A Randomized, Open-Label Phase 1/2 Study Evaluating Ramucirumab in Pediatric Patients and Young Adults With Relapsed, Recurrent, or Refractory Desmoplastic Small Round Cell Tumor
Phase: PHASE1
Conditions: Desmoplastic Small Round Cell Tumor
Sponsor: Eli Lilly and Company

7KLVVWXG\-60&-91&7LVDVXEVWXG\RI0DVWHU3URWRFRO-60&-$$$1&7
1URWRFRO-60&-99HUVLRQJ
$5DQGRPL]HG2SHQ/DEHO3KDVH6WXG\(YDOXDWLQJ5DPXFLUXPDELQ3HGLDWULF3DWLHQWVDQG<RXQJ$GXOWV:LWK
5HODSVHG5HFXUUHQWRU5HIUDFWRU\'HVPRSODVWLF6PDOO5RXQG&HOO7XPRU
1&7
$SSURYDO'DWH'HF

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 1
LY900023; LY3009806
1. Protocol Addendum J1S-MC-JV01(g)
A Randomized, Open-Label Phase 1/2 Study Evaluating 
Ramucirumab in Pediatric Patients and Young Adults with 
Relapsed, Recurrent, or Refractory Desmoplastic Small 
Round Cell Tumor
Confidential Information
The information contained in this protocol addendum 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 ramucirumab (LY3009806), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  This document and 
its associated attachments are subject to United States Freedom of Information Act (FOIA) 
Exemption 4. 
LY900023 (JAAA CAMPFIRE Protocol); Ramucirumab (LY3009806)
This addendum is to be performed in addition to all procedures required by 
Protocol J1S-MC-JAAA or any subsequent amendments to that protocol.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Addendum JV01 Electronically Signed and Approved by Lilly on 7 December 2018 
Protocol Addendum Amendment JV01(a) Electronically Signed and Approved by Lilly on 
23 January 2019
Protocol Addendum Amendment JV01(b) Electronically Signed and Approved by Lilly on 
2 August 2019
Protocol Addendum Amendment JV01(c) Electronically Signed and Approved by Lilly on 
26 September 2019
Protocol Addendum Amendment JV01(d) Electronically Signed and Approved by Lilly on 
17 October 2019
Protocol Addendum Amendment JV01(e) Electronically Signed and Approved by Lilly on 18-
May-2020
Protocol Addendum Amendment JV01(f) Electronically Signed and Approved by Lilly on 09-Oct-
2020
Protocol Addendum Amendment JV01(g) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 13-Dec-2021 GMT

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 2
LY900023; LY3009806
2. Table of Contents
Protocol Addendum J1S-MC-JV01(g)
A Randomized, Open-Label Phase 1/2 Study Evaluating 
Ramucirumab in Pediatric Patients and Young Adults with 
Relapsed, Recurrent, or Refractory Desmoplastic Small 
Round Cell Tumor
Section
Page
1.
Protocol Addendum J1S-MC-JV01(g) A Randomized, Open-Label 
Phase 1/2 Study Evaluating Ramucirumab in Pediatric Patients and 
Young Adults with Relapsed, Recurrent, or Refractory Desmoplastic 
Small Round Cell Tumor ....................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Protocol J1S-MC-JV01(g) Addendum.................................................................................8
3.1.
Synopsis.........................................................................................................................8
3.2.
Schedule of Activities ..................................................................................................10
3.3.
Introduction..................................................................................................................18
3.3.1.
Study Rationale....................................................................................................18
3.3.2.
Background..........................................................................................................19
3.3.2.1.
Desmoplastic Small Round Cell Tumor..........................................................19
3.3.2.2.
Ramucirumab .................................................................................................19
3.3.2.3.
Cyclophosphamide and Vinorelbine ...............................................................20
3.3.3.
Benefit/Risk Assessment......................................................................................21
3.4.
Objectives and Endpoints.............................................................................................23
3.5.
Study Design................................................................................................................23
3.5.1.
Overall Design.....................................................................................................23
3.5.2.
Number of Patients...............................................................................................26
3.5.3.
End of Study Definition .......................................................................................26
3.5.4.
Scientific Rationale for Study Design...................................................................26
3.5.5.
Justification for Dose ...........................................................................................27
3.6.
Study Population..........................................................................................................30
3.6.1.
Inclusion Criteria .................................................................................................30
3.6.1.1.
Exceptions to the CAMPFIRE Master Protocol Inclusion 
Criteria ...........................................................................................................31
3.6.2.
Exclusion Criteria ................................................................................................34
3.6.2.1.
Exceptions to the CAMPFIRE Master Protocol 
Exclusion Criteria...........................................................................................36
3.6.3.
Lifestyle Restrictions ...........................................................................................36

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 3
LY900023; LY3009806
3.7.
Treatments ...................................................................................................................36
3.7.1.
Treatments Administered .....................................................................................36
3.7.1.1.
Premedication.................................................................................................36
3.7.1.1.1.
Ramucirumab ...........................................................................................36
3.7.1.2.
Dosing Schedule.............................................................................................36
3.7.1.3.
Dose-Limiting Toxicity Determination ...........................................................38
3.7.2.
Method of Treatment Assignment ........................................................................41
3.7.3.
Blinding...............................................................................................................41
3.7.4.
Dose Modification................................................................................................41
3.7.4.1.
Guidelines for Hematological and Nonhematological 
Dose Modifications ........................................................................................42
3.7.4.2.
Ramucirumab Dose Modifications for Adverse Events of 
Special Interest ...............................................................................................49
3.7.5.
Treatment Compliance .........................................................................................55
3.7.6.
Concomitant Therapy...........................................................................................55
3.7.6.1.
Supportive Care..............................................................................................55
3.7.6.1.1.
Transfusions .............................................................................................55
3.7.6.1.2.
Supportive Management for Constipation and Bowel 
Obstruction...............................................................................................55
3.7.6.1.3.
Antiemetic Agents ....................................................................................55
3.7.6.1.4.
Analgesic Agents......................................................................................55
3.7.6.1.5.
Appetite Stimulants ..................................................................................55
3.7.6.1.6.
Growth Factors.........................................................................................55
3.7.6.1.7.
Other Supportive Care Agents ..................................................................56
3.7.6.1.8.
Supportive Care by Adverse Event of Special 
Interest:  Ramucirumab.............................................................................56
3.7.6.1.8.1.
Infusion-Related Reactions (Including 
Hypersensitivity Reactions).................................................................56
3.7.6.1.8.2.
Hypertension.......................................................................................57
3.7.6.1.8.3.
Proteinuria ..........................................................................................57
3.7.6.1.8.4.
Thromboembolic Events .....................................................................57
3.7.6.1.8.5.
Bleeding/Hemorrhage .........................................................................58
3.7.6.1.8.6.
Gastrointestinal Perforation.................................................................58
3.7.6.1.8.7.
Posterior Reversible Encephalopathy Syndrome..................................58
3.7.6.1.8.8.
Congestive Heart Failure.....................................................................59
3.7.6.1.8.9.
Fistula Formation................................................................................59
3.7.6.1.8.10.
Surgery and Impaired Wound Healing ................................................59
3.7.6.1.8.11.
Liver Failure and Other Significant Liver Injury .................................59
3.8.
Discontinuation Criteria ...............................................................................................59

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 4
LY900023; LY3009806
3.9.
Study Assessments and Procedures ..............................................................................60
3.9.1.
Efficacy Assessments...........................................................................................60
3.9.2.
Adverse Events ....................................................................................................61
3.9.2.1.
Adverse Events of Special Interest:  Ramucirumab.........................................61
3.9.3.
Safety...................................................................................................................61
3.9.3.1.
Safety Monitoring...........................................................................................61
3.9.3.1.1.
Special Hepatic Safety Data Collection.....................................................61
3.9.3.1.2.
Monitoring for Specific Toxicities:  Growth Plate.....................................62
3.9.4.
Pharmacokinetics .................................................................................................63
3.9.5.
Pharmacodynamics ..............................................................................................63
3.9.5.1.
Immunogenicity Assessments.........................................................................63
3.9.6.
Biomarkers...........................................................................................................64
3.9.6.1.
Tissue Samples for Biomarker Research.........................................................64
3.9.6.2.
Other Samples for Biomarker Research ..........................................................64
3.9.7.
Health Economics ................................................................................................64
3.10. Statistical Considerations .............................................................................................65
3.10.1.
Sample Size Determination ..................................................................................65
3.10.2.
Populations for Analysis ......................................................................................66
3.10.3.
Statistical Analysis...............................................................................................66
3.10.3.1.
Efficacy Analysis ...........................................................................................66
3.10.3.2.
Safety Analysis...............................................................................................69
3.10.3.3.
Other Analysis................................................................................................69
3.10.3.3.1.
Pharmacokinetic/Immunogenicity Analyses..............................................69
3.10.3.3.2.
Biomarker Analyses..................................................................................69
3.10.3.4.
Subgroup Analysis..........................................................................................69
3.10.3.5.
Interim Analysis .............................................................................................69
4.
References ........................................................................................................................71

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 5
LY900023; LY3009806
List of Tables
Table
Page
Table JV01.1.
Baseline Schedule of Activities......................................................................10
Table JV01.2.
On-Study-Treatment Schedule of Activities...................................................12
Table JV01.3.
Post-Study-Treatment Follow-Up Schedule of Activities ...............................15
Table JV01.4.
Continued Access Schedule of Activities .......................................................17
Table JV01.5.
Rolling Six Rules (Ramucirumab at 12 mg/kg) ..............................................24
Table JV01.6.
Rolling Six Rules (Ramucirumab at 8 mg/kg)................................................25
Table JV01.7.
Treatment Regimens/Dosing Schedule...........................................................37
Table JV01.8.
Dose Reductions for Treatment-Related Toxicities ........................................42
Table JV01.9.
General Guidelines for Study Treatment Dose Modification Due to 
Toxicities Related to Ramucirumab, Cyclophosphamide, or Vinorelbine .......44
Table JV01.10.
Dosing Algorithm on Days 1 ,8, and 15 for Cyclophosphamide, 
Vinorelbine, Ramucirumab, and G-CSF Use Based on Absolute 
Neutrophil Count and Platelet Count..............................................................45
Table JV01.11.
Additional Guidelines for Dose Modification Due to Study 
Drugs-Related Non-Hematologic Toxicities...................................................47
Table JV01.12.
Dose-Modification Guidelines for Ramucirumab for Adverse Events at 
Least Possibly Related to Ramucirumab, including Adverse Events of 
Special Interest ..............................................................................................50
Table JV01.13.
PFS Event/Censoring Scheme........................................................................68
Table JV01.14
Simulated Operating Characteristics ..............................................................68
Table JV01.15
Impact of Heterogeneous Effect-Size Between Tumors..................................68

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 6
LY900023; LY3009806
List of Figures
Figure
Page
Figure JV01.1.
Illustration of Study JV01 and Study JV02 Designs .......................................26

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 7
LY900023; LY3009806
List of Attachments
Attachment
Page
Attachment 1.
Protocol Addendum JV01 Abbreviations and Definitions ..............................76
Attachment 2.
Protocol Addendum JV01 Clinical Laboratory Tests......................................80
Attachment 3.
Protocol Addendum JV01 Sampling Schedule for Genetics/ 
Biomarkers/Immunogenicity/Pharmacokinetics .............................................83
Attachment 4.
Protocol Addendum JV01 Hepatic Monitoring Tests for Treatment 
Emergent Abnormality ..................................................................................87
Attachment 5.
Protocol JV01 Restricted and Prohibited Concomitant Therapy .....................88
Attachment 6.
Protocol Addendum Amendment J1S-MC-JV01(f)
A Randomized, Open-Label Phase 1/2 Study Evaluating Ramucirumab 
in Pediatric Patients and Young Adults with Relapsed, Recurrent, or 
Refractory Desmoplastic Small Round Cell Tumor........................................91

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 8
LY900023; LY3009806
3. Protocol J1S-MC-JV01(g) Addendum
3.1.
Synopsis
Protocol Title:
A Randomized, Open-Label Phase 1/2 Study Evaluating Ramucirumab in Pediatric Patients and 
Young Adults with Relapsed, Recurrent, or Refractory Desmoplastic Small Round Cell Tumor
Rationale:
Study J1S-MC-JV01 (JV01) is designed to investigate the efficacy of ramucirumab in 
combination with low-dose cyclophosphamide and vinorelbine for the treatment of pediatric and 
young adult patients with Desmoplastic Small Round Cell Tumor (DSRCT).
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the efficacy of ramucirumab in combination 
with cyclophosphamide and vinorelbine compared with 
cyclophosphamide and vinorelbine in pediatric and 
young adult patients with DSRCT.
PFS
Secondary
To evaluate the safety and tolerability of ramucirumab in 
combination with cyclophosphamide and vinorelbine 
compared with cyclophosphamide and vinorelbine in 
pediatric and young adult patients with DSRCT.
SAEs, AEs, safety laboratory assessments, and vital 
signs
To evaluate the efficacy of ramucirumab in combination 
with cyclophosphamide and vinorelbine compared with 
cyclophosphamide and vinorelbine in pediatric and 
young adult patients with DSRCT
ORR, DoR, CR
To characterize the PK of ramucirumab when 
co-administered with cyclophosphamide and vinorelbine 
in pediatric and young adult patients with DSRCT
Cmax and Cmin
To assess the immunogenicity of ramucirumab when 
co-administered with cyclophosphamide and vinorelbine 
in pediatric and young adult patients with DSRCT
Incidence of immunogenicity
Abbreviations:  AE = adverse event; Cmax = maximum concentration; Cmin = minimum concentration; 
CR = complete response; DSRCT= desmoplastic small round cell tumor; DoR = duration of response; ORR = 
overall response; PFS = progression-free survival; PK = pharmacokinetics; SAE = serious adverse event.
Overall Design:
Study JV01 is a randomized, open-label Phase 1/2 study evaluating ramucirumab in combination 
with low-dose cyclophosphamide and vinorelbine in pediatric and young adult patients with 
relapsed, recurrent, or refractory DSRCT.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 9
LY900023; LY3009806
Number of Patients:
Approximately 30 patients will be enrolled.
The study must enroll a minimum of 10 patients ≤17 years old with DSRCT.
Treatment Arms and Duration:
Treatment period:  patients will receive treatment until evidence of disease progression or other 
discontinuation criteria have been fulfilled.
Follow-up period (post-discontinuation):  approximately 30 days.
Dose and Schedule (q 28 days)
Arm
Ramucirumab
IV, D1, and D15
Cyclophosphamide
PO, QD
Vinorelbine
IV, D1, D8, and D15
Number of Cycles
1
12 mg/kg
25 mg/m2
25 mg/m2
Treatment will continue 
until a discontinuation 
criterion is met.
2
NA
25 mg/m2
25 mg/m2
Abbreviations:  D = day; IV = intravenous; PO = by mouth; q = every; QD = daily.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 10
LY900023; LY3009806
3.2.
Schedule of Activities
Table JV01.1.
Baseline Schedule of Activities
Day Relative to C1D1
28
7
Procedure
Instructions
Informed consent
X
ICF must be signed before any 
protocol-specific procedures are 
performed
Inclusion/exclusion criteria
X
Physical examination
X
Including height, weight, and vital 
signs (temperature, blood pressure, and 
pulse rate).
ECOG/Lansky/Karnofsky 
performance status
X
Medical history
X
Including assessment of preexisting 
conditions, historical illnesses, and 
habits.
Prior and current anticancer 
therapy
X
Concomitant medications
X
AE collection
X
CTCAE, Version 5.0
Radiologic imaging and 
measurement of palpable or 
visible lesions; and chest, 
abdomen, and pelvis CT
X

Perform according to RECIST 1.1 
criteria

See Section 3.9.1
Plain anteroposterior radiograph 
of a single proximal tibial growth 
plate
X
Only for patients <18 years of age.  See 
Section 3.9.3.1.2.
ECHO/MUGA
X
ECG
X
Local testing.
Hematology
X
See Attachment 2 for designation of 
local or central testing.
Coagulation
X
See Attachment 2 for designation of 
local or central testing.
Clinical chemistry
X
See Attachment 2 for designation of 
local or central testing.
Urinalysis
X
See Attachment 2 for designation of 
local or central testing.
Pregnancy test
X
Serum or urine per institutional 
standard.  Applies only to female of 
childbearing potential. 
See Attachment 2 for designation of 
local or central testing.
TSH and FreeT4
X
See Attachment 2 for designation of 
local or central testing.
Sample collection for:
Pharmacokinetics
See Attachment 3
Immunogenicity
See Attachment 3

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 11
LY900023; LY3009806
Genetics
See Attachment 3
Biomarkers
See Attachment 3
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events (NCI 2017); ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); Free T4 = thyroxine; ICF = informed consent 
form; MUGA = multigated acquisition; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 
1.1 (Eisenhauer et al. 2009); TSH = thyroid-stimulating hormone.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 12
LY900023; LY3009806
Table JV01.2.
On-Study-Treatment Schedule of Activities
For C1D1, evaluations must be done on the day of visit or within 7 days prior.  For all subsequent visits, evaluations must be done on 
the day of visit or within 3 days prior. In case of dose interruption, these evaluations will also be done at a minimum frequency every 
28 days.
Treatment Period 28-Day Cycle
Cycle 1
Cycle 2-n
Day within cycle
1
8
15
1
8
15
Procedure
Instructions
Physical examination
X
X
X
X
Perform prior to administering study drug(s).
Weight and height
X
X
Perform prior to administering study drug(s).
Height to be collected for patients <18 years of age only.
Vital Signs
X
X
X
X
X
X
Perform prior to administering study drug(s).

Including temperature, blood pressure, and pulse rate.
Concomitant 
medication
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
CTCAE, Version 5.0.  To be performed before treatment. 
ECOG/Lansky/ 
Karnofsky 
performance status
X
X
Radiologic imaging 
and measurement of 
palpable or visible 
lesions; and chest, 
abdomen, and pelvis 
CT
Perform every 8 wk (±7 days)

Perform according to RECIST 1.1 criteria, by the same method used at baseline, q 8 wk 
(±7 days) starting from C1D1 until documented disease progression per RECIST 1.1 criteria, 
death, or study completion, whichever occurs first.

After third evaluation of stable disease (or better) or following complete resection, may 
obtain every 3 months (±14 days) thereafter. 

Perform as scheduled, even if study treatment is delayed or omitted.

Local testing.

See Section 3.9.1

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 13
LY900023; LY3009806
Treatment Period 28-Day Cycle
Cycle 1
Cycle 2-n
Day within cycle
1
8
15
1
8
15
Procedure
Instructions
Plain anteroposterior 
radiograph of a single 
proximal tibial 
growth plate (only for 
patients randomized 
to ramucirumab and 
with open growth 
plate at baseline)
See Instructions
Perform every 4 months according to Section 3.9.3.1.2.
Patients must be followed for duration of study or until closure of growth plate.
In some geographies, an MRI of the knee may be an alternate option instead of plain radiograph.
ECG
Single, at baseline.  Perform additional evaluations in the setting of cardiac symptoms and/or at 
the discretion of the investigator.
Local testing.
Hematology
X
X
X
X
X
X
For C1D1: ≤7 days prior; subsequent collections: ≤3 days prior to administration of study 
treatment, unless more frequent assessment is clinically indicated (Refer to Section 3.7.4 for Dose 
Modifications).
See Attachment 2 for designation of local or central testing.
Coagulation
X
X
For C1D1: ≤7 days prior; subsequent collections: ≤3 days prior to administration of study 
treatment, unless more frequent assessment is clinically indicated.
See Attachment 2 for designation of local or central testing.
Clinical chemistry
X
X
X
X
X
X
For C1D1: ≤7 days prior; subsequent collections: ≤3 days prior to administration of study 
treatment, unless more frequent assessment is clinically indicated.
See Attachment 2 for designation of local or central testing.
Urinalysis
X
X
X
X
For C1D1: ≤7 days prior; subsequent collections: ≤3 days prior to administration of study 
treatment, unless more frequent assessment is clinically indicated.  See Attachment 2 for 
designation of local or central testing.
Pregnancy test
X
X
Serum or urine per institutional standard.  Applies only to females of childbearing potential.
Where required by local law or regulation, perform monthly/once every 28 days (±7 days) prior to 
administration of study treatment.
See Attachment 2 for designation of local or central testing.
Administer 
ramucirumab 
(investigational arm)
X
X
X
X
Premedicate according to Section 3.7.1.1.  Patients must be closely monitored for a 1-hour 
observation period following the ramucirumab infusions for the first 2 infusions (see 
Section 3.7.6.1.8.1).

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 14
LY900023; LY3009806
Treatment Period 28-Day Cycle
Cycle 1
Cycle 2-n
Day within cycle
1
8
15
1
8
15
Procedure
Instructions
Administer 
cyclophosphamide
X
Administer 
vinorelbine
X
X
X
X
X
X
Sample collection 
for:
Pharmacodynamics
See Attachment 3
Pharmacokinetics
See Attachment 3
Immunogenicity
See Attachment 3
Genetics
See Attachment 3
Biomarkers
See Attachment 3
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events 
(NCI 2017); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); hr = hour; IV = intravenous; q = every; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1 (Eisenhauer et al. 2009); wk = week.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 15
LY900023; LY3009806
Table JV01.3.
Post-Study-Treatment Follow-Up Schedule of Activities
Short-Term 
Follow-Upa
Long-Term 
Follow-Up
Visit
801
802-8XX
Procedure
Instructions
Physical examination
X
X
(only for 
patients with 
abnormal 
growth plate 
findings at 
V801)
Short-Term Follow-up: Including weight and vital 
signs (temperature, blood pressure, and pulse rate)
Include height only for patients being followed with 
open growth plates on study.
Long-Term Follow-up: continue to obtain height 
periodically at investigator’s discretion until 
resolution of growth plate abnormalities or growth
plate closure.
Concomitant medication
X
AE collection
X
CTCAE, Version 5.0
Lansky/Karnofsky/ECOG 
performance status
X
Radiologic imaging and 
measurement of palpable or 
visible lesions; and chest, 
abdomen, and pelvis CT
See instructions

Perform q 8 week (±7 days) according to 
RECIST 1.1 criteria or q 3 months (±14 days) 
after third evaluation of stable disease or 
following surgical resection with clean margins,  
by the same method used at baseline and 
throughout the study, until one of the following 
occurs:
o
the patient has documented disease 
progression
o
patient has started new anti-cancer therapy
o
the study’s primary/final analysis of OS.
Plain anteroposterior 
radiograph of a single 
proximal tibial growth 
plate for patients
randomized to 
ramucirumab with open 
growth plates at baseline
being followed on study
X
X
(only for 
patients with 
abnormal 
growth plate 
findings at 
V801)
In some geographies, an MRI of the knee may be an 
alternate option instead of plain radiograph. 
Long-Term Follow-Up:
Frequency of radiographs in Long-Term Follow-Up 
is per the investigator’s discretion according to 
Section 3.9.3.1.2. Continue to perform until 
resolution of growth plate abnormalities or growth 
plate closure.
Collection of survival 
information
X
Perform q 3 months (±14 days).  If an in-person visit 
is not possible, confirm survival by contacting the 
patient directly via phone until death or study 
completion.
Collection of 
poststudy-treatment 
anticancer therapy 
information
X
X
Perform q 3 mo (±14 days) for the first 2 years after 
discontinuation from study treatment and q 6 months 
(±14 days) thereafter until death or study completion.
Hematology
X
See Attachment 2 for designation of local or central 
testing.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 16
LY900023; LY3009806
Short-Term 
Follow-Upa
Long-Term 
Follow-Up
Visit
801
802-8XX
Procedure
Instructions
Coagulation
X
See Attachment 2 for designation of local or central 
testing.
Clinical chemistry
X
See Attachment 2 for designation of local or central 
testing.
Urinalysis
X
See Attachment 2 for designation of local or central 
testing.
TSH and FreeT4
X
See Attachment 2 for designation of local or central 
testing.
Sample collection for:
Pharmacodynamics
See Attachment 3
Pharmacokinetics
See Attachment 3
Immunogenicity
See Attachment 3
Genetics
See Attachment 3
Biomarkers
See Attachment 3
Abbreviations:  AE = adverse event; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events (NCI 2017); ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); Free T4 = 
thyroxine; OS = overall survival; q = every; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (Eisenhauer et al. 2009); TSH = thyroid-stimulating hormone.
a
Short-term follow-up begins when the patient and the investigator agree that the patient will no longer continue 
study treatment and lasts approximately 30 days.  In all cases, no follow-up procedures will be performed for a 
patient who withdraws informed consent unless he or she has explicitly provided permission and consent.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 17
LY900023; LY3009806
Table JV01.4.
Continued Access Schedule of Activities
Study 
Treatment
Follow-Upa
Visit
501-5XX
901
Procedureb
Instructions
AE collection
X
X
CTCAE, Version 5.0
PK, IG, and hypersensitivity 
labs for IRR events
(including hypersensitivity 
reactions)
See instructions
In the event of an IRR (including hypersensitivity 
reactions), blood samples will be collected as 
outlined in Section 3.7.6.1.8.1 and Attachment 3.
Administer ramucirumab
(investigational arm)
X
Premedicate according to Section 3.7.1.1.  
Administer 
cyclophosphamide
X
Administer vinorelbine
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2017); 
IG = immunogenicity; IRR = infusion-related reaction; IV = intravenous; PK = pharmacokinetics; PO = by 
mouth.
a
Continued-access follow-up begins when the patient and the investigator agree that the patient will no longer 
continue treatment in the continued-access period and lasts approximately 30 days.  In all cases, 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.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 18
LY900023; LY3009806
3.3.
Introduction
3.3.1. Study Rationale
Angiogenesis is a biologic process that is important for cancer growth and metastasis.  As a 
result, the pathways that mediate angiogenesis are considered important targets in cancer drug 
development.  Vascular endothelial growth factors (VEGFs; including VEGF-A, VEGF-B, 
VEGF-C, and VEGF-D) and placental growth factor have emerged as key regulators of 
angiogenesis.  VEGF-A is distinct within the VEGF ligand family in that it acts as a dominant 
endothelial cell-specific mitogen during angiogenesis.  VEGF Receptor 2 is the primary mediator 
of proangiogenic effects of VEGF A and experimental evidence suggests that the VEGF-
A/VEGF Receptor 2 interaction plays an important role in tumor angiogenesis.  Therefore, 
disruption of the interaction between VEGF-A and VEGF Receptor 2 may have therapeutic 
application in the treatment of cancer.
Angiogenesis is upregulated in pediatric embryonal tumors, making it an important pathway.  
VEGF and its downstream signaling play a vital role in tumor growth and metastasis in children. 
Studies have shown high levels of circulating VEGF levels in children with tumors at baseline 
(Blann et al 2001; Holzer et al 2001).  
Tumor angiogenesis is a prime process involved in tumor growth and requires the interaction of 
various cell factors, cells, and tissues (Ellis and Hicklin 2008).  Targeting multiple processes, 
such as angiogenesis and cell cycle control, is known to effectively treat many cancers (DeVita 
et al. 1975; Sawyers 2004; Knight et al. 2010; Carmeleit and Jain 2011).
Soft tissue sarcomas (STSs) have been shown to express VEGF and/or VEGFR-2 to varying 
degrees. Multiple clinical trials targeting the VEGF pathway with mAb agents or tyrosine kinase 
inhibitors (TKIs) have been conducted in patients with STSs and demonstrated activity (George 
et al. 2009; Maki et al. 2009; Sleijfer et al. 2009; Fox et al. 2010; van der Graaf et al. 2012; 
Glade Bender et al. 2013; Chisholm et al. 2017). The PALATTE study, a randomized, double-
blind, placebo-controlled Phase 3 trial, investigating the use of pazopanib in adult patients with 
advanced non-adipocytic STS, demonstrated improved median progression-free survival (PFS)
in the TKI arm (van der Graaf et al. 2012).  The BERNIE trial, a pediatric, open-label, 
randomized Phase 2 study, investigated the addition of bevacizumab to standard front-line 
chemotherapy and maintenance therapy versus chemotherapy and maintenance alone for patients 
with metastatic rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma STS (NRSTS). While 
the study did not meet its primary end point of event-free survival (EFS) across all patients with
STS, a subset analysis identified a potentially compelling benefit in the NRSTS cohort with the 
addition of the anti-VEGF agent. Furthermore, the safety profile of the anti-VEGF inhibitor in 
combination with standard front-line chemotherapy and maintenance therapy in pediatric patients 
with STSs was consistent with the known safety profile in adults and did not enhance toxicity in 
the very dense chemotherapy protocol (Chisholm et al. 2017).
In preclinical patient-derived xenograft studies using DSRCT (CTG-0926, CTG-1458) and 
synovial sarcoma (SS) (CTG-0331, CTG-1173) models, a mouse surrogate inhibitor targeting 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 19
LY900023; LY3009806
VEGF Receptor 2 (DC101) had better tumor efficacy in combination with standard of care 
treatments (doxorubicin, docetaxel/gemcitabine, or cyclophosphamide) versus standard of care 
alone.
Therefore, Studies JV01 and J1S-MC-JV02 (JV02) are Phase 1/2 studies evaluating 
ramucirumab in pediatric patients and young adults with relapsed, recurrent, or refractory 
DSRCT (JV01) or SS (JV02) in combination with known chemotherapy backbones used in these 
settings.  Tumor-specific conclusions regarding improvements in efficacy will be made for each 
study.  As adding ramucirumab may similarly improve outcomes for patients with both diseases, 
the statistical analysis will also incorporate a formal mechanism to adaptively borrow 
information regarding relative benefit observed across both studies.
This addendum (JV01) describes the hypothesis and details of the DSRCT investigation. When 
relevant to the discussion, references to the synovial sarcoma investigation (JV02) will be 
included.
3.3.2. Background
3.3.2.1.
Desmoplastic Small Round Cell Tumor
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare tumor that is primarily found in 
adolescents and young adults typically involving the abdominal and pelvic peritoneum.  DSRCT, 
originally described as a mesenchymal entity, is diagnosed based on the histological and 
immunohistochemically features of the tumor and contains the molecular hallmark of the 
EWS-WT1 fusion protein that results from the t(11;22)(p13;q12) translocation (Gerald and Rosai 
1989; Iyer et al. 2013).  Patients diagnosed with DSRCT have a median survival ranging from 17 
to 25 months and long-term survival is uncommon (Dufresne et al. 2012).  Irrespective of the 
stage of disease, age, and treatment received, the prognosis of patients with DSRCT is poor, with 
a 5-year survival of <20%, and an overall median survival time of 2.1 years (Lal et al. 2005; 
Honoré et al. 2015; Bent et al. 2016).  For patients of all ages, aggressive surgical debulking 
(removal of at least 90% of the tumor burden) is the mainstay of the treatment strategy.  The 
most commonly used treatment plans include multimodality treatment (radiation, chemotherapy, 
and surgery).  Desmoplastic small round cell tumor has been shown to be chemosensitive and 
regimens designed for treatment of Ewing’s disease are most often followed for initial treatment.  
However, no defined standard treatment regimens exist for the treatment of either upfront or 
relapsed DSRCT.
3.3.2.2.
Ramucirumab
Ramucirumab is a human receptor-targeted monoclonal antibody (mAb) that specifically binds 
VEGF Receptor 2.  The binding of ramucirumab to VEGF Receptor 2 prevents its interaction 
with activating ligands (VEGF-A, VEGF-C, and VEGF-D).  As a result, ramucirumab inhibits 
ligand-stimulated activation of VEGF Receptor 2 and its downstream signaling components, 
including p44/p42 mitogen-activated protein kinases. This neutralizes ligand-induced 
proliferation and migration of human endothelial cells and ultimately inhibits tumor growth and 
propagation.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 20
LY900023; LY3009806
Ramucirumab has not been approved in pediatrics; however, is being studied in the ongoing 
I4T-MC-JVDA (JVDA) trial.  In adults, ramucirumab has improved outcomes, including overall 
survival, in multiple indications as both a monotherapy and in combination with other agents. 
Ramucirumab is approved as monotherapy or in combination with paclitaxel in the United 
States (US), the European Union (EU), Japan, and other countries for the treatment of adult 
patients with advanced gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma with 
disease progression on or after prior platinum and/or fluoropyrimidine chemotherapy.  The 
approvals were based on the clinical efficacy and safety demonstrated in 2 global, randomized, 
double-blind, and placebo-controlled Phase 3 studies, REGARD (Fuchs et al. 2014) and 
RAINBOW (Wilke et al. 2014).
In the US and the EU, ramucirumab in combination with FOLFIRI (irinotecan, 5-fluorouracil, 
and folinic acid) is approved for the treatment of metastatic colorectal cancer in adult patients 
with disease progression on or after therapy with bevacizumab, oxaliplatin, and a 
fluoropyrimidine (RAISE; Tabernero et al. 2015).
In the US, ramucirumab in combination with docetaxel is approved for the treatment of advanced 
non-small cell lung cancer (NSCLC) in adult patients with disease progression on or after 
platinum-based chemotherapy (REVEL; Garon et al. 2014).  
3.3.2.3.
Cyclophosphamide and Vinorelbine
Vinorelbine is a cell-cycle-dependent vinca alkaloid agent with a proven broad spectrum of 
activity.  Pilot studies have reported vinorelbine activity in STSs such as rhabdomyosarcoma 
(RMS), osteosarcoma, Ewing’s sarcoma, and in some brain tumors (Casanova et al. 2002;
Biassoni et al. 2006; Minard-Colin et al. 2012).  A Phase 1 Children’s Oncology Group (COG) 
trial of vinorelbine demonstrated that the spectrum of hematologic and other types of toxicity in 
pediatric patients was much the same as in adults (Johansen et al. 2006).  
Cyclophosphamide is active in the majority of pediatric malignancies, including sarcomas.  
Low-dose continuous oral dosing of cyclophosphamide has been used in adult and pediatric 
studies, usually in combination with other cytotoxic agents, with minimal toxicity (Bolis et 
al. 1980; Casanova et al. 2004).
The combination of vinorelbine and low-dose cyclophosphamide has been investigated in 
pediatric sarcomas and demonstrated tolerability in children and adolescents (Casanova et 
al. 2004; Ferrari et al. 2007; Minard-Colin et al. 2012; Chisholm et al. 2017).  Case reports 
describing use of a low-dose cyclophosphamide with vinorelbine regimen have demonstrated 
benefit and efficacy in DSRCT patients specifically, justifying further exploration (Ferrari et 
al. 2007).
The European pediatric Soft tissue Sarcoma Group (EpSSG) piloted a study that assessed the 
combination and its efficacy in pediatric sarcoma.  The maximum tolerated vinorelbine dose was 
found to be 30 mg/m2, with neutropenia identified as the dose-limiting toxicity (DLT). At the 
recommended vinorelbine dose (25 mg/m2), Grade 3 or 4 neutropenia was observed in 37% of 
all cycles, but no other major toxic events were noted. The overall acceptability and feasibility 
of the study regimen are supported by the finding that no patient had treatment discontinued on 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 21
LY900023; LY3009806
account of toxicity and by the observation that many patients were treated for an extended 
duration, with 40% of all patients receiving at least 6 cycles of therapy (Casanova et al. 2004).  
Consequently, the recommended dose was oral daily cyclophosphamide 25 mg/m2 for 28 days 
and intravenous (IV) vinorelbine 25 mg/m2 on Days 1, 8, and 15. 
In Minard-Colin et al. (2012), vinorelbine and continuous low-dose cyclophosphamide was 
evaluated in children and young adults with relapsed or refractory malignant solid tumors.  The 
combination provided evidence for the efficacy of vinorelbine 25 mg/m2 on Days 1, 8, and 15 
administered IV in combination with oral cyclophosphamide 25 mg/m2 per day over 28 days.  
Myelosuppression was the main treatment-related toxicity. Grade 3/4 neutropenia occurred in 
38% of patients and 15% of patients experienced febrile neutropenia. Grade 3/4 non-
hematologic toxicities were limited, occurring in <5% of patients.
In the randomized, multicenter BERNIE study of 154 pediatric patients with STS conducted by 
EpSSG and the European Innovative Therapies for Children with Cancer consortium, the 
backbone was a standard induction chemotherapy course followed by surgery and/or radiation 
and a maintenance therapy of low-dose cyclophosphamide and vinorelbine (Chisholm et al.
2017).  The addition of bevacizumab to the chemotherapy backbone to the experimental arm was 
well tolerated.  Overall, the median EFS for patients with all STS patients receiving 
chemotherapy with bevacizumab (n=74) was 20.6 months compared to 14.9 months for patients 
receiving chemotherapy alone (n=80; HR 0.93 95% CI: 0.61 to 1.41; p=.72), which did not meet 
the primary EFS endpoint to demonstrate a statistically significant improvement with the 
addition of bevacizumab across the entire population.  However, in a subset analysis, a 
potentially meaningful benefit in EFS in the NRSTS cohort (n=49) was suggested, with the 
addition of the anti-VEGF agent (17.2 months vs 7.4 months; HR 0.64; 95% CI: 0.32 to 1.26), 
whereas in the RMS cohort (n=103) no difference in EFS was observed (21.3 months vs 20.1 
months; HR 1.24; 95% CI: 0.73 to 2.09).  Of note, DSRCT patients made up a quarter of the 
NRSTS population (n=12).  The response rate for DSRCT patients was 40% (2 of 5 patients) in 
those treated with bevacizumab plus chemotherapy compared to 16.7% (1 of 6 patients) in those 
treated with chemotherapy alone (Chisholm et al. 2016).  When considering the potential benefit 
a VEGF pathway inhibitor might add for patients with relapsed or refractory metastatic DSRCT, 
these data support exploration of the combination of ramucirumab with a non-induction 
chemotherapy regimen such as low-dose cyclophosphamide and vinorelbine in the relapsed and 
refractory setting.
3.3.3. Benefit/Risk Assessment
DSRCT is a rare tumor that is primarily found in adolescents and young adults, typically 
involving the abdominal and pelvic peritoneum.  Currently, there is no standard of care for 
treating pediatric and young adult patients with DSRCT in the relapsed setting, and the outcomes 
are unsatisfactory, with a 5-year survival of <20%, and an overall median survival ranging from 
17 to 38 months (Lal et al. 2005; Dufresne et al. 2012; Honoré et al. 2015; Bent et al. 2016).  
Thus, even with the common use of regimens such as cyclophosphamide and vinorelbine, there 
is still need for more effective treatments (Scheer et al. 2019).  As DSRCT tumors display robust 
expression of VEGF pathway components, including VEFGR-2, VEGF-A, -C, and -D, there is 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 22
LY900023; LY3009806
the potential for therapeutic benefit for patients resulting from VEGFR-2 inhibition with 
ramucirumab.  Improved efficacy with ramucirumab in combination with cyclophosphamide and 
vinorelbine chemotherapy is expected to enhance these effects within evolving tumors by 
impeding the VEGF pathway’s maintenance of vascular endothelial cell survival and ability to 
drive angiogenesis.  Compelling efficacy and acceptable safety findings have also been observed 
when the related VEGF pathway inhibitor bevacizumab was added to a cyclophosphamide and 
vinorelbine backbone in 2 prospective STS studies in pediatric and young adult patients 
(Mascarenhas et al. 2014; Chisholm et al. 2017;).
Gastrointestinal (GI) perforation and severe bleeding including GI hemorrhage are considered 
key risks for the overall benefit/risk assessment of ramucirumab in the treatment of patients.  
However, the overall reporting rate of these events is low, and these risks are mitigated in the 
JV01 protocol through ongoing surveillance, identification (and exclusion) of patients with high 
bleeding risk, and dose modification or discontinuation of ramucirumab if a patient experiences a 
GI perforation/hemorrhage.  In addition, the currently available data from Study JVDA indicate 
that the pediatric safety profile of ramucirumab is consistent with that observed in adults, and the 
majority of events are low grade, monitorable, and manageable.  These risks, along with the 
potential pediatric-specific concerns of osteochondropathy of the epiphyseal growth plate and 
effects on renal function, which are monitored in the study, are considered acceptable when 
weighed against survival benefits for patients in this disease setting for which there are no other 
approved alternatives and a very short survival is expected.  Combining ramucirumab with 
cyclophosphamide and vinorelbine chemotherapies—all with well-established safety profiles—is 
anticipated to offer improved therapeutic benefit in an area of unmet medical need and with a 
manageable safety profile that will be closely monitored throughout the study.  Therefore, the 
benefit/risk assessment for ramucirumab in combination with cyclophosphamide and vinorelbine 
is considered favorable and supports the conduct of this trial.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 23
LY900023; LY3009806
3.4.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the efficacy of ramucirumab in combination 
with cyclophosphamide and vinorelbine compared with 
cyclophosphamide and vinorelbine in pediatric and 
young adult patients with DSRCT.
PFS
Secondary
To evaluate the safety and tolerability of ramucirumab in 
combination with cyclophosphamide and vinorelbine 
compared with cyclophosphamide and vinorelbine  in 
pediatric and young adult patients with DSRCT
SAEs, AEs, safety laboratory assessments, and vital 
signs
To evaluate the efficacy of ramucirumab in combination 
with cyclophosphamide and vinorelbine compared with 
cyclophosphamide and vinorelbine in pediatric and 
young adult patients with DSRCT

ORR 

DoR 

CR
To characterize the PK of ramucirumab when 
co-administered with cyclophosphamide and vinorelbine 
in pediatric and young adult patients with DSRCT
Cmax and Cmin
To assess the immunogenicity of ramucirumab when 
co-administered with cyclophosphamide and vinorelbine 
in pediatric and young adult patients with DSRCT
Incidence of immunogenicity
Exploratory
To explore additional measures of the efficacy of 
ramucirumab in combination with cyclophosphamide 
and vinorelbine compared with cyclophosphamide and 
vinorelbine in pediatric and young adult patients with 
DSRCT.

OS 

PFS2 

Difference in proportion of patients who become 
eligible for surgical resection of lesions due to 
documented tumor response while on study therapy
To explore the associations between biomarkers, disease 
state, and clinical outcomes
Biomarkers may be assessed from blood and tumor
tissue samples, unless precluded by local regulations
Abbreviations:  AE = adverse event; Cmax = maximum concentration; Cmin = minimum concentration; 
CR = complete response; DSRCT = desmoplastic small round cell tumor; DoR = duration of response; ORR = 
overall response rate; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event.
3.5.
Study Design
3.5.1. Overall Design
Study JV01, combined with Protocol J1S-MC-JAAA (hereinafter referred to as the CAMPFIRE
Master Protocol), is a Phase 1/2 randomized investigation in pediatric patients and young adults 
diagnosed with relapsed, recurrent, or refractory DSRCT evaluating ramucirumab in 
combination with low-dose cyclophosphamide and vinorelbine.  Patients will be randomized at a 
ratio of 2:1 to receive either experimental or control therapy, respectively. 
The primary endpoint of the study (PFS) will be evaluated via a Bayesian analysis incorporating 
information regarding historical control outcomes as well as effect-size observed in Study JV02.
This design allows for a reduced proportion of patients to be randomized to control therapy while 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 24
LY900023; LY3009806
maintaining power in light of sample-size limitations associated with the underlying rarity of the 
disease. Details of the Bayesian analysis are provided in the Statistical Analysis Plan (SAP),
Section 6.6.1. 
The study design is illustrated in Figure JV01.1.
Safety Lead-in Period: To assess excessive toxicity associated with the experimental 
ramucirumab-based combination, a safety lead-in period will be observed via the rolling six 
decision framework of Skolnik et al. (2008).  Based on the first 2 to 6 DLT-evaluable patients 
randomized in the ramucirumab arm at the planned 12-mg/kg dose (on a D1, D15 every 28 day 
schedule), the ramucirumab dose will be de-escalated to 8 mg/kg (on a D1, D15 every 28 day 
schedule) for Study JV01 should any of the ‘de-escalate’ criteria (Table JV01.5) be met, based 
on the totality of the data for which the DLTs are attributable to ramucirumab exposure.
Otherwise, enrollment will continue as planned. If the dose is de-escalated, Study JV01 will be 
terminated for safety should any of the criteria for terminating the study be met due to DLTs 
observed at 8 mg/kg (Table JV01.6) based on the totality of the data.  Otherwise, enrollment will 
continue with ramucirumab dosing at 8 mg/kg as planned. Enrollment in Study JV01 may be 
temporarily paused in certain circumstances in which 6 ramucirumab patients have enrolled at 
the current dose, but DLT data are pending in more than one patient (Table JV01.5).  Patients 
that complete the lead-in period will continue until one of the discontinuation criteria is met.  See 
Section 3.7.1.3 for determination of DLTs.
Table JV01.5.
Rolling Six Rules (Ramucirumab at 12 mg/kg)
Number 
Enrolled
Number with 
DLT
Number 
without DLT
Number 
Pending DLT 
Data
Safety Lead-In 
Rules
2
0,1
Any
Any
Continue Lead-In at 12 mg/kg
2
2
0
0
De-Escalate to 8 mg/kg
3
0
0,1,2
3,2,1
Continue Lead-In at 12 mg/kg
3
0
3
0
Lead-In Period Ends
3
1
Any
Any
Continue Lead-In at 12 mg/kg
3
≥2
Any
Any
De-Escalate to 8 mg/kg
4
0
0,1,2,3
4,3,2,1
Continue Lead-In at 12 mg/kg
4
0
4
0
Lead-In Period Ends
4
1
Any
Any
Continue Lead-In at 12 mg/kg
4
≥2
Any
Any
De-Escalate to 8 mg/kg
5
0
0,1,2,3,4
5,4,3,2,1
Continue Lead-In at 12 mg/kg
5
0
5
0
Lead-In Period Ends
5
1
Any
Any
Continue Lead-In at 12 mg/kg
5
≥2
Any
Any
De-Escalate to 8 mg/kg
6
0
<5
≥2
Pause Enrollment for DLT Data
6
0
5,6
1,0
Lead-In Period Ends 
6
1
<5
≥2
Pause Enrollment for DLT Data
6
1
5
0
Lead-In Period Ends
6
≥2
Any
Any
De-Escalate to 8 mg/kg
Abbreviation:  DLT = dose-limiting toxicity.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 25
LY900023; LY3009806
Table JV01.6.
Rolling Six Rules (Ramucirumab at 8 mg/kg)
Number 
Enrolled
Number with 
DLT
Number 
without DLT
Number 
Pending DLT 
Data
Safety Lead-In
Rules
2
0,1
Any
Any
Continue Lead-In at 8 mg/kg
2
2
0
0
Terminate
3
0
0,1,2
3,2,1
Continue Lead-In at 8 mg/kg
3
0
3
0
Lead-In Period Ends
3
1
Any
Any
Continue Lead-In at 8 mg/kg
3
≥2
Any
Any
Terminate
4
0
0,1,2,3
4,3,2,1
Continue Lead-In at 8 mg/kg
4
0
4
0
Lead-In Period Ends
4
1
Any
Any
Continue Lead-In at 8 mg/kg
4
≥2
Any
Any
Terminate
5
0
0,1,2,3,4
5,4,3,2,1
Continue Lead-In at 8 mg/kg 
5
0
5
0
Lead-In Period Ends
5
1
Any
Any
Continue Lead-In at 8 mg/kg
5
≥2
Any
Any
Terminate
6
0
<5
≥2
Pause Enrollment for DLT Data
6
0
5,6
1,0
Lead-In Period Ends 
6
1
<5
≥2
Pause Enrollment for DLT Data
6
1
5
0
Lead-In Period Ends
6
≥2
Any
Any
Terminate
Abbreviation:  DLT = dose-limiting toxicity.
Interim Futility Analysis: An interim futility analysis for Study JV01 will be triggered when 
approximately 24 total PFS events have been observed across Study JV01 and Study JV02, with 
a minimum of 8 events in each study. At the interim futility look, the Bayesian analysis must 
provide a minimum of 60% confidence in treatment superiority (PFS hazard ratio [HR] <1 for 
DSRCT patients) in order for enrollment on Study JV01 to continue. Otherwise, enrollment on 
Study JV01 will be stopped. 
Primary Analysis: If Study JV01 passes the futility analysis (and thus continues enrollment), 
the primary analysis will be triggered when PFS events have occurred for approximately 80% of 
the enrolled patients (across both Study JV01 and Study JV02, regardless of whether Study JV02 
passed its futility look). In order to conclude success for the investigation in DSRCT, Study 
JV01 must carry a minimum of 99% confidence in treatment superiority (PFS HR<1 for DSRCT 
patients) evaluated via the Bayesian analysis.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 26
LY900023; LY3009806
Abbreviations:  d = day; n = approximate number of patients per group; qd = daily.
Note: PFS to be analyzed via Bayesian analysis, which includes adaptive borrowing on 
effect-size between JV01 and JV02 and augmentation of control arms with historical 
data.
Figure JV01.1.
Illustration of Study JV01 and Study JV02 Designs
3.5.2. Number of Patients
Approximately 30 patients older than 12 months and ≤29 years of age will be enrolled in 
Study JV01. The study must enroll a minimum of 10 patients ≤17 years old with DSRCT.   
Patients will be allocated between the ramucirumab and control arm at a 2:1 ratio.  
3.5.3. End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 3.2) for the last patient.
3.5.4. Scientific Rationale for Study Design
There is currently no standard of care or approved agents for treating relapsed or recurrent 
DSRCT in either the pediatric or adult setting.  Superiority of any one regimen has not been 
determined for DSRCT, though many systemic treatment regimens have been tried, likely chosen 
in part due to patients’ past exposure, toxicity profiles, access to agents, and regional treatment 
preferences for pretreated sarcomas.  Reports have described activity using cyclophosphamide 
and vinorelbine for DSRCT, with and without temsirolimus (Ferrari et al. 2007; Tarek et 
al. 2018).

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 27
LY900023; LY3009806
Given DSRCT is a disease that straddles adolescence into early adulthood, with little to no 
expectation of difference in clinical presentation or outcome, Study JV01 will include children, 
adolescents, and young adult patients ≤29 years of age to ensure the study is feasible.  Emphasis 
will be placed on enrolling patients younger than 18 years old by partnering with investigators 
and consortia that focus on treating pediatric patients.
3.5.5. Justification for Dose
A ramucirumab dosing regimen of 12 mg/kg once every 2 weeks (Q2W) in combination with 
cyclophosphamide (25 mg/m2 once daily [QD]) and vinorelbine (25 mg/m2 onDays 1, 8, and 15 
of a 28-day [4 weeks] cycle) will be evaluated in DSCRT patients in Study JV01.
Ramucirumab dosing and schedule are based on the recommended Phase 2 dose (RP2D) dose 
determined in Part A of Study JVDA in conjunction with the schedule of the 
cyclophosphamide/vinorelbine backbone being used. 
To optimize the dosing regimen sought to treat pediatric and young adult patients, the RP2D in 
Study JVDA was defined as the dose achieving the steady-state minimum concentration (Cmin)
of ≥50 μg/mL in a majority of patients, assuming a maximally tolerated dose was not reached. 
Justification for this target was based on the observed association between ramucirumab 
exposure and an improvement in OS and PFS in Phase 3 studies, in which exposure-response 
analysis across the studies indicated an EC50 value of ~50 µg/mL. A minimum of 50 µg/mL was 
therefore used as the targeted efficacious concentration level for selection of the RP2D in Study 
JVDA. 
Results of the dose-finding component of Study JVDA identified the RP2D for pediatric and 
young adult patients as 12 mg/kg when administered as monotherapy on a Q2W schedule. The 
safety profile at the RP2D was also found to be acceptable and consistent with ramucirumab’s 
well-characterized safety profile in the approved adult dosing regimens of 8 mg/kg Q2W and 
10 mg/kg Q3W.  Of interest, the 12-mg/kg Q2W ramucirumab dosing regimen has also been 
shown to be well tolerated in adult studies when given as monotherapy (Study JVDB) and in 
combination with paclitaxel (Study JVCZ) in patients with gastric cancer.  As the RP2D of 
12 mg/kg Q2W follows a 28-day cycle like the cyclophosphamide/vinorelbine backbone 
regimen-planned Study JV01, this ramucirumab regimen of 12 mg/kg Q2W has been chosen for 
treatment of patients with DSRCT.
To verify the weight-based dosing approach for ramucirumab in the age range proposed for 
Study JV01, preliminary pharmacokinetic (PK) data from Study JVDA was evaluated (ages: 3
to 21 years; body weight: 11 to 91 kg). A higher exposure was generally observed in patients 
receiving the 12-mg/kg dose as compared to those receiving an 8-mg/kg dose (data on file).  The 
exposures observed in Study JVDA were similar to those observed in adult patients (data on 
file).  Moreover, within each dose level, similar ramucirumab exposures were observed across 
the age and body weight ranges studied in Study JVDA (data on file), indicating the body 
weight-based dosing regimen is expected to produce comparable exposure levels for patients
within the age range from 3 to 21 years old.  The PK data from adult patients also suggested a 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 28
LY900023; LY3009806
similar exposure level for patients from 21 to 29 years following the same body weight-based 
dosing regimen. Of note, PK data is not available for patients less than 3 years old.
Safety data from the non-central nervous system (CNS) arm of JVDA (Part A) includes data 
from 23 patients.  There were no deaths or life-threatening events reported due to 
treatment-emergent adverse events (TEAEs) during the study.  One patient experienced a 
dose-limiting toxicity (DLT) at each dose level.  Both events were Grade 2 proteinuria, which 
resulted in each patient discontinuing treatment on their respective dose level.  No other patients 
discontinued treatment due to TEAEs.
Nine out of 23 patients experienced at least 1 serious adverse event (SAE) (39.1%), 2 (25.0%) at 
Dose Level 1 and 7 (46.7%) at Dose Level 2.  The most frequently reported SAEs were pyrexia 
(3 patients) and dyspnoea and hypoxia (2 patients each), all reported at Dose Level 2.  Other 
relevant SAEs were pulmonary hemorrhage, lung infection, and possible infection (1 patient 
each). The SAEs reported were Grades 2 and 3, none of which required patients to discontinue 
from treatment.  Most SAEs were consistent with the expected courses for the underlying 
diseases and/or for patients on ramucirumab treatment.
All patients experienced at least 1 TEAE.  A higher incidence of individual TEAEs was observed 
at Dose Level 2 compared with Dose Level 1 for the majority of events reported; however, most 
of the TEAEs were low-grade (Grade 1 or 2), with a similar number of Grade 3 events in both 
dose levels.  Overall, the most common TEAEs, occurring in >40% of patients, were aspartate 
aminotransferase (AST) increased (13 patients), anaemia and nausea (11 patients each), and 
vomiting and headache (10 patients each).  A total of 13 patients (56.5%) experienced Grade 3 
TEAEs, 5 patients in Dose Level 1 (62.5%) and 8 patients in Dose Level 2 (53.3%).  The most 
common Grade 3 TEAEs included lymphocyte count decreased and pyrexia and hypoxia (2 
patients each).  
Adverse events of special interest (AESIs) typically seen in adult patients treated with 
ramucirumab, including bleeding/hemorrhage, hypertension, and proteinuria, were also observed 
in pediatric and young adult patients, and were primarily Grade 1 or 2 events.
As these are recognized events occurring with ramucirumab, the JV01 study incorporates risk 
minimization measures for these AESIs including exclusion of patients at higher risk of these 
events, i.e., those with uncontrolled hypertension, increased risk for bleeding, or high levels of 
urine protein at baseline.  In addition, throughout the study there is routine and frequent 
monitoring, with guidelines for supportive care, dose modifications, and treatment 
discontinuation to assist in the management of these events. 
To further mitigate potential safety risks and ensure the proposed regimen maintains an 
acceptable safety profile in DSCRT patients, a safety lead-in will be conducted to assess the 
safety and tolerability of ramucirumab administered IV at a dose of 12 mg/kg every 2 weeks in 
combination with cyclophosphamide and vinorelbine, since the selected combination has not 
been previously studied.  Based upon the review of the early safety analysis, study modifications 
may be warranted.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 29
LY900023; LY3009806
In summary, the dosing regimen of ramucirumab 12 mg/kg IV on Day 1 every 2 weeks in 
combination with cyclophosphamide (25 mg/m2 QD) and vinorelbine (25 mg/m2 onDays 1, 8, 
and 15 of a 28-day [4 weeks] cycle) was selected for this study to potentially maximize clinical 
benefit, and is anticipated to produce a favorable benefit-risk profile in DSCRT patients.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
3.6.
Study Population
3.6.1. Inclusion Criteria
Patients are eligible to be included in the Study JV01 only if they meet all of the inclusion 
criteria in Section 6.1 of the CAMPFIRE Master Protocol and the following criteria:
[14] Patients must be 12 months to ≤29 years of age at the time of study enrollment.  
a) In the European Union (EU) countries participating in Voluntary 
Harmonization Procedure (VHP, see Attachment 1), patients must be 36 
months to ≤29 years of age, >11 kg at the time of study enrollment, and must be 
able to swallow cyclophosphamide tablets. 
[15] Patients with relapsed, recurrent, or refractory DSRCT.
[16] Patients must:

have measurable disease by RECIST 1.1.

have received at least one prior line of systemic treatment (including 
neoadjuvant and adjuvant chemotherapy).  This prior treatment must include 
approved therapies for which they are eligible, unless the patient is not a 
suitable candidate for the approved therapy. 

not be eligible for surgical resection at time of enrollment.
[17] Patients must not have received prior exposure to ramucirumab.
[18] Adequate cardiac function, defined as:

Shortening fraction of ≥27% by echocardiogram, or

Ejection fraction of ≥50% by gated radionuclide study.
[19] Adequate blood pressure (BP) control, defined as:

Patients ≥18 year-old: 
o
The patient has controlled hypertension defined as systolic 
BP≤150 mmHg or diastolic BP≤90 mmHg where standard medical 
management is permitted. Please note that ≥2 serial BP readings 
should be obtained and averaged to determine baseline BP.

Patients <18 years-old:
o
A BP≤95th percentile for age, height, and gender measured as 
described in NHBPEPWG on High Blood Pressure in Children and 
Adolescents (2004), where standard medical management is 
permitted. Please note that ≥2 serial BP readings should be obtained 
and averaged to determine baseline BP.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
[20] The patient has an adequate coagulation function as defined by International Normalized 
Ratio ≤1.5 or prothrombin time ≤1.5×ULN, and partial thromboplastin time ≤1.5×ULN if 
not receiving anticoagulation therapy.  For patients receiving anticoagulants, exceptions 
to these coagulation parameters are allowed if they are within the intended or expected 
range for their therapeutic use.  Patients must have no history of clinically significant
active bleeding (defined as within 14 days of first dose of study drug) or pathological 
condition that carries a high risk of bleeding (for example, tumor involving major vessels 
or known esophageal varices).
3.6.1.1.
Exceptions to the CAMPFIRE Master Protocol Inclusion Criteria
For Study JV01, the below inclusion criteria should be used in place of the 
CAMPFIRE Master Protocol inclusion criteria of the corresponding number.
[4]
Patients must have discontinued all previous treatments for cancer or 
investigational agents ≥7 days after the last dose or as shown below, and must 
have recovered from the acute effects to ≤Grade 2 for alopecia and decreased 
tendon reflex and to ≤Grade 1 for all other effects at the time of enrollment, 
unless otherwise noted.  For agents with known AEs occurring beyond the 
required wait period outlined in the table, this period must be extended until 
after the time during which the AE is known to occur.  Consult with the Lilly 
CRS/CRP for the appropriate length of time prior to the first dose of study 
treatment on additional therapies not mentioned.
Previous Treatment
Length of Time Prior to First Dose of Study 
Treatment
Cytotoxic and myelosuppressive chemotherapy
≥14 days after the last dose of cytotoxic or 
myelosuppressive chemotherapy (or ≥42 days if 
prior nitrosourea)
Hematopoietic growth factors
≥14 days after the last dose of a long-acting 
growth factor (for example, pegfilgrastim) or 
≥48 hours for short-acting growth factor
Cellular therapy
≥42 days after the completion of any type of 
cellular therapy (eg modified T cells, NK cells, 
dendritic cells, etc.) agent
Interleukins, interferons, and cytokines (other than 
hematopoietic growth factors)
≥21 days after the completion of interleukins, 
interferon, or cytokines (other than hematopoietic 
growth factors)
Antibody therapy
≥21 days after the last infusion of antibody
therapy.  For patients in the EU countries 
participating in VHP, the washout-period after 
previous antibody therapy is defined as 4 half-
lives after the last dose of the antibody.
Radiotherapy
≥ 14 days since local palliative radiation therapy 
(RT) (small port); craniospinal XRT, or 50% or 
greater pelvic radiation; ≥ 42 days for other 
substantial radiation (such as 
metaiodobenzylguanidine therapy)
Radiopharmaceutical therapy (eg, radiolabeled 
≥42 days after systemically administered 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
Previous Treatment
Length of Time Prior to First Dose of Study 
Treatment
antibody, 131I-MIBG)
radiopharmaceutical therapy
Stem cell infusion without TBI
≥84 days must have elapsed after auto-transplant 
or stem cell infusion
Corticosteroids
≥14 days for patients who have received a course 
of systemic corticosteroids (≥5 days) to modify 
immune AEs related to prior therapy. 
Note:  Patients who are on chronic replacement 
dose for endocrine disorders or are on a stable 
or decreasing dose for indications other than 
treating the underlying cancer, may still be 
eligible (consult Lilly CRP/CRS)
Live vaccines
≥28 days after last live vaccine
[5]
The patient has adequate hematologic, organ, and coagulation function ≤1 week 
(7 days) prior to first dose of study drug:
System
Laboratory Value
Hematologic
ANC
750/µL (1500/µL for patients in the EU countries 
participating in VHP)
G-CSF permitted up to 48 hours prior.
Patients with documented history of benign ethnic 
neutropenia or other conditions could be considered with a 
lower ANC after discussion with and approval from the Lilly 
CRP/CRS
Platelets
75,000/mm3 (100,000/mm3 for patients in the EU 
countries participating in VHP)
Platelet transfusion permitted up to 72 hours prior.
Hemoglobin
8 g/dL (≥80 g/L)
Transfusions to increase the patient’s hemoglobin level to at 
least 8 g/dL are permitted; however, study treatment must not 
begin until 7 days after the transfusion, and CBC criteria for 
eligibility are confirmed within 24 hr of C1D1
Hepatic
Total bilirubin
1.5×ULN
Except patients with document history of Gilbert Syndrome 
who must have a total bilirubin level of <3.0×ULN
ALT and AST
2.5×ULN OR
5.0×ULN if the liver has tumor involvement
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; CBC = complete blood count; G-CSF = granulocyte-colony stimulating factor;
ULN = upper limit of normal.
Adequate renal function, defined as:

Creatinine clearance or radioscope glomerular filtration rate (GFR) 
≥60 mL/min/m2 (Appendix 4) OR

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806

Serum creatinine meeting the following parameters: 
o
for patients ≥18 years of age serum creatinine ≤1.5×upper limit of 
normal (ULN);
o
for patients <18 years of age, serum creatinine based on age/gender 
as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
1 to <2 years
0.6
0.6
2 to <6 years
0.8
0.8
6 to <10 years
1.0
1.0
10 to <13 years
1.2
1.2
13 to <16 years
1.5
1.4
16 to <18 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for 
estimating glomerular filtration rate (Appendix 4).

Urine protein meeting the following parameters:
o
for patients ≥18 years of age: <2+ on dipstick or routine urinalysis.  
If urine dipstick or routine analysis indicates proteinuria ≥2+, then a 
24-hour urine must be collected and must demonstrate <2 g of 
protein in 24 hours or the urine protein to creatinine (UPC) ratio 
from a random urine sample can be calculated and must be <1 to 
allow participation in the study.
o
for patients <18 years of age: ≤30 mg/dl urine analysis or <2+ on 
dipstick. If urine dipstick or routine analysis indicates proteinuria 
>30mg/dl or ≥2+, then either a 24-hour urine can be collected and 
must demonstrate <1 g of protein in 24 hours or the urine protein to 
creatinine (UPC) ratio from a random urine sample can be 
calculated and must be <1 to allow participation in the study.
[7]
Both female and male patients of childbearing potential must agree to use highly 
effective contraceptive precautions during the trial, for at least 3 months following 
the last dose of ramucirumab and vinorelbine, and 12 months following the last 
dose of cyclophosphamide in order to prevent pregnancy.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
Females of child-bearing potential (FOCBP) and males who are abstinent (if 
this is complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must agree 
to either remain abstinent or stay in a same-sex relationship without sexual 
relationships with someone of the opposite sex. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post ovulation methods), declaration of 
abstinence just for the duration of the trial, and withdrawal are not acceptable 
methods of contraception.
Females: FOCBP participating must test negative for pregnancy prior to 
initiation of treatment as indicated by a negative urine or serum pregnancy test 
at the screening visit.  Two forms of effective contraception, where at least 
one form is highly effective (less than 1% failure rate; includes combination 
oral contraceptives, implanted contraceptives, or intrauterine devices) must be 
used. Effective contraception (such as male or female condoms with 
spermicide, diaphragms with spermicide, or cervical sponges) may be used as 
the second therapy. Barrier protection methods without concomitant use of a 
spermicide are not a reliable or acceptable method. Thus, each barrier method 
must include use of a spermicide (i.e., condom with spermicide, diaphragm 
with spermicide, or female condom with spermicide). It should be noted that 
the use of male and female condoms as a double barrier method is not 
considered acceptable due to the high failure rate when these methods are 
combined.
Males:  Males, regardless of their fertility status, with nonpregnant FOCBP
partners must agree to use condoms as well as one additional highly effective 
method of contraception (less than 1% failure rate; includes combination oral 
contraceptives, implanted contraceptives, or intrauterine devices) for the 
duration of the study and up to 3 months following the last dose of study drug, 
or longer, if appropriate for other study drugs according to their label in order 
to prevent pregnancy.
Barrier protection methods without concomitant use of a spermicide are not an 
effective or acceptable method of contraception. Thus, each barrier method 
must include use of a spermicide. It should be noted, however, that the use of 
male and female condoms as a double barrier method is not considered 
acceptable due to the high failure rate when these barrier methods are 
combined.  Males with pregnant partners should use condoms during 
intercourse for the duration of the study and for at least 3 months after the last 
dose of study drug, or longer, if appropriate for any study drug according to 
the label.
3.6.2. Exclusion Criteria
Patients will be excluded from Study JV01 if they meet any of the exclusion criteria in 
Section 6.2 of the CAMPFIRE Master Protocol or the following criteria:
[21] Are currently taking any prohibited medications outlined in Attachment 5.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
[22] Bleeding and thrombosis:

Patients with evidence of active bleeding or a history of significant (≥Grade 3) 
bleeding event within 3 months prior to enrollment are not eligible.

Patients with a bleeding diathesis or vasculitis are not eligible.

Patients with known or prior history in the prior 3 months of esophageal varices are 
not eligible.

Patients with a history of deep vein thrombosis requiring medical intervention
(including pulmonary embolism) within 3 months prior to study enrollment are not 
eligible. 

Patients with a history of hemoptysis or other signs of pulmonary hemorrhage 
within 3 months prior to study enrollment are not eligible. 
[23] Cardiac:

Patients with a history of central nervous system (CNS) arterial/venous 
thromboembolic events (VTEs) including transient ischemic attack (TIA) or 
cerebrovascular accident (CVA) within 6 months prior to study enrollment are not 
eligible.

Patients with myocardial infarction or unstable angina within the prior 6 months.

Patients with New York Heart Association Grade 2 or greater congestive heart failure
(CHF).

Patients with serious and inadequately controlled cardiac arrhythmia.

Patients with significant vascular disease (eg, aortic aneurysm, history of aortic 
dissection).

Patients with clinically significant peripheral vascular disease.
[24] Patients who have a history of fistula, gastrointestinal (GI) ulcer or perforation, or 
intra-abdominal abscess within 3 months of study enrollment are not eligible. 
[25] Patients with a history of hypertensive crisis or hypertensive encephalopathy within 
6 months of study enrollment are not eligible.
[26] Patients who have non-healing wound, unhealed or incompletely healed fracture, or a 
compound (open) bone fracture at the time of enrollment are not eligible.
[27] Patients previously treated and progressed on combination cyclophosphamide and 
vinorelbine regimen.  Patients who received combination as maintenance therapy, 
without progression, would be eligible. 
[28] Patients with a known hypersensitivity to ramucirumab, cyclophosphamide, vinorelbine
or any of the excipients of the medicinal products.
[29] Hepatic impairment:

Severe liver cirrhosis Child-Pugh Class B (or worse) 

Cirrhosis with a history of hepatic encephalopathy

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806

Clinically meaningful ascites resulting from cirrhosis and requiring ongoing treatment 
with diuretics and/or paracentesis

History of hepatorenal syndrome.
[30] The patient has a bowel obstruction, history or presence of inflammatory 
enteropathy or extensive intestinal resection (eg, hemicolectomy or extensive 
small intestine resection with chronic diarrhea), Crohn's disease, ulcerative 
colitis, or chronic diarrhea.
[31] The patient has a urinary outflow obstruction
[32] The patient has Grade 2 hematuria or non-infectious cystitis at the time of 
screening. 
[33] Patients with CNS involvement are ineligible.
3.6.2.1.
Exceptions to the CAMPFIRE Master Protocol Exclusion Criteria
There are no exceptions to the CAMPFIRE Master Protocol exclusion criteria. 
3.6.3. Lifestyle Restrictions
Patients should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study due to the effect on cytochrome P450 (CYP)3A4 and the potential for 
toxicities related to cyclophosphamide.
3.7.
Treatments
3.7.1. Treatments Administered
A delay of a dose due to holiday, weekend, bad weather, or other unforeseen circumstances will 
be permitted for a maximum of ±3 days and not counted as a protocol deviation.  However, 
clinical assessment time frames relative to drug administration, as shown in the schedule of 
activities, must be maintained.
3.7.1.1.
Premedication
All premedication administered must be adequately documented in the electronic case report 
form (eCRF).
3.7.1.1.1. Ramucirumab
Patients should receive premedication with diphenhydramine or an alternative antihistamine 
within 30 to 60 minutes prior to each infusion with ramucirumab.
3.7.1.2.
Dosing Schedule
The following treatments will be administered in this study every 4-week (28-day) cycle:

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
Table JV01.7.
Treatment Regimens/Dosing Schedule
Study Drug
Arm
Dose
Route
Timing
Ramucirumaba
1
12 mg/kgb
IV
Approximately 1-hour infusion 
on Days 1 and 15 of each 
28-day cycle. 
Cyclophosphamide
1 and 2
25 mg/m2
PO
Daily on Days 1-28 of each 
28-day cycle
Vinorelbine
1 and 2
25 mg/m2
IV
Days 1, 8, and 15 of each 
28-day cycle
Abbreviations:  kg = kilogram; IV = intravenous; mg = milligram; PO = by mouth.
a
Patients must be closely monitored for a 1-hour observation period following the ramucirumab infusions for the 
first 2 infusions (see Section 3.7.6.1.8.1).
b
During the rolling-six safety lead-in, de-escalation of ramucirumab to 8 mg/kg may be necessary per
      Table JV01.5.
A cycle is defined as an interval of 28 days.  
For patients on the ramucirumab arm, ramucirumab is to be administered first, followed by 
vinorelbine on days when both are to be given.  During the first two ramucirumab infusions, 
patients must be closely monitored for a 1-hour observation period following the ramucirumab 
infusions prior to being administered vinorelbine (see Section 3.7.6.1.8.1).  On these visits, 
cyclophosphamide must also be taken in clinic following the ramucirumab infusion observation 
period.  On all other days, including days of study treatment, cyclophosphamide may be taken at 
home prior to clinic visits.  In addition, vinorelbine may be given without the post-ramucirumab 
observation period after the first two ramucirumab infusions, unless an infusion-related reaction 
(IRR) has occurred.
Cyclophosphamide will be administered orally at a dose of 25 mg/m2 every day (no rest between 
cycles) in the morning.  It is recommended patients take cyclophosphamide with adequate fluid 
intake (at least 1 L/m2 per day) in order to minimize damage to the transitional epithelium.  If 
oral cyclophosphamide is administered in capsules/tablets of 50 mg, which cannot be cut into 
smaller capsules/tablets, the doses should be divided over an adequate number of days to 
maintain an average daily dose over 28 days (or 1 cycle) within the 10% margin for body surface 
area (BSA) as per institutional guidelines.  There should be no more than 2 planned days
between consecutive doses of cyclophosphamide capsules/tablets.  For example, in the case of a 
patient with a BSA of 1.3 m2, the daily dose should be 32.5 mg, corresponding to about 100 mg 
every 3 days; therefore, one entire capsule/tablet (50 mg) should be given for two consecutive 
days followed by one day off.  
Cyclophosphamide may be reconstituted to a concentration of 2 mg cyclophosphamide per mL 
in aromatic elixir, USP for oral administration for subjects who are unable to swallow tablets.  
The oral administration may be prepared by dissolving cyclophosphamide for injection in 
aromatic elixir, USP, which is a compendial product with a defined composition of a suitable 
essential oil, sucrose syrup, talc, ethyl alcohol, and purified water.  Such preparations should be 
stored under refrigeration in glass containers and used within 14 days.  See the pharmacy manual 
for more information.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
After the start of a cycle, treatment should continue on schedule if possible, but a variance of 
±3 days may be allowed to accommodate holidays, weekends, inclement weather, or other 
justifiable events.  If the patient’s weight fluctuates by more than ±10% from the weight used to 
calculate the prior dose, the dose of study drugs must be recalculated.  Study treatment may be 
modified according to Section 3.7.4.
If ramucirumab Day-1 dose is delayed, a minimum of 2 weeks between ramucirumab
administration is required. 
Intravenous study drugs can only be administered at the investigational site, at-home 
administration is not permitted in this study. In the event of treatment delays of IV study drugs
that is greater than 1 treatment cycle (28 days), unrelated to AEs but due to unforeseeable 
circumstances (e.g., COVID-19 pandemic resurgence) and in the principal investigator’s 
discretion the patient has experienced clinical benefit, a discussion with Lilly CRP/CRS should 
occur before resuming IV study drugs. In addition, all on-treatment SoA as in Table JV01.2 must 
resume. 
If a dose de-escalation is deemed appropriate during the safety lead-in period due to DLTs
(Table JV01.5), the dose of ramucirumab will de-escalate from 12 mg/kg to 8 mg/kg intravenous 
(IV). No changes to the procedures will be affected with the exception of the dose of 
ramucirumab. 
During the course of study treatment, patients may become eligible and undergo surgical 
resection of their disease.  These patients may continue to receive study treatment if deemed 
beneficial in consultation with the Lilly CRP/CRS.  Treatment should be held before surgery and 
resume at least 14 days postsurgery when acute toxicities of surgery are recovered per 
investigator discretion.  Patients should continue to follow study procedures outlined in the 
protocol including radiologic evaluation.  
Ramucirumab contains 0.1 mg of polysorbate 80 in each 1 ml of medicinal product, which is 
equivalent to 0.12 mg/kg per dose. Rarely, patients can experience severe allergic reactions to 
polysorbates.  Each ramucirumab 10 ml vial contains 17 mg of sodium which is less than 1 mmol 
sodium (23 mg), that is, essentially ‘sodium free.’  
See guidelines on supportive care (Section 3.7.6.1) while administering study treatment.  For any 
specific concerns not discussed in the guidelines, investigators should consult the PI for 
additional precautions.
3.7.1.3.
Dose-Limiting Toxicity Determination
A DLT is defined as one of the following adverse events (AEs) reported during Cycle 1 of the 
rolling six safety lead-in (Table JV01.5), if considered to be definitely, probably, or possibly 
related to ramucirumab by the investigator; and fulfills any one of the following criteria using 
NCI CTCAE Version 5.0:
1.
Hepatic biochemical tests will be considered DLTs as follows:

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
Patients with normal or near normal alanine aminotransferase (ALT) or AST at baseline 
(<1.5x ULN):

ALT or AST ≥8× ULN on 2 or more consecutive tests (at least 2 days apart) in 
the absence of a clear cause of hepatic injury other than the study drug. 

ALT or AST ≥3× ULN and TBL ≥2× ULN on 2 or more consecutive tests (at 
least 2 days apart) in the absence of significant cholestasis and in the absence of a 
clear cause of hepatic injury other than the study drug. 
Patients with elevated ALT or AST at baseline (≥1.5x ULN):

ALT or AST ≥5× baseline on 2 or more consecutive tests (at least 2 days apart) in 
the absence of a clear cause of hepatic injury other than the study drug. 

ALT or AST ≥3× baseline and TBL ≥2× ULN on 2 or more consecutive tests (at 
least 2 days apart) in the absence of significant cholestasis and in the absence of a 
clear cause of hepatic injury other than the study drug. 
2.
Any other nonhematologic toxicity Grade ≥3 will be considered as DLT with the 
following exceptions:
a) Grade 3 nausea, vomiting, diarrhea, and constipation that can be controlled 
with treatment.  If persisting more than 72 hours despite maximal supportive 
intervention, considered a DLT.
b) Asymptomatic transient Grade 3 electrolyte disturbance that can be controlled 
with oral substitution therapy or by IV infusions, and does not require 
hospitalization.
c) Grade 3 fatigue. 
d) Grade 3 fever or Grade 4 fever <48 hours. 
e) Grade 3 infection.
Note: Allergic reactions are NOT considered a DLT, even if necessitating 
discontinuation of a study drug.
3.
The following hematologic toxicities will be considered DLTs:
a) Grade 4 anemia, persistent despite maximal supportive intervention
b) Platelet count <20,000/mm3 on 2 separate days, or requiring a platelet transfusion on 
2 separate days, within a 7-day period
c) Platelet count <50,000/mm3 if associated with medically relevant bleeding
d) Absolute neutrophil count (ANC) <500/mm3 for >7 days
o
Note: Febrile neutropenia will only be considered a DLT if the ANC<500/mm3
for >7 days. 
e) Myelosuppression that causes a delay of >14 days in initiating Cycle 2.
f)
Other hematological DLTs:

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
• Any arterial thromboembolic event (ATE; including cerebrovascular 
ischemia, peripheral or visceral arterial ischemia)
• Any ≥Grade 3 VTE
• Any thrombotic event requiring systemic anti-coagulation
• Any ≥Grade 3 hemorrhage
4.
Hypertension: 
a) Patients ≥18 years old: Grade 3 or 4 as defined in the CTCAE v5.0
b) Patients <18 years old: 
o
Any Grade 4 hypertension
o
BP>25 mmHg above the 95th percentile for age, height, and gender confirmed by 
repeated measurement is dose-limiting
o
In patients who begin and are compliant on antihypertensive therapy BP>10 
mmHg, but ≤25 mmHg, above the 95th percentile for age, height, and gender 
(NHBPEPWG on High Blood Pressure in Children and Adolescents, 2004) for 
>14 days despite appropriate management with antihypertensive therapy is 
dose-limiting.
5.
Proteinuria:
a) Patients ≥18 years old: 24-hour urine protein of 2 to 3 g/24 hours confirmed with a 
second measurement within 72 hours; or ≥3 g/24 hours on first assessment.
b) Patients <18 years old: urine protein/creatinine (P/C) ratio of >1 and <1.9, calculated 
from a random urine collection and confirmed with a second measurement within 72 
hours; or a UPC ratio >1.9 on first assessment.
6.
Any GI perforation event 
7.
Grade ≥2 posterior reversible encephalopathy syndrome (PRES)
8.
Grade 5 toxicity (that is, death), if considered related to study treatment
9.
Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose-limiting, for example:
a) Any toxicity that is possibly related to study treatment that requires the withdrawal of 
the patient from the study during observation period
b) A delay of >14 days due to persistent Grade ≥2 treatment-related toxicities in Cycle 1 
with the exception of fatigue
Other potentially reversible risk factors for the AE should be identified and addressed as 
appropriate.  Potential DLTs that are reasonably anticipated AEs for concomitant medication 
should be reviewed by the treating investigator and Lilly CRP before final determination as a 
DLT.  Review and discussion may include additional participating investigators.  Such review 
may determine that confounding factors render the case to be not evaluable for the purposes of 
dose selection.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
A DLT-evaluable patient is considered to be one who either completed 1 cycle of treatment or 
discontinued from the treatment due to a DLT.  A DLT-non-evaluable patient is considered one 
who experienced disease progression, was noncompliant, discontinued for reasons other than 
AEs within the first cycle of treatment, or did not complete the safety monitoring for the DLT 
Assessment Period for any reason other than a DLT.  Additional patients may be included in the 
safety lead-in to replace any patient deemed non-evaluable. 
3.7.2. Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomly assigned to receive study
treatment.  Before each patient’s enrollment into the study, an eligibility check must be 
conducted between the investigational site and the Lilly clinical research personnel to confirm 
that each patient meets all enrollment criteria.  Upon confirmation of eligibility, the site will 
register the patient by assigning the patient a unique study identification number via the 
Interactive Web-Response System (IWRS), which is accessible 24 hours a day.  Study treatment
will be allocated to patients using the IWRS.
Patients who meet all criteria for enrollment will be randomly assigned to receive 
cyclophosphamide and vinorelbine with or without ramucirumab.
Approximately 30 patients will be randomized in a 2:1 ratio (ramucirumab arm versus control,
respectively).  
Randomization will be stratified by staging at relapse (metastatic disease versus locally 
advanced).
3.7.3. Blinding
This is an open-label study.
3.7.4. Dose Modification
Dose adjustments (suspensions, reductions, or discontinuations) will be made based on the 
clinical assessment of hematologic and nonhematologic toxicities (defined as an AE possibly 
related to study treatment per investigator judgment).  The CTCAE v 5.0 will be used to assess 
AEs.  Treatment may be suspended for a maximum of 28 days to allow a patient sufficient time 
for recovery from study treatment-related toxicity.  Other potentially reversible risk factors for 
the AE should be identified and addressed as appropriate.  If a patient does not recover from the 
toxicity within 28 days from the time of last treatment, the patient should be considered for 
permanent discontinuation from study treatment.  In exceptional circumstances, a delay >28 days 
is permitted upon agreement between the investigator and the Lilly CRP/CRS.
In general, dose adjustments of one study drug (ramucirumab, cyclophosphamide, or 
vinorelbine) due to toxicity guidances outlined in Section 3.7.4.1 will not necessitate 
suspensions, reductions, or discontinuation of the other unrelated study drug(s).  However, close 
consideration must be made by the investigator to administer all study treatments per the 
schedule outlined in Section 3.7.1.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
Any patient who requires a dose reduction for drug-related toxicity will continue to receive the 
reduced dose for the remainder of the study.  For ramucirumab, cyclophosphamide, or 
vinorelbine, any patient who has had 2 dose reductions in the same agent and who experiences a 
toxicity that would cause a third dose reduction must be discontinued from that study treatment.  
If cyclophosphamide is held, patients may restart on the same day as recovery from the AE, 
irrespective of when in the cycle that might be.  If an IV agent is held, patients may restart upon 
resolution of the AE at the next scheduled dose.  If both IV agents are held beyond the duration 
of one cycle, when reinitiated deem that Day 1 of the subsequent cycle.
Table JV01.8 presents the dose reduction for ramucirumab, cyclophosphamide, and vinorelbine.  
Dose adjustments required for hematologic and nonhematologic toxicities due to ramucirumab, 
cyclophosphamide, or vinorelbine are presented in Table JV01.10 and Table JV01.11,
respectively.
Table JV01.8.
Dose Reductions for Treatment-Related Toxicities
Study Drug
Starting Dose
Dose Reduction
First
Second
Ramucirumab
12 mg/kg
10 mg/kg
8 mg/kg
if de-escalated
8 mg/kg
6 mg/kg
5 mg/kg
Cyclophosphamide
25 mg/m2
20 mg/m2
15 mg/m2
Vinorelbine
25 mg/m2
20 mg/m2
15 mg/m2
3.7.4.1.
Guidelines for Hematological and Nonhematological Dose Modifications
In general, ramucirumab therapy does not need to be altered for either cyclophosphamide- or 
vinorelbine-related toxicity.  Similarly, cyclophosphamide or vinorelbine do not need to be 
altered for ramucirumab-related toxicity.  Investigators will interpret and document whether or 
not an AE has a reasonable possibility of being related to each of the study drugs, taking into 
account the disease, concomitant treatments, or pathologies, in order to individually adjust study 
drug doses.
In the case of toxicity for which the relative roles of each agent are impossible to separate, it is 
expected that omissions and/or dose reductions of all involved agents would result.  Thus, it is 
expected such toxicity would result in omissions and/or dose reductions of involved agents.  In 
cases in which AEs, in the opinion of the investigator, are more likely due to 1 drug than another, 
adjustment of 1 of the agents and not the others are permissible. General guidelines for study 
treatment dose modifications due to toxicities are presented in 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 43
LY900023; LY3009806
Table JV01.9.  Dose adjustment guidelines for specific hematologic and nonhematologic toxicity 
due to cyclophosphamide, vinorelbine, and/or ramucirumab are presented in Table JV01.10 and 
Table JV01.11, respectively. 
See Section 3.7.4.2 and Table JV01.12 for additional requirements and dose adjustment 
guidelines related to potential IRRs and adverse events of special interest (AESIs) that may occur 
during or following ramucirumab administration.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 44
LY900023; LY3009806
Table JV01.9.
General Guidelines for Study Treatment Dose Modification Due to Toxicities Related to Ramucirumab, 
Cyclophosphamide, or Vinorelbine
Reaction Grade
Required Dose Modification
Grade 1
No dose modification is required.
Grade 2
Persistent or recurrent Grade 2 not resolving with maximal supportive measures:  at the investigator’s discretion, the patient may 
continue to receive study drug per protocol, provided that the event does not pose a serious health risk or is easily treated.
Grade 3 
For a Grade 3 toxicity not adequately controlled with appropriate supportive care and assessed as related to study drug, the dose 
must be withheld until toxicity is ≤Grade 1 or has returned to pretreatment baseline; then treatment may resume at a reduced dose 
level.  An exception to this would be isolated lab-only increases in GGT or ALP.  If toxicity recurs after therapy resumes, despite 
up to two dose reductions, then treatment should be discontinued.

First occurrence:  Delay agent until resolved to Grades 0-1.
o
If resolved to Grades 0-1, reduce dose.
o
If NOT resolved to Grades 0-1 within a reasonable timeframe (i.e. within 28 days), discontinue agent at 
investigator’s discretion.

Second occurrence:  Delay agent until resolved to Grades 0-1.
o
If resolved to Grades 0-1, reduce dose.
o
If NOT resolved to Grades 0-1 within a reasonable timeframe (i.e. within 28 days), discontinue agent.
Grade 4
Permanent discontinuation should be considered for any patient experiencing Grade 4 toxicity assessed as related to study drug.  
An exception to this would be isolated lab-only increases in GGT or ALP.  However, if resumption of dosing is deemed 
appropriate by the investigator, treatment may resume only after consultation with the Lilly CRP/CRS, with the dose reduced. If 
Grade 4 toxicity recurs after therapy resumes, study drug will be discontinued.
Exceptions are Grade 4 fever or Grade 4 laboratory abnormality, in which case:

First occurrence:  Delay agent until resolved to Grades 0-1.
o
If resolved to Grades 0-1, may resume agent at original dose at the discretion of the investigator.
o
If NOT resolved to Grades 0-1 within a reasonable timeframe (i.e. within 28 days), discontinue agent at 
investigator’s discretion.

Second occurrence:  Delay agent until resolved to Grades 0-1.
o
If resolved to Grades 0-1, reduce dose.
o
If NOT resolved to Grades 0-1 within a reasonable timeframe (i.e. within 28 days), discontinue agent at 
investigator’s discretion.
Abbreviations: ALP = alkaline phosphatase; CRP = clinical research physician; CRS = clinical research scientist; GGT = gamma-glutamyl transferase.
Note: If a patient does not recover from the toxicity within 28 days from the time of last treatment, the patient should be considered for permanent 
discontinuation from study treatment.  In exceptional circumstances, a delay >28 days is permitted upon agreement between the investigator and the Lilly 
CRP/CRS.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 45
LY900023; LY3009806
Table JV01.10.
Dosing Algorithm on Days 1 ,8, and 15 for Cyclophosphamide, Vinorelbine, Ramucirumab, and G-CSF 
Use Based on Absolute Neutrophil Count and Platelet Count
Toxicity
Day 1b
Day 8
Day 15
Cycloc
Vin
Ramd
Cycloc
Vin
Ramd
Cycloc
Vin
Ramd
NOTES and G-CSF Usea
Absolute Neutrophil Count (cells/μL)
≥750
Administer Administer Administer Administer Administer
Not 
Applicable
Administer Administer Administer G-CSF not required
<750
Omit until 
cell count 
parameters 
are met
Omit on 
Day 1
Administer Omit until 
cell count 
parameters 
are met
Omit. See 
note for 
further 
instruction. 
Not 
Applicable
Omit until 
cell count 
parameters 
are met
Omit. See 
note for 
further 
instruction.
Administer If >7 days until counts recover:  
o
1st occurrence:  
administer G-CSF and 
resume 
cyclophosphamide once 
cell parameters are met 
at the next lower dosee
for current and all 
subsequent cycles.
Consider omitting D-15 
of vinorelbine for current 
and all subsequent cycles
and reducing dose of 
vinorelbine on D-1 and 
D-8 of all subsequent 
cyclese. 
o
2nd and subsequent 
occurrences:  administer 
G-CSF and resume 
cyclophosphamide once 
cell parameters are met 
at next lower dose 
reductione and/or reduce 
vinorelbine (D1 and D8e; 
omit D15 during that and 
all subsequent cycles.
Platelet Count (cells/μL)
≥75,000
Administer Administer Administer Administer Administer
Not 
Applicable
Administer Administer Administer
<75,000
Omit until 
cell count 
parameters 
Omit on 
Day 1
Administer Omit until 
cell count 
parameters 
Omit only if 
not 
administered 
Not 
Applicable
Omit until 
cell count 
parameters 
Omit only if 
not 
administered 
Administer If >7 days until counts recover, on 
subsequent cycle(s):
o
1st occurrence:  reduce 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 46
LY900023; LY3009806
Toxicity
Day 1b
Day 8
Day 15
Cycloc
Vin
Ramd
Cycloc
Vin
Ramd
Cycloc
Vin
Ramd
NOTES and G-CSF Usea
are met
are met
on Day 1.  
See note for 
further 
instruction.
are met
on Day 1.  
See note for 
further 
instruction.
cyclophosphamide 
and/or vinorelbine on 
D1, D8e, and consider 
omitting D15 vinorelbine 
if thrombocytopenia 
recurs during that cycle. 
o
2nd and subsequent 
occurrences:  reduce 
cyclophosphamide 
and/or reduce 
vinorelbine (D1 and D8e; 
omit D15 vinorelbine if 
thrombocytopenia recurs 
during that or subsequent 
cycles despite dose 
reductions).
Abbreviations: Cyclo = cyclophosphamide; G-CSF = granulocyte-colony stimulating factor; Ram = ramucirumab; Vin = vinorelbine.
Note:  For other hematologic toxicities not specified, please refer to Table JV01.9.
a
G-CSF use is recommended per the guidelines outlined in Section 3.7.6.1.6.  
b
Day 1 treatment may be delayed for up to 14 days to allow a patient sufficient time for recovery from study drug-related toxicity or non-study-drug-related 
events at the investigator’s discretion (eg, an automobile accident).  In exceptional cases, longer suspensions may be allowed after discussion with the Lilly
CRP/CRS.
c
Cyclophosphamide can resume at any day once cell count parameters are met. 
d
Investigational arm. 
e   Reduction dose per Section 3.7.4 and Table JV01.8

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 47
LY900023; LY3009806
Table JV01.11.
Additional Guidelines for Dose Modification Due to Study Drugs-Related Non-Hematologic Toxicities
Toxicity
All Daysa
Notes
Cyclo
Vin
Ramb
Total bilirubin >2 to 3× ULN or 
>2 to 3x baseline if baseline 
abnormal
Administer per
Table JV01.9.c
Administer per
Table JV01.9d but must 
reduce dose per 
Table JV01.8
Administer per
Table JV01.9 c
Exception:  Patients with Gilbert’s 
Syndrome may have a total bilirubin <3 
mg/dL before requiring a dose reduction 
in vinorelbine.
Refer to Sections 3.9.3.1.1 and 
Attachment 4 for hepatic safety 
monitoring.
Total bilirubin >3x ULN or >3x 
baseline if baseline abnormal 
(Grade ≥3 bilirubin elevation)
Hold and follow 
guidelines per
Table JV01.9d
Hold per Table JV01.9d and 
reduce dose for subsequent 
administration per 
Table JV01.8
Hold and follow 
guidelines 
Table JV01.9d
Refer to Sections 3.9.3.1.1 and 
Attachment 4 for hepatic safety 
monitoring.
Grade ≥3 elevations in AST or
ALT
Hold and follow 
guidelines per 
Table JV01.9.d
Hold per Table JV01.9d and 
reduce dose for subsequent 
administration per 
Table JV01.8
Table JV01.9d
Refer to Section 3.9.3.1.1 and 
Attachment 4 for hepatic safety 
monitoring.
Grade ≥3 neurologic toxicity
Administer per
Table JV01.9d c
Discontinue
Administer per
Table JV01.9.c
Severe pulmonary toxicity
Discontinue
Discontinue
Administerc
For vinorelbine, MUST discontinue for 
Grade ≥2 Interstitial Pneumonitis and 
ARDS, and HOLD for unexplained 
dyspnea (may restart if 
resolved/short-lived).
HUS, Gross Hemorrhagic Cystitis, 
or severe renal/bladder 
impairment
Discontinue
Administerc
Administerc

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 48
LY900023; LY3009806
Abbreviations: ALT = alanine aminotransferase; ARDS = acute respiratory distress syndrome; AST = aspartate aminotransferase; Cyclo = cyclophosphamide; 
Ram = ramucirumab; ULN = upper limit of normal; Vin = vinorelbine.
a
Day 1 treatment may be delayed for up to 14 days to allow a patient sufficient time for recovery from study drug-related toxicity or non-study-drug-related 
events at the investigator’s discretion (eg, an automobile accident).  In exceptional cases, longer suspensions may be allowed after discussion with the Lilly 
CRP/CRS.
b
Investigational arm. 
c
Continue with treatment unless investigator considers possibly related.
d
Hold treatment unless investigator considers not related.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 49
LY900023; LY3009806
3.7.4.2.
Ramucirumab Dose Modifications for Adverse Events of Special Interest
The ramucirumab dose may need to be modified if the patient experiences an AE, including an 
AESI (Section 3.9.2.1).  Doses may be delayed to allow time for the patient to recover from the 
event.  Certain AEs require immediate and permanent discontinuation of study treatment (see 
Table JV01.12).  If administration of ramucirumab is delayed for more than 4 weeks  from last 
planned administration, the patient should be discontinued from ramucirumab treatment, unless a 
longer suspension has specifically been deemed appropriate for a given patient in discussion with 
the Lilly CRP/CRS.  Any patient who requires a dose reduction will continue to receive a 
reduced dose until discontinuation from ramucirumab or discontinuation from the study.  Any 
patients requiring dose reduction to less than 8 mg/kg (5 mg/kg for patients treated on dose de-
escalation) of ramucirumab will have ramucirumab discontinued.  Such patients may continue 
with cyclophosphamide and/or vinorelbine as per protocol.
Table JV01.8 presents the ramucirumab dose reductions.
Table JV01.12 presents the criteria for dose modifications and dose discontinuations applicable 
if the patient experiences a ramucirumab AESI or other AEs at least possibly related to 
ramucirumab.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 50
LY900023; LY3009806
Table JV01.12.
Dose-Modification Guidelines for Ramucirumab for Adverse Events at Least Possibly Related to 
Ramucirumab, including Adverse Events of Special Interest
Adverse Event
NOTE:  All specific adverse events listed are 
defined as AESIs in Section3.7.6.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Table JV01.8
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
1.
Infusion-related reaction (including 
hypersensitivity reactions)
1.a.
Infusion-related reaction
2
Interrupt and reduce the infusion rate by 50% for the duration of the infusion and 
for all future infusions.
Prior to all future infusions of ramucirumab, premedicate with:

an intravenous histamine H1 antagonist, such as diphenhydramine 
hydrochloride

dexamethasone or equivalent

acetaminophen/paracetamol
1.b.
Infusion-related reaction
3-4
Immediately and permanently discontinue ramucirumab
2.
Hypertension for patients ≥18 years old
2.a.
Hypertension (non-life-threatening and associated 
with symptoms)
NOTE:  Hypertension should be monitored prior to 
each ramucirumab infusion.
3

Delay ramucirumab until the hypertension is controlled with medication and 
is resolved to Grades 0-2.
o
If controlled with medication and resolved to Grades 0-2, then may 
resume ramucirumab at current dose.

If NOT controlled with medication and not resolved to Grades 0-2 within a 
reasonable timeframe (e.g. 28 days), discontinue ramucirumab at 
investigator’s discretion.
2.b.
Uncontrolled hypertension, hypertensive crisis, or 
hypertensive encephalopathy
4
Immediately and permanently discontinue ramucirumab.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 51
LY900023; LY3009806
Adverse Event
NOTE:  All specific adverse events listed are 
defined as AESIs in Section3.7.6.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Table JV01.8
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
3
Hypertension for patients <18 years old

BP ULN in children:  ≤95th percentile for age, height, and gender measured 
as described in NHBPEPWG on High Blood Pressure in Children and 
Adolescents (2004). 

Baseline BP is the average of the serial BPs obtained at least 5 min apart on 
the same extremity, in the same position with an appropriate sized cuff.

Elevation in either systolic or diastolic BP is valid for dose modifications

Elevated BP should be re-evaluated on the same day for confirmation.  If 
elevated, BP monitoring should occur at least twice weekly until BP ≤ULN
Hypertension should be managed with appropriate anti-hypertensive agent(s) as 
clinically indicated.  Highly recommended to consult pediatric cardiology or 
nephrology for evaluation and management of hypertension in the pediatric 
population
3.a.
BP:  ≤10 mmHg above ULN for age 

Administer ramucirumab at the current dose.

Recheck BP within 3 days
o
If BP ≤ULN, then continue on current ramucirumab dose
o
If >ULN, start anti-hypertensive therapy and continue on current 
ramucirumab dose

if BP ≤ULN within 14 days, continue on anti-hypertensive therapy 
and current ramucirumab dose
If BP >ULN after 14 days on anti-hypertensive therapy; see line 3.c.
3.b.
BP:  >10 mmHg to 25 mmHg above ULN for age or 
>35 mmHg above baseline

Start anti-hypertensive therapy and continue on current ramucirumab dose

if BP ≤ULN within 14 days, continue on anti-hypertensive therapy 
and current ramucirumab dose
If BP >ULN after 14 days on anti-hypertensive therapy; see line 3.c.
3.c.
BP:  >25 mmHg above ULN

Hold ramucirumab and start or continue anti-hypertensive therapy

if BP ≤ULN within 14 days, continue on anti-hypertensive therapy 
and resume ramucirumab at a reduced dose
If BP >ULN after 14 days on anti-hypertensive therapy immediately and 
permanently discontinue ramucirumab.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 52
LY900023; LY3009806
Adverse Event
NOTE:  All specific adverse events listed are 
defined as AESIs in Section3.7.6.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Table JV01.8
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
3.d.
Hypertension, hypertensive crisis, or hypertensive 
encephalopathy
4
Immediately and permanently discontinue ramucirumab.
4.
Proteinuria for patients ≥18 years old
4.a.
Proteinuria = 2+ (dipstick or routine urinalysis)a

Administer ramucirumab at the current dose if clinically indicated.

Obtain 24-hour urine protein results within 3 days prior to the next 
ramucirumab dose.
o
If urine protein is <2 g/24 hr, administer ramucirumab at the patient's 
current dose.
o
If urine protein is 2 g/24 hr, modify the ramucirumab dose based on 
24-hour collection.  See Proteinuria 2 g/24 hr (24-hour urine 
collection), line 4.c and 4.d.
4.b.
Proteinuria >2+ (dipstick or routine urinalysis)a

Omit ramucirumab and obtain 24-hour urine protein results within 3 days 
prior to the next ramucirumab dose.

Delay ramucirumab until urine protein returns to <2 g/24 hr. 
o
If urine protein is <2 g/24 hr, no further dose delay or dose reduction is 
required.
o
If urine protein remains 2 g/24 hr, see line 4.c and 4.d.
4.c.
Proteinuria 2 to 3 g/24 hr (24-hour urine 
collection)a

First or second occurrence:  delay ramucirumab until urine protein returns 
to <2 g/24 hr.
o
If urine protein returns to <2 g/24 hr, reduce ramucirumab dose.
o
If urine protein remains 2 g/24 hr and is not resolved within a 
reasonable timeframe, discontinue ramucirumab at investigator’s 
discretion.

Third occurrence:  discontinue ramucirumab.
4.d.
Proteinuria >3 g/24 hr or in the setting of nephrotic 
syndromea
Immediately and permanently discontinue ramucirumab.
5. 
Proteinuria for patients <18 years old:
5.a.
Proteinuria trace (dipstick or routine urinalysis)a
Hold ramucirumab and obtain a random urine sample to calculate the UPC ratio.  
See lines 5.b.to 5.d.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 53
LY900023; LY3009806
Adverse Event
NOTE:  All specific adverse events listed are 
defined as AESIs in Section3.7.6.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Table JV01.8
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
5.b.
UPC ratio <1a
Administer ramucirumab at patient’s current dose as scheduled.
5.c.
UPC ratio 1-1.9a

Hold ramucirumab and repeat a second measurement within 72 hours of the 
next scheduled dose. 
o
If UPC ratio returns to <1, administer ramucirumab at current dose.
o
If UPC ratio remains 1-1.9, omit ramucirumab until UPC ratio returns to 
<1.

If UPC ratio returns to <1 within 14 days, resume ramucirumab 
with dose reduction.
If UPC ratio remains ≥1 for 14 days or more, immediately and permanently 
discontinue ramucirumab.
5.d.
UPC ratio >1.9a
Immediately and permanently discontinue ramucirumab.
6.
Arterial thromboembolic events, venous 
thromboembolic events
3 or 4
Immediately and permanently discontinue ramucirumab.
7.
Bleeding/Hemorrhage
Bleeding/Hemorrhage
2
Continue with treatment unless investigator considered related.  See
Table JV01.9.
Bleeding/Hemorrhage
3 or 4
Immediately and permanently discontinue ramucirumab.
8.
Gastrointestinal perforation
Immediately and permanently discontinue ramucirumab.
9.
Posterior reversible encephalopathy syndrome
Immediately and permanently discontinue ramucirumab.
10.
Congestive heart failure
Congestive heart failure
2
Continue with treatment unless investigator considered related.  See 
Table JV01.9
Congestive heart failure
3 or 4
Immediately and permanently discontinue ramucirumab.
11.
Fistula formation
Immediately and permanently discontinue ramucirumab.
12.
Impaired wound healing
12.a.
Prior to planned surgery
Withhold ramucirumab.
12.b
After surgery
Resume ramucirumab based on clinical judgment.
12.c.
Wound-healing complications developed during 
study treatment
Delay ramucirumab dosing until the wound is fully healed.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 54
LY900023; LY3009806
Adverse Event
NOTE:  All specific adverse events listed are 
defined as AESIs in Section3.7.6.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Table JV01.8
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
13.
Hypothyroidism
2-4
Therapy with ramucirumab can be continued while treatment for the thyroid 
disorder is instituted.
14.
Hepatic encephalopathy and/or hepatorenal 
syndrome resulting from liver cirrhosis
Immediately and permanently discontinue ramucirumab,
Dose-Modification Guidelines for Ramucirumab for Adverse Events at least Possibly Related to Ramucirumab, including Adverse Events of Special 
Interest (concluded)
Abbreviations:  AESI = adverse event of special interest; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; 
UPC = urine protein to creatinine.
a
Perform urinalysis within 3 days prior to each infusion of ramucirumab.  If 24-hour urine collection or UPC ratio (<18 years of age) is also performed, the 
results of these collections should be used for clinical decision-making.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 55
LY900023; LY3009806
3.7.5. Treatment Compliance
No additional requirements.  Refer to the CAMPFIRE Master Protocol for treatment compliance. 
3.7.6. Concomitant Therapy
A list of restricted and excluded concomitant therapies and exceptions is provided in 
Attachment 5.  All premedication, supportive care, and concomitant medication must be reported 
on the CRF at each visit.
3.7.6.1.
Supportive Care
Patients should receive full supportive care to maximize quality of life.  Patients will receive 
supportive care as judged by the treating physician.  If it is unclear whether a therapy should be 
regarded as supportive care, the investigator should consult with the Lilly CRP/CRS.  Use of any 
supportive care should be recorded on the eCRF. Investigators should consult the PI for 
additional precautions.  Specific AEs have been identified based on past data for special 
monitoring and, when necessary, supportive care.  For ramucirumab, these are referred to as 
AESI.
3.7.6.1.1. Transfusions
Transfusions of red blood cells, platelets, or other blood products are permitted at the 
investigator’s discretion.
3.7.6.1.2. Supportive Management for Constipation and Bowel Obstruction
Severe and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation can 
occur with vinorelbine administration. Supportive measures such as adequate dietary fiber 
intake, hydration, and routine use of stool softeners are recommended to mitigate potential 
constipation, bowel obstruction, and/or paralytic ileus. In the event of constipation, a 
prophylactic bowel regimen should be initiated. 
3.7.6.1.3. Antiemetic Agents
The use of antiemetic agents is permitted at the discretion of the investigator.  Acceptable 
antiemetic agents include 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (eg, ondansetron), 
dopamine receptor antagonists (eg, metoclopramide), corticosteroids (eg, dexamethasone), and 
others.
3.7.6.1.4. Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.  Opiate and 
non-opiate analgesic agents are permitted (including acetaminophen/paracetamol); however, use 
of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or aspirin is restricted (Attachment 5).
3.7.6.1.5. Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.  Examples 
include megestrol acetate, dronabinol, and others.
3.7.6.1.6. Growth Factors
Growth factors should not be administered to enable a patient to satisfy study inclusion criteria.  

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 56
LY900023; LY3009806
The as-needed use of granulocyte-colony stimulating factor (G-CSF) is permitted at the 
discretion of the investigator based on American Society of Clinical Oncology (ASCO; Smith et 
al. 2006) and European Society for Medical Oncology (Crawford et al. 2009) guidelines.
In the event of Grade 3 or 4 neutropenia >7 days, initiate G-CSF as per Table JV01.10..
The as-needed use of erythroid-stimulating factors (eg, erythropoietin) is permitted at the 
discretion of the investigator based on ASCO guidelines (Rizzo et al. 2010) (Attachment 5).
3.7.6.1.7. Other Supportive Care Agents
The use of benzodiazepines, antidepressants, laxatives, and other agents that may be helpful in 
controlling disease-related symptoms are also permitted and encouraged, except as prohibited in 
Attachment 5.
3.7.6.1.8. Supportive Care by Adverse Event of Special Interest: Ramucirumab
Refer to Table JV01.12 for AESI dose modification guidelines.
3.7.6.1.8.1.
Infusion-Related Reactions (Including Hypersensitivity Reactions)
Administration of monoclonal antibodies such as ramucirumab can result in hypersensitivity 
reactions (HSRs), including immediate reactions like anaphylactic reactions or IRRs, and 
delayed reactions such as those involving the mucocutaneous system. In the event of an IRR, 
every effort should be made to collect blood samples for PK and immunogenicity analysis for 
ramucirumab (see Attachment 3), at the following time points:  
(i)
as close as possible to the onset of the IRR, 
(ii)
at the resolution of the IRR, and 
(iii)
30 days following the IRR.
In addition, in the case of generalized urticaria or anaphylaxis, blood and urine samples should 
be collected as described in Attachment 3 hypersensitivity labs): 
(i)
After the patient has been stabilized, obtain a sample within 1-2 hours of the event;
however, samples may be obtained as late as 12 hours after the event as analytes can 
remain altered for an extended period of time. Record the time at which the sample 
was collected.
(ii)
Obtain a follow-up sample 30 days following the IRR or at the next regularly 
scheduled visit following the IRR, whichever is later.
The IRRs may occur during or following ramucirumab administration.  Patients should be 
closely monitored for signs and symptoms indicative of an IRR from the initiation of the infusion 
in an area where resuscitation equipment and other agents (such as epinephrine and 
corticosteroids) are readily available.
Signs and symptoms usually develop during or shortly after infusion and generally resolve 
within 24 hours.  Symptoms of IRRs include rigors/tremors, back pain/spasms, chest pain and/or 
tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.  In severe cases, 
symptoms include bronchospasm, supraventricular tachycardia, and hypotension.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 57
LY900023; LY3009806
Table JV01.12 presents ramucirumab dose modification for patients who experience an IRR 
associated with ramucirumab.
Patients must be closely monitored for a 1-hour observation period following the ramucirumab 
infusions for the first 2 infusions.  If the patient shows no evidence of an IRR with the first 2 
infusions of each study drug, no observation period is required for subsequent infusions.  In the 
event an IRR occurs thereafter, the 1-hour observation should be reinstituted.
For the first 2 ramucirumab infusions, measure BP and pulse at the following time 
points: (i) within 15 minutes prior to the infusion, (ii) after completion of the infusion, and 
(iii) at the end of the 1-hour post-infusion observation period.  For all subsequent infusions of 
ramucirumab, measure BP and pulse prior to the infusion.  Measure other vital signs as clinically 
indicated.
Supportive care should be employed in accordance with the symptoms or signs. Participants 
should be treated appropriately by the investigator. If a significant HSR occurs (Grades 3 or 4), 
discontinue ramucirumab permanently.
3.7.6.1.8.2.
Hypertension
An increased incidence of severe hypertension (CTCAE Grade 3) has been reported in patients 
receiving ramucirumab compared with placebo.  In most cases, hypertension was controlled 
using standard antihypertensive treatment.  Preexisting hypertension should be controlled before 
starting ramucirumab treatment.
Monitoring of BP is required during participation on trial, and must occur prior to ramucirumab 
therapy to ensure appropriate dosing and administration.  Every attempt should be made to 
control BP prior to starting treatment with ramucirumab and throughout the study to systolic 
<140 mmHg and diastolic <90 mmHg for patients >18 years old, and < ULN for patients under 
18 years of age.  Routine clinical and laboratory monitoring is required in patients who again 
develop hypertension or experience a deterioration in previous hypertension.
3.7.6.1.8.3.
Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGFR2 pathway, 
including ramucirumab.  In ramucirumab clinical trials, the majority of events were Grade 1 or 2.  
Monitoring for the development or worsening of proteinuria during ramucirumab therapy is 
required.  Discontinue ramucirumab if the patient experiences proteinuria >3 g/24 hours for 
patients >18 years old, UPC ratio >1.9 for patients under 18 years of age, or nephrotic syndrome.
3.7.6.1.8.4.
Thromboembolic Events
3.7.6.1.8.4.1.
Arterial Thromboembolic Events
Serious, sometimes fatal ATEs, including myocardial infarction, cardiac arrest, CVA, and 
cerebral ischemia, have been reported in clinical trials.
3.7.6.1.8.4.2.
Venous Thromboembolic Events
Venous thromboembolic events (VTEs) are associated with cancer; however, the incidence of 
VTEs likely varies depending on the type of cancer, stage, and intensity of imaging.  
Additionally, VTEs have been associated with some antiangiogenic therapy, although the 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 58
LY900023; LY3009806
incidence varies depending on the type of therapy, use of concomitant chemotherapy agents, and 
specific disease state.  VTEs have been reported from clinical studies investigating ramucirumab, 
particularly in the context of metastatic disease or in regions adjacent to implanted venous access 
devices.
3.7.6.1.8.5.
Bleeding/Hemorrhage
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding.  Severe GI hemorrhages, including fatal events, have been reported in patients with 
gastric-GEJ cancer treated with ramucirumab in combination with paclitaxel.
Serious hemorrhagic AEs have been reported from clinical studies investigating ramucirumab.  
Hemorrhagic complications are associated with some malignancies (ie, variceal bleeding from 
portal hypertension in hepatocellular carcinoma, lower GI hemorrhage from bowel metastases in 
ovarian carcinoma), although the rate of these complications varies considerably.  As detailed in 
the ramucirumab IB, the incidences of hemorrhagic events to date, significant background 
incidence of bleeding in some malignancies, and use of concomitant antiplatelet therapy in some 
of the reported cases preclude any definitive association between bleeding and ramucirumab, 
although ongoing surveillance and identification (and exclusion) of patients with high bleeding 
risk remain essential and are detailed in the inclusion/exclusion criteria.
3.7.6.1.8.6.
Gastrointestinal Perforation
An infrequent incidence of GI perforations has been associated with some antiangiogenic 
therapeutic agents, most specifically in the context of colorectal cancer (treated with combination 
regimens, including anti-VEGF antibodies and cytotoxic chemotherapy) and in advanced ovarian 
cancer.  These events may be associated with extensive abdominal/peritoneal disease burden.  
Gastrointestinal perforation has been reported from clinical studies investigating ramucirumab.  
The incidences of these events to date and presence of significant comorbidities and risk factors 
preclude any definitive association with ramucirumab, although ongoing surveillance remains 
essential.  More information about GI perforation may be found in the IB.
3.7.6.1.8.7.
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome is an acute neurological disorder characterized by 
various neurological signs and symptoms in conjunction with distinctive neuroimaging findings 
reflecting vasogenic edema, often in association with elevated BP (Bartynski and Boardman 
2007; Bartynski 2008; Fugate and Rabinstein 2015; Fischer and Schmutzhard 2017). Both 
clinical and imaging features are usually reversible (Hinchey et al. 1996; Lee et al. 2008; Fugate 
and Rabinstein 2015). 
Cases of PRES, including fatal cases, have been rarely reported in patients receiving 
ramucirumab. Posterior reversible encephalopathy syndrome symptoms may include seizure, 
headache, nausea/vomiting, blindness, or altered consciousness, with or without associated 
hypertension. 
Posterior reversible encephalopathy syndrome should be identified and treated promptly in order 
to minimize potential for permanent neurological damage.  A diagnosis of PRES can be 
confirmed by brain imaging (e.g., magnetic resonance imaging [MRI]). Treatment encompasses 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 59
LY900023; LY3009806
careful control of BP, withdrawal of potentially causative medication, and administration of 
anticonvulsant agents to those experiencing seizures (Stott et al. 2005). 
Permanently discontinue ramucirumab in patients who experience PRES.
3.7.6.1.8.8.
Congestive Heart Failure
An increased risk of CHF has been associated with some antiangiogenic therapeutic agents, 
particularly in patients with metastatic breast cancer previously treated with anthracyclines.  A 
small number of CHF events (including fatal) were also reported in patients who had received 
ramucirumab after prior treatment with anthracyclines in the Phase 2 and Phase 3 studies.
Patients with risk factors should be closely monitored for signs and symptoms of CHF.
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease, such as preexisting coronary artery disease or CHF.  Ramucirumab should be 
discontinued in the event of any Grade 3 or 4 events consistent with CHF.
3.7.6.1.8.9.
Fistula Formation
Because fistula formation has been associated with antiangiogenic agents, patients may be at 
increased risk for the development of fistula when treated with ramucirumab.  Some fistulas can 
be resolved with surgical procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and 
Cleck 2009).
3.7.6.1.8.10. Surgery and Impaired Wound Healing
Because ramucirumab is an antiangiogenic therapy, it may have the potential to adversely affect 
wound healing.  Ramucirumab did not impair wound healing in a study conducted in animals; 
however, the impact of ramucirumab on serious or nonhealing wounds has not been evaluated in 
humans.
3.7.6.1.8.11. Liver Failure and Other Significant Liver Injury
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  Patients with 1) cirrhosis at a level of Child-Pugh 
Class B (or worse) or 2) cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis should not be enrolled in clinical trials with 
ramucirumab.  “Clinically meaningful ascites” is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.
3.8.
Discontinuation Criteria

Related to Investigator/Physician decisions
o
the investigator/physician decides that the patient should be discontinued from the 
study or study drug(s).
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of DSRCT, 
discontinuation from the study drug(s) occurs prior to introduction of the other 
agent.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 60
LY900023; LY3009806

Related to patient, parent, or legal guardian
o
the patient or the patient’s designee (for example, parents or legal guardian) 
requests to be discontinued from the study or study drug.

Related to Sponsor
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP.

The patient becomes pregnant during the study.

The patient has radiographic progressive disease or significant symptomatic disease 
deterioration characterized as progression of disease, in the opinion of investigator, in the 
absence of radiographic evidence of PD. In the event a patient is discontinued from 
treatment due to symptomatic deterioration, every effort should be made to document 
disease progression, unless it is not medically appropriate.

The patient experiences unacceptable toxicity (for example, a persistent moderate toxicity 
that is intolerable to the patient).

The patient is noncompliant with study procedures and/or treatment.  Example, unable to 
take oral or liquid cyclophosphamide.

The patient has had maximum dose reductions of ramucirumab, cyclophosphamide or 
vinorelbine allowed per protocol and experiences an AE that would cause an additional 
dose reduction.

The patient is enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.
For additional treatment discontinuation criteria see Section 3.7.4.
3.9.
Study Assessments and Procedures
Section 3.2 provides the Schedule of Activities for this study.
Attachment 2 provides a list of the laboratory tests that will be performed for this study.
Attachment 3 provides the schedule for collection of samples in this study.
3.9.1. Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 3.2).
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, MRI is also acceptable 
in certain situations, such as when body scans are indicated or if there is a concern about 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 61
LY900023; LY3009806
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 
1.1 (Eisenhauer et al. 2009).
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Radiologic scans of the thorax, abdomen, and pelvis are required.
See Section 3.10.3.1 for definitions of the efficacy endpoints.
3.9.2. Adverse Events
Refer to the CAMPFIRE Master Protocol for Adverse Event general definitions, responsibilities,
and reporting information.
3.9.2.1.
Adverse Events of Special Interest:  Ramucirumab
Section 3.7.6.1.8 describes supportive care measures for each ramucirumab AESI.  Table
JV01.12 presents the dose-modification guidelines for ramucirumab AESIs.  Contact the Lilly 
CRP if questions arise concerning AESIs.
Any treatment-related IRRs are defined according to the CTCAE Version 5.0 definition (General 
Disorders and Administration-Site Conditions).  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 (Immune System Disorders).  In the 
setting of symptoms occurring during or following infusion of investigational therapy, 
investigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.
3.9.3. Safety
3.9.3.1.
Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study. 
The study will be monitored for excessive toxicity experienced beyond the DLT assessment 
period.  If excessive toxicity is observed, the study may be amended, or treatment with the 
combination halted to address the safety concern, as appropriate.
3.9.3.1.1. Special Hepatic Safety Data Collection
If, following the initiation of close hepatic monitoring as per master protocol Section 9.4.2, one 
or more of the following conditions are met, additional hepatic data should be collected as per 
Attachment 4:

Patients enrolled with normal or near normal ALT or AST (<1.5× ULN):
o
elevation of serum ALT or AST ≥8× ULN; or

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 62
LY900023; LY3009806
o
elevated ALT or AST ≥5× ULN and total bilirubin ≥2× ULN
Patients enrolled with elevated ALT or AST (≥1.5× ULN):
o
ALT or AST ≥4× baseline; or
o
ALT or AST ≥3× baseline and total bilirubin ≥2× ULN

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests

occurrence of a hepatic event considered to be an SAE.
3.9.3.1.2. Monitoring for Specific Toxicities:  Growth Plate
In addition to monitoring height on trial, patients randomized to the ramucirumab arm and <18 
years of age will have a plain anteroposterior (AP) radiograph of a single proximal tibial growth 
plate obtained prior to the first dose of protocol therapy. 

If patients randomized to the ramucirumab arm are found to have a closed tibial growth 
plate, no further radiographs will be required. 

If patients randomized to the ramucirumab arm are found to have an open tibial growth 
plate, then repeat plain AP radiographs of the same location every 4 months and at short-
term follow-up, or until the growth plate has closed.
In some geographies, an MRI of the knee may be an alternate option instead of a plain AP 
radiograph.
Patients with evidence of growth plate thickening or other changes should have a knee MRI 
performed to further assess the degree of physeal pathology and undergo more frequent x-ray 
follow-up at least every 3 months or as clinically indicated. MRI should be performed without 
contrast. 
Patients with knee MRI changes should be managed in an individualized manner. Decisions 
regarding continuation of ramucirumab should be made after discussion with the Lilly CRP, 
taking into account the presence of any symptoms referable to the knee as well as the patient’s 
response to ramucirumab. Consultation with an orthopedic surgeon may also be indicated. Plans 
for follow-up imaging will also be made on an individualized basis, taking into account the 
presence of symptoms at the knee or other joints as well as the decision to continue ramucirumab 
or not.

Monitoring in the Follow-up period for patients with open tibial growth plate on study
and randomized to the ramucirumab arm:
o
Short term follow-up: All patients with an open growth plate while on study 
should repeat plain AP radiograph and obtain a height measurement.
o
In some geographies, an MRI of the knee may be an alternate option instead of a 
plain AP radiograph.
o
Long-term follow-up: Only for patients with an abnormal growth plate finding at 
short-term follow-up, continue to perform plain AP radiologic evaluations and 
obtain height measurements until resolution of growth plate abnormalities or 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 63
LY900023; LY3009806
growth plate closure, whichever occurs first.  Frequency of both the radiographs 
and height measurements are per the investigator’s discretion/patient convenience 
during long-term follow-up.
o
In some geographies, an MRI of the knee may be an alternate option instead of a 
plain AP radiograph.
3.9.4. Pharmacokinetics
Blood samples will be collected from study patients on the ramucirumab arm to assess 
ramucirumab concentrations in serum as specified in Attachment 3.  Instructions and supplies for 
the collection, handling, and shipping of samples will be provided by Lilly or the central 
laboratory.
For all patients (whether in the ramucirumab arm or the control arm), in the event of an IRR, 
every attempt should be made to collect blood samples for anti-ramucirumab antibody and serum 
ramucirumab concentration determination at those given time points, as described in Attachment 
3.  Refer to Attachment 3 for the timing of blood sample collection during the continued-access 
period.
Serum concentrations of ramucirumab will be analyzed at a laboratory designated by the sponsor 
using a validated method.
Bioanalytical samples collected to measure ramucirumab concentration will be retained for a 
maximum of 1 year following the last patient visit for the study.
3.9.5. Pharmacodynamics
See Section 3.9.6 for Biomarkers
3.9.5.1.
Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected on all patients to determine antibody 
production against ramucirumab at specified time points and in the event of an IRR (Attachment 
3).  Refer to Attachment 3 for the timing of immunogenicity testing during the continued-access 
period.
Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies in 
the presence of ramucirumab.  Antibodies may be further characterized and/or evaluated for their 
ability to neutralize the activity of ramucirumab.
To interpret the results of immunogenicity in the ramucirumab arm, the concentration of 
ramucirumab in the blood will also be measured at the same time points (Attachment 3).
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by Lilly to enable further analysis of immune responses to ramucirumab.  The 
duration allows Lilly to respond to regulatory requests related to ramucirumab.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 64
LY900023; LY3009806
3.9.6. Biomarkers
Biomarker research will address questions as described in Sections 9.7 and 9.8 of CAMPFIRE 
Master Protocol.  This study will analyze biomarkers relevant to ramucirumab, mechanism of 
action of ramucirumab, the variable response to study drug(s), immune function, angiogenesis, 
and pathways associated with DSRCT.  
Samples for biomarker research will be collected as specified in Attachment 3, where local 
regulations allow. Collection of samples for biomarker research will be optional.
3.9.6.1.
Tissue Samples for Biomarker Research
Tissue samples for biomarker research will be collected for the purposes described in 
Section 3.9.6.  The following samples for biomarker research will be collected according to the 
sampling schedule in Attachment 3, where local regulations allow.
Collection of the following tumor tissue sample(s) is optional for all patients participating in this 
study:

an archived tumor sample

a tumor tissue sample from a newly obtained biopsy specimen may be requested at a later 
time point (eg after a strong response or disease progression). Such additional biopsies 
are optional and should be performed only if clinically feasible. If these additional 
samples are requested, they will be used to further investigate biomarkers that may 
explain treatment response and resistance mechanisms.  If a biopsy is submitted, due 
diligence should be used to ensure that tumor specimens (not a normal adjacent or a 
tumor margin sample) are provided and that the tumor sample contains tumor cells prior 
to shipment to the central laboratory.  See the Laboratory Manual for details regarding 
sample collection and handling. 
3.9.6.2.
Other Samples for Biomarker Research
The following samples for biomarker research will be collected according to the sampling 
schedule in Attachment 3, where local regulations allow:

whole blood for pharmacogenomic research (as described in Section 9.7 of the 
CAMPFIRE Master Protocol) 

serum

plasma
A maximum of 4 samples may be collected at additional study time points, if warranted and 
agreed upon by the investigator and Lilly.
3.9.7. Health Economics
Health economics and medical resource utilization parameters will not be evaluated in this study.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 65
LY900023; LY3009806
3.10. Statistical Considerations
3.10.1. Sample Size Determination
Traditional operating characteristics associated with the proposed Bayesian design (SAP,
Section 6.6.1) were evaluated via trial simulation. Note that due to the adaptive borrowing on 
PFS effect-size between Studies JV01 and JV02, joint scenarios of truth in both SS and DSRCT 
must be considered when evaluating operating characteristics for Study JV01 (and likewise for 
Study JV02). Under the proposed analysis framework, the sample size is considered adequate to 
support the primary objective:
•
Type I error: Reported Type I errors are one-sided. Type I Error here refers to the 
event the 99% success criterion for Study JV01 is met when in reality ܪܴ஽ௌோ஼்ൌ1.
Given the stringency of the Bayesian success criterion (ie, 99% probability of superiority 
threshold), false positives are unlikely for Study JV01. In particular, when neither tumor 
cohort truly benefits from ramucirumab-based therapy (ie, ܪܴௌௌൌܪܴ஽ௌோ஼்ൌ1), the 
Type I error rate for Study JV01 is approximately .003. Importantly, the Type I error rate 
remains low even under scenarios of strong heterogeneity in effect-size between JV01 
and JV02. In particular, if ܪܴ஽ௌோ஼்ൌ1 but ܪௌௌൌ.5, the probability of Type I error 
for Study JV01 is still less than 2%. This is due to both the adaptive nature of the 
hierarchical borrowing and the stringent primary success criterion.  
•
Power: Given the large magnitude of PFS benefit targeted in the young adult/pediatric 
setting, JV01 is unlikely to miss truly standard of care-changing improvements due to 
Type II error. Under the target scenario in which both tumors benefit substantially from 
ramucirumab-based therapy on the basis of PFS 
(ie, ܪܴௌௌൌܪܴ஽ௌோ஼்ൌ.33), the Bayesian analysis of PFS yields statistical power of 
approximately 82% to conclude success in DSRCT. For reference, a traditional log-rank 
analysis of DSRCT at 24 PFS events (independently from SS) at ߙൌ.003 (1-sided) 
carries approximately 43% power at ܪܴௌௌൌ.33 (note this calculation did not include a 
futility analysis such as that proposed in Studies JV01 and JV02, so a fairer assessment of 
power under the traditional approach would actually be lower than 43%).
•
Simulation results over additional joint null/alternative and control scenarios (including 
scenarios of strong heterogeneity in effect-size between the two addenda and mismatch of 
historical/prospective controls) are tabulated and reviewed in the SAP, Section 6.6.1.
Trial simulations were implemented using the statistical software package R. Simulation results 
were independently replicated.
The stringent primary success criterion, Prሺܪܴ஽ௌோ஼்൏1ሻ൐99%, was calibrated to ensure that 
meeting the primary endpoint should imply both statistical significance and large estimated 
magnitude of patient benefit (3 months of additional PFS) for the pediatric/young adult 
population of interest. The interpretation of the stringent success criterion is that the posterior 
probability of the HR being less than 1 is greater than 99%, given the observed data from JV01, 
observed data from JV02 incorporated via dynamic borrowing, and prior distributions. Based on 
a large simulation study (SAP, Section 6.6.1), when the 99% posterior probability threshold is 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 66
LY900023; LY3009806
reached, the associated estimate of the PFS HR (ܪܴ஽ௌோ஼்ሻis no larger than approximately .51. 
Under an example assumption of three months for control median PFS (and a further assumption 
of exponentially distributed PFS), the minimal effect size of ܪܴ஽ௌோ஼்ൌ.51 would correspond 
to approximately 3 months of additional PFS in this population with high unmet medical need.
3.10.2. Populations for Analysis
The following analysis sets will be defined for this study:
Intention-to-treat (ITT) analysis set: will include all randomized patients. Should the 
ramucirumab dose be de-escalated during the safety lead-in period, all randomized patients will 
still be included in the ITT analysis set regardless of assigned dose.  The ITT analysis of efficacy 
data will consider allocation of patients to treatment groups as randomized and not by actual 
treatment received.  This analysis set will be used for all baseline and efficacy assessments.
Safety analysis set:  will include all randomized patients who received any quantity of study 
treatment, regardless of their eligibility for the study.  The safety evaluation will be performed 
based on the first dose of study treatment a patient actually received, regardless of the arm to 
which he or she was randomized.  The safety analysis set will be used for all dosing/exposure, 
safety, and resource utilization analyses.
Pharmacokinetic analysis set:  will include all randomized patients who received at least 1 full 
dose of study treatment and have at least 1 postbaseline evaluable PK sample.
Biomarker analysis set:  will include the subset of patients from the ITT analysis set from 
whom a valid assay result has been obtained.
3.10.3. Statistical Analysis
Statistical analysis of this study will be the responsibility of Lilly or its designee.
For Bayesian analyses, posterior medians and 80% (equal-tailed) Bayesian credible intervals will 
be provided for relevant quantities unless otherwise stated. Full details regarding specification of 
prior distributions will be outlined in the SAP. 
All frequentist tests of treatment effect will be conducted at a 1-sided alpha level of .1, unless 
otherwise stated, and all confidence intervals (CIs) will be computed with (2-sided) coverage 
equal to 80%.
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 SAP and the clinical study report.  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
3.10.3.1. Efficacy Analysis
This section discusses statistical analyses of primary and secondary efficacy endpoints. 
Exploratory efficacy analyses will be discussed in the SAP.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 67
LY900023; LY3009806
Progression-free survival is defined as the time from randomization until the first occurrence of 
documented disease progression per RECIST v1.1 criteria or death from any cause in the 
absence of progressive disease.  Patients known to be alive and without disease progression will 
be censored at the time of the last adequate tumor assessment (a detailed PFS event/censoring 
scheme is provided in the Table JV01.13).  
Progression-free survival will be compared between treatment arms using the Bayesian 
hierarchical Weibull model outlined in the SAP, Section 6.6.1, with associated success/futility 
criteria based on the posterior distribution of the ܪܴ஽ௌோ஼். 
The Bayesian model involves two mechanisms of statistical borrowing to boost power in light of 
limited sample size via acknowledgement of relevant data exogenous to the JV01 enrolled 
population. First, a Bayesian augmented control (BAC) approach will incorporate historical PFS 
outcomes from propensity-matched real world historical control patients. The historical control 
data will be down-weighted using a fixed power prior (Ibrahim et al. 2015). The BAC approach 
reduces the required proportion of patients randomized to the prospective control arm in JV01. 
Second, the Bayesian model includes a mechanism for dynamic borrowing on effect-size (log 
PFS HR) between the two addenda, JV01 and JV02. This is accomplished via a simple random-
effects meta-analytic framework within the Bayesian model. The dynamic borrowing on effect-
size boosts power substantially under key scenarios in which both tumors (both JV01 and JV02 
populations) truly benefit from the addition of ramucirumab to standard chemotherapy, while 
maintaining acceptable control of Type I error in scenarios of strong heterogeneity in effect-size 
(see Table JV01.14 and Table JV01.15). 
Full mathematical detail (including prior specification) regarding the Bayesian model for PFS is 
elaborated in the SAP along with computer code in the JAGS language (Plummer et al. 2017) 
used for implementing Markov Chain Monte Carlo (MCMC) simulation from the approximate 
posterior distribution. 
To correspond with the 99% superiority threshold for success, a 98% (equal-tailed) Bayesian 
credible interval will be provided to accompany the median of the posterior distribution of the 
ܪܴ஽ௌோ஼். In addition, PFS curves, median PFS, and PFS rates at various time points will be 
estimated via corresponding posterior summaries and reported along with associated 80% 
Bayesian credible intervals, where appropriate.  Per sensitivity, these quantities will also be 
estimated using the traditional method of Kaplan-Meier (Kaplan and Meier 1958).  Additional 
details are available in SAP Section 6.6.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 68
LY900023; LY3009806
Table JV01.13.
PFS Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate tumor assessment, per 
RECIST 1.1 criteria, or date of randomization 
(whichever is later)b
Unless
No baseline radiologic tumor assessment 
available
Censored
Date of randomization
No adequate postbaseline tumor assessment 
available and death reported after 2 scan 
intervals following randomizationb,c
Censored
Date of randomization
Tumor progression or death documented
immediately after 2 or more scan intervals 
following last adequate tumor assessment 
or randomization (whichever is later)b,c
Censored
Date of last adequate tumor assessment, per 
RECIST 1.1 criteria, or date of randomization 
(whichever is later)b
Abbreviations:  CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SD = stable disease.
a
Symptomatic deterioration (ie, symptomatic progression that is not confirmed per RECIST 1.1 criteria) will not 
be considered as tumor progression.
b
Adequate tumor assessment per RECIST 1.1 criteria refers to an assessment with one of the following responses:  
CR, PR, SD, or PD.
c
Refer to the statistical analysis plan for the definition of 2 scan intervals, including any adjustment for scan 
window.
Table JV01.14
Simulated Operating Characteristics
True Hazard Ratio
Pr(Pass Interim)
Pr(Pass Final)
SS
DSRCT
SS
DSRCT
SS
DSRCT
1.00
1.00
0.44
0.44
0.003
0.003
0.50
0.50
0.96
0.96
0.37
0.37
0.33
0.33
0.99
0.99
0.82
0.82
Table JV01.15
Impact of Heterogeneous Effect-Size Between Tumors
True Hazard Ratio
Pr(Pass Interim)
Pr(Pass Final)
SS
DSRCT
SS
DSRCT
SS
DSRCT
1
0.80
0.50
0.61
0.008
0.018
1
0.50
0.60
0.88
0.015
0.164
Overall response rate is defined as the number of patients who achieve a best overall response 
of complete response (CR) or partial response (PR) divided by the total number of patients 
randomized to the corresponding treatment arm (ITT population).  Confirmation of PR or CR is 
required. The ORR, with 80% CI based on the method of Clopper and Pearson (1934), will be 
summarized for each treatment arm and compared between treatment arms using Fisher’s exact 
test at 1-sided level ߙൌ.1.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 69
LY900023; LY3009806
Duration of response is defined as the time from the date that measurement criteria for CR or 
PR (whichever is first recorded) are first met until the first date that disease is recurrent or 
documented disease progression is observed, per RECIST 1.1 criteria, or the date of death from 
any cause in the absence of documented disease progression or recurrence.
3.10.3.2. Safety Analysis
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.
Refer to the CAMPFIRE Master Protocol Section 10.3.1 for additional safety analysis. 
3.10.3.3. Other Analysis
3.10.3.3.1.Pharmacokinetic/Immunogenicity Analyses
Serum concentrations of study drug (ramucirumab) prior to infusion (trough concentration) and 
at the end of the infusion (approximately peak concentration) will be summarized using 
descriptive statistics.  Additional analysis utilizing the population PK approach may also be 
conducted if deemed appropriate.  Relationships between ramucirumab exposure and measures 
of efficacy and safety will be explored.  Details will be described in the SAP.
Immunogenicity incidence will be tabulated and correlation of immunogenicity to ramucirumab 
drug level, activity, and safety will be assessed as appropriate.
3.10.3.3.2.Biomarker Analyses
Biomarkers relevant to ramucirumab, mechanism of action of ramucirumab, the variable 
response to study drug(s), immune function, angiogenesis, and pathways associated with cancer 
will be analyzed for association with disease state and clinical outcomes.
3.10.3.4. Subgroup Analysis
A prespecified list of subgroups will be identified in the SAP and will include (at a minimum) a 
comparison between adults and pediatrics with respect to certain safety and efficacy measures.  
The treatment effect within each subgroup will be summarized.  Other subgroup analyses not 
specified in the SAP may be performed as deemed appropriate.  These subgroups will be based 
on important characteristics, for example, prognostic significance.
3.10.3.5. Interim Analysis
Data will be reviewed on an ongoing basis during the safety lead-in period to inform the 
rolling-six decision rules.
An interim futility analysis will be triggered when minimum 24 total PFS events have been 
observed across Study JV01 and Study JV02 with a minimum of 8 events in each study. At the 
interim futility look, the Bayesian of PFS analysis must provide a minimum of 60% posterior 
probability of superiority (PFS HR<1 for DSRCT patients) in order for enrollment on 
Study JV01 to continue. Otherwise, enrollment on Study JV01 will be stopped.
In order to minimize the operational and statistical bias that result from performing an interim 
analysis, the interim analyses for this study will be conducted under the auspices of an 
Independent Data Monitoring Committee (IDMC).  The purpose of the IDMC is to advise Lilly 

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 70
LY900023; LY3009806
regarding the continuing safety of study participants and the continuing validity and scientific 
merit of the trial.  Details of the IDMC are provided in the IDMC charter.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 71
LY900023; LY3009806
4. References
Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior 
reversible encephalopathy syndrome. Am J Neuroradiol. 2007;28(7):1320-1327.
Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding 
pathophysiology of vasogenic edema. Am J Neuroradiol. 2008;29(6):1043-1049.
Bent MA, Padilla BE, Goldsby RE, DuBois SG. Clinical characteristics and outcomes of 
pediatric patients with desmoplastic small round cell tumor. Rare Tumors. 2016;8(1):24-26.
Biassoni V, Casanova M, Spreafico F, Gandola L, Massimino M. A case of relapsing 
glioblastoma multiforme responding to vinorelbine. J Neurooncol. 2006;80(2):195-201.
Blann AD1, Li JL, Li C, Kumar S. Increased serum VEGF in 13 children with Wilms' tumour 
falls after surgery but rising levels predict poor prognosis. Cancer Lett. 2001;173(2):183-186.
Bolis G, Bortolozzi G, Carinelli G, D'Incalci M, Gramellini F, Morasca L, Mangioni C. 
Low-dose cyclophosphamide versus adriamycin plus cyclophosphamide in advanced ovarian
cancer. A randomized clinical study. Cancer Chemother Pharmacol. 1980;4(2):129-132.
Carmeleit P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 
2011;473:298-307.
Casanova M, Ferrari A, Bisogno G, Merks JH, De Salvo GL, Meazza C, Tettoni K, Provenzi M, 
Mazzarino I, Carli M. Vinorelbine and low-dose cyclophosphamide in the treatment of 
pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. 
Cancer. 2004;101(7):1664-1671.
Casanova M, Ferrari A, Spreafico F, Terenziani M, Massimino M, Luksch R, Cefalo G, Polastri 
D, Marcon I, Bellani FF. Vinorelbine in previously treated advanced childhood sarcomas: 
evidence of activity in rhabdomyosarcoma. Cancer. 2002;94(12):3263-3268.
Chen HX, Cleck JC. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev 
Clin Oncol. 2009;6(8):465-477.
Chisholm JC, Merks JHM, Casanova M, Bisogno G4 Orbach D, Gentet JC, 
Thomassin-Defachelles AS, Chastagner P, Lowis S, Ronghe M, McHugh K, van Rijn RR, 
Hilton M, Bachir J, Fürst-Recktenwald S, Geoerger B, Oberlin O; European paediatric Soft 
tissue sarcoma Study Group (EpSSG) and the European Innovative Therapies for Children 
with Cancer (ITCC) Consortium. Open-label, multicentre, randomised, Phase II study of the 
EpSSG and the ITCC evaluating the addition of bevacizumab to chemotherapy in childhood 
and adolescent patients with metastatic soft tissue sarcoma (the BERNIE study). Eur J Cancer. 
2017;83:177-184.
Chisholm JC, Merks JHM, Casanova M, Bisogno G4 Orbach D, Gentet JC, Thomassin 
Defachelles AS, Chastagner P, Lowis S, Ronghe M, McHugh K, van Rijn RR, Hilton M, 
Bachir J, Fürst-Recktenwald S, Geoerger B, Oberlin O; European paediatric Soft tissue 
sarcoma Study Group (EpSSG) and the European Innovative Therapies for Children with 
Cancer (ITCC) Consortium. BERNIE: Open-label, randomized, phase II study of bevacizumab 
plus chemotherapy in pediatric metastatic rhabdomyosarcoma (RMS) and non-

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 72
LY900023; LY3009806
rhabdomyosarcoma soft tissue sarcoma (NRSTS). J Clin Onc. 2016 34:15_suppl, 11054-
11054.
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Biometrika. 1934;26(4):404-413.
Crawford J, Armitage J, Balducci L, Bennett C, Blayney DW, Cataland SR, Dale DC, Demetri 
GD, Erba HP, Foran J, Freifeld AG, Goemann M, Heaney ML, Htoy S, Hudock S, Kloth DD, 
Kuter DJ, Lyman GH, Michaud LB, Miyata SC, Tallman MS, Vadhan-Raj S, Westervelt P, 
Wong MK; National Comprehensive Cancer Network. Myeloid growth factors. J Natl Compr 
Cancer Netw. 2009;7(1):64-83.
DeVita VT, Young RC, Canellos GP. Combination versus single agent chemotherapy: a review 
of the basis for selection of drug treatment of cancer. Cancer. 1975;35(1):98-110.
Dufresne A, Cassier P, Couraud L, Marec-Bérard P, Meeus P, Alberti L, Blay JY. Desmoplastic 
small round cell tumor: current management and recent findings. Sarcoma. 2012;2012:714986. 
doi:10.1155/2012/714986.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev 
Cancer. 2008;8(8):579-591.
Ferrari A, Grosso F, Stacchiotti S, Meazza C, Zaffignani E, Marchianò A, Casanova M. 
Response to vinorelbine and low-dose cyclophosphamide chemotherapy in two patients with 
desmoplastic small round cell tumor. Pediatr Blood Cancer. 2007;49(6):864-866.
Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol.
2017;264(8):1608-1616.
Fox E, Aplenc R, Bagatell R, Chuk MK, Dombi E, Goodspeed W, Goodwin A, Kromplewski M, 
Jayaprakash N, Marotti M, Brown KH, Wenrich B, Adamson PC, Widemann BC, Balis FM. A 
Phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan–vascular 
endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid 
tumors. J Clin Oncol. 2010;28(35):5174-5181.
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos 
Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, 
Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, 
Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated 
advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an 
international, randomised, multicenter, placebo-controlled, phase 3 trial. Lancet. 
2014;383(9911):31-39.
Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and 
radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 
2015;14(9):914-925.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 73
LY900023; LY3009806
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, 
Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, 
Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, 
Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel 
for second-line treatment of stage IV non-small-cell lung cancer after disease progression on 
platinum-based therapy (REVEL): a multicentre, double-blind, randomised Phase 3 trial. 
Lancet. 2014;384(9944):665-673.
Gerald WL, Rosai J. Case 2. Desmoplastic small cell tumor with divergent differentiation. 
Pediatr Pathol. 1989;9(2):177-83.
George S, Merriam P, Maki RG, Van den Abbeele AD, Yap JT, Akhurst T, Harmon DC, 
Bhuchar G, O’Mara MM, D’Adamo DR, Morgan J, Schwarz GK, Wagner AJ, Butrynski JE, 
Demetri GD, Keohan ML. Multicenter Phase II trial of sunitinib in the treatment of 
nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27(19):3154-3160.
Glade Bender JL, Lee A, Reid JM, Baruchel S, Roberts T, Voss SD, Wu B, Ahern CH, 
Ingle AM, Harris P, Weigel BJ, Blaney SM. Phase I pharmacokinetic and pharmacodynamic 
study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a 
Children’s Oncology Group Phase I consortium report. J Clin Oncol. 2013;31(24):3034-3043.
Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas JL, 
Caplan LR. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 
1996;334(8):494-500.
Holzer G, Obermair A, Koschat M, Preyer O, Kotz R, Trieb K. Concentration of vascular 
endothelial growth factor (VEGF) in the serum of patients with malignant bone tumors. Med 
Pediatr Oncol. 2001;36(6):601-604.
Honoré C, Amroun K, Vilcot L, Mir O, Domont J, Terrier P, Le Cesne A, Le Péchoux C, 
Bonvalot S. Abdominal desmoplastic small round cell tumor: multimodal treatment combining 
chemotherapy, surgery, and radiotherapy is the best option. Ann Surg Oncol. 2015;22(4):1073-
1079.
Ibrahim JG, et al. The power prior: theory and applications. Stat Med. 2015;34(28):3724-3749.
Iyer RS, Schaunaman G, Pruthi S, Finn LS. Imaging of pediatric desmoplastic small-round-cell 
tumor with pathologic correlation. Curr Probl Diagn Radiol. 2013;42(1):26-32.
Johansen M, Kuttesch J, Bleyer WA, Krailo M, Ames M, Madden T. Phase I evaluation of oral 
and intravenous vinorelbine in pediatric cancer patients: a report from the Children's Oncology 
Group. Clin Cancer Res. 2006;12(2):516-522.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481.
Knight ZA, Lin H, Shokat KM. Targeting the cancer kinome through polypharmacology. 
Nat Rev Cancer. 2010;10(2):130-137.
Lal DR, Su WT, Wolden SL, Loh KC, Modak S, La Quaglia MP. Results of multimodal 
treatment for desmoplastic small round cell tumors. J Pediatr Surg. 2005;40(1):251-255.
Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior 
leukoencephalopathy syndrome. Arch Neurol. 2008;65(2):205-210.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 74
LY900023; LY3009806
Maki RG, D’Adamo DR, Keohan ML, Saulle M, Schuetze SM, Undevia SD, Livingston MB, 
Cooney MM, Hensley ML, Mita MM, Takimoto CH, Kraft AS, Elias AD, Brockstein B, 
Blachère NE, Edgar MA, Schwartz LH, Qin L-X, Antonescu CR, Schwartz GK. Phase II study 
of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 
2009;27(19):3133-3140.
Mascarenhas L, Meyer WH, Lyden E, Rodeberg DA, Indelicato DJ, Linardicjames CM, 
Anderson JR, Hawkins DS. Randomized phase II trial of bevacizumab and temsirolimus in 
combination with vinorelbine (V) and cyclophosphamide (C) for first relapse/disease 
progression of rhabdomyosarcoma (RMS): a report from the Children’s Oncology Group 
(COG). J Clin Oncology. 2014;32(suppl 15). Abstract 10003.
Minard-Colin V, Ichante JL, Nguyen L, Paci A, Orbach D, Bergeron C, Defachelles AS, 
André N, Corradini N, Schmitt C, Tabone MD, Blouin P, Sirvent N, Goma G, Geoerger B, 
Oberlin O. Phase II study of vinorelbine and continuous low doses cyclophosphamide in 
children and young adults with a relapsed or refractory malignant solid tumour: good tolerance 
profile and efficacy in rhabdomyosarcoma--a report from the Société Française des Cancers et 
leucémies de l'Enfant et de l'adolescent (SFCE). Eur J Cancer. 2012;48(15):2409-2416.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 5.0, DCTD, NCI, NIH, DHHS. 2017. Published 27 
November 2017.
[NHBPEPWG] National High Blood Pressure Education Program Working Group on High 
Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, 
and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(suppl 2 
4th Report):555-576.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655.
Plummer M. JAGS Version 4.3.0 user manual. 2017.
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, 
Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR; American Society of 
Clinical Oncology; American Society of Hematology. American Society of Clinical 
Oncology/American Society of Hematology clinical practice guideline update on the use of 
epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996-5010.
Sawyers C. Targeted cancer therapy. Nature. 2004;432(7015):294-297.
Scheer M, Vokuhl C, Blank B, Hallmen E, von Kalle T, Münter M, Wessalowski R, Hartwig M, 
Sparber-Sauer M, Schlegel PG, Kramm CM, Kontny U, Spriewald B, Kegel T, Bauer S, 
Kazanowska B, Niggli F, Ladenstein R, Ljungman G, Jahnukainen K, Fuchs J, Bielack SS, 
Klingebiel T, Koscielniak E; Cooperative Weichteilsarkom Studiengruppe [CWS]. 
Desmoplastic small round cell tumors: Multimodality treatment and new risk factors. Cancer 
Med. 2019;8(2):527-542. 
Skolnik JM1, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of 
pediatric Phase I trials: the rolling six design. J Clin Oncol. 2008;26(2):190-195.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 75
LY900023; LY3009806
Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schöffski P, Collin F, Pandite L, 
Marreaud S, De Brauwer A, von Glabbeke M, Verweij J, Blay J-Y. Pazopanib, a multikinase 
angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a 
Phase II study from the European Organisation for Research and Treatment of Cancer–Soft 
Tissue and Bone Sarcoma Group (EORTC Study 62043). J Clin Oncol. 2009;27(19):3125-
3132.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, 
Cantor SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, 
Schwartzberg L, Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff 
AC. 2006 Update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205.
Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a 
misnomer reviewed. Int Med J. 2005;35(2):83-90.
Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, 
Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, 
Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE 
Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI 
in patients with metastatic colorectal carcinoma that progressed during or after first-line 
therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, 
double-blind, multicentre, Phase 3 study. Lancet Oncol. 2015;16(5):499-508.
Tajima Y, Isonishi K, Kashiwaba T, Tashiro K. Two similar cases of encephalopathy, possibly a 
reversible posterior leukoencephalopathy syndrome: serial findings of magnetic resonance 
imaging, SPECT and angiography. Intern Med. 1999;38(1):54-58.
Tarek N, Hayes-Jordan A, Salvador L, McAleer MF, Herzog CE, Huh WW. Recurrent 
desmoplastic small round cell tumor responding to an mTOR inhibitor containing regimen. 
Pediatr Blood Cancer. 2018;65(1).
van der Graaf WTA, Blay J-Y, Chawla SP, Kim D-W, Bui-Nguyen B, Casali PG, Schöffski P, 
Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, 
Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, 
Hohenberger P. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, 
double-blind, placebo-controlled Phase 3 trial. Lancet. 2012;379(9829):1879-1886.
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, 
Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, 
Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab 
plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced 
gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, 
randomised Phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 76
LY900023; LY3009806
Attachment 1.
Protocol Addendum JV01 Abbreviations 
and Definitions
The list of abbreviations and definitions found in the Study JV01 Addendum is included below.
Term
Definition
5-HT3
5 hydroxytryptamine 3
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 event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
BP
blood pressure
BSA
body surface area
CHF
congestive heart failure
CI
confidence interval
Cmax
maximum concentration
Cmin
minimum concentration
CNS
central nervous system
COG
Children’s Oncology Group
collection database
A computer database in which clinical study data are entered and validated.
CR
complete response
CRF
case report form

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 77
LY900023; LY3009806
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, global safety physician, or other medical officer.
CRS
Clinical Research Scientist
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CVA
cerebrovascular accident
CYP
cytochrome P450
DLT
dose-limiting toxicity
DSRCT
desmoplastic small round cell tumor
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
end of study
Date of the last visit or last scheduled procedure shown in the Schedule of Activities 
(Section 3.2) for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
EU
European Union
FOCBP
Females of child bearing potential
G-CSF
granulocyte-colony stimulating factor
GEJ
gastroesophageal junction
GI
gastrointestinal
GGT
gamma-glutamyl transferase
HR
hazard ratio
HSR
hypersensitivity reactions
IB
Investigator’s Brochure
ICF
informed consent form

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 78
LY900023; LY3009806
interim analysis
An analysis of clinical study data conducted before the final reporting database is 
created/locked.
IRB
institutional review board
IRR
infusion-related reaction
ITT
intention-to-treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (ie, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed-up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive Web-response system
LLT
MedDRA Lower Level Term
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PT
MedDRA Preferred Term
Q2W
every two weeks
QD
once daily
randomize
The process of assigning patients to an experimental group on a random basis.
RECIST
Response Evaluation Criteria in Solid Tumors

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 79
LY900023; LY3009806
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.
RMS
rhabdomyosarcoma
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SOC
MedDRA System Organ Class
study completion
Occurs following the final analysis of progression-free survival, as determined by Lilly.
TIA
transient ischemic attack
ULN
upper limit of normal
UPC
urine protein to creatinine
VEGF
vascular endothelial growth factor
VHP
Voluntary Harmonization Procedure (participating countries include: Belgium, 
Germany PEI, Italy, Netherlands, and Spain) 
VTE
venous thromboembolic event

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 80
LY900023; LY3009806
Attachment 2.
Protocol Addendum JV01 Clinical 
Laboratory Tests
Clinical Laboratory Tests
Hematology – laboratorya
Local
Central
Leukocytes (WBC)
x
Neutrophilsb
x
Lymphocytes
x
Monocytes
x
Eosinophils
x
Basophils
x
Erythrocytes (RBC)
x
Hemoglobin (HGB)
x
Hematocrit (HCT)
x
Mean corpuscular volume (MCV)
x
Mean corpuscular hemoglobin concentration (MCHC)
x
Platelets (PLT)
x
Manual Differential – laboratory
Local:   x
Central
Coagulation- laboratory
Local
Central
Activated partial thromboplastin time (aPTT) or Partial 
thromboplastin time (PTT)
x
International normalized ratio (INR) or Prothrombin time (PT)
x

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 81
LY900023; LY3009806
Clinical Chemistry – laboratory
Local
Central
Serum Concentrations of:
Alanine aminotransferase (ALT)
x
Albumin
x
Alkaline phosphatase
x
Aspartate aminotransferase (AST)
x
Bilirubin, direct
x
Bilirubin, total
x
Blood urea nitrogen (BUN) or blood urea
x
Calcium
x
Creatinine
x
Glucose nonfasting
x
Magnesium
x
Phosphate
x
Potassium
x
Protein
x
Sodium
x
Urinalysis – laboratory
Local
Central
Blood
X
Glucose
X
Ketones
X
pH
X
Protein
x
Specific gravity
x
Urine leukocyte esterase
x
Pregnancy Test (for female patients of childbearing potential) -
laboratory
Local
Central
Serum/urine pregnancy test
x
TSH and FreeT4 – laboratory
Local:   x
Central
Hypersensitivity Tests – laboratory
Local
Central
Tryptasec
x
Urine N-methylhistamine
x
Complements

C3a

C5a
x
Cytokine Panel

IL-6

IL-1β

IL-10
x

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 82
LY900023; LY3009806
Abbreviations:  CRF = case report form; EGFR = epidermal growth factor receptor; Free T4 = thyroxine; IL = 
interleukin; K-ras = Kirsten rat sarcoma; RBC = red blood cells; TSH = thyroid-stimulating hormone; WBC = 
white blood cells.
a
Treatment and enrollment decisions will be based on local laboratory results.
b Neutrophils reported by 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
If a tryptase sample is obtained more than 2 hours after the event (i.e. within 2-12 hours) or is not obtained 
because more than 12 hours have lapsed since the event, obtain urine for N-methylhistamine (NMH) testing. 
Note that for tryptase serum samples obtained within 2-12 hours of the event, urine NMH testing is performed in 
addition to tryptase testing. Collect the first void urine following the event. Obtain a follow-up urine for NMH 
testing at the next regularly scheduled visit or after 4 weeks, whichever is later.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 83
LY900023; LY3009806
Attachment 3.
Protocol Addendum JV01 Sampling 
Schedule for Genetics/ 
Biomarkers/Immunogenicity/Pharmacokinetics
Pharmacokinetic samples will be collected for ramucirumab in patients in the ramucirumab arm.  
Immunogenicity (IG) samples will be collected for patients in both the ramucirumab and control 
arms.  Predose samples should be taken as close as possible to the start of first infusion, that is 
ramucirumab infusion, but can be drawn up to 1 hour (60 minutes) prior to start of infusion, and 
exact clock readings should be recorded.  Postdose (post end of infusion) samples for PK should 
be drawn, preferably within 15 minutes after the end of the ramucirumab infusion, and an exact 
clock reading for the sample draw should be recorded.
Preferred time windows for each PK/IG sample collection are also provided in the tables in this 
section.  While best efforts should be made to draw the blood sample for PK/IG within the time 
window provided, it is more important to ensure the predose sample is actually collected before 
the start of ramucirumab infusion and post-dose samples (post end of infusion samples) are 
collected after infusion is actually completed.  It is also equally important to record the actual 
date and time of blood collection for the PK/IG sample on the Requisition Form after drawing 
the sample (ie, do not record planned time of collection).  Sample collection for post-infusion 
PK/IG must be from the opposite arm to that used for study drug infusion.  If the drug was 
administered via a central venous catheter, the sample collection should be from a different site.
In addition, if a patient in either the ramucirumab or control arm experiences an IRR, blood 
samples should be drawn for PK and IG.  Samples 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 
after the IRR.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 84
LY900023; LY3009806
Sampling Schedule for Genetics/Biomarkers/Immunogenicity/Pharmacokinetics
Procedure
Sample Time
Cycle 1
Cycle 2
Cycle 4
Cycle 7
Cycle 10
Short-Term
Follow-Up
Day 1
Day 15
Day 1
Day 1
Day 8
Day 1
Day 1
Week 0
Week 2
Week 4
Week 
12
Week 13
Week 24
Week 30
Pharmacokineticsa (for 
ramucirumab arm only)
Prior to 
ramucirumab 
infusionb,c
X
X
X
X
X
X
Any time during the 
short-term follow-up 
visit
Within 0.5 hours 
after the end of 
the ramucirumab 
infusion and prior 
to vinorelbine 
infusionc
X
Immunogenicitya
Prior to 
chemotherapy
infusionb,c
X
X
X
Any time during the 
short-term follow-up 
visit
Tumor tissued,e
Prior to 
chemotherapy
infusionb
X
Serum for biomarkersd ( 
for both treatment arms).
Prior to 
chemotherapy b 
infusionb
X
X
Plasma for biomarkersd
(for both treatment 
arms).
Prior to 
chemotherapy
infusionb
X
X
Any time during the 
short-term follow-up 
visit
Whole bloodd (for both 
treatment arms).
Prior to 
chemotherapy
infusionb
Xf

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 85
LY900023; LY3009806
Abbreviations:  C4D8 = Cycle 4 Day 8; eCRF = electronic case report form; hr = hour; IG = immunoglobulin; IRR = infusion-related reaction; 
PK = pharmacokinetic.
Note:  For those patients on the ramucirumab arm, ramucirumab infusion is given every 2 weeks.  The infusion duration is 1 hr.  Each cycle is a 28-day cycle.
a
In the event of an IRR (including hypersensitivity reactions), additional blood samples will be collected from all patients, whether in the ramucirumab arm or 
the control arm, for both PK and IG analysis at the following time points:  (i) as close as possible to the onset of the IRR, (ii) at the resolution of the IRR, and 
(iii) 30 days following the IRR (see table below).
b
Cycle 1 Day 1 samples can be collected within 7 days prior to ramucirumab infusion; Cycle 1 Day 15 and Cycle 2 to Cycle 9 Day 1 samples can be collected 
within 3 days prior to ramucirumab infusion, but predose samples should be preferably collected within 1 hour prior to start of ramucirumab infusion if 
possible.  Serum and plasma biomarkers collected at C4D8 can be collected at anytime during the scheduled visit.
c
While best efforts should be made to draw the blood sample for PK/IG within the time windows provided above, it is more important to ensure the predose 
sample is actually collected before the start of first infusion and postdose samples are collected after the infusion is actually completed.  It is also equally 
important to record ACTUAL date and time of blood collection for the PK/IG sample on the Requisition Form AFTER drawing the sample and to accurately 
record the ACTUAL infusion start and end dates and times on the eCRF to be able to use the data for analyses.  Sample collection for post-infusion PK/IG 
must be from the opposite arm to that used for study drug infusion.  If the drug was administered via a central venous catheter, the sample collection should be 
from a different site. 
d
Collection of tumor tissue and biomarkers (serum, plasma, whole blood) is optional.  Previously archived formalin-fixed paraffin-embedded tumor tissue 
obtained from the primary tumor or metastatic site should be provided as a whole block or unstained slides.
e
Optional collection of an additional biopsy specimen after treatment start may be requested.
f
A pretreatment blood sample is preferred; however, the whole blood sample for genetic analysis (as described in Section 9.7 of the main protocol) may be 
collected at a later time point if necessary.
Infusion-Related Reaction (Including Hypersensitivity Reactions) Immunogenicity/Pharmacokinetics Sampling for ALL 
Patientsa
Procedure
Sample Time
Onset of the IRR
Once
Hemodynamically 
Stableb
Resolution of the IRR
30 days following the IRR
PK
X
X
X
Immunogenicity
X
X
X
Hypersensitivity testing 
X
Xc

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 86
LY900023; LY3009806
Abbreviations: IRR = infusion-related reaction; PK = pharmacokinetics.
a
In the event of an IRR (including hypersensitivity reactions), additional blood samples will be collected from all patients, whether in the ramucirumab arm or 
the control arm, for both PK and IG analysis at the following time points:  (i) as close as possible to the onset of the IRR, (ii) at the resolution of the IRR, and 
(iii) 30 days following the IRR.
b
After the patient has been stabilized obtain a sample within 1-2 hours of the event; however, samples may be obtained as late as 12 hours after the event as 
analytes can remain altered for an extended period of time. Record the time at which the sample was collected.
c
Obtain a follow-up sample at the 30-day follow-up or at the next regularly scheduled visit following the IRR, whichever is later.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 87
LY900023; LY3009806
Attachment 4.
Protocol Addendum JV01 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 Serology
Aspartate aminotransferase (AST)
Anti-nuclear antibodya
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibodya
Creatine phosphokinase (CPK) 
Anti-actin antibodya
Abbreviations:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by local laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 88
LY900023; LY3009806
Attachment 5.
Protocol JV01 Restricted and Prohibited 
Concomitant Therapy
The table below describes medications, treatments, and drug classes restricted or prohibited, with 
exceptions and conditions for use during the study treatment period (there are no prohibited 
therapies during the follow-up period).  Patients who, in the assessment by the investigator, 
require the use of any of the prohibited treatments for clinical management should be removed 
from the trial.  Patients may receive other supportive therapy or vaccinations that the investigator 
deems to be medically necessary.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 89
LY900023; LY3009806
Therapy
Allowed 
As Needed
Allowed 
for 
Chronic 
Use
Exceptions or Conditions for Use
Anti-platelet therapy 
and NSAIDs
Yes
Yes, with 
restrictions
Chronic use of aspirin up to 325 mg/day is permitted.  Chronic 
use of NSAIDs is not permitted. However, in certain medical 
situations, NSAIDs may be the best treatment option (for 
example, for pain management) and are therefore permitted as
needed. Increased risk of bleeding should be considered by the 
treating physician and the patient.
Anticoagulation 
therapy
No
Yes, with 
restrictions
At enrollment, patients on full-dose anticoagulation must be on 
a stable dose (minimum duration 14 days) of oral anticoagulant 
or low molecular weight heparin or similar agent.  If on 
warfarin, the patient must have an INR≤3 and no active bleeding 
or pathological condition present that carries a high risk of 
bleeding (eg, tumor involving major vessels or known varices).
Anti-cancer biological 
therapy
No
No
Chemotherapy
No
No
CYP3A strong 
inhibitors
No
No
See list in table.
Erythroid growth 
factors
Yes
No
Follow local guidelines.
Experimental 
medicines or 
investigational 
agents
No
No
Other than ramucirumab, cyclophosphamide, vinorelbine.
Glucocorticoids
Yes
Yes, with 
restrictions
Systemic glucocorticoids are permitted to modulate symptoms 
from an event of clinical interest of suspected immunologic 
etiology. Use in patients with contrast allergies is acceptable. A 
temporary course of corticosteroids will be allowed for other 
indications, at the discretion of the principal investigator (eg, 
chronic obstructive pulmonary disease, radiation, nausea, etc.).  
The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.  
Note:  Inhaled steroids are allowed for management of asthma.
Immunotherapy 
No
No
Other than inhaled steroids and vaccinations.
Radiation therapy
No
No
Localized radiation therapy to a symptomatic, solitary lesion or 
to the brain may be allowed after consultation with the Sponsor.
Live Vaccines
No
N/A
Prohibited as concomitant therapy during the study and for at 
least 3 months after last dose of study drug.
Abbreviations:  INR = international normalized ratio; NSAID = nonsteroidal anti-inflammatory drug.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 90
LY900023; LY3009806
Restricted Strong inhibitors of CYP3Aa
All HIV protease inhibitors
Boceprevir
Clarithromycin
Conivaptan
Danoprevir and ritonavir
Diltiazem
Elvitegravir and ritonavir
Idelalisib
Itraconazole
Ketoconazole
Nefazodone
Paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
Posaconazole
Telaprevir
Troleandomycin
Voriconazole
a
This is not an all-inclusive list and due diligence should be followed.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 91
LY900023; LY3009806
Attachment 6.Protocol Addendum Amendment J1S-MC-
JV01(g)
A Randomized, Open-Label Phase 1/2 Study Evaluating 
Ramucirumab in Pediatric Patients and Young Adults with 
Relapsed, Recurrent, or Refractory Desmoplastic Small 
Round Cell Tumor
DOCUMENT HISTORY
Document
Date
Amendment f
9-Oct-2020
Amendment e
18-May-2020
Amendment d
17-Oct-2019
Amendment c
26-Sep-2019
Amendment b
2-Aug-2019
Amendment a
23-Jan-2019
Original Protocol
7-Dec-2018
Amendment g
This amendment is considered to be nonsubstantial.
Overall Rationale for the Amendment:
This amendment is being updated to align urinalysis collection in the schedule of activities with 
monitoring table in later sections. Other changes and clarifications were made based on  recent 
feedback from sites.
Section # and Name
Description of Change
Brief Rationale
3.2 Schedule of Activities; 
3.9.3.1.2 Monitoring for Special 
Toxicities: Growth Plate
Added text to clarify “Plain 
anteroposterior radiograph of a 
single proximal tibial growth 
plate” are for participants 
randomized to the 
ramucirumab treatment arm 
only.
Update based on site and 
regulatory feedback.
3.2 Schedule of Activities
Added text to clarify timing of 
radiologic imaging begins at 
C1D1.
Minor clarification.

J1S-MC-JV01(g) Clinical Protocol Addendum
Page 92
LY900023; LY3009806
Section # and Name
Description of Change
Brief Rationale
3.2 Schedule of Activities; 
3.9.3.1.2 Monitoring for Special 
Toxicities: Growth Plate
Added text to allow an 
alternate option of MRI of the 
knee in some geographies for 
growth-plate monitoring
instead of a plain AP 
radiograph.
Regulatory requirement.
3.2 Schedule of Activities
Added Day 15 Urinalysis 
throughout the treatment 
period.
Align with monitoring table 
in protocol.
3.7.1.2 Dosing Schedule
Added text to indicate a 
minimum of 2 weeks be 
observed between 
ramucirumab administration if 
the ramucirumab dose is 
delayed.
Site clarification.
3.7.1.2 Dosing Schedule
Added information related to 
treatment delays due to 
unforeseeable circumstances.
Added to address instances 
of exceptional 
circumstances.
3.7.4.1 Guidelines for 
Hematological and 
Nonhematological Dose 
Modifications
Updated Table JV01.10 with 
new G-CSF use 
recommendations for 
cyclophosphamide and 
vinorelbine dose adjustments.
Updated based on emerging 
information.
3.7.4.1 Guidelines for 
Hematological and 
Nonhematological Dose 
Modifications
Added “footnote d” in Table 
JV01.10 to clarify that Table 
JV02.8 should be used for 
dose reductions.
Site clarification.
Attachment 3 Protocol Addendum 
JV01 Sampling Schedule for 
Genetics/ Biomarkers/ 
Immunogenicity/ Pharmacokinetics
Clarified “serum for 
biomarkers,” “plasma for 
biomarkers,” and “whole 
blood” are to be collected for 
both arms and are optional.
Site clarification.
Throughout
Minor editorial and document 
formatting revisions
These are minor changes; 
therefore, they have not 
been summarized.

Leo Document ID = 5df72415-6552-4c0c-96ea-d551fb92533d
Approver: 
Approval Date & Time: 13-Dec-2021 17:12:57 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-Dec-2021 17:47:57 GMT
Signature meaning: Approved
PPD
PPD