfamide and Mesna.....................................................................54
7.5.3.
Granulocyte-Colony Stimulating Factors..............................................................54
7.5.4.
Dexrazoxane ........................................................................................................55
7.6.
Preparation/Handling/Storage/Accountability...............................................................55
7.6.1.
Olaratumab ..........................................................................................................55
7.6.2.
Doxorubicin.........................................................................................................55
7.6.3.
Ifosfamide............................................................................................................55
7.6.4.
Mesna ..................................................................................................................56
7.7.
Treatment Compliance .................................................................................................56
7.8.
Concomitant Therapy and Supportive Care ..................................................................56
7.8.1.
Olaratumab Infusion-Related Reactions ...............................................................56
7.8.2.
Granulocyte-Colony-Stimulating Factors and Erythroid 
Growth Factors ....................................................................................................57
7.8.3.
Transfusion of Blood Products.............................................................................58
7.8.4.
Antiemetic Therapy..............................................................................................58
7.8.5.
Inducers and Inhibitors of CYP3A4, CYP2D6 and P-gp.......................................58
7.8.6.
Other Concomitant Therapies...............................................................................58

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7.9.
Treatment after the End of the Study............................................................................59
7.9.1.
Continued Access.................................................................................................59
8.
Discontinuation Criteria ....................................................................................................61
8.1.
Discontinuation from Study Treatment.........................................................................61
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................61
8.2.
Discontinuation from the Study....................................................................................61
8.3.
Lost to Follow-Up........................................................................................................62
9.
Study Assessments and Procedures ...................................................................................63
9.1.
Efficacy Assessments...................................................................................................63
9.1.1.
Secondary Efficacy Assessments..........................................................................63
9.1.2.
Appropriateness of Assessments ..........................................................................63
9.2.
Adverse Events ............................................................................................................63
9.2.1.
Serious Adverse Events........................................................................................64
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................65
9.2.3.
Adverse Events of Special Interest .......................................................................66
9.2.4.
Complaint Handling.............................................................................................66
9.3.
Treatment of Overdose.................................................................................................66
9.4.
Safety...........................................................................................................................66
9.4.1.
Other Safety Measures .........................................................................................66
9.4.2.
Safety Monitoring ................................................................................................66
9.5.
Pharmacokinetics .........................................................................................................67
9.6.
Genetics .......................................................................................................................68
9.6.1.
Whole Blood Samples for Pharmacogenetic Research..........................................68
9.7.
Biomarkers...................................................................................................................68
9.7.1.
Samples for Nonpharmacogenetic Biomarker Research........................................69
9.7.2.
Tissue Samples for Biomarker Research...............................................................69
9.8.
Immunogenicity Assessments.......................................................................................70
10.
Statistical Considerations ..................................................................................................72
10.1. Sample Size Determination ..........................................................................................72
10.2. Populations for Analyses..............................................................................................72
10.3. Statistical Analyses ......................................................................................................73
10.3.1.
Efficacy Analyses ................................................................................................73
10.3.2.
Safety Analyses....................................................................................................73
10.3.3.
Other Analyses.....................................................................................................74
10.3.3.1.
Patient Disposition..........................................................................................74
10.3.3.2.
Patient Characteristics ....................................................................................74
10.3.3.3.
Concomitant Therapy .....................................................................................74
10.3.3.4.
Post-study Treatment Discontinuation Therapy...............................................74

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10.3.3.5.
Treatment Compliance....................................................................................74
10.3.4.
Pharmacokinetic Analyses....................................................................................74
10.3.5.
Biomarker Analyses.............................................................................................75
10.3.6.
Immunogenicity Analyses....................................................................................75
10.3.7.
Subgroup Analyses ..............................................................................................75
10.3.8.
Interim Analyses..................................................................................................75
11.
References ........................................................................................................................76

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List of Tables
Table
Page
Table JGDR.1.
Pretreatment Schedule of Activities ........................................................14
Table JGDR.2.
On-Study Treatment Schedule of Activities............................................16
Table JGDR.3.
Post-Treatment Follow-Up Schedule of Activities ..................................19
Table JGDR.4.
Continued Access Schedule of Activities................................................21
Table JGDR.5.
Objectives and Endpoints .......................................................................26
Table JGDR.6.
Treatments Administered (Dosing Schedule)..........................................38
Table JGDR.7.
Dose-Limiting Toxicity Thresholds for Study JGDR ..............................43
Table JGDR.8.
General Guidelines for Olaratumab Dose Modification due to 
Hematologic Toxicities...........................................................................47
Table JGDR.9.
Olaratumab Day 8 Dosing Algorithm Based on ANC and Platelet 
Count .....................................................................................................48
Table JGDR.10.
General Guidelines for Olaratumab Dose Modification due to 
Nonhematologic Toxicities.....................................................................49
Table JGDR.11.
General Guidelines for Doxorubicin Dose Modification Due to 
Neutropenia............................................................................................51
Table JGDR.12.
General Guidelines for Dose Modification of Ifosfamide due to 
Toxicity..................................................................................................52
Table JGDR.13.
Dose Modification of Ifosfamide due to Hepatic Impairment..................53
Table JGDR.14.
Dose Modification of Ifosfamide due to Renal Impairment.....................54
Table JGDR.15.
Olaratumab Infusion-Related Reaction Treatment Guidelines.................57

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List of Figures
Figure
Page
Figure JGDR.1.
Illustration of study design......................................................................29
Figure JGDR.2.
Continued access diagram.......................................................................60

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................79
Appendix 2.
Study Governance, Regulatory and Ethical Considerations.....................83
Appendix 3.
Clinical Laboratory Tests........................................................................86
Appendix 4.
Pharmacokinetic, Biomarker, Pharmacogenetics and 
Immunogenicity Sampling Schedules .....................................................87
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............91
Appendix 6.
Creatinine Clearance Formula.................................................................92
Appendix 7.
Fridericia’s QT Correction Formula........................................................93
Appendix 8.
Protocol Amendment I5B-MC-JGDR(a) Summary A Phase 1b 
Study of Olaratumab, Doxorubicin and Ifosfamide in the 
Treatment of Patients with Advanced or Metastatic Soft Tissue 
Sarcoma .................................................................................................94

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1. Synopsis
Protocol Title:
A Phase 1b Study of Olaratumab, Doxorubicin and Ifosfamide in the Treatment of Patients with Advanced or 
Metastatic Soft Tissue Sarcoma
Rationale:
Study I5B-MC-JGDG (Study JGDG) was a Phase 1b/randomized Phase 2 study evaluating the efficacy of 
doxorubicin with or without olaratumab in the treatment of advanced soft tissue sarcoma (STS).  The study met its 
primary endpoint for progression-free survival (PFS) (hazard ratio [HR] = 0.67; p = 0.06 as compared to a 
prespecified alpha level of 0.2) with an improvement in median PFS and overall survival (OS) of 2.5 months and 
11.8 months, respectively, for olaratumab plus doxorubicin over doxorubicin alone, with a manageable safety 
profile.  The OS HR of 0.46 was highly statistically significant (p = 0.0003; Tap et al. 2016).  Based on these results, 
olaratumab has received conditional approval in the United States and European Union in combination with 
doxorubicin for the treatment of adult patients with STS.
While doxorubicin alone or in combination with other chemotherapeutic agents has been the mainstay of treatment 
for decades (Linch et al. 2014), in more recent years the combination of doxorubicin, ifosfamide and mesna has 
demonstrated increased tumor response and PFS compared to doxorubicin alone. However, this regimen is 
associated with a higher rate of Grade 3 and 4 toxicities and no improvement in OS (Judson et al. 2014), limiting the 
use of this regimen to distinct clinical settings, such as when shrinkage of the tumor is important and the risk of 
greater toxicity is felt to represent an acceptable benefit-risk. This regimen has also been evaluated in the 
neoadjuvant and adjuvant settings for patients with STS (Gortzak et al. 2001; Grobmyer et al. 2004; Pisters et al. 
2016).
The positive efficacy results seen with olaratumab in combination with doxorubicin in Study JGDG provide strong 
rationale for determining whether olaratumab can also be safely added to the doxorubicin, ifosfamide and mesna
regimen. It is plausible that the addition of olaratumab to doxorubicin, ifosfamide and mesna may further increase
efficacy endpoints such as tumor response rate, PFS and OS, without a clinically significant increase in toxicity.
Study I5B-MC-JGDR (Study JGDR) will characterize the safety and tolerability of olaratumab in combination with 
doxorubicin, ifosfamide and mesna in patients with advanced STS, and if acceptable, determine the dosing regimen 
of olaratumab in combination with doxorubicin and ifosfamide appropriate for future studies of this combination.

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Objectives and Endpoints:
Objectives
Endpoints
Primary

To characterize the safety profile of olaratumab 
when given in combination with doxorubicin, 
ifosfamide and mesna and to determine the 
dosing regimen appropriate for a future Phase 2 
study

DLTs, TEAEs, SAEs and clinical laboratory 
abnormalities per NCI-CTCAE Version 4.0 
Secondary

To evaluate the PK of olaratumab when 
combined with doxorubicin, ifosfamide and 
mesna

To evaluate the immunogenicity of olaratumab 
when combined with doxorubicin, ifosfamide
and mesna

To document any antitumor activity of 
olaratumab when combined with doxorubicin, 
ifosfamide and mesna

PK:  Cmax and AUC from time 0 to the last 
time point with a measurable concentration, and 
AUC from time 0 to infinity of olaratumab.  
Other noncompartmental parameters, such as 
half-life, clearance and volume of distribution 
may be reported.  Plasma doxorubicin and 
ifosfamide concentrations will be summarized 
by descriptive statistics

Immunogenicity:  Anti-olaratumab antibody 
levels at baseline, during the study, at the 
30-day follow-up visit and in the event of 
olaratumab IRRs

Antitumor activity:  Radiographic 
assessments according to RECIST Version 1.1 
criteria every 6 weeks (-7 days) until 
radiographic documentation of PD.  Efficacy 
endpoints will include objective response rate, 
PFS, duration of response, disease control rate 
and OS
Exploratory

To explore biomarkers related to, but not 
limited to tumor microenviroment, immune 
cells/immune functioning, mechanism of action 
of study drugs, PDGF, cancer-related pathways 
and disease state, and their association with 
demographics, disease state and clinical 
outcomes

Biomarker assay results with other trial data
Abbreviations: AUC = area under the concentration curve; Cmax = maximum observed concentration; DLT = dose-
limiting toxicity; IRR = infusion-related reaction; NCI-CTCAE = National Cancer Institute-Common 
Terminology Criteria for Adverse Events; OS = overall survival; PD = progressive disease; PDGF = platelet-
derived growth factor; PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event; STS = soft tissue sarcoma; TEAE = treatment-emergent 
adverse event.

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Overall Design:
Study JGDR is a Phase 1b, multicenter, nonrandomized, open-label study of olaratumab combined with 
doxorubicin, ifosfamide and mesna in the treatment of patients with advanced or metastatic STS.
Dose-Finding Phase:
Olaratumab 15 mg/kg and Loading Dose Cycle Cohorts – Approximately 15 patients will be initially enrolled 
and treated with a 15-mg/kg dose of olaratumab (on Days 1 and 8 of a 21-day cycle) in combination with 
doxorubicin, ifosfamide and mesna and assessed for safety after 1 cycle of therapy.  If safety of the 15-mg/kg dose 
of olaratumab is established, 15 additional patients will be enrolled and receive a 20-mg/kg loading dose cycle of 
olaratumab on Days 1 and 8 of a 21-day cycle in Cycle 1 only, followed by 15 mg/kg on Days 1 and 8 of subsequent 
cycles in combination with doxorubicin, ifosfamide and mesna.
Should unacceptable toxicity be observed at the olaratumab 15-mg/kg dose, the study will include an option to 
explore the same regimen using a reduced ifosfamide dose.  Provided safety is established at this lower dose of 
ifosfamide, a loading dose cycle of olaratumab as previously described will also be explored using the reduced 
ifosfamide dose.
Dose Confirmation Phase:
If a safe and tolerable dosing regimen of olaratumab is identified, approximately15 additional patients will be 
enrolled in a Dose Confirmation Phase to confirm the safety of this treatment regimen for use in any future studies 
of this combination.
Patients in both study phases will continue treatment for a maximum of 6 cycles, or until there is documented 
disease progression, unacceptable toxicity, death, or other discontinuation criteria are met.  Patients who discontinue 
doxorubicin, ifosfamide and mesna treatment without evidence of disease progression will receive olaratumab as 
monotherapy until there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria 
are met.  Patients who undergo surgical tumor resection following study treatment are not eligible to receive 
olaratumab as monotherapy.
Number of Patients:  approximately 45-60 total enrolled
Dose-Finding Phase:
Entered: approximately 33-48
Enrolled:  approximately 30-45
Dose Confirmation Phase:
Entered:  approximately 17
Enrolled:  approximately 15

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Treatment Arms and Duration:
Phase and 
Dose Cohort
Drug Name and Dose
Day of 21-day (±3 days) 
Cycle
Total Dose
Dose-Finding Phase
Olara 15 mg/kg
Olara 15 mg/kga
D1 and D8
Dox 25 mg/m2 per day
D1, D2, D3 
75 mg/m2
Ifos 2.5 g/m2 per dayb
D1, D2, D3, D4a
10 g/m2a
Mesna dose ≥60% of ifos doseb
D1, D2, D3, D4
Loading Dose
Cycle
Olara 20 mg/kg Cycle 1
Olara 15 mg/kg Cycles 2 to 6a
D1 and D8
D1 and D8
Dox 25 mg/m2 per day
D1, D2, D3 
75 mg/m2
Ifos 2.5 g/m2 per dayb
D1, D2, D3, D4 
10 g/m2
Mesna dose ≥60% of ifos doseb
D1, D2, D3, D4
Dose Confirmation
Phase
Olara 
recommended 
dose
Olara dose determined from Dose-
Finding Phasea
D1 and D8
Dox 25 mg/m2 per day
D1, D2, D3 
75 mg/m2
Ifos 2.5 g/m2 per dayb
D1, D2, D3, D4 
10 g/m2
Mesna dose ≥60% of ifos doseb
D1, D2, D3, D4
Abbreviations:  D = day; DLT = dose-limiting toxicity; dox = doxorubicin; g = grams; ifos = ifosfamide; IV = 
intravenous; kg = kilogram; m2 = square meters; mg = milligrams; olara = olaratumab.
a
All patients will receive study therapy (olaratumab + doxorubicin/ifosfamide/mesna) for a maximum of 6 cycles, 
or until a discontinuation criterion is met.  Patients who discontinue doxorubicin, ifosfamide and mesna treatment
without evidence of disease progression will receive olaratumab as monotherapy until there is evidence of 
disease progression, death, intolerable toxicity, or other withdrawal criteria are met.
b
If DLT rules are exceeded in the olaratumab 15-mg/kg cohort, a reduced dose of ifosfamide (7.5 g/m2 total dose) 
will be explored.  This will be accomplished by omitting the Day 4 dose (that is, ifosfamide will be administered 
at a dose of 2.5 g/m2 on D1, D2 and D3).  The Day 4 dose of mesna will be correspondingly omitted.  A Loading 
Dose Cycle of olaratumab (20 mg/kg on Days 1 and 8 of C1, then 15 mg/kg on Days 1 and 8 of subsequent 
cycles) may also be explored in combination with the reduced dose of ifosfamide.

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2.
Schedule of Activities

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Table JGDR.1.
Pretreatment Schedule of Activities
Day Relative to C1D1
28
14
7
Instructions
Procedure
Informed consent 
X
ICF must be signed before any 
protocol-specific procedures are performed. 
Assessments performed prior to the date of 
consent may be used as study-required 
assessments, provided they are appropriately 
documented.
Inclusion/exclusion criteria
X
Physical examination
X
Including height, weight and vital signs 
(temperature, blood pressure, pulse rate, 
respiration rate)
ECOG performance status
X
Medical history
X
Including assessment of preexisting conditions
and historical illnesses.
Prior and current medication
X
Prior therapies for treatment of 
underlying disease
X
AE collection
X
After consent, collect AEs continuously 
throughout pretreatment period.
CTCAE Version 4.0
Radiologic imaging and measurement 
of palpable or visible lesions
X
RECIST 1.1
Scans performed prior to the date of consent 
may be used, provided they are within 28 days 
of enrollment.  Imaging requirements include 
CT scan or MRI of the chest, abdomen and 
pelvis and other areas, as clinically indicated. 
It is recommended that CT imaging of the 
abdomen/pelvis be performed with IV contrast, 
whenever possible. If this is not 
feasible/advisable secondary to hypersensitivity 
or other conditions, then gadolinium-enhanced 
MRI is preferred. For patients with known 
serious allergic reactions to CT contrast 
material, a CT of the chest without contrast and 
contrast-enhanced MRI of the abdomen/pelvis 
are encouraged.
ECG
X
Echocardiogram and/or MUGA scan
X
Hematology 
X
See Appendix 3.  To be performed locally for 
patient management and centrally for analysis 
purposes.
Coagulation
X
See Appendix 3.  To be performed locally.
Clinical chemistry
X
See Appendix 3. To be performed locally for 
patient management and centrally for analysis 
purposes.
Urinalysis 
X
See Appendix 3. To be performed locally.

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Serum pregnancy test
X
Applies only to women of childbearing 
potential.  See Appendix 3.  To be performed 
locally.
Tumor tissue 
X
See Section 9.7.2.
Sample collection
See Appendix 4.
Pharmacodynamics
Pharmacokinetics
Immunogenicity
Pharmacogenetics
Other biomarkers
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events (NCI 2009); ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group (Oken et al. 1982); ICF = informed consent form; IV = intravenous; MRI = magnetic resonance 
imaging; MUGA = multiple-gated acquisition; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1 
(Eisenhauer et al. 2009).

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Table JGDR.2.
On-Study Treatment Schedule of Activities
Day within Cycle
Procedure
Cycles 1-6
(olaratumab + doxorubicin 
+ ifosfamide;
(Cycle = 21 days)
Cycles 7-N
Olaratumab 
Monotherapya
(Cycle = 21 
days)
Instructions
1
2
3
4
8
15
1
8
Physical 
examination
X
X
X

Perform prior to infusion of study drug(s).

Includes weight and BSA.
Vital signs
X
X
X
X
X
X
X
Vital signs include temperature, blood pressure, pulse rate, respiration rate.  
Concomitant 
medication
X
X
Concomitant medications will be recorded continuously throughout the treatment period.
AE collection
X
X
Collect continuously throughout the treatment period; CTCAE Version 4.0.
ECOG performance 
status
X
X
Radiologic imaging 
and measurement of 
palpable or visible
lesions
X
X

Perform according to RECIST 1.1, by the same method used at baseline, q 6 weeks (-7 days) 
from the start of treatment until radiographic disease progression, death, or study completion, 
whichever occurs first.

Perform as scheduled, even if study treatment is delayed or omitted.
ECG
X
X

Perform local 12-lead ECG on Day 1 of Cycle 1 through Cycle 6.

Perform local 12-lead ECG on Day 1 of Cycle 7 and approximately 6 months (±14 days) and 
12 months (±14 days) after discontinuation of doxorubicin and ifosfamide treatment
Echocardiogram 
and/or MUGA scan
X
C4 and C6
X

Perform at the end of C4 and C6; perform additional evaluations in the setting of cardiac 
symptoms and/or at the discretion of the investigator.

For patients receiving olaratumab as monotherapy following discontinuation of combination 
therapy, perform approximately 6 months (±14 days) and 12 months (±14 days) after 
discontinuation of doxorubicin and ifosfamide treatment.
Hematology 
X
X
X
X
X
3 days prior to administration of study treatment on D1 and ≤1 day prior to administration of 
study treatment on D8, unless more frequent assessment is clinically indicated. Day 15 labs may 
be drawn within ±1 day of Day 15.  See Appendix 3.  To be performed locally for patient 
management and centrally for analysis purposes.

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Day within Cycle
Procedure
Cycles 1-6
(olaratumab + doxorubicin 
+ ifosfamide;
(Cycle = 21 days)
Cycles 7-N
Olaratumab 
Monotherapya
(Cycle = 21 
days)
Instructions
1
2
3
4
8
15
1
8
Coagulation
X
X
3 days prior to administration of study treatment on D1, unless more frequent assessment is 
clinically indicated.  For patients receiving olaratumab as monotherapy following combination 
therapy discontinuation, perform on D1 of every other cycle.  See Appendix 3.  To be performed 
locally.
Clinical chemistry
X
X
X
X
3 days prior to administration of study treatment on D1 and ≤1 day prior to administration of 
study treatment on D8, unless more frequent assessment is clinically indicated. Day 15 labs may 
be drawn within ±1 day of Day 15.  See Appendix 3.  To be performed locally for patient 
management and centrally for analysis purposes.
Urinalysis 
X
X
X
X
Monitor patients for evidence of micro- and/or macroscopic hematuria and treat according to 
institutional standards.
Pregnancy test
X
X

Applies only to women of childbearing potential

Where required by local law or regulation, perform once every 21 days (-7 days) prior to 
administration of study treatment. 

To be performed locally
Administer 
olaratumab
X
X
X
X
Administer IV over 60 (±5) min.  Administer until a maximum of 6 cycles is complete, or until 
PD, unacceptable toxicity, death, or other withdrawal criteria are met.  Patients who discontinue 
doxorubicin, ifosfamide and mesna treatment without evidence of disease progression will receive 
olaratumab as monotherapy until there is evidence of disease progression, death, intolerable 
toxicity, or other withdrawal criteria are met.  Patients who undergo surgical tumor resection 
following study treatment are not eligible to receive olaratumab as monotherapy.  See section 
7.1.1 for olaratumab premedication requirements.  See section 7.8.1 for olaratumab IRR 
monitoring period requirements.
Administer 
doxorubicin 
X
X
X
Administer IV over less than 60 (±5) min or as a continuous IV infusion (according to 
institutional guidelines) after completion of olaratumab infusion and any required observation 
period.  Administer until a maximum of 6 cycles is complete, or until PD, unacceptable toxicity, 
death, or other withdrawal criteria are met. See Section 7.1.2 for details of dexrazoxane 
administration.

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Day within Cycle
Procedure
Cycles 1-6
(olaratumab + doxorubicin 
+ ifosfamide;
(Cycle = 21 days)
Cycles 7-N
Olaratumab 
Monotherapya
(Cycle = 21 
days)
Instructions
1
2
3
4
8
15
1
8
Administer 
ifosfamide
X
X
X
X
*
Administer IV over 3 hours (±15 min).  Administer until a maximum of 6 cycles is complete, or 
until PD, unacceptable toxicity, death, or other withdrawal criteria are met. 
*Patients treated in cohorts with ifosfamide dose reduction will have the Day 4 dose omitted (that 
is, ifosfamide will be administered at a dose of 2.5 g/m2 on D1, D2 and D3).
Administer mesna
X
X
X
X
See Section 7.1.3 for details of mesna administration.
G-CSF
X
The use of G-CSFs is required.  Administer according to ASCO and NCCN guidelines.  In 
general, G-CSF products like filgrastim or pegfilgrastim should be administered approximately 24 
hours after the completion of cytotoxic chemotherapy (for example, on Day 5 for patients in full-
dose ifosfamide cohorts or Day 4 for patients in reduced-dose ifosfamide cohorts).
Sample collection
For all sample collection, see Appendix 4.
Pharmacodynamics 
Pharmacokinetics
Immunogenicity
Pharmacogenetics
Other biomarkers
Abbreviations:  AE = adverse event; ASCO = American Society of Clinical Oncology; BSA = body surface area; C = cycle; CTCAE = Common Terminology 
Criteria for Adverse Events (NCI 2009); D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); G-CSF = 
granulocyte-colony stimulating factor; IRR = infusion-related reaction; IV = intravenously; LVEF = left ventricular ejection fraction; min = minutes; MUGA 
= multiple-gated acquisition; NCCN = National Comprehensive Cancer Network; PD = progressive disease; q = every; RBC = red blood cell; RECIST 
1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).
a
Olaratumab monotherapy schedule applies to patients who have completed 6 cycles of olaratumab plus doxorubicin and ifosfamide and are continuing 
treatment with olaratumab monotherapy or have discontinued doxorubicin plus ifosfamide and are continuing with olaratumab monotherapy.  Note: if a 
patient discontinues doxorubicin plus ifosfamide treatment prior to completing 6 cycles and is continuing treatment with olaratumab monotherapy, perform 
procedures according to the olaratumab monotherapy schedule beginning the next cycle after the patient discontinues doxorubicin/ifosfamide.

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Table JGDR.3.
Post-Treatment Follow-Up Schedule of Activities
Procedure
Short-Term 
Follow-Upa
Long-Term 
Follow-Up
Instructions
Visit
801
802–8XX
Physical examination
X
Including weight and vital signs (temperature, blood pressure, pulse rate, 
respiration rate)
Concomitant medication
X
AE collection
X
CTCAE Version 4.0. 
ECOG performance status
X
Radiologic imaging and measurement of 
palpable or visible lesions
X
X*
*For patients whose disease has not progressed:
Perform q 6 weeks × 2, then q 3 mo until:

the patient has objective disease progression according to 
RECIST 1.1 or

the study’s primary/final analysis
Perform using the same method used at baseline and throughout the study.
For patients who have had objective disease progression:
Radiologic tests and measurement of palpable or visible lesions are no 
longer required; these patients should be followed up for OS and 
collection of post-study treatment anticancer therapy information 
collection as indicated below.
Collection of survival information
X
Perform q 2 mo (±7 days) for the first 2 years after discontinuation from 
study treatment and q 6 mo (±14 days) thereafter until death or study 
completion.  If an in-person visit is not possible, confirm survival by 
contacting the patient directly via phone.
Collection of post-study treatment anticancer 
therapy information
X
X
Perform q 2 mo (±7 days) for the first 2 years after discontinuation from 
study treatment and q 6 mo (±14 days) thereafter until death or study 
completion.
ECG
X
X

All patients should have a 12-lead ECG performed at short-term 
follow-up.

Patients should also have a 12-lead ECG performed approximately 6 
months (±7 days) and 12 months (±7 days) after the end of treatment 
with doxorubicin and ifosfamide.

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Procedure
Short-Term 
Follow-Upa
Long-Term 
Follow-Up
Instructions
Visit
801
802–8XX
Echocardiogram and/or MUGA scan
X
Perform at 6 months (±7 days) and 12 months (±7 days) after the end of 
treatment with doxorubicin and ifosfamide.  Echocardiograms/MUGA 
scans may be discontinued if the patient begins another anticancer therapy.  
Perform additional evaluations in the setting of cardiac symptoms and/or 
at the discretion of the investigator.
Hematology 
X
See Appendix 3.  To be performed locally for patient management and 
centrally for analysis purposes.
Coagulation
X
See Appendix 3.  To be performed locally.
Clinical chemistry
X
See Appendix 3.  To be performed locally for patient management and 
centrally for analysis purposes.
Urinalysis 
X
See Appendix 3.  To be performed locally.
Sample collection
For all sample collection, see Appendix 4.
Pharmacodynamics
Pharmacokinetics
Immunogenicity
Pharmacogenetics
Other biomarkers
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); ECOG = Eastern Cooperative Oncology Group 
(Oken et al. 1982); mo = month; MUGA = multiple-gated acquisition; OS = overall survival; q = every; RECIST 1.1 = Response Criteria in Solid Tumors 
Version 1.1 (Eisenhauer et al. 2009).
a
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).  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly 
provided permission and consent.

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Table JGDR.4.
Continued Access Schedule of Activities
Visit
Study Treatment
Follow-Upa
Instructions
501-5XX
901
Procedureb
AE collection
X
X
CTCAE Version 4.0
See Section 9.2.
Pharmacokinetics and immunogenicity
X
If a patient experiences an IRR, collect blood samples for 
pharmacokinetics and immunogenicity analysis 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 days after the IRR.
Administer olaratumab
X
21-day cycles
Administer until PD, unacceptable toxicity, death, or other withdrawal 
criteria are met. 
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction.
a
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 30 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.
b
Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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3.
Introduction
3.1.
Background
3.1.1.Soft Tissue Sarcoma
Soft tissue sarcoma (STS) is a heterogeneous group of malignant tumors that arise from tissue of 
mesenchymal origin. Soft tissue sarcoma arises primarily from the embryonic mesoderm, with 
some neuroectodermal contribution and differentiation to non-epithelial extraskeletal tissue, 
including striated skeletal and smooth muscle, adipose and fibrous tissue (Sharma et al. 2013; 
D’Angelo et al. 2014; Linch et al. 2014).  There are approximately 50 different types of STS that 
can be found in almost any anatomic location (American Cancer Society 2014; Linch et al. 
2014).  STS is rare, comprising approximately 1% of adult cancers.  The annual incidence of 
STS in the United Kingdom and United States (US) is 3300 and 10,000, respectively (Jemal et 
al. 2009; Soft tissue sarcoma statistics page [WWW] 2010).  A multidisciplinary setting with 
teams specializing in the treatment of STS is the best treatment approach for these tumors.  
Management of localized disease is usually with curative intent, using surgical resection with or 
without radiotherapy and chemotherapy. In spite of initial aggressive management, there is 
frequent recurrence of local inoperable or metastatic disease, and at this point systemic therapy 
plays a prominent role in the multidisciplinary management of STS (Linch et al. 2014).
The mainstay therapy for treating advanced-stage STS has been chemotherapy, which in the 
first-line setting has provided overall response rates of approximately 25% (Linch et al. 2014).  
Even with the use of chemotherapy, advanced-stage STS is usually fatal and there remains a 
need for novel and effective therapies.  Doxorubicin either alone or in combination has served as 
the initial treatment for metastatic sarcoma for many years. Various other drug combinations 
have also been explored (Linch et al. 2014).  In more recent years, the addition of ifosfamide to 
doxorubicin has demonstrated increased tumor response and progression-free survival (PFS)
compared to doxorubicin alone, with a similar overall survival (OS) and a higher incidence of 
Grade 3 and 4 toxicities (Judson et al. 2014).  This regimen is used in the clinical setting where 
shrinking of the tumor is important and where the patient can tolerate the risk of greater toxicities 
compared to doxorubicin alone; this regimen has also been evaluated in the neoadjuvant and 
adjuvant settings for patients with STS (Gortzak et al. 2001; Grobmyer et al. 2004; Pisters et al. 
2016). 
3.1.2.Olaratumab
Olaratumab is a recombinant human immunoglobulin G subclass 1-type monoclonal antibody 
that binds to platelet-derived growth factor receptor alpha (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 mitogen-activated protein kinase (Loizos et al. 2005; 
Study Report IMC-3G3-01).

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In normal mesenchymal biology, PDGF/PDGFR signaling has a significant role in mesenchymal 
stem cell differentiation, growth of mesenchymal cells, angiogenesis and wound healing (Andrae 
et al. 2008; Ng et al. 2008; Li et al. 2014). PDGF/PDGFRα signaling has been implicated in the 
pathogenesis of multiple cancers, including osteosarcoma, chondrosarcoma, 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. 
PDGFRα is expressed on stromal cells, as well as the cancer cells themselves, within certain 
tumors. Furthermore, studies have shown that PDGF/PDGFRα signaling affects tumor 
vasculature through paracrine mediation of vascular endothelial growth factor production (Shah 
et al. 2010).
3.2.
Study Rationale
Study I5B-MC-JGDG (Study JGDG) was a Phase 1b/randomized Phase 2 study evaluating the 
efficacy of doxorubicin with or without olaratumab in the treatment of advanced STS.  The study 
met its primary endpoint for PFS (hazard ratio [HR] = 0.67; p = 0.06 as compared to a 
prespecified alpha level of 0.2) with an improvement in median PFS and OS of 2.5 months and 
11.8 months, respectively, for olaratumab plus doxorubicin over doxorubicin alone, with a 
manageable safety profile.  The OS HR of 0.46 was highly statistically significant (p = 0.0003; 
Tap et al. 2016).  Based on these results, olaratumab has received conditional approval in the US 
and European Union in combination with doxorubicin for the treatment of adult patients with 
STS. 
While doxorubicin alone or in combination with other chemotherapeutic agents has been the 
mainstay of treatment for decades (Linch et al. 2014), in more recent years the combination of 
doxorubicin, ifosfamide and mesna has demonstrated increased tumor response and PFS 
compared to doxorubicin alone. However, this regimen is associated with a higher rate of Grade 
3 and 4 toxicities and no improvement in OS (Judson et al. 2014), limiting the use of this 
regimen to distinct clinical settings, such as when shrinkage of the tumor is important and the 
risk of greater toxicity is felt to represent an acceptable benefit-risk.  This regimen has been 
evaluated in the neoadjuvant and adjuvant settings for patients with STS (Gortzak et al. 2001; 
Grobmyer et al. 2004; Pisters et al. 2016).
The positive efficacy results seen with olaratumab in combination with doxorubicin in Study 
JGDG provide strong rationale for determining whether olaratumab can also be safely added to 
the doxorubicin, ifosfamide and mesna regimen. It is plausible that the addition of olaratumab to 
doxorubicin, ifosfamide and mesna may further increase efficacy endpoints such as tumor 
response rate, PFS and OS, without a clinically significant increase in toxicity. Study 
I5B-MC-JGDR (Study JGDR) will characterize the safety and tolerability of olaratumab in 
combination with doxorubicin, ifosfamide and mesna in patients with advanced STS, and if 
acceptable, determine the dosing regimen of olaratumab in combination with doxorubicin and 
ifosfamide appropriate for future studies of this combination.

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3.2.1.Rationale for Amendment (a)
The original Study JGDR protocol, version dated 14 March 2017, was amended to remove visits 
and/or procedures not intended for patients receiving olaratumab monotherapy only after 
completing 6 cycles of olaratumab plus doxorubicin and ifosfamide (or discontinued doxorubicin 
and ifosfamide before).  In particular, visits and procedures specifically used to administer and 
monitor for toxicity from the doxorubicin and ifosfamide combination have been removed for 
patients receiving olaratumab monotherapy.
The timing of ECHO/MUGA scans after discontinuation of doxorubicin plus ifosfamide 
treatment was clarified and ECG evaluations were added at the same frequency to ensure 
complete evaluation of any potential cardiotoxic effects following treatment with doxorubicin 
plus ifosfamide.
The wording pertaining to required contraceptive use following study treatment has been 
clarified to align with label requirement for doxorubicin.
In addition, some minor editorial changes have been made throughout the protocol to improve 
clarity and practicality of the protocol and secure alignment with the intended study design.
3.3.
Benefit-Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of olaratumab are to be found in the 
Investigator’s Brochure (IB).

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4.
Objectives and Endpoints
Table JGDR.5 shows the objectives and endpoints of the study.

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Table JGDR.5.
Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the safety profile of olaratumab 
when given in combination with doxorubicin, 
ifosfamide and mesna and to determine the 
dosing regimen appropriate for a future Phase 2 
study

DLTs, TEAEs, SAEs and clinical laboratory 
abnormalities per NCI-CTCAE Version 4.0 
Secondary

To evaluate the PK of olaratumab when 
combined with doxorubicin, ifosfamide and 
mesna

To evaluate the immunogenicity of olaratumab 
when combined with doxorubicin, ifosfamide 
and mesna

To document any antitumor activity of 
olaratumab when combined with doxorubicin, 
ifosfamide and mesna

PK:  Cmax and AUC from time 0 to the last 
time point with a measurable concentration, and 
AUC from time 0 to infinity of olaratumab.  
Other noncompartmental parameters, such as 
half-life, clearance and volume of distribution 
may be reported.  Plasma doxorubicin and 
ifosfamide concentrations will be summarized 
by descriptive statistics

Immunogenicity:  Anti-olaratumab antibody 
levels at baseline, during the study, at the 
30-day follow-up visit and in the event of 
olaratumab IRRs

Antitumor activity:  Radiographic 
assessments according to RECIST Version 1.1 
criteria every 6 weeks (-7 days) until 
radiographic documentation of PD.  Efficacy 
endpoints will include objective response rate, 
PFS, duration of response, disease control rate 
and OS
Exploratory

To explore biomarkers related to, but not 
limited to tumor microenvironment, immune 
cells/immune functioning, mechanism of action 
of study drugs, PDGF, cancer-related pathways 
and disease state, and their association with 
demographics, disease state and clinical 
outcomes

Biomarker assay results with other trial data
Abbreviations: AUC = area under the concentration curve; Cmax = maximum observed concentration; DLT = 
dose-limiting toxicity; IRR = infusion-related reaction; NCI-CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events; OS = overall survival; PD = progressive disease; PFS = progression-
free survival; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious 
adverse event; TEAE = treatment-emergent adverse event.

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5.
Study Design
5.1.
Overall Design
Study JGDR is a multicenter, nonrandomized, open-label, Phase 1b study of intravenous (IV) 
olaratumab in combination with doxorubicin, ifosfamide and mesna in patients with advanced or 
metastatic STS.
Dose-Finding Phase
Bone marrow suppression occurs relatively frequently with the doxorubicin, ifosfamide and 
mesna regimen and can lead to complications such as fever and neutropenia, infection, or 
bleeding, which are generally considered DLT-level toxicities and thus can confound 
determination of DLT in the setting of combination with olaratumab.  The EORTC Phase 3 study 
(Judson et al. 2014) demonstrated a 46% rate of febrile neutropenia in patients with STS who 
were treated with doxorubicin, ifosfamide and mesna.  Because of this relatively high rate of  
DLT-level toxicity with the backbone doxorubicin, ifosfamide and mesna regimen and the 
generally acceptable toxicity profile of the 15-mg/kg dose of olaratumab (Days 1 and 8 every 
21 days) in combination with other chemotherapeutic agents including doxorubicin, 
approximately 15 patients will be enrolled at the first dose level of olaratumab (and evaluated 
after 6, 9 and 15 patients have received 1 cycle of therapy) to allow sufficient patient numbers to 
judge initial tolerability of olaratumab in combination with doxorubicin, ifosfamide and mesna.  
See Table JGDR.7 for a detailed explanation of the dose-limiting toxicity (DLT) thresholds that 
will be used to govern enrollment in the Dose-Finding Phase and Section 10.1 for the statistical 
justification of the study design.
Olaratumab 15-mg/kg Dose Level:  The first phase of the study (Dose-Finding Phase) will 
evaluate the safety and tolerability of adding olaratumab to the regimen of doxorubicin 
(75 mg/m2 plus given as IV infusions of 25 mg/m2 on Days 1 to 3), ifosfamide (10 g/m2 given as 
IV infusions of 2.5 g/m2 on Days 1 to 4) and mesna according to a 21-day cycle.  Fifteen patients 
will be initially enrolled and treated with a 15-mg/kg dose of olaratumab (on Days 1 and 8 of a 
21-day cycle) in combination with doxorubicin, ifosfamide and mesna and assessed for safety 
after 1 cycle of therapy. The full cohort of 15 patients will be enrolled if 5 or fewer patients with
DLTs are observed in the first 6 and 9 patients, respectively.
Olaratumab 20-mg/kg Loading Dose Cycle Dose Level:  Following an evaluation of safety in 
the full cohort of 15 patients (and provided 8 or fewer of these patients have experienced DLTs), 
the study will progress to evaluate a loading dose cycle of olaratumab (20 mg/kg IV on Days 1 
and 8 of Cycle 1 only, then 15 mg/kg on Days 1 and 8 of subsequent cycles) in combination with
doxorubicin, ifosfamide and mesna in a new cohort of 15 patients. Section 5.5.1 details the 
rationale for the loading dose. The full cohort of 15 patients will be enrolled if 5 or fewer
patients with DLTs are observed in the first 6 and 9 patients, respectively.  
Olaratumab 15-mg/kg Dose Level:  Ifosfamide Dose Reduction Option
If during enrollment into the olaratumab 15-mg/kg dose level, DLTs are observed in 6 of the first 
6 patients, in ≥6 of the first 9 patients, or in ≥9 of the full cohort of 15 patients, the study will 

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proceed to explore a reduced ifosfamide dose (7.5 g/m2 total dose) in combination with 
olaratumab 15 mg/kg and the same doxorubicin dose in a new cohort of 15 patients.  If DLTs are 
observed in 6 of the first 6 patients, in ≥6 of the first 9 patients, or in ≥9 of the full cohort of 15 
patients at this reduced ifosfamide dose, the study will halt and no further patients will be 
enrolled.  If 8 or fewer patients with DLTs are observed in this full cohort of 15 patients, the 
study will progress to explore the olaratumab Loading Dose Cycle as previously described in 
combination with the reduced ifosfamide dose (and same doxorubicin dose) as previously 
described.
Olaratumab 20-mg/kg Loading Dose Cycle Dose Level:  Ifosfamide Dose Reduction Option
If during enrollment into the olaratumab 20-mg/kg Loading Dose Cycle dose level, DLTs are 
observed in 6 of the first 6 patients, in ≥6 of the first 9 patients, or in ≥9 of the full cohort of 
15 patients, no further patients will be enrolled at this dose level and olaratumab 15 mg/kg will 
be declared the recommended dose for combination with reduced-dose ifosfamide/mesna and 
doxorubicin.  If 8 or fewer patients with DLTs are observed in this full cohort, the olaratumab 
20-mg/kg loading dose cycle together with a reduced ifosfamide/mesna dose will be declared the 
recommended doses for combination with doxorubicin.
Dose Confirmation Phase:  If a safe and tolerable regimen of olaratumab in combination with 
doxorubicin, ifosfamide and mesna is established in the Dose-Finding Phase, the second phase of 
the study (Dose Confirmation Phase) will open to further evaluate the regimen at the 
recommended doses of olaratumab and ifosfamide/mesna in combination with doxorubicin in an 
additional 15 patients, with the goal of treating a total of 30 patients with the recommended 
regimen.  Patients will continue combination treatment for up to a maximum of 6 cycles, unless
there is documented disease progression, unacceptable toxicity, death, or other discontinuation 
criteria are met (Section 8).  Patients who discontinue doxorubicin, ifosfamide and mesna
treatment without evidence of disease progression will receive olaratumab as monotherapy until 
there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria 
are met (Section 8).  Patients who undergo surgical tumor resection following study treatment 
are not eligible to receive olaratumab as monotherapy.
Figure JGDR.1 illustrates the study design.

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Abbreviations:  D = day; DLT = patients experiencing a dose-limiting toxicity; Dox = doxorubicin; g = grams; Ifos = ifosfamide; kg 
= kilogram; m2 = square meters; mg = milligrams; Olara = olaratumab; N = number; TBD = to be determined.
a
Patients who discontinue combination study therapy without evidence of disease progression will receive olaratumab as 
monotherapy until there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.
Figure JGDR.1.
Illustration of study design.

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5.1.1.Dose-Finding Phase:  Olaratumab 15-mg/kg Dose Level
The purpose of this single-arm cohort is to determine whether a 15-mg/kg dose of olaratumab
(on Days 1 and 8) may be safely added to the doxorubicin, ifosfamide and mesna regimen in
patients with advanced or metastatic STS. No intrapatient dose escalation is permitted in this 
cohort. Patients who do not complete Cycle 1 treatment for reasons other than a DLT will be 
replaced.  Safety data for this patient cohort will be reviewed prior to dose escalation. The total
number of patients with DLTs and the type of DLTs will be considered prior to making a 
decision to escalate the olaratumab dose.
5.1.2.Dose-Finding Phase: Olaratumab 20 mg/kg Loading Dose Cycle
Level
The purpose of this single arm cohort is to determine whether a 20 mg/kg loading dose cycle of 
olaratumab (given on Days 1 and 8 of Cycle 1 only, followed by 15 mg/kg on Days 1 and 8 of 
subsequent cycles) may be safely added to the doxorubicin, ifosfamide and mesna regimen in 
patients with advanced or metastatic STS.  Patients who do not complete Cycle 1 treatment for 
reasons other than a DLT will be replaced. Safety data for this will be reviewed prior to dose 
determination for the Dose Confirmation Phase.  The total number of patients with DLTs and the 
type of DLTs will be considered prior to making a dose determination.
5.1.3.Dose-Finding Phase:  Ifosfamide Dose Reduction Options
If DLT rules (see Section 7.2.2.1) are exceeded at the olaratumab 15-mg/kg dose, the study 
includes the option to explore a reduced ifosfamide dose (7.5 g/m2 given as daily IV infusions of 
2.5 g/m2 on Days 1 to 3) in combination with olaratumab 15 mg/kg (and doxorubicin).  See 
Section 5.5.2 for the rationale for this reduced dose. If the 15-mg/kg dose of olaratumab is 
determined to be safe and tolerable in combination with the reduced ifosfamide dose (see Section 
7.2.2 for DLT criteria to advance to next phase), a second cohort exploring a 20-mg/kg loading 
dose cycle of olaratumab in combination with ifosfamide at the reduced dose will be enrolled.  
These cohorts will be evaluated in the same manner as described in Sections 5.1.1 and 5.1.2.
5.1.4.Dose Confirmation Phase
Provided a safe and tolerable dose of olaratumab in combination with doxorubicin, ifosfamide 
and mesna (ifosfamide/mesna at full dose or reduced dose) is identified, this dose will be 
explored in a Dose Confirmation Phase of the study.
5.2.
Number of Patients
Study JGDR aims to enroll approximately 45 to 60 patients in total, with the goal of treating a 
total of approximately 30 patients with the recommended regimen.
5.3.
Study Completion Definition
The study will be considered complete 30 days after all patients in the Dose Confirmation Phase 
complete or discontinue olaratumab and doxorubicin, ifosfamide and mesna combination 
therapy.  See Section 7.9 for details on treatment after the completion of the study.

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5.4.
Scientific Rationale for Study Design
See Section 3.2.
5.5.
Justification for Dose
5.5.1.Olaratumab
In combination with doxorubicin, ifosfamide and mesna, this study will start at an olaratumab 
dose of 15 mg/kg on Days 1 and 8 of a 21-day cycle.  This dosing regimen has been 
demonstrated to have an acceptable safety profile in combination with doxorubicin
(Study JGDG) and was associated with improvement in PFS and OS. If this dose of olaratumab 
is found to be safe and tolerable with the doxorubicin and ifosfamide combination, then an 
olaratumab Loading Dose Cycle of 20 mg/kg on Days 1 and 8 of a 21-day cycle in Cycle 1 only, 
followed by 15 mg/kg on Days 1 and 8 of subsequent cycles will be explored.
In Study JGDG, PK model simulations indicated that olaratumab loading doses of 20 mg/kg 
administered on Day 1 and Day 8 of Cycle 1 would allow steady-state olaratumab serum levels 
to be achieved with the first administration and would minimize the number of patients whose 
serum trough level at the end of the first cycle of treatment (Cmin1) falls below 61 µg/mL during 
the first 2 cycles.  Additionally, a dose of 20 mg/kg olaratumab administered on Day 1 and Day 8 
during the first cycle, followed by 15 mg/kg administered on Day 1 and Day 8 of all subsequent 
cycles is predicted to yield maximum serum concentrations within the overall range observed in 
Study JGDG.  Therefore, olaratumab-related safety risks related to high serum concentrations or 
exposure using this loading dose approach are expected to be similar to those in Study JGDG.  
This dosing strategy is expected to minimize the number of patients exposed to subtherapeutic 
olaratumab serum levels without an increased risk of toxicity, thereby optimizing the benefit-risk 
ratio. This loading dose cycle strategy is analogous to that used in Study JGDK and under study 
in the ongoing Phase 3 Study JGDJ. 
5.5.2.Doxorubicin, Ifosfamide and Mesna
The doxorubicin, ifosfamide and mesna regimen is an effective option for patients with sarcoma 
and has been studied using a diverse range of doses and across subtypes (Worden et al. 2005; 
Maurel et al. 2009; Judson et al. 2014).  The doses of doxorubicin, ifosfamide and mesna chosen 
for Study JGDR are based on the EORTC study reported by Judson et al, the largest randomized 
study to date using the doxorubicin, ifosfamide and mesna regimen in patients with STS. In that 
study, patients received doxorubicin 25 mg/m2 per day on Days 1 to 3 and ifosfamide 2.5 g/m2
per day on Days 1 to 4 (plus mesna), followed by pegfilgrastim. Treatment was repeated every 
3 weeks until disease progression or unacceptable toxic effects, up to a maximum of 6 cycles.  
In the event the 15-mg/kg dose of olaratumab in combination with doxorubicin, ifosfamide and 
mesna is not tolerated, the study includes an option to explore a reduced dose of ifosfamide 
(7.5 g/m2 given as daily IV infusions of 2.5 g/m2 on Days 1 to 3, a dose of ifosfamide used in 
clinical practice [Grobmyer et al. 2004]) during the Dose-Finding phase.

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6.
Study Population
All patients meeting the eligibility requirements will be considered for enrollment regardless of 
race, religion, or gender. The investigator or the sponsor will not grant exceptions to eligibility 
criteria.  Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Have a histological diagnosis of advanced STS (by local pathology review), 
for which treatment with doxorubicin, ifosfamide and mesna is deemed 
appropriate by the investigator.  Patients with a diagnosis of Grade 1 
liposarcoma (atypical lipomatous neoplasms) are eligible if there is 
histological or radiographic evidence of evolution to more aggressive disease.
[2]
Have measurable or nonmeasurable but evaluable disease as defined by the 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (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.
[3]
Are 18 years of age at the time of consent.
[4]
Have given written informed consent prior to any study-specific procedures.
[5]
Have adequate hematologic, organ and coagulation function within 2 weeks 
(14 days) prior to enrollment:

Absolute neutrophil count (ANC) ≥1.5 × 109/L.  Granulocyte-colony-
stimulating factor (G-CSF) cannot be administered within 2 weeks (14 days) 
prior to enrollment.

Platelet count ≥100 × 109/L

Hemoglobin ≥9.0 g/dL.  No transfusions are allowed within 2 weeks 
(14 days) prior to enrollment.

Serum creatinine ≤1.5 times upper limit of normal (ULN).  If creatinine is 
above the ULN, the patient’s creatinine clearance must be ≥65 mL/min 
(refer to Appendix 6 for the Cockcroft-Gault formula for creatinine 
clearance).

Total bilirubin within 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

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
An adequate coagulation function as defined by international normalized 
ratio (INR) ≤1.5 × ULN or prothrombin time ≤1.5 × ULN, and partial 
thromboplastin time ≤1.5 × ULN (unless receiving anticoagulant therapy).  
Patients receiving warfarin are recommended to switch to low molecular 
weight heparin and should have achieved stable coagulation status prior to 
the first dose of study treatment.
[6]
Have a performance status of 0 to 1 on the Eastern Cooperative Oncology 
Group scale.
[7]
Have received no prior lines of systemic therapy (adjuvant or neo-adjuvant
treatment will not be counted as a prior line) and are suitable to receive 
doxorubicin, ifosfamide and mesna.  All previous anticancer treatments must 
have completed ≥3 weeks (21 days) prior to the first dose of study treatment.
[8]
Have left ventricular ejection fraction (LVEF) ≥50% assessed within 28 days 
prior to enrollment.
[9]
Have resolution of AEs, with the exception of alopecia, and of all clinically 
significant toxic effects of prior locoregional therapy, surgery or radiotherapy 
to ≤Grade 1, by National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Version 4.0.
[10] Have sufficient available material from archived formalin-fixed 
paraffin-embedded tumor tissue for biomarker-related studies.  If such tissue 
is not available, a newly obtained core or excisional biopsy of a tumor lesion 
must be performed.  Patients for whom it is inadvisable to undergo a new 
biopsy in the opinion of the investigator (for example, due to technically 
challenging tumor location) may be enrolled, after prior discussion with the 
Lilly clinical research physician (CRP). Refer to Section 9.7.2 regarding 
tissue collection requirements.
[11] Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[12] If male, must be sterile or agree to use an effective method of contraception or 
a highly effective method of contraception during the study and for at least: 

3 months following the last dose of olaratumab

6 months following the last dose of doxorubicin or ifosfamide
Refer to Appendix 1 for definitions of effective method of contraception and 
highly effective method of contraception.
[13] If female and of child-bearing potential, must:
a.
have a negative serum pregnancy test within 7 days prior to the first dose 
of study treatment, and

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b. agree to use a highly effective method of contraception during the study 
and for at least 3 months following the last dose of olaratumab and 6 
months following the last dose of doxorubicin or ifosfamide.
Refer to Appendix 1 for the definitions of highly effective method of
contraception and effective method of contraception.
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
are permitted on the study.
A post-menopausal 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
[14] Have a life expectancy of at least 3 months, in the opinion of the investigator.
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[15] Are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study.
[16] Have participated within the past 30 days in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed.
[17] Have previously completed or withdrawn from any study investigating 
olaratumab.
[18] Have received prior treatment with olaratumab, doxorubicin, or ifosfamide, or 
have participated in other trials investigating olaratumab.
[19] Have received prior radiotherapy of the mediastinal/pericardial area or whole 
pelvis radiation.
[20] Have known urinary outflow obstruction, or inflammation of the urinary 
bladder (cystitis).
[21] Are diagnosed with gastrointestinal stromal tumor or Kaposi sarcoma.

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[22] Have active central nervous system (CNS) or leptomeningeal metastasis
(brain metastasis) at the time of enrollment.  Patients with a history of CNS
metastasis (previously treated with curative intent [for example, stereotactic 
radiation or surgery]) that has 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.
[23] Have a history of another primary malignancy, with the exception of:
a.
curatively treated non-melanomatous skin cancer
b. curatively treated cervical carcinoma in situ
c.
non-metastatic prostate cancer, or 
d. other primary nonhematologic malignancies treated with curative 
intent, no known active disease, and no treatment administered 
during the last 3 years prior to enrollment, that the investigator 
and Lilly Medical representative agree will not affect 
interpretation of study results or would be unsuitable for 
participation in the study.
[24] Have an active fungal, bacterial and/or known viral infection including human 
immunodeficiency virus or viral (A, B, or C) hepatitis (screening is not 
required). 
[25] Have Grade 3 or 4 peripheral neuropathy per NCI-CTCAE Version 4.0.
[26] Have a serious cardiac condition, such as:

unstable angina pectoris

angioplasty, cardiac stenting or myocardial infarction within 6 months of 
enrollment

valvulopathy that is severe, moderate, or deemed clinically significant

arrhythmias that are symptomatic or require treatment
[27] Have a resting heart rate of >100 bpm.
[28] Have a QTcF interval of >450 msec for males and >470 msec for females on 
screening electrocardiogram (ECG) utilizing Fridericia’s correction (refer to 
formula in Appendix 7).  
[29] Have uncontrolled intercurrent illness including, but not limited to, an 
ongoing/active infection requiring parenteral antibiotics.
[30] Have a psychiatric illness/social situation that would limit compliance with 
study requirements.

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[31] Have electively planned or will require major surgery during the course of the 
study.
[32] Are females who are pregnant or breastfeeding.
6.3.
Screen Failures
The duration of the screening period is 14 days for the majority of procedures (see Section 2); 
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 extended 28-day screening period
(screen failure) may be re-screened after discussion with the Lilly CRP. Individuals may be 
re-screened a maximum of 1 time.  The interval between re-screenings should be at least 28 days.
If re-screening is performed, the individual must sign a new informed consent form (ICF) and 
will be assigned a new identification number.
Repeating laboratory tests during the 28-day screening period does not constitute re-screening.  
Screening laboratory tests may not be repeated more than once in order to meet eligibility during 
the 28-day screening period. If a repeat screening laboratory value meets eligibility, it is 
recommended that the test is rechecked to confirm stability.

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7.
Treatments
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient and study site personnel

verifying that instructions are followed properly

maintaining accurate records of study drug dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless Lilly and sites have agreed all unused medications have to be destroyed by 
the site, as allowed by local law.
7.1.
Treatment Administered (Dosing Schedule)
Table JGDR.6 shows the treatment regimens.  On days where multiple study drugs are to be 
administered, the drugs should be administered in the order shown in Table JGDR.6.

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Table JGDR.6.
Treatments Administered (Dosing Schedule)
Phase and 
Dose Cohort
Drug Name and Dose
Day of 21-day 
(±3 days) cycle
Total 
dose 
Route and duration of 
administration
Notes
Dose-Finding Phase
Olara 15 mg/kg
Olaratumab 15 mg/kga
D1 and D8
IV over 60 (±5) min
Infusion rate should not exceed 25 
mg/min
See Section 7.1.1 for premedication 
requirements and Section 7.8.1 for 
IRR monitoring period requirements
Doxorubicin 25 mg/m2 per daya
D1, D2, D3 
75 mg/m2
IV over less than 60 min
or 
continuous IV infusion (according to 
institutional practice)
Administer after olara on D1 and 
after any required observation period
Ifosfamide 2.5 g/m2 per daya
D1, D2, D3, D4b
10b g/m2
IV over 3 hours (±15 min) 
Administer after dox on D1, D2, D3
Mesna dose ≥60% of ifos dosea
D1, D2, D3, D4b
According to institutional practice
Olara Loading Dose Cycle
Olaratumab 20 mg/kg Cycle 1
Olaratumab 15 mg/kg Cycles 2 to 6a
D1 and D8
D1 and D8
IV over 60 (±5) min
Infusion rate should not exceed 25 
mg/min
See Section 7.1.1 for premedication 
requirements and Section 7.8.1 for 
IRR monitoring period requirements
Doxorubicin 25 mg/m2 per daya
D1, D2, D3 
75 mg/m2
IV over less than 60 min
or 
continuous IV infusion (according to 
institutional practice)
Administer after olara on D1 and 
after any required observation period
Ifosfamide 2.5 g/m2 per daya
D1, D2, D3, D4b
10b g/m2
IV over 3 hours (±15 min)
Administer after dox on D1, D2, D3
Mesna dose ≥60% of ifos dosea
D1, D2, D3, D4b
According to institutional practice
Dose Confirmation Phase
Recommended Olara Dose
Olaratumab dose determined from 
Dose-Finding Phasea
D1 and D8
IV over 60 (±5) min
Infusion rate should not exceed 25 
mg/min
See Section 7.1.1 for premedication 
requirements and Section 7.8.1 for 
IRR monitoring period requirements
Doxorubicin 25 mg/m2 per daya
D1, D2, D3 
75 mg/m2
IV over less than 60 min
or 
continuous IV infusion (according to 
institutional practice)
Administer after olara on D1 and 
after any required observation period
Ifosfamide 2.5 g/m2 per daya
D1, D2, D3, D4b
10b g/m2
IV over 3 hours (±15 min)
Administer after dox on D1, D2, D3
Mesna dose ≥60% of ifos dosea
D1, D2, D3, D4b
According to institutional practice

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Abbreviations:  C = cycle; CRP = clinical research physician; D = day; DLT = dose-limiting toxicity; dox = doxorubicin; g = grams; ifos = ifosfamide; IRR= 
infusion-related reaction; IV = intravenous; kg = kilogram; m2 = square meters; mg = milligrams; min = minutes; olara = olaratumab.
a
All patients will receive study therapy (olaratumab + doxorubicin/ifosfamide/mesna) for a maximum of 6 cycles, or until a discontinuation criterion is met. 
Patients who discontinue doxorubicin, ifosfamide and mesna treatment without evidence of disease progression will receive olaratumab as monotherapy until 
there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.
b
If DLT rules (see Section 7.2.2.1) are exceeded in the olaratumab 15-mg/kg cohort, a reduced dose of ifosfamide (7.5 g/m2 total dose) will be explored.  This 
reduced dose will be communicated by the Lilly CRP and will be accomplished by omitting the Day 4 dose (that is, ifosfamide will be administered at a dose 
of 2.5 g/m2 on D1, D2 and D3).  The Day 4 dose of mesna will be correspondingly omitted.  A Loading Dose Cycle of olaratumab (20 mg/kg on Days 1 and 8 
of C1, then 15 mg/kg on Days 1 and 8 of subsequent cycles) may also be explored in combination with the reduced dose of ifosfamide.

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7.1.1.Olaratumab Premedications and Required Monitoring
The infusion rate of olaratumab should not exceed 25 mg/min.  Infusion durations longer than 
60 min 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 or 2 
infusion-related reaction [IRR]); the infusion duration must always be accurately recorded.
Premedicate patients prior to administration of olaratumab as below: 

On Days 1 and 8 of Cycle 1:  Mandatory administration of a histamine H1 antagonist 
(for example, diphenhydramine) and dexamethasone prior to the start of the olaratumab 
infusion.

For subsequent cycles, premedication with a histamine H1 antagonist (for example, 
diphenhydramine) is recommended prior to each dose of olaratumab.
Additional premedication(s) may be provided at the investigator’s discretion.  Premedication 
must be provided in the setting of a prior Grade 1 or 2 olaratumab IRR, as detailed in 
Section 7.8.1.  All premedications administered must be adequately documented in the electronic 
case report form (eCRF).
Patients are required to be monitored for 1 hour after the olaratumab infusion in Cycles 1 and 2 
for signs or symptoms of IRRs; see Section 7.8.1 for full description of required olaratumab 
monitoring period in Cycles 1 and 2.  Patients should complete the required monitoring period 
prior to the start of the doxorubicin administration.
7.1.2.Doxorubicin Premedications and Dexrazoxane Administration
Given the emetogenic potential of doxorubicin, premedication with antiemetics per institutional 
guidelines is recommended.  Additional premedication(s) may be provided at the investigator’s 
discretion.
If antiemetic premedication is required prior to the doxorubicin infusion, this must be done after 
the completion of the olaratumab infusion (not before the olaratumab infusion).  This 
premedication may be administered immediately following the end of observation period (if 
applicable) or after the completion of the olaratumab infusion.
Patients may receive dexrazoxane for the prevention of cardiotoxicity at the discretion of the 
investigator according to institutional protocol. 
7.1.3.Ifosfamide Premedications and Mesna Administration
Mesna must be administered to all patients for the prevention of ifosfamide-induced hemorrhagic 
cystitis.  Mesna should be administered at a minimum dose equal to 60% of the ifosfamide dose 
according to institutional guidelines.  Note that as the dose of mesna administered is dependent 
on the dose of ifosfamide administered, any dose modifications to ifosfamide will require a 
corresponding dose modification to mesna in order to maintain the correct dosage (mesna dose = 
minimum 60% of ifosfamide dose).

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Ifosfamide should be given with extensive hydration consisting of oral or IV fluid (≥2 L/m2 per 
day IV) to prevent bladder toxicity or according to institutional guidelines.
Ifosfamide is associated with moderate emetic potential and antiemetics are recommended to 
prevent nausea or vomiting.
If ifosfamide premedication is required, it should be administered together with any doxorubicin 
premedications prior to doxorubicin administration.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be assigned to receive olaratumab in 
combination with doxorubicin, ifosfamide and mesna in this study. 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.
7.2.1.Selection and Timing of Doses
A cycle is defined as an interval of 21 days.  In Cycle 2 and beyond, up to 3 days delay of a cycle
(that is, Day 1) or Day 8 will be permitted due to holidays, weekends, bad weather, or other 
unforeseen circumstances and will not count as a protocol deviation.  In exceptional cases, longer 
delays may be allowed in later cycles following consultation with Lilly medical representative.
The actual dose of olaratumab to be administered will be determined by measuring the patient’s 
weight in kilograms on Days 1 and 8 of each cycle.  See also Section 7.5 for further details on 
olaratumab.  The actual doses of doxorubicin, ifosfamide and mesna 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% from the weight used to calculate prior doses, the 
olaratumab and doxorubicin, ifosfamide and mesna doses will not need to be recalculated, unless 
deemed clinically meaningful.  A 5% variance in the calculated total doses will be allowed for 
ease of dose administration.
Patients will continue treatment for a maximum of 6 cycles, or until there is documented disease 
progression, unacceptable toxicity, death, or other discontinuation criteria are met (Section 8).  
Patients who discontinue doxorubicin, ifosfamide and mesna treatment without evidence of 
disease progression will receive olaratumab as monotherapy until there is evidence of disease 
progression, death, intolerable toxicity, or other withdrawal criteria are met (Section 8). Patients 
who undergo surgical tumor resection following study treatment are not eligible to receive 
olaratumab as monotherapy.
7.2.2.Dose-Finding Phase
7.2.2.1.
Dose-Limiting Toxicity Determination
Because of the relatively high rate of DLT-level toxicity with the backbone doxorubicin, 
ifosfamide and mesna regimen (Judson et al. 2014) and the generally acceptable toxicity profile 

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of the 15-mg/kg dose of olaratumab (Days 1 and 8 every 21 days) in combination with other 
chemotherapeutic agents including doxorubicin, approximately 15 patients will be enrolled at the 
first dose level of olaratumab (provided safety data confirms the required number of patients 
without DLTs have been met for each DLT threshold as described in Table JGDR.7) to allow 
sufficient patient numbers to judge initial tolerability of olaratumab in combination with 
doxorubicin, ifosfamide and mesna.
In the Dose-Finding Phase, DLT assessment will be performed.  A DLT is defined as events such 
as the following, graded according to the NCI-CTCAE Version 4.0, when it occurs within 
Cycle 1 and is considered to be related to study treatment by the investigator in conjunction with 
the sponsor:
1. Grade 3 or 4 febrile neutropenia, or sepsis.
2. Grade 4 neutropenia lasting 7 days or longer.
3. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage.
4. Nonhematologic Grade ≥3 toxicity, except for toxicities (such as nausea, vomiting, 
transient electrolyte abnormalities, diarrhea) that can be controlled with optimal 
medical management within 48 hours or clinically non-significant laboratory 
abnormalities.
A dose-limiting equivalent toxicity is an AE that meets the DLT criteria as defined above and 
occurs in any cycle other than Cycle 1.  In addition to the DLT assessment period in Cycle 1, 
available safety data beyond Cycle 1 may also be taken into consideration prior to a decision to 
advance to the next dose level or the determination of the Confirmation Phase dose.
Note: Infusion-related reactions will not be considered as DLTs, as they occur independent of 
dose level.
Table JGDR.7 shows the DLT thresholds that will be used to determine study progression.  

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Table JGDR.7.
Dose-Limiting Toxicity Thresholds for Study JGDR
Dose Level
Regimen
If…
Thenb…
Olara 15 mg/kg
(Starting Dose 
Level)
Olara 15 mg/kg D1, D8
Ifos 10 g/m2 D1 to D4a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Proceed to Olara 15 mg/kg with Ifos Reduction Dose Level (new cohort of 
approximately 15 patients).
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Proceed to Olara 15 mg/kg with Ifos Reduction Dose Level (new cohort of 
approximately 15 patients).
≥9 DLTs in full 15 patients
Proceed to Olara 15 mg/kg with Ifos Reduction Dose Level (new cohort of 
approximately 15 patients).
≤8 DLTs in full 15 patients
Proceed to Olara 20-mg/kg Loading Dose Cycle Dose Level.
Olara 15 mg/kg 
with Ifos 
Reduction
Olara 15 mg/kg D1, D8
Ifos 7.5 g/m2 D1 to D3a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Halt study.  No further patients enrolled.
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Halt study.  No further patients enrolled.
≥9 DLTs in full 15 patients
Halt study.  No further patients enrolled.
≤8 DLTs in full 15 patients
Proceed to Olara 20-mg/kg Loading Dose Cycle Dose Level with Ifos 
Reduction.
Olara 20-mg/kg 
Loading Dose 
Cycle
Olara 20 mg/kg D1, D8 
of C1; then 15 mg/kg D1, 
D8 of C2 to C6 
Ifos 10 g/m2 D1 to D4a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg as recommended dose.
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg as recommended dose.
≥9 DLTs in full 15 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg as recommended dose.
≤8 DLTs in full 15 patients
Proceed to Recommended Dosing Regimen cohort with Olara 20-mg/kg 
Loading Dose Cycle as recommended dose.

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Dose Level
Regimen
If…
Thenb …
Olara 20-mg/kg 
Loading Dose 
Cycle with Ifos 
Reduction
Olara 20 mg/kg D1, D8 
of C1; then 15 mg/kg D1, 
D8 of C2 to C6 
Ifos 7.5 g/m2 D1 to D3a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg with Ifos reduction as recommended 
dose.
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg and Ifos 7.5 g/m2 as recommended 
doses.
≥9 DLTs in full 15 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg and Ifos 7.5 g/m2 as recommended 
doses.
≤8 DLTs in full 15 patients
Proceed to Recommended Dosing Regimen cohort with Olara 20 mg/kg 
Loading Dose Cycle and Ifos 7.5 g/m2 as recommended doses.
Recommended 
Dosing Regimen
Olara dose TBD
Ifos dose TBD
Dox 75 mg/m2 D1 to D3
Enroll 15 patients and treat with Recommended Dosing Regimen.
Abbreviations:  D = day; DLT = patients experiencing a dose-limiting toxicity; dox = doxorubicin; g = grams; Ifos = ifosfamide; kg = kilogram; m2 = square 
meters; mg = milligrams; Olara = olaratumab; TBD = to be determined.
a
With concomitant mesna administration.
b
If a sufficient number of patients successfully complete the DLT period at a given dose level (ensuring the DLT threshold will not be exceeded), further 
enrollment may proceed as described in Table JGDR.7, upon agreement of the Sponsor and Investigators.

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7.3.
Blinding
This is an open-label study.
7.4.
Dosage Delays, Discontinuations and Modifications
To begin dosing at Cycle 2 and each Day 1 thereafter (for cycles in which olaratumab is 
administered with doxorubicin and ifosfamide), the following criteria must be fulfilled (see 
Table JGDR.9 for hematological parameters for dosing olaratumab on Day 8):

ANC ≥1.5 × 103 cells/µL (≥1500 cells/µL; ≥1.5 × 109/L)

Platelets ≥100 × 103 cells/µL (≥100,000 cells/µL; ≥100 × 109 cells/L)

Hemoglobin ≥8.0 g/dL.  Note: For study inclusion, hemoglobin ≥9.0 g/dL

Total bilirubin below ULN.  In patients with Gilbert’s syndrome, total bilirubin should be 
3 mg/dL

Serum creatinine ≤1.5 times ULN.  If creatinine is above ULN, the patient’s creatinine 
clearance is ≥60 mL/min (refer to Appendix 6 for the Cockcroft-Gault formula for 
creatinine clearance)

AST and ALT ≤3 × ULN, or ≤5 × ULN if the transaminase elevation is due to liver 
metastases

Nonhematologic toxicity must be Grade ≤2 or must have returned to baseline, unless the 
toxicity is deemed not clinically significant by the investigator or is a laboratory 
abnormality that is manageable by institutional standards (for example, low serum 
potassium, magnesium, or phosphate).
In addition, patients should be monitored for evidence of micro- and/or macroscopic hematuria 
and treated according to institutional standards.
7.4.1.Delays
In general, dose delays of 1 study drug (olaratumab, doxorubicin, or ifosfamide/mesna) due to 
toxicities outlined in Section 7.4.3 will not necessitate delays of the other study drugs.  However, 
close consideration must be made by the investigator to administer all study treatments per the 
schedule outlined in Section 7.1.
Treatment may be delayed for up to 14 days to allow a patient sufficient time for recovery from 
study drug-related toxicity.  If Day 8 treatment is delayed >7 days, treatment may be resumed 
with planned Day 1 treatment of the next cycle.
Dosing delay beyond 14 days may be permissible if AEs are not considered to be primarily 
related to olaratumab and the investigator deems continuation of study treatment to have clinical 
benefit for the patient. This decision has to be documented and be jointly made by the 
investigator and the Lilly team.
In the event of unforeseen circumstances or scheduling issues that require adjustments to the 
schedule, appropriate adjustments or delays to the schedule may be made following discussion 
between the investigator and the sponsor and written approval by the Lilly medical 
representative.

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7.4.2.Discontinuations
The need to permanently discontinue doxorubicin and/or ifosfamide due to drug-related toxicity 
should be done according to local standard of care and labels.  Criteria for olaratumab 
discontinuation are discussed in the olaratumab dose modification section (7.4.3.1) and in the 
olaratumab infusion-related reaction section (7.8.1).
Patients whose disease has not progressed at the time of doxorubicin, ifosfamide and mesna 
discontinuation will receive olaratumab as monotherapy until there is evidence of disease 
progression, death, intolerable toxicity, or other withdrawal criteria are met (Section 8). These 
patients will continue study assessments as outlined in Table JGDR.2. Patients who undergo 
surgical tumor resection following study treatment are not eligible to receive olaratumab as 
monotherapy.
Patients who exhibit disease progression at the time of doxorubicin, ifosfamide and mesna 
discontinuation will receive post-treatment follow-up assessments as outlined in Table JGDR.3.
7.4.3.Dose Modifications
General guidelines for dose modifications are provided below.  Sections 7.4.3.2 and 7.4.3.3
outline guidelines for dose modifications of doxorubicin and ifosfamide, respectively; variations 
from these guidelines may be allowed according to local standard of care and labels.
7.4.3.1.
Olaratumab Dose Modifications
A reduction in the dose of olaratumab will be permitted if the doses of doxorubicin and 
ifosfamide have been previously reduced for toxicity, and the same or similar toxicity has 
recurred despite reduction of doxorubicin, ifosfamide and mesna, and the toxicity is deemed 
potentially related to the addition of olaratumab in combination with doxorubicin, ifosfamide and 
mesna.  In this scenario, an olaratumab dose reduction should occur in conjunction with a 
reduction in the doxorubicin and ifosfamide doses according to the guidance outlined in 
Sections 7.4.3.1.1 and 7.4.3.1.2.
A second reduction in the olaratumab dose will not be permitted during treatment with 
combination therapy of olaratumab plus doxorubicin and ifosfamide.  
Patients who have not progressed on study will receive olaratumab as monotherapy following 
discontinuation of the combination therapy until there is evidence of disease progression, death, 
intolerable toxicity, or other withdrawal criteria are met.  Patients receiving olaratumab as 
monotherapy will have assessments performed as per Table JGDR.2
Patients who have a dose reduction of olaratumab during the combination therapy portion and 
then proceeding to receive olaratumab monotherapy after discontinuation of doxorubicin and 
ifosfamide combination may have their dose of olaratumab re-escalated to the original dose level
at the investigator’s discretion.

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7.4.3.1.1.
Hematologic Toxicity
Table JGDR.8 shows olaratumab dose modifications that should be made for hematologic 
toxicities judged as potentially related to olaratumab in combination with doxorubicin, 
ifosfamide and mesna, and that have recurred or failed to improve/resolve despite 1 reduction in 
doxorubicin and ifosfamide doses.  These guidelines should be used for olaratumab dosing, when 
given in combination with doxorubicin and ifosfamide.
Table JGDR.8.
General Guidelines for Olaratumab Dose Modification due to 
Hematologic Toxicities
Toxicity
Dose Modification
Neutropenia
  ANC Grades 1-3
No dose modification required
  ANC <500 cells/µL (Grade ≥4)
No treatment administered; treatment cycle delayed
  At re-treatment:
  If ≥Grade 3 neutropenic fever/infection
has occurred and 1 reduction in 
doxorubicin, ifosfamide and mesna doses 
has already occurred
Withhold dose until ANC is ≥1500 cells/µL; 

15-mg/kg Dose Level:  Reduce dose to 12 mg/kg

20-mg/kg Loading Dose Cycle Level:  Reduce dose to 
15 mg/kg
  If Grade 4 neutropenia lasting ≥1 week
has occurred and 1 reduction in 
doxorubicin, ifosfamide and mesna doses 
has already occurred
Withhold dose until ANC is ≥1500 cells/µL; 

15-mg/kg Dose Level:  Reduce dose to 12 mg/kg

20-mg/kg Loading Dose Cycle Level:  Reduce dose to 
15 mg/kg
  Grade 4 ANC without fever/infection 
lasting ≤1 week
Administer next olaratumab at full dose, at investigator’s discretion
After 1 reduction of olaratumab and 2 
reductions of doxorubicin, ifosfamide 
and mesna, recurrence of either:
  1) ≥Grade 3 neutropenic fever/infection
  2) Grade 4 neutropenia lasting ≥1 week
Discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna).  Patients who have not progressed 
will receive olaratumab as monotherapy until there is evidence of 
disease progression, death, intolerable toxicity, or other withdrawal 
criteria are met.
Abbreviation:  ANC = absolute neutrophil count.
Omitting the Day 8 dose of olaratumab based on ANC and platelet counts judged as potentially 
related to olaratumab in combination with doxorubicin, ifosfamide, and mesna is permissible as 
shown in Table JGDR.9.

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Table JGDR.9.
Olaratumab Day 8 Dosing Algorithm Based on ANC and Platelet 
Count
Treatment Day
ANC
(cells/µL)
Platelet Count
(cells/µL)
Olaratumab
Day 8
≥500
and
≥75,000
Administer
<500
and
Any
Omita
Any
and
<75,000
Omit 
Abbreviations: ANC = absolute neutrophil count; µL = microliter.
a
Day 8 administration of olaratumab may be delayed for a maximum of 7 days.  If the ANC level has not
increased to 500 cells/µL 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. 
7.4.3.1.2.
Nonhematologic Toxicity
Specific guidelines for dose adjustments in patients who experience olaratumab-related IRRs 
may be found in Section 7.8.1.
Table JGDR.10 shows olaratumab dose modifications that should be made for nonhematologic 
toxicities judged as potentially related to olaratumab in combination with doxorubicin, 
ifosfamide and mesna and that have recurred despite 1 reduction in doxorubicin, ifosfamide and 
mesna dose.

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Table JGDR.10.
General Guidelines for Olaratumab Dose Modification due to 
Nonhematologic Toxicities
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 at the full 
dose, provided the event does not pose a serious health risk or is easily treated.
Grade 3 and 1 
reduction in 
doxorubicin, 
ifosfamide and 
mesna doses has 
already occurred
If not adequately controlled with appropriate supportive care, withhold dose until ≤Grade 1 or 
has returned to pretreatment baseline.
Treatment may resume as follows:

15-mg/kg Dose Level:  Reduce dose to 12 mg/kg

20-mg/kg Loading Dose Cycle Level:  Reduce dose to 15 mg/kg
If toxicity recurs after therapy resumes, discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna).  Patients who have not progressed will receive olaratumab as 
monotherapy until there is evidence of disease progression, death, intolerable toxicity, or 
other withdrawal criteria are met.
Grade 4 and 1
reduction in 
doxorubicin, 
ifosfamide and 
mesna doses has 
already occurred
Withhold dose until toxicity is ≤Grade 1 or has returned to pretreatment baseline.
Permanent discontinuation of olaratumab should be considered for any patient experiencing 
Grade 4 nonhematologic 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 CRP as follows:

15-mg/kg Dose Level:  Reduce dose to 12 mg/kg

20-mg/kg Loading Dose Cycle Level:  Reduce dose to 15 mg/kg
If toxicity recurs after therapy resumes, discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna).  Patients who have not progressed will receive olaratumab as 
monotherapy until there is evidence of disease progression, death, intolerable toxicity, or 
other withdrawal criteria are met.

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7.4.3.2.
Doxorubicin Dose Modifications
Dose modifications of doxorubicin will follow the guidelines outlined below and may be 
adjusted according to local standard of care and label.
7.4.3.2.1.
Hematologic Toxicity
Doxorubicin will not be administered after the initial dose if the patient’s ANC is <1500 cells/µL 
or if the platelet count is <100,000 cells/µL.  When necessary, the next treatment cycle should be 
delayed until the ANC is ≥1500 cells/µL and the platelet count is ≥100,000 cells/µL and any 
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 should occur.
Therapeutic and prophylactic use of pegfilgrastim or other G-CSFs is required per current 
American Society of Clinical Oncology (ASCO; Smith et al. 2006) and National Comprehensive 
Cancer Network (NCCN) guidelines (NCCN 2014).  In general, G-CSF products like filgrastim 
or pegfilgrastim should be administered approximately 24 hours after the completion of 
cytotoxic chemotherapy (for example, on Day 5 for patients in full-dose ifosfamide cohorts or 
Day 4 for patients in reduced-dose ifosfamide cohorts).  For patients with Grade 4 ANC without 
fever/infection lasting less than 1 week, re-treatment will be allowed at the investigator’s 
discretion with the full dose of doxorubicin (75 mg/m2) with required use of G-CSFs per current 
ASCO guidelines (Smith et al. 2006).  See Table JGDR.11 for doxorubicin dose modification for 
neutropenia.

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Table JGDR.11.
General Guidelines for Doxorubicin Dose Modification Due to 
Neutropenia
Toxicity
Required Dose Modification
ANC <1500 cells/µL
No doxorubicin administered; entire treatment 
cycle delayed.
At re-treatment:
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.
If Grade 4 neutropenia without fever/infection lasting less than 
1 week has occurred
Retreatment with doxorubicin at full dose at
investigator’s discretion with required use of 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.
Third incidence of either:
1) ≥Grade 3 neutropenic fever/infection
2) Grade 4 neutropenia lasting longer than 1 week
Discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna) and follow per 
Section 7.4.2.
Abbreviations:  ANC = absolute neutrophil count; G-CSR = granulocyte-colony-stimulating factor.
7.4.3.2.2.
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, which require 
mandatory discontinuation (see Section 7.4.3.2.3), treatment may only resume after consultation 
with the Lilly CRP, with the dose reduced to 60 mg/m² (or less if agreed by the investigator and 
Lilly CRP).  If Grade 4 nonhematological toxicity recurs after therapy resumes, doxorubicin (in 
combination with ifosfamide and mesna) will be permanently discontinued and the patient will 
be followed as outlined in Section 7.4.2.
For appropriate management of cardiac toxicities, refer to Section 7.4.3.2.3.
7.4.3.2.3.
Monitoring for Doxorubicin-Associated Cardiotoxicity
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 echocardiogram (ECHO)/multiple-gated acquisition (MUGA) scan.
Changes in ECG, arrhythmias, tachycardia and/or chest pain should be managed based on the
specific findings.  
Patients will undergo baseline LVEF determination using ECHO or MUGA scan.  This 
evaluation may be repeated at any time during the study if clinically indicated.  A decrease in 
LVEF of 10% and below the lower limit of normal, or 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).

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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.
7.4.3.3.
Ifosfamide Toxicities and Dose Modifications
Dose modifications of ifosfamide will follow the guidelines outlined below and may be adjusted 
according to local standard of care and label. Two reductions in ifosfamide dose for toxicity will 
be permitted during the study.  If a third dose reduction is necessary, the patient will be 
discontinued from the combination therapy (olaratumab + doxorubicin/ifosfamide/mesna) and
followed as outlined in Section 7.4.2.
General guidelines for ifosfamide dose modification are shown in Table JGDR.12.  Dose 
modifications of ifosfamide due to hepatic impairment are shown in Table JGDR.13.
Table JGDR.12.
General Guidelines for Dose Modification of Ifosfamide due to 
Toxicity
Worst Toxicity/Counts in Previous Cycle
Ifosfamide Dose Reductiona
Febrile neutropenia
First episode:  Maintain full dose
Subsequent episodes:  Decrease 20%
Platelets <75,000/mm3
If less than 1 week duration:  Maintain full dose
If greater than 1 week duration:  Decrease 20%
Thrombocytopenic bleeding
Decrease 20%
Somnolence or other signs of encephalopathy
Discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna) and follow per 
Section 7.4.2. Administer methylene blue 50 mg 
intravenously every 4 hours until resolution.
Grade 3 or 4 neurotoxicity other than encephalopathy
Discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna) and follow per 
Section 7.4.2.
Grade 3 related organ toxicity/nonhematologic
Decrease 20%
Grade 4 related organ toxicity/nonhematologic
Discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna) and follow per 
Section 7.4.2. 
Abbreviation:  mg = milligrams.
a
Do not re-treat until criteria in Section 7.4 are met.

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Table JGDR.13.
Dose Modification of Ifosfamide due to Hepatic Impairment
Bilirubin
and/or
AST/ALT
Ifosfamide Dose Reductiona
1-2 × ULN
<2 × ULN
Full dose
2-4 × ULN
2-5 × ULN
75% of initial dose
>4 × ULN
>5 ULN
Discontinue combination 
therapy (olaratumab + 
doxorubicin/ifosfamide/mesna) 
and follow per Section 7.4.2.
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.
a
Based on clinical judgment – less conservative adjustments can be considered if hepatic changes are secondary to 
metastases rather than hepatic cirrhosis or hepatitis.
7.4.3.3.1.
Ifosfamide-Associated Central Nervous System Toxicity
Central nervous system toxicity appears to be dose dependent, and is variable in onset, but 
usually resolves when ifosfamide is discontinued. Incidence is higher with higher doses, 
concomitant use of aprepitant, electrolyte imbalances, renal/hepatic impairment, or preexisting 
CNS disorders. It may manifest as transient mental status changes (somnolence, confusion, 
hallucination, disorientation and lethargy), cerebellar dysfunction, extrapyramidal symptoms, 
transient weakness, cranial nerve dysfunction, or seizure activity.  Methylene blue, which may 
act as an electron acceptor or decrease chloroacetaldehyde formation, has been suggested as 
treatment or prophylaxis for ifosfamide-induced encephalopathy.  Due to the potential for 
additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or 
antihistamines) must be used with particular caution or, if necessary, be discontinued in case of 
ifosfamide-induced encephalopathy.
7.4.3.3.2.
Ifosfamide-Associated Urotoxic Effects
The incidence of urotoxic effects without an uroprotector can be up to 40% and is dose 
dependent; coadministration of mesna and adequate hydration are mandatory in this study.  
Patients may present with hematuria, symptomatic cystitis, or bladder fibrosis.  Past or 
concomitant radiation of the bladder or busulfan treatment may increase the risk of hemorrhagic 
cystitis.  Several methods of treatment for established hematuria have been described:  bladder 
irrigation with water or normal saline, intravesical instillation of astringents (alum, silver nitrate), 
systemic administration of antifibrinolytics (aminocaproic acid, tranexamic acid), cystoscopy to 
evacuate the bladder of clots, continuous bladder irrigation and intravesical prostaglandins.  For 
severe or refractory hematuria, intravesical formalin, phenol, or prostaglandin has been used with 
or without surgical intervention (electrocautery, cryosurgery, diversion of urine flow, 
hypogastric artery ligation, or cystectomy).  Discontinuation or dose reduction of ifosfamide 
should follow local standard of care and label for patients with macroscopic hematuria.

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7.4.3.3.3.
Ifosfamide-Associated Proximal Tubular Damage
Glomerular, proximal, or distal tubular impairment may all occur, often in combination and may 
progress even after ifosfamide has been discontinued.  Proximal tubular damage often presents as 
Fanconi syndrome with low serum bicarbonate, proteinuria, glucosuria, aminoaciduria and 
hypochloremic metabolic acidosis.  Risk factors for the development of nephrotoxicity include 
preexisting renal impairment, concurrent use of nephrotoxic drugs, reduced renal reserve 
(unilateral nephrectomy), hydronephrosis and total cumulative dose.  Renal impairment may 
increase the risk of myelosuppression and possibly, cardiotoxicity.  Mesna does not appear to be 
protective against the proximal tubular abnormalities induced by ifosfamide.  Dose modifications 
guidelines of ifosfamide due to renal impairment are shown in Table JGDR.14.
Table JGDR.14.
Dose Modification of Ifosfamide due to Renal Impairment
Creatinine Clearance (mL/min)a
Ifosfamide Dose Reduction
>60
Full dose
40-60
Reduce to 75% of initial dose
20-40
Reduce to 50% of initial dose
<20
Discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna) and follow per Section 7.4.2.
Abbreviations:  min = minutes; mL = milliliters.
a
Calculated using Cockcroft and Gault formula (see Appendix 6). 
7.5.
Packaging and Labeling
7.5.1.Olaratumab
Olaratumab will be provided to study sites by Lilly. Clinical trial materials will be labeled 
according to the country’s regulatory requirements.
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, with a pH of 5.5.  All excipients used in the formulation of 
olaratumab drug product are of pharmacopoeia grade.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.5.2.Doxorubicin, Ifosfamide and Mesna
Where commercially available, doxorubicin, ifosfamide and mesna will be purchased by the 
sites.  In the event that there are regional restrictions or supply limitations, doxorubicin, 
ifosfamide and/or mesna may be provided to the sites by Lilly.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.5.3.Granulocyte-Colony Stimulating Factors
G-CSFs will be purchased by the sites.

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7.5.4.Dexrazoxane
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.
7.6.
Preparation/Handling/Storage/Accountability
7.6.1.Olaratumab
Olaratumab drug product must be stored under refrigeration at 2°C to 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.
7.6.2.Doxorubicin
Investigators should consult the approved doxorubicin hydrochloride package insert for complete 
preparation, handling and storage requirements.  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 is administered as an IV infusion. Doxorubicin may be administered either as a 
bolus over 60 minutes or less, or as a 24-hour continuous infusion, depending on institutional 
protocol.
If erythematous streaking along the vein proximal to the site of infusion or facial flushing occur, 
decrease the rate of doxorubicin administration.
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 (2°C to 
8°C). 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.
7.6.3.Ifosfamide
Investigators should consult the approved ifosfamide package insert for complete preparation, 
handling and storage requirements.
Ifosfamide single-dose vials should be stored at controlled room temperature from 20°C to 25°C 
(68°F to 77°F) and protected from temperatures above 30°C (86°F).
Exercise caution while handling ifosfamide. The handling and preparation of ifosfamide should 
always be in accordance with current guidelines on safe handling of cytotoxic agents. Several

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guidelines on this subject have been published (OSHA 1999; NIOSH 2004; ASHP 2006;
Polovich et al. 2014).  Skin reactions associated with accidental exposure to ifosfamide may 
occur. To minimize the risk of dermal exposure, always wear impervious gloves while handling 
vials and solutions containing ifosfamide.  If ifosfamide solution contacts the skin or mucosa, 
immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious 
amounts of water.
7.6.4.Mesna
Investigators should consult the approved mesna package insert for complete preparation, 
handling and storage requirements.
Mesna injection solution should be stored at 20°C to 25°C (68°F to 77°F), with excursions 
permitted to 15°C to 30°C (59°F to 86°F).
7.7.
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.
7.8.
Concomitant Therapy and Supportive Care
7.8.1.Olaratumab Infusion-Related Reactions
As with other monoclonal antibodies, hypersensitivity reactions may occur during or following 
olaratumab administration.
A 1-hour observation period is required after the administration of olaratumab in the first and 
second cycles.  If there is no evidence of an IRR 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.  During the observation period, patients 
treated with olaratumab should be closely monitored for signs and symptoms indicative of an 
IRR by the medical staff from the start of the infusion until at least 1 hour after the end of the 
infusion in an area where emergency medical resuscitation equipment and other agents 
(epinephrine, prednisolone equivalents, etc.) are available.
Treatment guidelines for olaratumab IRRs as well as premedications for subsequent infusions are 
described in Table JGDR.15.
Olaratumab infusion reactions 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 categories 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 

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use the AE term “infusion-related reaction” and any additional terms (including those not listed 
here) that best describe the event.
Table JGDR.15.
Olaratumab Infusion-Related Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication 
at Subsequent Infusions
Grade 1 or 2
Stop infusion and monitor symptoms.
Additional appropriate medical therapy should be given 
according to standard medical practice; may include, but 
is not limited to:

antihistamines (for example, 
diphenhydramine HCl)

steroids (for example, dexamethasone)

acetaminophen

oxygen
After recovery, the infusion rate should be decreased 
50% for the duration of the infusion.  
Patients should be premedicated 
with antihistamines, steroids, 
acetaminophen, etc., as 
appropriate.
Grades 3 or 4
Stop infusion.
Administer immediate treatment; may include, but is not 
limited to:

epinephrine

bronchodilators and/or glucocorticoids for 
symptomatic bronchospasm

IV fluids and/or pressors for hypotension
Treatment with olaratumab should be immediately 
and permanently discontinued.
No subsequent dosing
All attempts should be made to obtain an anti-olaratumab antibody and olaratumab PK blood samples as 
close to the onset of the event as possible, at the resolution of the event and 30 days (±3 days) following the 
event.  The procedure for sample collection and handling is described in a separate procedural manual.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
Abbreviations:  HCl = hydrochloride; IV = intravenous; NCI CTCAE = National Cancer Institute-Common 
Terminology Criteria for Adverse Events.
7.8.2.Granulocyte-Colony-Stimulating Factors and Erythroid Growth 
Factors
Because the doxorubicin, ifosfamide and mesna regimen is known to be highly suppressive of 
the bone marrow, G-CSFs such as pegfilgrastim must be used at each cycle and should be 

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administered according to ASCO guidelines (Smith et al. 2006) and NCCN guidelines (NCCN 
2014). In general, G-CSF products like filgrastim or pegfilgrastim should be administered 
approximately 24 hours after the completion of cytotoxic chemotherapy (for example, on Day 5 
for patients in full-dose ifosfamide cohorts or Day 4 for patients in reduced-dose ifosfamide 
cohorts). Erythroid-stimulating factors (such as erythropoietin) may be used at the discretion of 
the investigator and should also be administered according to ASCO and NCCN guidelines.
7.8.3.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.
7.8.4.Antiemetic Therapy
Both prophylactic and symptom-directed antiemetic therapy are recommended and should be 
used in accordance with institutional guidelines and/or at the investigator’s discretion.
7.8.5.Inducers and Inhibitors of CYP3A4, CYP2D6 and P-gp
Avoid concurrent use of doxorubicin HCl with inhibitors and inducers of cytochrome 
(CYP)3A4, CYP2D6 and/or P-gp.  Doxorubicin is a major substrate of CYP450, CYP3A4 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.
Ifosfamide is a substrate for both CYP3A4 and CYP2B6.  CYP3A4 inducers (for example, 
carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John’s Wort) may increase 
the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may 
increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. 
Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider 
dose adjustment.  CYP3A4 inhibitors (for example, ketoconazole, fluconazole, itraconazole, 
sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of 
ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide 
treatment.
7.8.6.Other Concomitant Therapies
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or
experimental drugs will be permitted while the patients are on this study. An exception will be
made for: 

prostate cancer patients continuing GnRH agonist therapy or breast cancer patients 
continuing anti-estrogen therapy (for example, an aromatase inhibitor) as long as those 

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therapies have been installed for at least 3 months and are known to have been well 
tolerated

bisphosphonate osteoclast inhibitors (for example, zoledronic acid or pamidronate) for 
treatment of bone metastases will be permitted while patients are on study treatment. The
osteoclast inhibitor denosumab is also allowed.  Denosumab is a monoclonal antibody 
and is associated with a risk of hypersensitivity reactions. Therefore, denosumab should 
not be administered within 3 days of olaratumab administration.

palliative local treatment (for example, radiotherapy of ≤14 calendar days) in Cycles 2 
and beyond following discussions between the investigators and the sponsor (for 
example, for pain control of a solitary [non-skull] skeletal metastasis) and written 
approval by the sponsor, as long as the patient has not developed another reason for study 
discontinuation.
7.9.
Treatment after the End of the Study
7.9.1.Continued Access
Patients who are still on olaratumab monotherapy at the time of study completion may continue 
to receive olaratumab monotherapy if they are experiencing clinical benefit.
A continued access period will apply to this study only if at least 1 patient is still on olaratumab 
monotherapy when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
The patient’s continued access to olaratumab study drug will end when a criterion for 
discontinuation is met (Section 8).  Continued access follow-up will begin the day after the 
patient and the investigator agree to discontinue olaratumab monotherapy and last approximately 
30±7 days (see Figure JGDR.2).  Follow-up procedures will be performed as shown in the 
Continued Access Schedule of Activities (Table JGDR.4).

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Abbreviations:  dox = doxorubicin; ifos = ifosfamide; olara = olaratumab.
Figure JGDR.2.
Continued access diagram.
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment under the following circumstances:

the patient is enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or 
treatment

the patient demonstrates disease progression

the patient has unacceptable toxicity

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 study treatment will occur prior to 
introduction of the new agent

the patient undergoes surgical tumor resection

the investigator decides that the patient should be discontinued from study 
treatment

the patient requests to be discontinued from study treatment

the patient’s designee (for example, legal guardian or caregiver) requests that 
the patient be discontinued from study treatment
Patients who are discontinued from study treatment will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1.Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate 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 study treatment.
8.2.
Discontinuation from the Study
Patients will be discontinued from the study under the following circumstances:

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations and good clinical 
practice (GCP)

the patient requests to be discontinued from the study

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Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Section 2).
8.3.
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 who the site is 
otherwise unable to follow-up.
Study site personnel, or an independent third party, will attempt to collect the survival status for 
all enrolled patients who are lost to follow-up, including enrolled patients who do not receive 
study treatment, within legal and ethical boundaries.  Public sources may be searched for 
survival status information.  If the patient’s survival status is determined, the survival status will 
be documented, and the patient will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect survival status information.

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9.
Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study.
Appendix 3 provides a list of laboratory tests that will be performed for this study.
Appendix 4 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1.Secondary Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2).
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, magnetic resonance 
imaging is also acceptable in certain situations, such as when body scans are indicated or if there 
is a concern about radiation exposure associated with CT.  Intravenous and oral contrast is
required unless medically contraindicated.
The CT portion of a positron emission tomography (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 
Version 1.1 (Eisenhauer et al. 2009).
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Radiological imaging of the chest, abdomen and pelvis and other areas, as clinically 
indicated, is required.
See Section 10.3.1 for definitions of the efficacy endpoints.
9.1.2.Appropriateness of Assessments
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials.
9.2.
Adverse Events
The investigator will use NCI-CTCAE Version 4.0 (NCI 2009) to assign AE terms and severity 
grades.
Investigators are responsible for:

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
monitoring the safety of patients in 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 appropriate medical care of patients during the study

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study treatment or the study, or that caused 
the patient to discontinue study treatment before completing the study.  The patient 
should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  Frequency of follow-up evaluation is left to the 
discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, study site personnel will record via eCRF any 
change in the preexisting conditions and any new conditions as AEs.  Investigators should record 
their assessment of the potential relatedness of each AE to study procedure or study treatment via 
eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies. A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuations that result 
from AEs to Lilly or its designee via eCRF, clarifying, if possible, the circumstances leading to 
the dose modification or discontinuation of treatment.
9.2.1.Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

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 serious, based upon appropriate medical judgment.

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Although all AEs after signing the ICF are recorded in the eCRF, 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.
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly-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.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported.  However, to fulfill regulatory requirements, any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus.
All AEs and SAEs, regardless of relatedness to study drugs or protocol procedures, occurring 
during the safety follow-up visit (Visit 801; approximately 30 days after completion of study 
therapy) must be reported to Lilly or its designee.  Investigators are not obligated to actively seek 
AEs or SAEs in patients beyond Visit 801.  However, if the investigator learns of any SAE, 
including a death, at any time after a patient has been discharged from the study, and he/she 
considers the event reasonably possibly related to the study treatment or study participation, the 
investigator must promptly notify Lilly.
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment.
9.2.2.Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  
United States 21 CFR 312.32 and 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 regulations and associated 
detailed guidances.

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9.2.3.Adverse Events of Special Interest
Adverse events of special interest (AESI) 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 Medical Dictionary for Regulatory 
Activities (MedDRA) preferred terms.
The following events will be considered as AESI for the combination of olaratumab and 
doxorubicin, ifosfamide and mesna:
infusion-related reactions
cardiac arrhythmias and cardiac dysfunction
encephalopathy
renal toxicity
Refer to Section 7.8.1 for treatment considerations relative to the occurrence of olaratumab IRRs.  
Refer to Section 7.4 for treatment considerations relative to dose delays, modifications and 
discontinuations from doxorubicin, including AEs of concern or AESI.
9.2.4.Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
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 investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the olaratumab IB for information on the treatment of olaratumab overdose.  Refer to 
the doxorubicin, ifosfamide and mesna product labels for information on overdose with these 
agents.
9.4.
Safety
9.4.1.Other Safety Measures
For each patient, ECGs, vital signs, laboratory tests, or other tests should be collected as shown 
in the Schedule of Activities (Section 2). 
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of study treatment should be reported to Lilly or its designee as an AE via 
eCRF.
9.4.2.Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.  In addition to the formal DLT period that occurs during Cycle 1, safety data from later 

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cycles that are available at the time of the DLT assessment may be used in the decision to move 
to the next cohort, or in the determination of the recommended Phase 2 dose.
Clinical and laboratory monitoring should be initiated by the investigator in the following 
circumstances:
1. The patient experiences elevation of serum ALT 10 × ULN 
2. A patient without liver tumors or liver metastatis experiences elevated ALT 5 × ULN 
and elevated total bilirubin 2 × ULN
3. A patient with liver tumor or liver metastatis experiences elevated ALT 8 × ULN and 
elevated total bilirubin 2 × ULN
4.
The patient is discontinued from treatment due to a hepatic event or abnormality of liver 
tests
5. The patient experiences a hepatic adverse event considered to be an SAE
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 regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Appendix 5).
9.5.
Pharmacokinetics
At the visits and times specified in the Pharmacokinetic, Immunogenicity and Biomarker 
Research Sampling Schedule (Appendix 4), venous blood samples will be collected for all 
patients enrolled in the study.  These samples will be used to determine the serum concentrations 
of olaratumab and the plasma concentrations of doxorubicin and ifosfamide.
A maximum of 5 additional samples (in addition to those shown in Appendix 4) may be 
collected at additional time points during the study if warranted and agreed upon between the 
investigator and Lilly.
Instructions for the collection and handling of blood samples will be provided by Lilly.  It is 
preferred that the blood samples be obtained from a peripheral location.  Blood samples can be 
collected via central access devices, but a sample drawn for PK from any type of central catheter 
cannot be diluted or it will not be viable for analysis.  If multiple samples are obtained centrally, 
the PK sample should be the last specimen drawn to reduce the potential for a diluted or 
improperly drawn sample.  The actual date and time (24-hour clock time) of each sampling will 
be recorded.
These samples will be analyzed at 1 or more laboratories designated by Lilly.  Serum 
concentrations of olaratumab will be assayed using a validated enzyme-linked immunosorbent 
assay method. Doxorubicin and ifosfamide concentrations in plasma will be analyzed using 
individual validated methods based on liquid chromatography with tandem mass spectrometry.
The PK samples will be stored at a facility designated by Lilly.  The remaining serum and 
plasma from the samples collected for PK may be pooled and used for exploratory drug 
metabolism work and other exploratory PK/pharmacodynamic (PD) work as deemed appropriate.

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Bioanalytical samples collected to measure olaratumab concentrations will be retained for a 
maximum of 1 year following the last patient visit for the study.
9.6.
Genetics
9.6.1.Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in Appendix 
4, where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to study treatment
and to investigate genetic variants thought to play a role in sarcoma. Assessment of variable 
response may include evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  Samples will be retained for a 
maximum of 15 years after the last patient visit for the study, or for a shorter period if local 
regulations and/or ethical review boards (ERBs)/institutional review boards (IRBs) impose 
shorter time limits, at a facility selected by Lilly.  This retention period enables use of new 
technologies, response to questions from regulatory agencies and investigation of variable 
response that may not be observed until later in the development of study drug(s) or after study 
drug(s) become(s) commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing technologies include whole genome and exome 
sequencing, genome-wide association studies, multiplex assays, candidate gene studies and 
epigenetic analyses.  Regardless of the technology utilized, data generated will be used only for 
the specific research scope described in this section.
9.7.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety) and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid, 
ribonucleic acid, proteins, lipids and other cellular elements.  Required samples for biomarker 
research to be collected from all patients in this study are the following:

blood (plasma) (see Section 9.7.1)

tumor tissue (see Section 9.7.2)
Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following:

newly obtained tumor specimens collected during or after the treatment period 
or at disease progression if medically feasible (see Section 9.7.2)

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Samples for biomarker research will be collected as specified in Appendix 4, where local 
regulations allow.
It is possible that biomarker data for patients in the study have already been generated from 
samples that were collected and analyzed prior to enrollment in this trial.  This may include data 
generated from genetic analyses.  If available, these data may be requested from medical records 
for use in the research described below.
9.7.1.Samples for Nonpharmacogenetic Biomarker Research
Blood samples for nonpharmacogenetic biomarker research will be collected as specified in 
Appendix 4 where local regulations allow.
Samples will be examined for biomarkers related to, but not limited to drug targets, disease 
process, immune cells/immune and tumor microenvironment functioning within the disease state 
and cancer-related conditions, pathways associated with cancer and study drugs, variable 
response to study drugs, the mechanism of action of study drugs and/or for research-related 
methods, or validating diagnostic tools or assays.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs/IRBs impose shorter time limits, at a facility 
selected by Lilly.  This retention period enables use of new technologies, response to questions 
from regulatory agencies and investigation of variable response that may not be observed until 
later in the development of study drug(s) or after study drug(s) become(s) commercially 
available.
9.7.2.Tissue Samples for Biomarker Research 
Tumor tissue will be examined for biomarkers related to, but not limited to drug targets, disease 
process, immune cells/immune and tumor microenvironment functioning within the disease state 
and cancer-related conditions, pathways associated with cancer and study drugs, variable 
response to study drugs, the mechanism of action of study drugs and/or for research-related 
methods, or validating diagnostic tools or assays.
Collection of the following tumor tissue sample is required for all patients in order to participate 
in this study unless restricted by local regulations:

To meet study eligibility criteria, and therefore mandatory for study participation, 
patients must have sufficient available material from an archived formalin-fixed 
paraffin-embedded tumor tissue.  If such tissue is not available, a newly obtained core 
or excisional biopsy of a tumor lesion must be performed.  Patients for whom it is 
inadvisable to undergo a new biopsy in the opinion of the investigator (for example, 
due to technically challenging tumor location) may be enrolled, after prior discussion 
with the Lilly CRP.

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Collection of the following tumor tissue sample(s) is optional for all patients participating in this 
study:

Newly obtained tumor specimens collected during or after the treatment period. If 
these additional samples are requested, they will be used to further investigate 
biomarkers that may explain treatment response and resistance mechanisms.  A tumor 
tissue sample will be requested from patients who undergo surgical tumor resection 
subsequent to study treatment.
Details for the handling and shipping of the tumor tissue will be provided by the sponsor in a 
separate document. If additional tumor biopsies are collected as part of clinical care, they should 
be submitted, along with pathology reports, for further analysis.  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. Cytological or fine-needle 
aspiration specimens and decalcified bone are not acceptable.  Previously obtained 
formalin-fixed paraffin-embedded tumor tissue should be provided as a block or unstained slides.  
Due diligence should occur to ensure that tumor sample (not a normal adjacent or a tumor 
margin sample) is provided.  The pathology report may also be requested to accompany the 
archival tissue sample. The report must be coded with the patient number. Personal identifiers, 
including the patient’s name and initials, must be removed from the institutional pathology report 
prior to submission. Lilly has a right to retain a portion of the submitted tissue and archival 
blocks will be returned to the study site. Slides and tissue samples collected on-study will not be 
returned. 
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs/IRBs impose shorter time limits, at a facility 
selected by Lilly.  This retention period enables use of new technologies, response to questions 
from regulatory agencies and investigation of variable response that may not be observed until 
later in the development of study drug(s) or after study drug(s) become(s) commercially 
available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  However, existing technologies, including mutation profiling, copy number 
variability, gene expression, multiplex assays and/or immunohistochemistry may be performed 
on these tissue samples to assess potential associations with these biomarkers and clinical 
outcomes.
9.8.
Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected as shown in Appendix 4 to 
determine antibody production against olaratumab.  Immunogenicity will be assessed using a 
validated assay designed to detect antidrug antibodies in the presence of olaratumab.  Antibodies 
may be further characterized and/or evaluated for their ability to neutralize the activity of 
olaratumab.

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Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if regulations and ERBs/IRBs impose shorter time limits, at a facility 
selected by Lilly.  The duration allows Lilly to respond to future regulatory requests related to 
olaratumab.

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10. Statistical Considerations
10.1. Sample Size Determination
The primary objective is to determine whether olaratumab can be safely added to the 
doxorubicin, ifosfamide and mesna regimen in patients with advanced or metastatic STS. 
Section 5.1 outlines the study design. A total of approximately 45 to 60 patients will be enrolled; 
at least 15 patients will be treated in the olaratumab 15-mg/kg phase.
A traditional 3 + 3 study design is not appropriate for this trial because of the relatively high rate 
of DLT-level toxicity associated with the backbone doxorubicin, ifosfamide and mesna regimen 
(Judson et al. 2014).  Instead, a total of approximately 15 patients will be enrolled at the first 
dose level of olaratumab (and incrementally evaluated after 6, 9 and 15 patients have received 1 
cycle of therapy) to allow sufficient patient numbers to judge initial tolerability of olaratumab in 
combination with doxorubicin, ifosfamide and mesna.
Before enrolling the full 15 patients at a given dose level, the study design requires that an initial
group of 6 will be enrolled and evaluated for DLTs. If 6 or more patents with DLTs are 
observed in the first 6 patients, enrollment at the current dose level will be stopped and 
appropriate dose de-escalation (or trial halt) will occur. Similarly, if 6 or more patients with
DLTs are observed in the first 9 patients, enrollment at the current dose level will be stopped and
appropriate dose de-escalation (or trial halt) will occur.
Assuming that the true DLT rate of olaratumab plus doxorubicin, ifosfamide and mesna is 
unacceptably high at 70%, this design will allow a 73% power to de-escalate the dose to an 
appropriate lower dose level. That is, when the true DLT rate is 70%, the probability of 
observing 6 or more DLT patients out of 9 patients is 0.73. Alternatively, assuming that the true 
DLT rate of olaratumab plus doxorubicin,ifosfamide and mesna is as low as 30%, then the 
probability of observing 6 or more DLT patients out of 9 patients is only 0.03 (false-positive rate 
when the true DLT rate is 30%).  
Assuming the true DLT rate of olaratumab plus doxorubicin, ifosfamide and mesna is 
unacceptably high at 70%, the current design will allow an 87% power to de-escalate the dose to 
an appropriate lower dose level.  That is, when the true DLT rate is 70%, the probability of 
observing 9 or more DLT patients out of 15 patients is 0.87. Alternatively, assuming the true 
DLT rate of olaratumab plus doxorubicin, ifosfamide and mesna is as low as 30%, then the 
probability of observing 9 or more DLT patients out of 15 patients is only 0.02 (false-positive 
rate when the true DLT rate is 30%).  
Although the study sample size is limited, the overall design allows satisfactory power and
false-positive rate.
10.2. Populations for Analyses
Safety population: All enrolled patients who receive any quantity of study treatment, regardless 
of their eligibility for the study, will be included in the safety analysis. Safety evaluation will be 

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performed based on the actual initial therapy a patient has received. Efficacy analysis will be 
performed on the safety population unless otherwise specified.
DLT-evaluable population: The DLT-evaluable population will include all enrolled patients 
who complete Cycle 1 or discontinue due to a DLT prior to completing Cycle 1 treatment.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report.  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
The interpretation of the study results will be the responsibility of 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.
10.3.1. Efficacy Analyses
Efficacy analysis will be performed to investigate antitumor activity within each phase. The 
investigator-assessed objective response rate (complete response [CR]+partial response [PR]) 
and disease control rate (DCR = CR+PR+stable disease) and the 90% exact confidence interval 
(CI) will be tabulated for each phase. The Kaplan-Meier method (Kaplan and Meier 1958) will 
be used to estimate the median with 90% CI for PFS, OS and duration of response. Additional 
analyses may be performed as necessary. The details will be outlined in the SAP.
10.3.2. Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.

Treatment-emergent adverse events will be summarized by MedDRA System Organ 
Class/preferred term, classified from verbatim terms. The incidence and percentage of 
patients with at least 1 occurrence of a preferred term will be included, according to the 
most severe NCI-CTCAE Version 4.0 grade. Causality (relationship to study drug), 
action taken, and outcome will be summarized separately. Duration of AE will be 
determined and included in the listings.

Study drug exposure will be summarized for each arm with following variables: number 
of infusions, number of cycles, duration of therapy, cumulative dose, dose intensity, and 
relative dose intensity.

Laboratory results will be classified according to NCI-CTCAE Version 4.0. Incidence of 
laboratory abnormalities will be summarized.

Hospitalizations due to AEs, transfusions and vital signs will be summarized.

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DLTswill be summarized by phasein the patients who are evaluable for DLT 
assessments and listed by patient. ECG, ECHO/MUGA and immunogenicity datawill 
also be summarized. Additional analyses may be performed as necessary. The details 
will be outlined in the SAP.
10.3.3.Other Analyses
10.3.3.1.
Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number andpercentage of patients who entered into the study, enrolled in the study and treated 
as well as the number and percentage of patients completing the study, as defined in the SAP, or 
discontinuing (overall and by reason for discontinuation).  A summary of all important protocol 
deviations will be provided.
10.3.3.2.
Patient Characteristics
A summaryof baseline patient and disease characteristics, historical diagnoses, preexisting 
conditionsand prior therapies will be reportedusing descriptive statistics. 
Other patient characteristics will be summarized as deemed appropriate.
10.3.3.3.
Concomitant Therapy
A summaryof prior and concomitant medicationswill be reported.
10.3.3.4.
Post-studyTreatmentDiscontinuation Therapy
The numbers and percentages of patients receiving post-studytreatmentdiscontinuation 
anticancer therapies will be provided by type of therapy (surgery, radiotherapy or systemic 
therapy), and by drug class and/or name, and overall.
10.3.3.5.
Treatment Compliance
The number of cycles received,dose omissions, dose reductions, dose delays and dose intensity 
will be summarized for all treated patients byeach phase.
Study treatment will be administered at the investigativesite, therefore treatment compliance is 
assured.
10.3.4.Pharmacokinetic Analyses
Unless stated otherwise, the Lilly pharmacokineticist will be responsible forthe PK and PK/PD 
analyses.
Pharmacokinetic parameter estimates for olaratumabwill be calculated usingstandard 
noncompartmental methods of analysis.  The primary parameters for analysis will be maximum 
concentration and area under the concentration-time curve (AUC
[0-tlast], AUC[0-∞]) of
olaratumab.  Other noncompartmental parameters, such as half-life, apparent clearance and 
apparent volume of distribution may be reported.  

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Additional analyses such as population PK analyses may also be conducted if deemed 
appropriate.  Other validated PK software programs (for example, NONMEM) may be used if 
appropriate and approved by Global Pharmacokinetic management.  The version of any software 
used for the analysis will be documented and the program will meet the Lilly requirements of 
software validation.
Plasma doxorubicin and ifosfamide concentrations at different time points will be summarized 
by descriptive statistics.
10.3.5. Biomarker Analyses
Biomarker assay results will be listed and summarized for all patients qualifying for the 
translational research portion of the study. Other exploratory analyses may also be undertaken to 
investigate the correlations and/or associations between marker status/level and drug disposition, 
target engagement, PD, mechanism of action, variability of patient response (including safety) 
and clinical outcomes. These assessments may include biomarker signatures consisting of 
marker status/levels of multiple biomarkers.  For biomarkers that are serially measured, change 
from baseline to a subsequent time point may also be used as a potential explanatory variable in 
correlative assessments involving other trial data endpoints and as a dependent variable in PD
analyses.
10.3.6. Immunogenicity Analyses
Incidence of treatment-emergent anti-olaratumab antibodies will be tabulated.  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 
treatment-emergent antidrug antibody (ADA)-negative and treatment-emergent-ADA-positive 
patients at correspondent visits, or before and after treatment-emergent-ADA development for 
patients who developed treatment-emergent-ADA.
In the event of an IRR, the immunogenicity and olaratumab serum concentrations will be 
tabulated.
10.3.7. Subgroup Analyses
Subgroup analyses will be performed as deemed appropriate.
10.3.8. Interim Analyses
Since this is a safety study, data will be reviewed on at least a cohort-by-cohort basis during the 
study. The purpose of these safety reviews is to evaluate the safety data at each phase to 
determine if the current safety profile supports continual enrollment based on the study design. 
The investigators and the Lilly study team will make the determination regarding the patient 
enrollment based upon their review of the safety and tolerability data as described in this 
protocol.

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11. References
[ACS] American Cancer Society. Sarcoma: adult soft tissue cancer. 2014. Available at: 
http://www.cancer.org/acs/groups/cid/documents/webcontent/003138-pdf.pdf. Accessed 
February 20, 2017.
Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and 
medicine. Genes Dev. 2008;22(10):1276-1312.
[ASHP] American Society of Health System Pharmacists. ASHP guidelines on handling 
hazardous drugs. Am J Health Syst Pharm. 2006;63:1172-1193.
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.
D’Angelo SP, Tap WD, Schwartz GK, Carvajal RD. Sarcoma immunotherapy: past approaches 
and future directions. Sarcoma. 2014;2014:391967.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
Gortzak E, Azzarelli A, Buesa J, Bramwell VH, van Coevorden F, van Geel AN, Ezzat A, 
Santoro A, Oosterhuis JW, van Glabbeke M, Kirkpatrick A, Verweij J, EORTC Soft Tissue 
Bone Sarcoma Group and the National Cancer Institute of Canada Clinical Trials 
Group/Canadian Sarcoma Group. A randomised phase II study on neo-adjuvant chemotherapy 
for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer. 2001;37(9):1096–1103.
Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF, Singer S. 
Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 
2004;15(11):1667–1672.
Jemal A, Center MM, Ward E, Thun MJ. Cancer occurrence. Methods Mol Biol. 2009;471:3–29.
Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, Kerst JM, Sufliarsky J, 
Whelan J, Hohenberger P, Krarup-Hansen A, Alcindor T, Marreaud S, Litière S, Hermans C, 
Fisher C, Hogendoorn PC, dei Tos AP, van der Graaf WT. Adriamycin alone versus 
intensified adriamycin plus ifosfamide for first-line treatment of advanced or metastatic 
soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-323.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481.
Li A, Xia X, Yeh J, Kua H, Liu H, Mishina Y, Hao A, Li B. PDGF-AA promotes osteogenic 
differentiation and migration of mesenchymal stem cell by down-regulating PDGFRα and 
derepressing BMP-Smad1/5/8 signaling. PLoS One. 2014;9(12):e113785.
Linch M, Miah A, Thway K, Judson IR, Benson C. Systemic treatment of soft-tissue sarcoma -
gold standard and novel therapies. Nat Rev Clin Oncol. 2014;11:187-202.

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Loizos N, Xu Y, Huber J, Liu M, Lu D, Finnerty B. Targeting the platelet derived growth factor 
receptor α 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.
Maurel J, López-Pousa A, de las Peñas R, Fra J, Martín J, Cruz J, Casado A, Poveda A, 
Martínez-Trufero J, Balañá C, Gómez MA, Cubedo R, Gallego O, Rubio-Viqueira B, Rubió J, 
Andrés R, Sevilla I, de la Cruz JJ, del Muro XG, Buesa JM. Efficacy of sequential high-dose 
adriamycin and ifosfamide compared with standard-dose adriamycin in patients with advanced 
soft tissue sarcoma: an open-label randomized phase II study of the Spanish Group for 
Research on Sarcomas. J Clin Oncol. 2009;27:1893-1898.
[NCCN] National Comprehensive Cancer Network Guidelines. Myeloid growth factors. Version
2.2014. Available at: http://williams.medicine.wisc.edu/myeloid_growth.pdf. Accessed 
February 20, 2017.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. Publish date: 
29 May 2009.
Ng F, Boucher S, Koh S, Sastry KS, Chase L, Lakshmipathy U, Choong C, Yang Z, Vemuri MC, 
Rao MS, Tanavde V. PDGF, TGF-beta, and FGF signaling is important for differentiation and 
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signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and 
osteogenic lineages. Blood. 2008;112(2):295-307.
[NIOSH] NIOSH alert: preventing occupational exposure to antineoplastic and other hazardous 
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Occupational Safety and Health. DHHS (NIOSH) Publication No. 2004-165.
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occupational exposure to hazardous drugs. 1999. Available at: 
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Pisters PWT, Weiss M, Maki R, Raut CP. Cancer management; soft tissue sarcomas; role of 
adjuvant chemotherapy. Cancer Network website. 01 June 2016. Available at: 
http://www.cancernetwork.com/cancer-management/soft-tissue-sarcomas/page/0/5. Accessed 
February 09, 2017.
Polovich M, White JM, Kelleher LO, eds. Chemotherapy and biotherapy guidelines and 
recommendations for practice. 4th ed. Pittsburgh, PA: Oncology Nursing Society; 2014.
Shah GD, Loizos N, Youssoufian H, Schwartz JD, Rowinsky EK. Rationale for the development 
of IMC-3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the 
platelet-derived growth factor receptor alpha. Cancer. 2010;116(4 Suppl):1018-1026.

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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. Update 
of recommendations for the use of white blood cell growth factors: an evidence-based clinical 
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http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-
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Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias D, Adkins D, Agulnik M, Cooney MM, 
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Worden FP, Taylor JM, Biermann JS, Sondak VK, Leu KM, Chugh R, McGinn CJ, 
Zalupski MM, Baker LH. Randomized phase II evaluation of 6 g/m2 of ifosfamide plus 
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Appendix 1. Abbreviations and Definitions
Term
Definition
ADA
antidrug antibody
AE
adverse event:  any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment.  An adverse event 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 events 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 concentration versus time curve from time zero to time t, where t is the 
last time point with a measurable concentration
AUC[0-∞]
area under the first moment curve from zero to infinity
blinding/masking
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment.  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.  
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
CI
confidence interval
Cmin1
troughserum level at the end of the first cycle of treatment
CNS
central nervous system
collection database
Acomputer database where clinical trial data are entered and validated.
CR
complete response
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician,clinical research scientist
(CRS), global safety physician, or other medical officer.
CT
computed tomography

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DLT
dose-limiting toxicity
ECG
electrocardiogram
ECHO
echocardiogram
eCRF
electronic case report form
effective method of 
contraception
male condom with spermicide, female condom with spermicide, diaphragm with 
spermicide, cervical sponge, or cervical cap with spermicide.
Also see the definition of highly effective method of contraception.
EORTC
European Organisation for Research and Treatment of Cancer
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign 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
highly effective 
method of 
contraception
combined oral contraceptive pill and mini-pill, NuvaRing®, implantable contraceptives, 
injectable contraceptives (such as Depo-Provera®), intrauterine device (such as 
Mirena® and ParaGard®), contraceptive patch for women <90 kg (<198 pounds), total 
abstinence, or vasectomy.
Also see the definition of effective method of contraception.
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical trial data conducted before the final 
reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.

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IRR
infusion-related reaction
IV
intravenous/intravenously
IWRS
interactive web response system
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MUGA
multiple-gated acquisition
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
OS
overall survival
PD
pharmacodynamics(s)
PDGFR
platelet-derived growth factor receptor
PDGFRα
platelet-derived growth factor receptor alpha
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
QTc
corrected QT interval
QTcF
Fridericia’s QT corrected interval
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
To screen a patient who was previously declared a screen failure for the same study.
SAE
serious adverse event
SAP
statistical analysis plan
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 study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
STS
soft tissue sarcoma

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SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event:  an untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
ULN
upper limit of normal
US
United States

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Appendix 2. Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any study procedures and prior to the administration of study treatment

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 trial.
Ethical Review
Documentation of ERB/IRB approval of the protocol and the ICF must be provided to Lilly
before the study may begin at the investigative site(s).  Lilly or its representatives must approve 
the ICF, including any changes made by the ERBs/IRBs, before it is used at the investigative 
site(s).  All ICFs must be compliant with the International Council for Harmonisation (ICH)
guideline on GCP.
The study site’s ERBs/IRBs should be provided with the following:

the current IB and updates during the course of the study

the ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical guidelines

applicable ICH GCP guidelines

applicable laws and regulations.
Some obligations of Lilly may be assigned to a third-party organization.
Investigator Information
Licensed physicians specializing in oncology will participate as investigators in this clinical trial.

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Protocol Signatures
Lilly’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.
Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
The investigator with the most enrolled patients will serve as the clinical study report 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the clinical study report coordinating investigator.
Lilly’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.
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 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.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records and clinical notes.  If requested, the investigator will provide Lilly,
applicable regulatory agencies, and applicable ERBs/IRBs with direct access to original source 
documents.

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Data Capture System
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 Lilly-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data or ECG data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the 
ERB/IRB of the study site judges it necessary for medical, safety, regulatory, or other reasons
consistent with applicable laws, regulations and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations and GCP.

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Appendix 3. Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology - local and central laboratorya
Leukocytes (WBC)
Erythrocytes (RBC)
Neutrophilsb
Hemoglobin (HGB)
Lymphocytes
Hematocrit (HCT)
Monocytes
Mean corpuscular volume (MCV)
Eosinophils
Mean corpuscular hemoglobin concentration (MCHC)
Basophils
Platelets (PLT)
Coagulation - local laboratory
Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT)
International normalized ratio (INR) or prothrombin time (PT) 
Clinical Chemistry - local and central laboratorya
Serum Concentrations of:
Alanine aminotransferase (ALT)
Cholesterol
Albumin
Creatinine
Alkaline phosphatase
Glucose, random
Aspartate aminotransferase (AST)
Magnesium
Bilirubin, direct
Phosphorous
Bilirubin, total
Potassium
Blood urea nitrogen (BUN) or blood urea
Sodium
Calcium
Uric acid
Urinalysis - local laboratory
Blood
Protein
Glucose
Specific gravity
Ketones
Urine leukocyte esterase
pH
Pregnancy Test (for female patients of childbearing potential) - local laboratory
Serum pregnancy test (screening)
Serum or Urine pregnancy test (on study)
Confirmation of Menopause (for female patients of menopausal age) – local laboratory
Follicle-stimulating hormone (FSH)c
Abbreviation:  CRF = case report form. 
a
Treatment decisions will be based on local laboratory results.
b
Neutrophils reported using automated differential hematology instruments include both segmented and band 
forms. When 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
To be performed at screening only when needed to confirm post-menopausal status; applicable for women who
have experienced spontaneous amenorrhea for 6 to 12 months. 

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Appendix 4. Pharmacokinetic, Biomarker, 
Pharmacogenetics and Immunogenicity Sampling 
Schedules
It is essential that the exact infusion start and stop times (actual clock readings) are recorded.  
The exact time of collection of each venous blood sample will be based on the clock used to 
record infusion times.  It is essential that the PK blood samples not be drawn from the same site 
as the drug infusion.

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Pharmacokinetic, Biomarker, Pharmacogenetic and Immunogenicity Sampling Schedule
Cycle
Day
Dosing
Sampling Timea
PK Sampling
Biomarker Sampling
PGx
IGe,f
Olara PKb,f
Dox PKc,l
Ifos 
PKd,l
Plasma
Tumor Tissueg
Baseline
-
X (mandatory)g
1
1
≤60 min pre-olara
Xh
X
Xi
X
Olara (1 hr)
≤5 min post-olara
X
Obs (1 hr)
60±10 min post-olara
X
Dox (<1 hr)j
≤5 min post-dox
Xj
Ifos (3 hr)
≤5 min post-ifos
X
X
2
Dox (<1 hr)
Ifos (3 hr)
≤5 min post-ifos
X
X
3
Dox (<1 hr)j
≤5 min post-dox
Xj
Ifos (3 hr)
≤5 min post-ifos
X
4
Ifos (3 hr)
≤5 min post-ifos
X
X
8
≤60 min pre-olara
Xh
X
X
Olara (1 hr)
≤5 min post-olara
X
Obs (1 hr)
60±10 min post-olara
X
4±0.5 hr post-olara
X
10
48±3 hr post-olara
X 
15
Anytime
X
2
1
≤60 min pre-olara
Xh
X
X
Olara (1 hr)
≤5 min post-olara
X
8
≤60 min pre-olara
Xh
Olara (1 hr)
≤5 min post-olara
X

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3
1
≤60 min pre-olara
Xh
X
X
Olara (1 hr)
≤5 min post-olara
X
Dox (<1 hr)i
≤5 min post-dox
X
Xj
Ifos (3 hr)
≤5 min post-ifos
X
X
2
Dox (<1 hr)
Ifos (3 hr)
≤5 min post-ifos
Xk
X
3
Dox (<1 hr)i
≤5 min post-dox
Xj
Ifos (3 hr)
≤5 min post-ifos
X
4
Ifos (3 hr)
≤5 min post-ifos
Xk
X
8
≤60 min pre-olara
Xh
Olara (1 hr)
≤5 min post-olara
X
60±10 min post-olara
X
4±0.5 hr post-olara
X
10
48±3 hr post-olara
X 
15
Anytime
X
4
1
≤60 min pre-olara
Xh
5 and then 
every 
other 
cycle
1
≤60 min pre-olara
Xh
X
Visit 801
Anytime
X
X
X (optional; for 
patients who 
undergo surgical 
tumor resection 
subsequent to study 
treatment)
X
Abbreviations:  C = cycle; D = day; dox = doxorubicin; hr = hour; ifos = ifosfamide; IG = immunogenicity; min = minute; IRR = infusion-related reaction; obs = 
observation; olara = olaratumab; PGx = pharmacogenetics; PK = pharmacokinetics.
a
Post-infusion is defined as after the completion of the infusion.
b
Samples of approximately 3 mL of whole blood will be drawn without anticoagulant for measurement of olaratumab in serum.

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c
Samples of approximately 2 mL of whole blood will be drawn into plastic tubes with anticoagulant for measurement of ifosfamide in plasma.
d
Samples of approximately 3 mL of whole blood will be drawn into plastic tubes with anticoagulant for measurement of doxorubicin in plasma.
e
For the immunogenicity assay, approximately 5 mL of whole blood will be drawn into a serum separator tube without anticoagulant to generate serum 
samples.
f
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 days (±3 days) after the IRR.
g
Patients must have sufficient available material from an archived formalin-fixed paraffin-embedded tumor tissue. If such tissue is not available, a newly 
obtained core or excisional biopsy of a tumor lesion must be performed. 
h
Pretreatment samples may be collected any time during the day of the clinical visit, prior to the start of the olaratumab infusion and must be taken prior to 
administering any premedication.
i
It is highly recommended to draw the PGx sample prior to the first dose of study drug (C1D1); however, it can be collected at a later time point, if necessary.
j
If doxorubicin is administered as a 24 hour infusion, the doxorubicin PK sample should be collected at the same time as the ifosfamide PK sample (that is, 
approximately 3 to 4 hours after the start of the doxorubicin infusion).
k
For patients who have discontinued doxorubicin/ifosfamide early, these samples may be omitted if there is no other reason for the patient to visit the clinic.
l
Should a patient discontinue doxorubicin or ifosfamide, all subsequent PK samples for the corresponding chemotherapeutic agent can be omitted.

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Appendix 5. 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 CRP.
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 Serologya
Aspartate aminotransferase (AST)
Anti-nuclear antibody
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibody
Creatine phosphokinase (CPK) 
Anti-actin antibody
Abbreviations:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio.
a
Assayed by Lilly-designated laboratory.
b
Neutrophils reported using 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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Appendix 6. 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 =
(mL/min) 
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(mL/min)
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a
Age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault 1976.

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Appendix 7. Fridericia’s QT Correction Formula
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.

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Appendix 8. Protocol Amendment I5B-MC-JGDR(a)
Summary A Phase 1b Study of Olaratumab, 
Doxorubicin and Ifosfamide in the Treatment of 
Patients with Advanced or Metastatic Soft Tissue 
Sarcoma
Overview
Protocol I5B-MC-JGDR, A Phase 1b Study of Olaratumab, Doxorubicin and Ifosfamide in the 
Treatment of Patients with Advanced or Metastatic Soft Tissue Sarcoma has been amended.  The 
new protocol is indicated by Amendment (a) and will be used to conduct the study in place of 
any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The Schedule of Activities was amended to remove visits and/or procedures not 
intended for patients receiving olaratumab monotherapy after completing 6 cycles 
of olaratumab plus doxorubicin and ifosfamide or otherwise having discontinued 
doxorubicin and ifosfamide. Changes are as follows:
On-Study Treatment Schedule of Activities
-
Olaratumab monotherapy section added for Cycle 7 and beyond
-
Footnote was added to schedule to explain olaratumab monotherapy schedule 
for Cycle 7 and beyond
-
Vital sign assessments were reduced to just Day 1
-
Radiologic imaging and measurement of palpable or visible lesions procedure 
note was modified, deleting the 12-week timing for patients receiving 
olaratumab as monotherapy following discontinuation of combination therapy 
-
For ECGs, language was added for timing of ECGs in Cycle 7 and beyond, 
which will be performed Day 1 of Cycle 7 and approximately 6 months and 
12 months after discontinuation of of doxorubicin and ifosfamide treatment.
-
For patients receiving olaratumab as monotherapy following discontinuation 
of combination therapy, echocardiograms will be performed approximately 6 
months (±14 days) and 12 months (±14 days) after discontinuation of 
doxorubicin and ifosfamide treatment
-
For urinalysis, patients will be monitored for evidence of micro- and/or 
macroscopic hematuria and treated according to institutional standards.  For 
patients receiving olaratumab monotherapy Cycle 7 and beyond, urinalysis is 
not performed.
Post-Treatment Follow-Up Schedule of Activities

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-
ECGs were added during short- and long-term follow up.  All patients should 
have a 12-lead ECG performed at short-term follow-up.  Patients should also 
have a 12-lead ECG performed approximately 6 months (±7 days) and 12 
months (±7 days) after the end of treatment with doxorubicin and ifosfamide.  
-
For echo and MUGA, clarifying language was added to make clear the after 
the end of treatment with doxorubicin and ifosfamide, specificially.
Section 6.1 Inclusion Criteria
-
Clarifying language was added to inclusion criterion [7] explicitly stating that 
adjuvant or neo-adjuvant treatment will not be counted as a prior line of 
therapy
-
Inclusion criterion [12] was modified to delete general language and add 
treatment-specific duration requirements related to male contraception
-
Female pregnancy testing and contraception language in [13] was modified, 
increasing the prior-to-treatment pregnancy testing window to 7 days, and 
making the duration of contraception requirements treatment specific - at least 
3 months following the last dose of olaratumab and 6 months following the 
last dose of doxorubicin or ifosfamide.  
Section 6.2 Exclusion Criteria
-
Additional language was added to [23] regarding patients’ history of prior 
malignancies as follows:
o
non-metastatic prostate cancer, or 
o
other primary nonhematologic malignancies treated with curative intent, 
no known active disease, and no treatment administered during the last 3 
years prior to enrollment, that the investigator and Lilly Medical 
representative agree will not affect interpretation of study results or would 
be unsuitable for participation in the study 
-
In Section 7.1, Table JGDR.6, for clarity, footnote “b” was added to the 
ifosfamide rows in the Total Dose column (that is, 10b g/m2 ifosfamide)
-
Clarifying edits related to premedication were added in Section 7.1.1
-
In Section 7.2.1 clarifying language was added for delays for Cycle 2 and 
beyond
-
Clarifying language was added in Section 7.2.2.1 to explain DLTs in relation 
to further enrollment and patients.  A note was added making it clear that IRR 
are not considered DLTs.
-
A footnote was added to Table JGDR.7 to clarify threshholds patients 
experiencing DLTs and further patient enrollment.
-
In Section 7.4, text was added to make clear the section is referring to patients 
being treating with olaratumab plus doxorubicin and ifosfamide.  Additional 
text was inserted to state monitoring for hematuria.

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-
In Section 7.4.1, text was inserted to further detail guidance around dose 
delays.  If Day 8 treatment is delayed >7 days, treatment may be resumed with 
planned Day 1 treatment of the next cycle. Dosing delay beyond 14 days may 
be permissible if AEs are not considered to be primarily related to olaratumab 
and the investigator deems continuation of study treatment to have clinical 
benefit for the patient.  Dose delays do to unforeseen circumstances or 
scheduling issues are also addressed.
-
In Section 7.4.2, clarifying text was added to address discontinuations.
-
Section 7.4.3 was modified related to guidance for dose modification –
referring the reader to specific subsections, and addressing potential for 
variations from guidelines with respect to local standard of care and labels.
-
In Section 7.4.3.1, text related to number of and specifics of olaratumab dose 
modifications.
-
Section 7.4.3.1.1 was edited, indicating that the guidelines for dose 
modifications due to hematologic toxicities are outlined in Table JGDR.8 and 
should be used when olaratumab is given in combination with doxorubicin 
and ifosfamide.
-
Clarifying text was added to Section 7.4.3.2 explaining that doxorubicin dose 
modifications will follow guidelines outlined in the protocol, and that 
adjustments may be made based on local standard of care and label.
-
Section 7.4.3.3 was edited to explain that dose modifications will follow 
guidelines outlined in the protocol, and that adjustments may be made based 
on local standard of care and label.
-
Section 7.8.6 was added to provide detailed guidance regarding other 
concomitant therapies during Study JGDR.
-
Minor clarifying text was added to Section 9.1.1 regarding secondary efficacy 
assessment.
-
Serum pregnancy test was added as an option to urine pregnancy test in 
Appendix 3 for on-study pregnancy testing.
-
Footnotes were added to the the sampling table in Appendix 4.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2. Schedule of Activities

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Table JGDR.2.
On-Study Treatment Schedule of Activities
Day within Cycle
Procedure
Every CycleCycles 1-6 
(olaratumab + doxorubicin 
+ ifosfamide;
(Cycle = 21 days)
Cycles 7-N
Olaratumab 
Monotherapy
a (Cycle = 21 
days)
Instructions
1
2
3
4
8
15
1
8
Physical 
examination
X
X
X

Perform prior to infusion of study drug(s) on Day 1.

Includes weight and BSA.

For patients receiving olaratumab as monotherapy following discontinuation of combination 
therapy, perform on D1 of every cycle.
Vital signs
X
X
X
X
X
X
X
Vital signs include temperature, blood pressure, pulse rate, respiration rate.  
Concomitant 
medication
X
X
Concomitant medications will be recorded continuously throughout the treatment period.
AE collection
X
X
Collect continuously throughout the treatment period; CTCAE Version 4.0.
ECOG performance 
status
X
X
Radiologic imaging 
and measurement of 
palpable or visible 
lesions
X
q 6 weeks
X

Perform according to RECIST 1.1, by the same method used at baseline, q 6 weeks (-7 days) 
from the start of treatment until radiographic disease progression, death, or study completion, 
whichever occurs first.

Perform as scheduled, even if study treatment is delayed or omitted.
For patients receiving olaratumab as monotherapy following discontinuation of combination 
therapy, perform every 12 weeks (-7 days).
ECG
X
C1
-
C6
X

Perform local 12-lead ECG on Day 1 of Cycle 1 through Cycle 6.

Perform local 12-lead ECG on Day 1 of Cycle 7 and approximately 6 months (±14 days) and 
12 months (±14 days) after discontinuation of doxorubicin and ifosfamide treatment
Echocardiogram 
and/or MUGA scan
X
C4 and C6
X

Perform at the end of C4 and C6; perform additional evaluations in the setting of cardiac 
symptoms and/or at the discretion of the investigator.

For patients receiving olaratumab as monotherapy following discontinuation of combination 
therapy, perform approximately 6 months (±14 days) and 12 months (±14 days) after 
discontinuation of doxorubicin and ifosfamide treatment.

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Day within Cycle
Procedure
Every CycleCycles 1-6 
(olaratumab + doxorubicin 
+ ifosfamide;
(Cycle = 21 days)
Cycles 7-N
Olaratumab 
Monotherapy
a (Cycle = 21 
days)
Instructions
1
2
3
4
8
15
1
8
Hematology 
X
X
X
X
X
3 days prior to administration of study treatment on D1 and ≤1 day prior to administration of 
study treatment on D8, unless more frequent assessment is clinically indicated. Day 15 labs may be 
drawn within ±1 day of Day 15.  See Appendix 3.  To be performed locally for patient management 
and centrally for analysis purposes.
Coagulation
X
X
3 days prior to administration of study treatment on D1, unless more frequent assessment is 
clinically indicated.  For patients receiving olaratumab as monotherapy following combination 
therapy discontinuation, perform on D1 of every other cycle.  See Appendix 3.  To be performed 
locally.
Clinical chemistry
X
X
X
X
3 days prior to administration of study treatment on D1 and ≤1 day prior to administration of 
study treatment on D8, unless more frequent assessment is clinically indicated. Day 15 labs may be 
drawn within ±1 day of Day 15.  See Appendix 3.  To be performed locally for patient management 
and centrally for analysis purposes.
Urinalysis 
X
X
X
X
Monitor patients for evidence of micro- and/or macroscopic hematuria and treat according to 
institutional standards.  Prior to administration of study treatment on each treatment day. 
Patients must have ≤10 RBCs per high-power field present in urinalysis in order to proceed with 
ifosfamide dosing.  For patients receiving olaratumab as monotherapy following discontinuation of 
combination therapy, perform on D1 of every other cycle.  See Appendix 3.  To be performed 
locally.
Urine pregnancy 
Pregnancy test
X
X

Applies only to women of childbearing potential

Where required by local law or regulation, perform once every 21 days (-7 days) prior to 
administration of study treatment. 

To be performed locally

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Day within Cycle
Procedure
Every CycleCycles 1-6 
(olaratumab + doxorubicin 
+ ifosfamide;
(Cycle = 21 days)
Cycles 7-N
Olaratumab 
Monotherapy
a (Cycle = 21 
days)
Instructions
1
2
3
4
8
15
1
8
Administer 
olaratumab
X
X
X
X
Administer IV over 60 (±5) min.  Administer until a maximum of 6 cycles is complete, or until PD, 
unacceptable toxicity, death, or other withdrawal criteria are met.  Patients who discontinue 
doxorubicin, ifosfamide and mesna treatment without evidence of disease progression will receive 
olaratumab as monotherapy until there is evidence of disease progression, death, intolerable 
toxicity, or other withdrawal criteria are met.  Patients who undergo surgical tumor resection 
following study treatment are not eligible to receive olaratumab as monotherapy.  See section 7.1.1
for olaratumab premedication requirements.  See section 7.8.1 for olaratumab IRR monitoring 
period requirements.
Administer 
doxorubicin 
X
X
X
Administer IV over less than 60 (±5) min or as a continuous IV infusion (according to institutional 
guidelines) after completion of olaratumab infusion and any required observation period.  
Administer until a maximum of 6 cycles is complete, or until PD, unacceptable toxicity, death, or 
other withdrawal criteria are met. See Section 7.1.2 for details of dexrazoxane administration.
Administer 
ifosfamide
X
X
X
X
*
Administer IV over 3 hours (±15 min) after completion of doxorubicin administration.  Administer 
until a maximum of 6 cycles is complete, or until PD, unacceptable toxicity, death, or other 
withdrawal criteria are met. 
*Patients treated in cohorts with ifosfamide dose reduction will have the Day 4 dose omitted (that 
is, ifosfamide will be administered at a dose of 2.5 g/m2 on D1, D2 and D3).
Administer mesna
X
X
X
X
See Section 7.1.3 for details of mesna administration.
G-CSF
X
The use of G-CSFs is required.  Administer according to ASCO and NCCN guidelines.  In general, 
G-CSF products like filgrastim or pegfilgrastim should be administered approximately 24 hours 
after the completion of cytotoxic chemotherapy (for example, on Day 5 for patients in full-dose 
ifosfamide cohorts or Day 4 for patients in reduced-dose ifosfamide cohorts).
Sample collection
For all sample collection, see Appendix 4.
Pharmacodynamics 
Pharmacokinetics
Immunogenicity
Pharmacogenetics
Other biomarkers

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Abbreviations:  AE = adverse event; ASCO = American Society of Clinical Oncology; BSA = body surface area; C = cycle; CTCAE = Common Terminology 
Criteria for Adverse Events (NCI 2009); D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); G-CSF = 
granulocyte-colony stimulating factor; IRR = infusion-related reaction; IV = intravenously; LVEF = left ventricular ejection fraction; min = minutes; MUGA 
= multiple-gated acquisition; NCCN = National Comprehensive Cancer Network; PD = progressive disease; q = every; RBC = red blood cell; RECIST 
1.1 = Response Criteria in Solid Tumors Version 1.1 (Eisenhauer et al. 2009).
a
Olaratumab monotherapy schedule applies to patients who have completed 6 cycles of olaratumab plus doxorubicin and ifosfamide and are continuing 
treatment with olaratumab monotherapy or have discontinued doxorubicin plus ifosfamide and are continuing with olaratumab monotherapy.  Note: if a 
patient discontinues doxorubicin plus ifosfamide treatment prior to completing 6 cycles and is continuing treatment with olaratumab monotherapy, perform 
procedures according to the olaratumab monotherapy schedule beginning the next cycle after the patient discontinues doxorubicin/ifosfamide.

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Table JGDR.3.
Post-Treatment Follow-Up Schedule of Activities
Procedure
Short-Term 
Follow-Upa
Long-Term 
Follow-Up
Instructions
Visit
801
802–8XX
Physical examination
X
Including weight and vital signs (temperature, blood pressure, pulse rate, 
respiration rate)
Concomitant medication
X
AE collection
X
CTCAE Version 4.0. 
ECOG performance status
X
Radiologic imaging and measurement of 
palpable or visible lesions
X
X*
*For patients whose disease has not progressed:
Perform q 6 weeks × 2, then q 3 mo until:

the patient has objective disease progression according to 
RECIST 1.1 or

the study’s primary/final analysis
Perform using the same method used at baseline and throughout the study.
For patients who have had objective disease progression:
Radiologic tests and measurement of palpable or visible lesions are no 
longer required;  these patients should be followed up for OS and 
collection of post-study treatment anticancer therapy information 
collection approximately every 90 days (14 days) until death or study 
completion as indicated below.
Collection of survival information
X
Perform q 2 mo (±7 days) for the first 2 years after discontinuation from 
study treatment and q 6 mo (±14 days) thereafter until death or study 
completion.  If an in-person visit is not possible, confirm survival by 
contacting the patient directly via phone.
Collection of post-study treatment anticancer 
therapy information
X
X
Perform q 2 mo (±7 days) for the first 2 years after discontinuation from 
study treatment and q 6 mo (±14 days) thereafter until death or study 
completion.
ECG
X
X

All patients should have a 12-lead ECG performed at short-term 
follow-up.

Patients should also have a 12-lead ECG performed approximately 6 
months (±7 days) and 12 months (±7 days) after the end of treatment 
with doxorubicin and ifosfamide.

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Procedure
Short-Term 
Follow-Upa
Long-Term 
Follow-Up
Instructions
Visit
801
802–8XX
Echocardiogram and/or MUGA scan
X
Perform at 6 months (±7 days) and 12 months (±7 days) after the end of 
study treatment with doxorubicin and ifosfamide.  
Echocardiograms/MUGA scans may be discontinued if the patient begins 
another anticancer therapy.  Perform additional evaluations in the setting 
of cardiac symptoms and/or at the discretion of the investigator.
Hematology 
X
See Appendix 3.  To be performed locally for patient management and 
centrally for analysis purposes.
Coagulation
X
See Appendix 3.  To be performed locally.
Clinical chemistry
X
See Appendix 3.  To be performed locally for patient management and 
centrally for analysis purposes.
Urinalysis 
X
See Appendix 3.  To be performed locally.
Sample collection
For all sample collection, see Appendix 4.
Pharmacodynamics
Pharmacokinetics
Immunogenicity
Pharmacogenetics
Other biomarkers
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); ECOG = Eastern Cooperative Oncology Group 
(Oken et al. 1982); mo = month; MUGA = multiple-gated acquisition; OS = overall survival; q = every; RECIST 1.1 = Response Criteria in Solid Tumors 
Version 1.1 (Eisenhauer et al. 2009).
a
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).  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly 
provided permission and consent.

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3.2.1 Rationale for Amendment (a)
The original Study JGDR protocol, version dated 14 March 2017, was amended to remove visits 
and/or procedures not intended for patients receiving olaratumab monotherapy only after 
completing 6 cycles of olaratumab plus doxorubicin and ifosfamide (or discontinued doxorubicin 
and ifosfamide before).  In particular, visits and procedures specifically used to administer and 
monitor for toxicity from the doxorubicin and ifosfamide combination have been removed for 
patients receiving olaratumab monotherapy.
The timing of ECHO/MUGA scans after discontinuation of doxorubicin plus ifosfamide 
treatment was clarified and ECG evaluations were added at the same frequency to ensure 
complete evaluation of any potential cardiotoxic effects following treatment with doxorubicin 
plus ifosfamide.  
The wording pertaining to required contraceptive use following study treatment has been 
clarified to align with label requirement for doxorubicin.
In addition, some minor editorial changes have been made throughout the protocol to improve 
clarity and practicality of the protocol and secure alignment with the intended study design.

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5. Study Design
5.1 Overall Design
Study JGDR is a multicenter, nonrandomized, open-label, ….
Olaratumab 15-mg/kg Dose Level:  The first phase of the study (Dose-Finding Phase) will 
evaluate the safety and tolerability of adding olaratumab to the regimen of doxorubicin 
(75 mg/m2 plus given as IV infusions of 25 mg/m2 on Days 1 to 3), ifosfamide (10 g/m2 given as 
IV infusions of 2.5 g/m2 on Days 1 to 4) and mesna according to a 21-day cycle.  Fifteen patients 
will be initially enrolled and treated with a 15-mg/kg dose of olaratumab (on Days 1 and 8 of a 
21-day cycle) in combination with doxorubicin, ifosfamide and mesna and assessed for safety 
after 1 cycle of therapy.  The full cohort of 15 patients will be enrolled if 5 or fewer patients with
DLTs are observed in the first 6 and 9 patients, respectively.  
Olaratumab 20-mg/kg Loading Dose Cycle Dose Level:  Following an evaluation of safety in 
the full cohort of 15 patients (and provided 8 or fewer of these patients have experienced DLTs), 
the study will progress to evaluate a loading dose cycle of olaratumab (20 mg/kg IV on Days 1 
and 8 of Cycle 1 only, then 15 mg/kg on Days 1 and 8 of subsequent cycles) in combination with 
doxorubicin, ifosfamide and mesna in a new cohort of 15 patients.  Section 5.5.1 details the 
rationale for the loading dose.  The full cohort of 15 patients will be enrolled if 5 or fewer 
patients with DLTs are observed in the first 6 and 9 patients, respectively.  
Olaratumab 15-mg/kg Dose Level:  Ifosfamide Dose Reduction Option
If during enrollment into the olaratumab 15-mg/kg dose level, DLTs are observed in 6 of the first 
6 patients, in ≥6 of the first 9 patients, or in ≥9 of the full cohort of 15 patients, the study will 
proceed to explore a reduced ifosfamide dose (7.5 g/m2 total dose) in combination with 
olaratumab 15 mg/kg and the same doxorubicin dose in a new cohort of 15 patients.  If DLTs are 
observed in 6 of the first 6 patients, in ≥6 of the first 9 patients, or in ≥9 of the full cohort of 15 
patients at this reduced ifosfamide dose, the study will halt and no further patients will be 
enrolled.  If 8 or fewer patients with DLTs are observed in this full cohort of 15 patients, the 
study will progress to explore the olaratumab Loading Dose Cycle as previously described in 
combination with the reduced ifosfamide dose (and same doxorubicin dose) as previously 
described.
Olaratumab 20-mg/kg Loading Dose Cycle Dose Level:  Ifosfamide Dose Reduction Option
If during enrollment into the olaratumab 20-mg/kg Loading Dose Cycle dose level, DLTs are 
observed in 6 of the first 6 patients, in ≥6 of the first 9 patients, or in ≥9 of the full cohort of 
15 patients, no further patients will be enrolled at this dose level and olaratumab 15 mg/kg will 
be declared the recommended dose for combination with reduced-dose ifosfamide/mesna and 
doxorubicin.  If 8 or fewer patients with DLTs are observed in this full cohort, the olaratumab 
20-mg/kg loading dose cycle together with a reduced ifosfamide/mesna dose will be declared the 
recommended doses for combination with doxorubicin.
.

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Abbreviations:  D = day; DLT = patients experiencing a dose-limiting toxicity; Dox = doxorubicin; g = grams; Ifos = ifosfamide; kg 
= kilogram; m2 = square meters; mg = milligrams; Olara = olaratumab; N = number; TBD = to be determined.
a
Patients who discontinue combination study therapy without evidence of disease progression will receive olaratumab as 
monotherapy until there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.
Figure JGDR.1.
Illustration of study design.

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6. Study Population
All patients meeting the eligibility requirements will be considered for enrollment regardless of 
race, religion, or gender.  The investigator or the sponsor will not grant exceptions to eligibility 
criteria.  Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1. Inclusion Criteria
[7]
Have received no prior lines of systemic therapy (adjuvant or neo-adjuvant 
treatment will not be counted as a prior line) and are suitable to receive 
doxorubicin, ifosfamide and mesna.  All previous anticancer treatments must 
have completed ≥3 weeks (21 days) prior to the first dose of study treatment.
[12] If male, must be sterile or agree to use an effective method of contraception or 
a highly effective method of contraception during the study and for at least:
12 weeks following the last dose of study treatment.

3 months following the last dose of olaratumab

6 months following the last dose of doxorubicin or ifosfamide
Refer to Appendix 1 for definitions of effective method of contraception and 
highly effective method of contraception. 
[13] If female and of child-bearing potential, must:
a.  have a negative serum pregnancy test at the time of enrollment,
a.
have a negative urineserum pregnancy test within 24 hours7 days prior 
to the first dose of study treatment, and
b. agree to use a highly effective method of contraception during the 
study and for 3 months following the last dose of study treatment at 
least 3 months following the last dose of olaratumab and 6 months 
following the last dose of doxorubicin or ifosfamide.
Refer to Appendix 1 for the definitions of highly effective method of 
contraception and effective method of contraception.
6.2. Exclusion Criteria
[23] Have a history of another primary malignancy, with the exception of:
a.
curatively treated non-melanomatous skin cancer
b. curatively treated cervical carcinoma in situ
c.
non-metastatic prostate cancer, or 

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d. other primary nonhematologic malignancies treated with curative 
intent, no known active disease, and no treatment administered 
during the last 3 years prior to enrollment, that the investigator 
and Lilly Medical representative agree will not affect 
interpretation of study results or would be unsuitable for 
participation in the study.
7.1. Treatment Administered (Dosing Schedule)
Table JGDR.6 shows the treatment regimens.  On days where multiple study drugs are to be 
administered, the drugs should be administered in the order shown in Table JGDR.6.

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Table JGDR.6.
Treatments Administered (Dosing Schedule)
Phase and 
Dose Cohort
Drug Name and Dose
Day of 21-day 
(±3 days) cycle
Total 
dose 
Route and duration of 
administration
Notes
Dose-Finding Phase
Olara 15 mg/kg
Olaratumab 15 mg/kga
D1 and D8
IV over 60 (±5) min
Infusion rate should not exceed 25 
mg/min
See Section 7.1.1 for premedication 
requirements and Section 7.8.1 for 
IRR monitoring period requirements
Doxorubicin 25 mg/m2 per daya
D1, D2, D3 
75 mg/m2
IV over less than 60 min 
or 
continuous IV infusion (according to 
institutional practice)
Administer after olara on D1 and 
after any required observation period
Ifosfamide 2.5 g/m2 per daya
D1, D2, D3, D4b
10b g/m2
IV over 3 hours (±15 min) 
Administer after dox on D1, D2, D3
Mesna dose ≥60% of ifos dosea
D1, D2, D3, D4b
According to institutional practice
Olara Loading Dose Cycle
Olaratumab 20 mg/kg Cycle 1
Olaratumab 15 mg/kg Cycles 2 to 6a
D1 and D8
D1 and D8
IV over 60 (±5) min
Infusion rate should not exceed 25 
mg/min
See Section 7.1.1 for premedication 
requirements and Section 7.8.1 for 
IRR monitoring period requirements
Doxorubicin 25 mg/m2 per daya
D1, D2, D3 
75 mg/m2
IV over less than 60 min
or 
continuous IV infusion (according to 
institutional practice)
Administer after olara on D1 and 
after any required observation period
Ifosfamide 2.5 g/m2 per daya
D1, D2, D3, D4b
10b g/m2
IV over 3 hours (±15 min)
Administer after dox on D1, D2, D3
Mesna dose ≥60% of ifos dosea
D1, D2, D3, D4b
According to institutional practice
Dose Confirmation Phase
Recommended Olara Dose
Olaratumab dose determined from 
Dose-Finding Phasea
D1 and D8
IV over 60 (±5) min
Infusion rate should not exceed 25 
mg/min
See Section 7.1.1 for premedication 
requirements and Section 7.8.1 for 
IRR monitoring period requirements
Doxorubicin 25 mg/m2 per daya
D1, D2, D3 
75 mg/m2
IV over less than 60 min
or 
continuous IV infusion (according to 
institutional practice)
Administer after olara on D1 and 
after any required observation period
Ifosfamide 2.5 g/m2 per daya
D1, D2, D3, D4b
10b g/m2
IV over 3 hours (±15 min)
Administer after dox on D1, D2, D3
Mesna dose ≥60% of ifos dosea
D1, D2, D3, D4b
According to institutional practice

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Abbreviations:  C = cycle; CRP = clinical research physician; D = day; DLT = dose-limiting toxicity; dox = doxorubicin; g = grams; ifos = ifosfamide; IRR= 
infusion-related reaction; IV = intravenous; kg = kilogram; m2 = square meters; mg = milligrams; min = minutes; olara = olaratumab.
a
All patients will receive study therapy (olaratumab + doxorubicin/ifosfamide/mesna) for a maximum of 6 cycles, or until a discontinuation criterion is met.  
Patients who discontinue doxorubicin, ifosfamide and mesna treatment without evidence of disease progression will receive olaratumab as monotherapy until 
there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.
b
If DLT rules (see Section 7.2.2.1) are exceeded in the olaratumab 15-mg/kg cohort, a reduced dose of ifosfamide (7.5 g/m2 total dose) will be explored.  This 
reduced dose will be communicated by the Lilly CRP and will be accomplished by omitting the Day 4 dose (that is, ifosfamide will be administered at a dose 
of 2.5 g/m2 on D1, D2 and D3).  The Day 4 dose of mesna will be correspondingly omitted.  A Loading Dose Cycle of olaratumab (20 mg/kg on Days 1 and 8 
of C1, then 15 mg/kg on Days 1 and 8 of subsequent cycles) may also be explored in combination with the reduced dose of ifosfamide.

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7.1.1. Olaratumab Premedications and Required Monitoring
The infusion rate of olaratumab should not exceed 25 mg/min.  Infusion durations longer than 
60 min 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 or 2 
infusion-related reaction [IRR]); the infusion duration must always be accurately recorded.
All patients will receive the following (or equivalent) premedicationsPremedicate patients prior 
to administration of olaratumab as below:  

on On Days 1 and 8 of Cycle 1:  Mandatory administration of a histamine H1 
antagonist (for example, diphenhydramine) and dexamethasone IV 30 to 60 min prior to 
the start of the olaratumab infusion.

For subsequent cycles, premedication all patients will be premedicatedwith a histamine 
H1 antagonist (for example, diphenhydramine) IV 30 to 60 min is recommended prior to 
each dose of olaratumab.
Additional premedication(s) may be provided at the investigator’s discretion.  Premedication 
must be provided in the setting of a prior Grade 1 or 2 olaratumab IRR, as detailed in 
Section 7.8.1.  All premedications administered must be adequately documented in the electronic 
case report form (eCRF).
Patients are required to be monitored for 1 hour after the olaratumab infusion in Cycles 1 and 2 
for signs or symptoms of IRRs; see Section 7.8.1 for full description of required olaratumab 
monitoring period in Cycles 1 and 2.  Patients should complete the required monitoring period 
prior to the start of the doxorubicin administration.
7.2.1. Selection and Timing of Doses
A cycle is defined as an interval of 21 days.  In Cycle 2 and beyond, (up to 3 days’ delay of a 
cycle (that is, Day 1) or Day 8 will be permitted due to holidays, weekends, bad weather, or other 
unforeseen circumstances and will not count as a protocol deviation). In exceptional cases, 
longer delays may be allowed in later cycles following consultation with Lilly medical 
representative.
7.2.2. Dose-Finding Phase
7.2.2.1. Dose-Limiting Toxicity Determination
Because of the relatively high rate of  DLT-level toxicity with the backbone doxorubicin, 
ifosfamide and mesna regimen (Judson et al. 2014) and the generally acceptable toxicity profile 
of the 15-mg/kg dose of olaratumab (Days 1 and 8 every 21 days) in combination with other 
chemotherapeutic agents including doxorubicin, approximately 15 patients will be enrolled at the 
first dose level of olaratumab (provided safety data confirms the required number of patients 
without DLTs have been met for each DLT threshold as described in Table JGDR.7 and
evaluated after 6, 9 and 15 patients have received 1 cycle of therapy) to allow sufficient patient 

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numbers to judge initial tolerability of olaratumab in combination with doxorubicin, ifosfamide 
and mesna.
In the Dose-Finding Phase, DLT assessment will be performed.  A DLT is defined as events such 
as the following, graded according to the NCI-CTCAE Version 4.0, when it occurs within 
Cycle 1 and is considered to be related to study treatment by the investigator in conjunction with 
the sponsor:
1. Grade 3 or 4 febrile neutropenia, or sepsis., or
2. Grade 4 neutropenia lasting 7 days or longer.
3. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage.
4. Nonhematologic Grade ≥3 toxicity, except for toxicities (such as nausea, vomiting, 
transient electrolyte abnormalities, or diarrhea) that can be controlled with optimal 
medical management within 48 hours or clinically non-significant laboratory 
abnormalities.
A dose-limiting equivalent toxicity is an AE that meets the DLT criteria as defined above and 
occurs in any cycle other than Cycle 1.  In addition to the DLT assessment period in Cycle 1, 
available safety data beyond Cycle 1 may also be taken into consideration prior to a decision to 
advance to the next dose level or the determination of the Confirmation Phase dose.
Note: Infusion-related reactions will not be considered as DLTs, as they occur independent of 
dose level.
Table JGDR.7 shows the DLT thresholds that will be used to determine study progression.  

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Table JGDR.7.
Dose-Limiting Toxicity Thresholds for Study JGDR
Dose Level
Regimen
If…
Thenb…
Olara 15 mg/kg
(Starting Dose 
Level)
Olara 15 mg/kg D1, D8
Ifos 10 g/m2 D1 to D4a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Proceed to Olara 15 mg/kg with Ifos Reduction Dose Level (new cohort of 
approximately 15 patients).
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Proceed to Olara 15 mg/kg with Ifos Reduction Dose Level (new cohort of 
approximately 15 patients).
≥9 DLTs in full 15 patients
Proceed to Olara 15 mg/kg with Ifos Reduction Dose Level (new cohort of 
approximately 15 patients).
≤8 DLTs in full 15 patients
Proceed to Olara 20-mg/kg Loading Dose Cycle Dose Level.
Olara 15 mg/kg 
with Ifos 
Reduction
Olara 15 mg/kg D1, D8
Ifos 7.5 g/m2 D1 to D3a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Halt study.  No further patients enrolled.
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Halt study.  No further patients enrolled.
≥9 DLTs in full 15 patients
Halt study.  No further patients enrolled.
≤8 DLTs in full 15 patients
Proceed to Olara 20-mg/kg Loading Dose Cycle Dose Level with Ifos 
Reduction.
Olara 20-mg/kg 
Loading Dose 
Cycle
Olara 20 mg/kg D1, D8 
of C1; then 15 mg/kg D1, 
D8 of C2 to C6 
Ifos 10 g/m2 D1 to D4a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg as recommended dose.
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg as recommended dose.
≥9 DLTs in full 15 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg as recommended dose.
≤8 DLTs in full 15 patients
Proceed to Recommended Dosing Regimen cohort with Olara 20-mg/kg 
Loading Dose Cycle as recommended dose.

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Dose Level
Regimen
If…
Thenb … 
Olara 20-mg/kg 
Loading Dose 
Cycle with Ifos 
Reduction
Olara 20 mg/kg D1, D8 
of C1; then 15 mg/kg D1, 
D8 of C2 to C6 
Ifos 7.5 g/m2 D1 to D3a
Dox 75 mg/m2 D1 to D3
6 DLTs in first 6 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg with Ifos reduction as recommended 
dose.
≤5 DLTs in first 6 patients
Enroll 3 additional patients and evaluate DLTs in this group of first 9 
patients.
≤5 DLTs in first 9 patients
Enroll full cohort of 15 patients.
≥6 DLTs in first 9 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg and Ifos 7.5 g/m2 as recommended 
doses.
≥9 DLTs in full 15 patients
Discontinue enrollment into cohort.  Proceed to Recommended Dosing 
Regimen cohort with Olara 15 mg/kg and Ifos 7.5 g/m2 as recommended 
doses.
≤8 DLTs in full 15 patients
Proceed to Recommended Dosing Regimen cohort with Olara 20 mg/kg 
Loading Dose Cycle and Ifos 7.5 g/m2 as recommended doses.
Recommended 
Dosing Regimen
Olara dose TBD
Ifos dose TBD
Dox 75 mg/m2 D1 to D3
Enroll 15 patients and treat with Recommended Dosing Regimen.
Abbreviations:  D = day; DLT = patients experiencing a dose-limiting toxicity; dox = doxorubicin; g = grams; Ifos = ifosfamide; kg = kilogram; m2 = square 
meters; mg = milligrams; Olara = olaratumab; TBD = to be determined.
a
With concomitant mesna administration.
b
If a sufficient number of patients successfully complete the DLT period at a given dose level (ensuring the DLT threshold will not be exceeded), further 
enrollment may proceed as described in Table JGDR.7, upon agreement of the Sponsor and Investigators.

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7.4. Dosage Delays, Discontinuations and Modifications
To begin dosing at Cycle 2 and each cycle(Day 1) thereafter (for cycles in which olaratumab is 
administered with doxorubicin and ifosfamide), the following criteria must be fulfilled (see 
Table JGDR.9 for hematological parameters for dosing olaratumab on Day 8):

ANC ≥1.5 × 103 cells/µL (≥1500 cells/µL; ≥1.5 × 109/L)

Platelets ≥100 × 103 cells/µL (≥100,000 cells/µL; ≥100 × 109 cells/L)

Hemoglobin ≥8.0 g/dL.  Note:  For study inclusion, hemoglobin ≥9.0 g/dL

Total bilirubin below ULN.  In patients with Gilbert’s syndrome, total bilirubin should be 
3 mg/dL

Serum creatinine ≤1.5 times ULN.  If creatinine is above ULN, the patient’s creatinine 
clearance is ≥60 mL/min (refer to Appendix 6 for the Cockcroft-Gault formula for 
creatinine clearance)

AST and ALT ≤3 × ULN, or ≤5 × ULN if the transaminase elevation is due to liver 
metastases

Nonhematologic toxicity must be less thanGrade ≤2 or must have returned to baseline, 
unless the toxicity is deemed not clinically significant by the investigator or is a 
laboratory abnormality that is manageable by institutional standards (for example, low 
serum potassium, magnesium, or phosphate).
In addition, patients should be monitored for evidence of micro- and/or macroscopic hematuria 
and treated according to institutional standards.the following criteria must be fulfilled on each 
day of ifosfamide dosing (D1, D2, D3 and D4 of each cycle):
≤10 red blood cells per high-power field present in urinalysis.
7.4.1. Delays
In general, dose delays of 1 study drug (olaratumab, doxorubicin, or ifosfamide/mesna) due to 
toxicities outlined in Section 7.4.3 will not necessitate delays of the other study drugs.  However, 
close consideration must be made by the investigator to administer all study treatments per the 
schedule outlined in Section 7.1.
Treatment may be delayed for up to 14 days to allow a patient sufficient time for recovery from 
study drug-related toxicity.  If Day 8 treatment is delayed >7 days, treatment may be resumed 
with planned Day 1 treatment of the next cycle.
Dosing delay beyond 14 days may be permissible if AEs are not considered to be primarily 
related to olaratumab and the investigator deems continuation of study treatment to have clinical 
benefit for the patient. This decision has to be documented and be jointly made by the 
investigator and the Lilly team. 
In the event of unforeseen circumstances or scheduling issues that require adjustments to the 
schedule, appropriate adjustments or delays to the schedule may be made following discussion 
between the investigator and the sponsor and written approval by the Lilly medical 
representative.

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7.4.2. Discontinuations
The need to permanently discontinue doxorubicin and/or ifosfamide due to drug-related toxicity 
should be done according to local standard of care and labels.  Criteria for olaratumab 
discontinuation are discussed in the olaratumab dose modification section (7.4.3.1) and in the 
olaratumab infusion-related reaction section (7.8.1) The need to permanently discontinue 
doxorubicin, ifosfamide and mesna due to drug-related toxicity will result in the permanent 
discontinuation of all study drugs in the doxorubicin, ifosfamide and mesna regimen.
Patients whose disease has not progressed at the time of doxorubicin, ifosfamide and mesna 
discontinuation will receive olaratumab as monotherapy until there is evidence of disease 
progression, death, intolerable toxicity, or other withdrawal criteria are met (Section 8).  These 
patients will continue study assessments as outlined in Table JGDR.2.  Patients who undergo 
surgical tumor resection following study treatment are not eligible to receive olaratumab as 
monotherapy.
Patients who exhibit disease progression at the time of doxorubicin, ifosfamide and mesna 
discontinuation will receive post-treatment follow-up assessments as outlined in Table JGDR.3.
7.4.3. Dose Modifications
Any patient who requires a dose reduction for drug-related toxicity will continue to receive the 
reduced dose for the remainder of the study.
General guidelines for dose modifications are provided below.  Sections 7.4.3.2 and 7.4.3.3 
outline guidelines for dose modifications of doxorubicin and ifosfamide, respectively; variations 
from these guidelines may be allowed according to local standard of care and labels.  
7.4.3.1. Olaratumab Dose Modifications
A one-time reduction in the dose of olaratumab will be permitted if the doses of doxorubicin and 
ifosfamide have been previously reduced once for toxicity, and the same or similar toxicity has 
recurred despite reduction of doxorubicin, ifosfamide and mesna, and the toxicity is deemed 
potentially related to the addition of olaratumab in combination with doxorubicin, ifosfamide and 
mesna.  In this scenario, an olaratumab dose reduction should occur in conjunction with a 
secondreduction in the doxorubicin and ifosfamide doses according to the guidance outlined in 
Sections 7.4.3.2 and 7.4.3.3.
A second reduction in the olaratumab dose will not be permitted during treatment with 
combination therapy of olaratumab plus doxorubicin and ifosfamide.
Patients who have not progressed on study will receive olaratumab as monotherapy following 
discontinuation of the combination therapy until there is evidence of disease progression, death, 
intolerable toxicity, or other withdrawal criteria are met.  Patients receiving olaratumab as 
monotherapy will have assessments performed as per Table JGDR.2.
Patients who have a dose reduction of olaratumab during the combination therapy portion and 
then proceeding to receive olaratumab monotherapy after discontinuation of doxorubicin and 

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ifosfamide combination may have their dose of olaratumab re-escalated to the original dose level 
at the investigator’s discretion.
7.4.3.1.1. Hematologic Toxicity
Table JGDR.8 shows olaratumab dose modifications that should be made for hematologic 
toxicities judged as potentially related to olaratumab in combination with doxorubicin, 
ifosfamide and mesna, and that have recurred or failed to improve/resolve despite 1 reduction in 
doxorubicin and ifosfamide doses.  These guidelines should be used for olaratumab dosing, when 
given in combination with doxorubicin and ifosfamide.
Table JGDR.8.
General Guidelines for Olaratumab Dose Modification due to 
Hematologic Toxicities
Toxicity
Required Dose Modification
Neutropenia
  ANC Grades 1-3
No dose modification required
  ANC <500 cells/µL (Grade ≥4)
No treatment administered; treatment cycle delayed
  At re-treatment:
  If ≥Grade 3 neutropenic fever/infection 
has occurred and 1 reduction in 
doxorubicin, ifosfamide and mesna doses 
has already occurred
Withhold dose until ANC is ≥1500 cells/µL; 

15-mg/kg Dose Level:  Reduce dose to 12 mg/kg

20-mg/kg Loading Dose Cycle Level:  Reduce dose to 
15 mg/kg
  If Grade 4 neutropenia lasting ≥1 week 
has occurred and 1 reduction in 
doxorubicin, ifosfamide and mesna doses 
has already occurred
Withhold dose until ANC is ≥1500 cells/µL; 

15-mg/kg Dose Level:  Reduce dose to 12 mg/kg

20-mg/kg Loading Dose Cycle Level:  Reduce dose to 
15 mg/kg
  Grade 4 ANC without fever/infection 
lasting ≤1 week
Administer next olaratumab at full dose, at investigator’s discretion
After 1 reduction of olaratumab and 2 
reductions of doxorubicin, ifosfamide 
and mesna, recurrence of either:
  1) ≥Grade 3 neutropenic fever/infection
  2) Grade 4 neutropenia lasting ≥1 week
Discontinue combination therapy (olaratumab + 
doxorubicin/ifosfamide/mesna).  Patients who have not progressed 
will receive olaratumab as monotherapy until there is evidence of 
disease progression, death, intolerable toxicity, or other withdrawal 
criteria are met.
Abbreviation:  ANC = absolute neutrophil count.
Omitting the Day 8 dose of olaratumab based on ANC and platelet counts judged as potentially 
related to olaratumab in combination with doxorubicin, ifosfamide, and mesna is permissible as 
shown in Table JGDR.9.
7.4.3.2. Doxorubicin Dose Modifications
Dose modifications of doxorubicin will follow the guidelines outlined below and may be 
adjusted according to local standard of care and label.Two reductions in doxorubicin dose will be 
permitted during the study according to the guidance outlined in Sections 7.4.3.5 and 7.4.3.6.  If 

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a third dose reduction is necessary, the patient will be discontinued from the combination therapy 
(olaratumab + doxorubicin/ifosfamide/mesna) and will be followed as outlined in Section 7.4.2.
7.4.3.2.1. Hematologic Toxicity
Doxorubicin will not be administered after the initial dose if the patient’s ANC is <1500 cells/µL 
or if the platelet count is <100,000 cells/µL.  When necessary, the next treatment cycle should be 
delayed until the ANC is ≥1500 cells/µL and the platelet count is ≥100,000 cells/µL and any 
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 should occurwill be 
necessary.
7.4.3.3. Ifosfamide Toxicities and Dose Modifications
Dose modifications of ifosfamide will follow the guidelines outlined below and may be adjusted 
according to local standard of care and label. Two reductions in ifosfamide dose for toxicity will 
be permitted during the study.  If a third dose reduction is necessary, the patient will be 
discontinued from the combination therapy (olaratumab + doxorubicin/ifosfamide/mesna) and 
followed as outlined in Section 7.4.2.
General guidelines for ifosfamide dose modification are shown in Table JGDR.12.  Dose 
modifications of ifosfamide due to hepatic impairment are shown in Table JGDR.13.
7.4.3.3.2. Ifosfamide-Associated Urotoxic Effects
The incidence of urotoxic effects without an uroprotector can be up to 40% and is dose 
dependent; coadministration of mesna and adequate hydration are mandatory in this study.  
Patients may present with hematuria, symptomatic cystitis, or bladder fibrosis.  Past or 
concomitant radiation of the bladder or busulfan treatment may increase the risk of hemorrhagic 
cystitis.  Several methods of treatment for established hematuria have been described:  bladder 
irrigation with water or normal saline, intravesical instillation of astringents (alum, silver nitrate), 
systemic administration of antifibrinolytics (aminocaproic acid, tranexamic acid), cystoscopy to 
evacuate the bladder of clots, continuous bladder irrigation and intravesical prostaglandins.  For 
severe or refractory hematuria, intravesical formalin, phenol, or prostaglandin has been used with 
or without surgical intervention (electrocautery, cryosurgery, diversion of urine flow, 
hypogastric artery ligation, or cystectomy).  Ifosfamide should be discontinued or dose 
reducedDiscontinuation or dose reduction of ifosfamide should follow local standard of care and 
label for patients with macroscopic hematuria.

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7.4.3.3.3. Ifosfamide-Associated Proximal Tubular Damage
Glomerular, proximal, or distal tubular impairment may all occur, often in combination and may 
progress even after ifosfamide has been discontinued.  Proximal tubular damage often presents as 
Fanconi syndrome with low serum bicarbonate, proteinuria, glucosuria, aminoaciduria and 
hypochloremic metabolic acidosis.  Risk factors for the development of nephrotoxicity include 
preexisting renal impairment, concurrent use of nephrotoxic drugs, reduced renal reserve 
(unilateral nephrectomy), hydronephrosis and total cumulative dose.  Renal impairment may 
increase the risk of myelosuppression and possibly, cardiotoxicity.  Mesna does not appear to be 
protective against the proximal tubular abnormalities induced by ifosfamide.  Dose modifications 
guidelines of ifosfamide due to renal impairment are shown in Table JGDR.14.
7.7. 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.
7.8.6. Other Concomitant Therapies
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study.  An exception will be 
made for: 

prostate cancer patients continuing GnRH agonist therapy or breast cancer patients 
continuing anti-estrogen therapy (for example, an aromatase inhibitor) as long as those 
therapies have been installed for at least 3 months and are known to have been well 
tolerated

bisphosphonate osteoclast inhibitors (for example, zoledronic acid or pamidronate) for 
treatment of bone metastases will be permitted while patients are on study treatment. The 
osteoclast inhibitor denosumab is also allowed.  Denosumab is a monoclonal antibody 
and is associated with a risk of hypersensitivity reactions. Therefore, denosumab should 
not be administered within 3 days of olaratumab administration.

palliative local treatment (for example, radiotherapy of ≤14 calendar days) in Cycles 2 
and beyond following discussions between the investigators and the sponsor (for 
example, for pain control of a solitary [non-skull] skeletal metastasis) and written 
approval by the sponsor, as long as the patient has not developed another reason for study 
discontinuation.
9.1. Efficacy Assessments
9.1.1. Secondary Efficacy Assessments
Tumor assessments will …
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Radiological scan imaging of the chestthorax, abdomen and pelvis and other areas, as 
clinically indicated, is required.

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See Section 10.3.1 for definitions of the efficacy endpoints.

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10. Statistical Considerations
10.1. Sample Size Determination
The primary objective is to …
Before enrolling the full 15 patients at a given dose level, the study design requires that an initial 
group of 6 will be enrolled and evaluated for DLTs.  If 6 or more patents with DLTs are 
observed in the first 6 patients, enrollment at the current dose level will be stopped and 
appropriate dose de-escalation (or trial halt) will occur.  Similarly, if 6 or more patients with 
DLTs are observed in the first 9 patients, enrollment at the current dose level will be stopped and 
appropriate dose de-escalation (or trial halt) will occur.

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Appendix 3.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology - local and central laboratorya
Leukocytes (WBC)
Erythrocytes (RBC)
Neutrophilsb
Hemoglobin (HGB)
Lymphocytes
Hematocrit (HCT)
Monocytes
Mean corpuscular volume (MCV)
Eosinophils
Mean corpuscular hemoglobin concentration (MCHC)
Basophils
Platelets (PLT)
Coagulation - local laboratory
Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT)
International normalized ratio (INR) or prothrombin time (PT) 
Clinical Chemistry - local and central laboratorya
Serum Concentrations of:
Alanine aminotransferase (ALT)
Cholesterol
Albumin
Creatinine
Alkaline phosphatase
Glucose, random
Aspartate aminotransferase (AST)
Magnesium
Bilirubin, direct
Phosphorous
Bilirubin, total
Potassium
Blood urea nitrogen (BUN) or blood urea
Sodium
Calcium
Uric acid
Urinalysis - local laboratory
Blood
Protein
Glucose
Specific gravity
Ketones
Urine leukocyte esterase
pH
Pregnancy Test (for female patients of childbearing potential) - local laboratory
Serum pregnancy test (screening)
Serum or Urine pregnancy test (on study)
Confirmation of Menopause (for female patients of menopausal age) – local laboratory
Follicle-stimulating hormone (FSH)c
Abbreviation:  CRF = case report form. 
a
Treatment decisions will be based on local laboratory results.
b
Neutrophils reported using automated differential hematology instruments include both segmented and band 
forms.  When 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
To be performed at screening only when needed to confirm post-menopausal status; applicable for women who 
have experienced spontaneous amenorrhea for 6 to 12 months. 

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Appendix 4.
Pharmacokinetic, Biomarker, Pharmacogenetics and 
Immunogenicity Sampling Schedules
It is essential that the exact infusion start and stop times (actual clock readings) are recorded.  
The exact time of collection of each venous blood sample will be based on the clock used to 
record infusion times.  It is essential that the PK blood samples not be drawn from the same site 
as the drug infusion.

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Pharmacokinetic, Biomarker, Pharmacogenetic and Immunogenicity Sampling Schedule
Cycle
Day
Dosing
Sampling Timea
PK Sampling
Biomarker Sampling
PGx
IGe,f
Olara PKb,f
Dox PKc,l
Ifos 
PKd,l
Plasma
Tumor Tissueg
Baseline 
-
X (mandatory)g
1
1
≤60 min pre-olara
Xh
X
Xi
X
Olara (1 hr)
≤5 min post-olara
X
Obs (1 hr)
60±10 min post-olara
X
Dox (<1 hr)j
≤5 min post-dox
Xj
Ifos (3 hr)
≤5 min post-ifos
X
X
2
Dox (<1 hr)
Ifos (3 hr)
≤5 min post-ifos
X
X
3
Dox (<1 hr)j
≤5 min post-dox
Xj
Ifos (3 hr)
≤5 min post-ifos
X
4
Ifos (3 hr)
≤5 min post-ifos
X
X
8
≤60 min pre-olara
Xh
X
X
Olara (1 hr)
≤5 min post-olara
X
Obs (1 hr)
60±10 min post-olara
X
4±0.5 hr post-olara
X
10
48±3 hr post-olara
X 
15
Anytime
X
2
1
≤60 min pre-olara
Xh
X
X
Olara (1 hr)
≤5 min post-olara
X
8
≤60 min pre-olara
Xh
Olara (1 hr)
≤5 min post-olara
X

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3
1
≤60 min pre-olara
Xh
X
X
Olara (1 hr)
≤5 min post-olara
X
Dox (<1 hr)i
≤5 min post-dox
X
Xj
Ifos (3 hr)
≤5 min post-ifos
X
X
2
Dox (<1 hr)
Ifos (3 hr)
≤5 min post-ifos
Xk
X
3
Dox (<1 hr)i
≤5 min post-dox
Xj
Ifos (3 hr)
≤5 min post-ifos
X
4
Ifos (3 hr)
≤5 min post-ifos
Xk
X
8
≤60 min pre-olara
Xh
Olara (1 hr)
≤5 min post-olara
X
60±10 min post-olara
X
4±0.5 hr post-olara
X
10
48±3 hr post-olara
X 
15
Anytime
X
4
1
≤60 min pre-olara
Xh
5 and then 
every 
other 
cycle
1
≤60 min pre-olara
Xh
X
Visit 801
Anytime
X
X
X (optional; for 
patients who 
undergo surgical 
tumor resection 
subsequent to study 
treatment)
X
Abbreviations:  C = cycle; D = day; dox = doxorubicin; hr = hour; ifos = ifosfamide; IG = immunogenicity; min = minute; IRR = infusion-related reaction; obs = 
observation; olara = olaratumab; PGx = pharmacogenetics; PK = pharmacokinetics.
a
Post-infusion is defined as after the completion of the infusion.
b
Samples of approximately 3 mL of whole blood will be drawn without anticoagulant for measurement of olaratumab in serum.

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c
Samples of approximately 2 mL of whole blood will be drawn into plastic tubes with anticoagulant for measurement of ifosfamide in plasma.
d
Samples of approximately 3 mL of whole blood will be drawn into plastic tubes with anticoagulant for measurement of doxorubicin in plasma.
e
For the immunogenicity assay, approximately 5 mL of whole blood will be drawn into a serum separator tube without anticoagulant to generate serum 
samples.
f
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 days (±3 days) after the IRR.
g
Patients must have sufficient available material from an archived formalin-fixed paraffin-embedded tumor tissue.  If such tissue is not available, a newly 
obtained core or excisional biopsy of a tumor lesion must be performed. 
h
Pretreatment olaratumab PK samples may be collected up to 60 minutes prior to the olaratumab infusion and must be prior to administering any 
premedication.Pretreatment samples may be collected any time during the day of the clinical visit, prior to the start of the olaratumab infusion and must be 
taken prior to administering any premedication.
i
It is highly recommended to draw the PGx sample prior to the first dose of study drug (C1D1); however, it can be collected at a later time point, if necessary. 
j
If doxorubicin is administered as a 24 hour infusion, the doxorubicin PK sample should be collected at the same time as the ifosfamide PK sample (that is, 
approximately 3 to 4 hours after the start of the doxorubicin infusion).
k
For patients who have discontinued doxorubicin/ifosfamide early, these samples may be omitted if there is no other reason for the patient to visit the clinic.
l
Should a patient discontinue doxorubicin or ifosfamide, all subsequent PK samples for the corresponding chemotherapeutic agent can be omitted.

Leo Document ID = 162b3c09-f0fb-440a-956f-85d421fbbebd
Approver: 
Approval Date & Time: 26-Jun-2018 09:46:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 26-Jun-2018 09:46:55 GMT
Signature meaning: Approved
PPD
PPD