Clinical trial NCT04557384
Conditions: Advanced Solid Tumor
Keywords: Safety
Sponsor: Eli Lilly and Company
Start date: 2021-02-23; Completion date: 2021-05-25
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study in participants with advanced cancer is to learn more about the safety of ramucirumab when given by injection under the skin (subcutaneous injection). The study will also measure how much ramucirumab gets into the bloodstream and how long it takes the body to get rid of it.

Detailed description:

Arms: arm 1: Participants received starting dose of 700 milligram (mg) ramucirumab loading dose (LD) subcutaneously (SC) followed, a week later, by 350 mg ramucirumab maintenance dose (MD) administered SC once a week.
Interventions: intervention 1: Ramucirumab
Intervention descriptions: intervention 1: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I4T-MC-JVDU(e) 
 
A Phase 1, Nonrandomized, Open-Label Investigation of Subcutaneous Ramucirumab 
Administration in Participants with Advanced Solid Tumors 
 
NCT04557384  
 
Approval Date: 26-Feb-2021 
 
 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
1
Title Page
Confidential Information
The information contained in this document 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. 
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release.  In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title:
A Phase 1, Nonrandomized, Open-Label Investigation of Subcutaneous Ramucirumab 
Administration in Participants with Advanced Solid Tumors
Protocol Number: I4T-MC-JVDU
Amendment Number: e
Compound: Ramucirumab (LY3009806)
Study Phase: Phase 1
Short Title:
A Phase 1 Investigation of Subcutaneous Ramucirumab Administration in Participants with 
Advanced Solid Tumors
Sponsor Name:  Eli Lilly and Company
Legal Registered Address:  Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s)
IND: 148078
Approval Date: Protocol Electronically Signed and Approved by Lilly on 21 May 2020.
Protocol Amendment (a) Electronically Signed and Approved by Lilly on 14 September 2020.
Protocol Amendment (b) Electronically Signed and Approved by Lilly on 02 October 2020.
Protocol Amendment (c) Electronically Signed and Approved by Lilly on 05 November 2020.
Protocol Amendment (d) Electronically Signed and Approved by Lilly on 14 January 2021.
Approval Date: 26-Feb-2021 GMT


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
2
Protocol Amendment (e) Electronically Signed and Approved by Lilly on date provided below.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
3
Medical Monitor Name and Contact Information will be provided separately


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
4
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment d
14-Jan-2021
Amendment c
05-Nov-2020
Amendment b
02-Oct-2020
Amendment a
14-Sep-2020
Original Protocol
21-May-2020
Amendment [e]
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The overall rationale for the amendment is to enable investigation of additional dosage regimens.  
Preliminary interim analysis data from Study I4T-MC-JVDT, a single-site study in healthy participants 
who received a single dose of SC or IV ramucirumab indicated a 40% bioavailability for ramucirumab 
following SC administration (bioavailability previously predicted: >50%).  A Sub-Cohort B1 has been 
added to provide a second-dose level (in addition to cohort A), with the goal to generate PK data from at 
least 6 participants to inform dosing strategy for Sub-Cohort B2 (loading dose and maintenance weekly 
dose).
Section # and 
Name
Description of Change
Brief Rationale
Section 1.1. 
Synopsis
Added language to support flat dosing for 
Study JVDU
Based on preliminary interim analysis 
data from Study I4T-MC-JVDT
Section 1.1. 
Synopsis (Overall 
Design); Section 
1.2. Schema;
Section 4.1.1. 
Cohort A
Added language reflecting PK will also be 
assessed in all cohorts
Clarification
Section 1.1. 
Synopsis (Number 
of Participants);
Section 9.2. Sample 
Size Determination
Amended the range of number of study 
participants from 15-24 to 18-30
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens based on preliminary interim 
analysis data from Study I4T-MC-JVDT
Section 1.1.
Synopsis
(Intervention
Groups and
Duration);
Section 6.1. Study 
Intervention(s) 
Administered
Amended the Intervention Groups and 
Duration table and footnotes to reflect the 
expansion of Cohort B
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens based on preliminary interim 
analysis data from Study I4T-MC-JVDT


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
5
Section # and 
Name
Description of Change
Brief Rationale
Section 1.2. 
Schema
Amended Schema and footnotes to reflect the 
expansion of Cohort B
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens based on preliminary interim 
analysis data from Study I4T-MC-JVDT
Section 1.3. 
Schedule of 
Activities
Amended note above table
Clarification
Section 1.3. 
Schedule of 
Activities, 
Continued Access 
Schedule of 
Activities
Added reference to Section 10.3 in the AE 
collection row
Clarification
Section 1.3. 
Schedule of 
Activities
Added language stating an investigator 
designee may also assess the injection site 
assessments
To provide flexibility for sites
Section 1.3. 
Schedule of 
Activities
Amended instructional language in the 
Administer ramucirumab row
Clarification
Section 1.3.1. 
Pharmacokinetic 
Sampling Schedule
Amended general instructions for PK sampling
Clarification
Section 2.1. Study 
Rationale
Removed language related to prior dosing 
rationale
Added language referencing clinical outcome 
and PK parameters of IV and SC dosing of 
ramucirumab in Study I4T-MC-JVDT
Removed sentence referencing Eli Lilly’s SC 
formulation of ramucirumab 
Clarification; based on preliminary 
interim analysis data from Study I4T-
MC-JVDT
Section 2.3.1. Risk 
Assessment
Amended language to allude to recent clinical 
data for SC ramucirumab
Based on preliminary interim analysis 
data from Study I4T-MC-JVDT
Section 4.1. Overall 
Design; Section 
9.2.1. Cohort A
Described sub-cohorts and cohorts based on 
updated study design
Removed language about Study JVDT
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens based on preliminary interim 
analysis data from Study I4T-MC-JVDT
Section 4.1.1.
Cohort A
Removed sentence referencing “participants
with disease indications where ramucirumab is 
approved as a monotherapy”
Correction (missed in previous 
amendment), based on preliminary 
interim analysis data from Study I4T-
MC-JVDT revealing lower 
bioavailability than the assumption, 
previously eligible participants for 
approved ramucirumab monotherapy 
(2L Gastric, 2L HCC) would have 
received sub-optimal exposure on 
starting Cohort A dose


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
6
Section # and 
Name
Description of Change
Brief Rationale
Section 4.1.1.
Cohort A
Amended language related to enrolling an 
additional 3 participants into Cohort A
Clarification that additional enrollment 
in Cohort A may occur to numerous 
reasons
Section 4.1.2. 
Cohort B
Specified additional design elements in Cohort 
B, which now comprises B1, B2, and B3
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens based on preliminary interim 
analysis data from Study I4T-MC-JVDT
Section 4.3.2. 
Rationale for 
Cohort B (Sub-
Cohorts B1, B2, 
and B3) Dose 
Selection
Added rationale for dose selection and updated 
dosing table (based on bioavailability of 40%) 
for new Sub-Cohorts B1, B2, and B3
Removed rationale for initial Cohort B dose 
selection
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens based on preliminary interim 
analysis data from Study I4T-MC-JVDT
Section 5.1.
Inclusion Criteria
Amended Inclusion Criterion 3
Clarification
Section 6.1. Study 
Intervention(s) 
Administered
Added language specifying dosage in Sub-
Cohort B1
Specified when interim analysis will be 
performed (Sub-Cohort B2)
Specified ramucirumab dose may be adjusted 
in Sub-Cohort B3
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens
Section 6.1. Study 
Intervention(s) 
Administered; 
Section 6.6. Dose 
Modification
Changed injection site reaction grading 
threshold and moved to Section 6.1 (from 
Section 6.6.)
Allowing participants with mild-to-
moderate local injection site reactions 
due to ramucirumab SC administration 
to continue to receive it
Section 6.6. Dose 
Modification
Removed language related to pausing study on 
the basis of a new safety signal
Dose modifications are not relevant for 
the LD
Section 6.6. Dose 
Modification
Added fever as an example of a non-
threatening and reversible Grade 3 clinical AE
Moved language referencing Appendix 3 for 
AE grading to an earlier paragraph
Clarification
Section 6.6. Dose 
Modification
Added a dose reduction for the MD of the
newly described dosage regimen
To account for a newly added LD of 
1750 mg and MD of 875 mg QW based 
on preliminary interim analysis 
bioavailability data of 40%
Section 7.3. Lost to 
Follow up
Removed language related to collection of 
survival status
Correction, as long-term follow-up and
survival status is not being collected for 
this study
Section 9.1. 
Statistical 
Hypotheses
Specified Ctrough and the approved dose of IV 
ramucirumab
Clarification
Section 9.2.1. 
Cohort A
Amended number of participants/duration of 
PK and safety assessment required before 
opening enrollment for Cohort B
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens based on preliminary interim 
analysis data from Study I4T-MC-JVDT


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
7
Section # and 
Name
Description of Change
Brief Rationale
Section 9.2.2. 
Cohort B (Sub-
Cohorts B1, B2, 
and B3); Section 
9.5. Interim 
Analyses
Changed name from safety review team (SRT) 
or internal assessment committee to internal 
review committee
For consistency with other documents
Section 9.2.2. 
Cohort B (Sub-
Cohorts B1, B2, 
and B3)
Removed language related to PK data 
providing support for Cohort B dose selection
Added language related to Sub-Cohort B2 
dosing regimen determination based on Sub-
Cohort B1 results
To account for the expansion of Cohort 
B, to investigate additional dosing 
regimens
Section 9.2.3. 
Cohort C
Changed language to ensure flexibility of 
obtaining sufficient safety/PK data
To provide flexibility in participant 
enrollment
Section 9.5. Interim 
Analysis
Removed timing of interim analyses
To provide flexibility for data analysis
Section 10.3. 
Appendix 3: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow-
up, and Reporting
Removed language related to categorization of 
AE severity grade
Added language regarding grading of hepatic 
labs
This protocol will use the CTCAE v5.0 
to assign AE severity grades for all labs 
except hepatic labs which will use v4.03
Throughout the 
protocol
Minor formatting and editorial changes 
Minor, therefore not detailed


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
8
Table of Contents
Title Page...................................................................................................................................1
Protocol Amendment Summary of Changes Table ......................................................................4
Table of Contents ......................................................................................................................8
1.
Protocol Summary....................................................................................................12
1.1.
Synopsis.....................................................................................................................12
1.2.
Schema.......................................................................................................................15
1.3.
Schedule of Activities (SoA) ......................................................................................16
1.3.1.
Pharmacokinetic Sampling Schedule ..........................................................................24
2.
Introduction..............................................................................................................25
2.1.
Study Rationale ..........................................................................................................25
2.2.
Background ................................................................................................................27
2.3.
Benefit/Risk Assessment ............................................................................................28
2.3.1.
Risk Assessment.........................................................................................................28
2.3.2.
Benefit Assessment.....................................................................................................29
2.3.3.
Overall Benefit:  Risk Conclusion...............................................................................30
3.
Objectives and Endpoints.........................................................................................31
4.
Study Design .............................................................................................................32
4.1.
Overall Design............................................................................................................32
4.1.1.
Cohort A.....................................................................................................................32
4.1.2.
Cohort B.....................................................................................................................32
4.1.2.1.
Sub-Cohort B1................................................................................................32
4.1.2.2.
Sub-Cohort B2................................................................................................33
4.1.2.3.
Sub-Cohort B3................................................................................................33
4.1.3.
Cohort C.....................................................................................................................34
4.2.
Scientific Rationale for Study Design .........................................................................34
4.3.
Justification for Dose..................................................................................................34
4.3.1.
Rationale for Initial Cohort A Dose Selection .............................................................34
4.3.2.
Rationale for Cohort B (Sub-Cohorts B1, B2, and B3) Dose 
Selection.....................................................................................................................34
4.3.3.
Rationale for Cohort C Dose Selection........................................................................36
4.4.
End of Study Definition..............................................................................................36
5.
Study Population ......................................................................................................37
5.1.
Inclusion Criteria........................................................................................................37
5.2.
Exclusion Criteria.......................................................................................................40
5.3.
Lifestyle Considerations .............................................................................................42
5.4.
Screen Failures...........................................................................................................42
6.
Study Intervention....................................................................................................43
6.1.
Study Intervention(s) Administered ............................................................................44
6.1.1.
Treatment Requirements for Each Treatment Visit and Treatment 
Delays ........................................................................................................................45
6.1.2.
Treatment Delays and Omissions................................................................................47
6.2.
Preparation/Handling/Storage/Accountability.............................................................47


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
9
6.3.
Measures to Minimize Bias:  Randomization and Blinding .........................................48
6.4.
Study Intervention Compliance...................................................................................48
6.5.
Concomitant Therapy .................................................................................................48
6.5.1.
Palliative Medicine and Supportive Care ....................................................................48
6.5.1.1.
Injection Site Reactions ..................................................................................49
6.5.1.2.
Transfusions ...................................................................................................49
6.5.1.3.
Antiemetic Agents..........................................................................................49
6.5.1.4.
Analgesic Agents............................................................................................49
6.5.1.5.
Appetite Stimulants ........................................................................................49
6.5.1.6.
Growth Factors...............................................................................................49
6.5.1.7.
Other Supportive Care Agents ........................................................................49
6.5.1.8.
Supportive Care by Adverse Event of Special Interest ....................................50
6.6.
Dose Modification......................................................................................................53
6.6.1.
Ramucirumab Dose Modifications..............................................................................55
6.7.
Intervention after the End of the Study........................................................................59
6.7.1.
Intervention after Study Completion ...........................................................................59
6.7.1.1.
Continued Access...........................................................................................59
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................60
7.1.
Discontinuation of Study Intervention ........................................................................60
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................61
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................61
7.3.
Lost to Follow up .......................................................................................................62
8.
Study Assessments and Procedures .........................................................................63
8.1.
Efficacy Assessments .................................................................................................63
8.2.
Safety Assessments ....................................................................................................63
8.2.1.
Clinical Safety Laboratory Assessments .....................................................................64
8.2.2.
Safety Surveillance.....................................................................................................65
8.2.3.
Safety Monitoring.......................................................................................................66
8.2.4.
Hepatic Safety Monitoring..........................................................................................66
8.2.5.
Injection Site Reactions ..............................................................................................68
8.2.5.1.
Injection Site Pain Assessments......................................................................68
8.2.6.
Hypersensitivity Reactions, Including Anaphylaxis ....................................................68
8.3.
Adverse Events and Serious Adverse Events ..............................................................69
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................69
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................70
8.3.3.
Follow-up of AEs and SAEs.......................................................................................70
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................70
8.3.5.
Pregnancy...................................................................................................................70
8.3.6.
Adverse Events of Special Interest..............................................................................71
8.3.7.
Product Complaints ....................................................................................................71
8.4.
Treatment of Overdose ...............................................................................................72
8.5.
Pharmacokinetics........................................................................................................72
8.6.
Pharmacodynamics.....................................................................................................72
8.7.
Genetics .....................................................................................................................72


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
10
8.8.
Biomarkers.................................................................................................................72
8.9.
Immunogenicity Assessments.....................................................................................72
8.10.
Health Economics.......................................................................................................73
9.
Statistical Considerations.........................................................................................74
9.1.
Statistical Hypotheses.................................................................................................74
9.2.
Sample Size Determination.........................................................................................74
9.2.1.
Cohort A.....................................................................................................................74
9.2.2.
Cohort B (Sub-Cohorts B1, B2, and B3).....................................................................74
9.2.3.
Cohort C.....................................................................................................................75
9.3.
Populations for Analyses ............................................................................................75
9.4.
Statistical Analyses.....................................................................................................75
9.4.1.
General Considerations...............................................................................................76
9.4.1.1.
Participant Disposition....................................................................................76
9.4.1.2.
Participant Characteristics ..............................................................................76
9.4.1.3.
Concomitant Medications...............................................................................76
9.4.1.4.
Treatment Compliance....................................................................................76
9.4.1.5.
Extent of Exposure .........................................................................................76
9.4.1.6.
Post-Study Treatment Therapy........................................................................77
9.4.2.
Primary Endpoint........................................................................................................77
9.4.3.
Secondary Endpoint(s)................................................................................................77
9.4.4.
Tertiary/Exploratory Endpoint ....................................................................................77
9.4.5.
Other Safety Analyses ................................................................................................77
9.4.6.
Other Analyses ...........................................................................................................78
9.4.6.1.
Pharmacokinetic Analyses..............................................................................78
9.4.6.2.
Immunogenicity Analyses ..............................................................................78
9.5.
Interim Analyses.........................................................................................................78
9.6.
Data Monitoring Committee (DMC)...........................................................................79
10.
Supporting Documentation and Operational Considerations ................................80
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................80
10.1.1.
Regulatory and Ethical Considerations........................................................................80
10.1.2.
Financial Disclosure ...................................................................................................80
10.1.3.
Informed Consent Process ..........................................................................................81
10.1.4.
Data Protection...........................................................................................................81
10.1.5.
Committees Structure .................................................................................................81
10.1.6.
Dissemination of Clinical Study Data .........................................................................82
10.1.7.
Data Quality Assurance ..............................................................................................82
10.1.8.
Source Documents......................................................................................................84
10.1.9.
Study and Site Start and Closure.................................................................................84
10.1.10. Publication Policy.......................................................................................................84
10.1.11. Investigator Information .............................................................................................84
10.2.
Appendix 2:  Clinical Laboratory Tests.......................................................................85
10.3.
Appendix 3:  Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................87
10.3.1.
Definition of AE.........................................................................................................87
10.3.2.
Definition of SAE.......................................................................................................88


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
11
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................89
10.3.4.
Reporting of SAEs......................................................................................................90
10.4.
Appendix 4:  Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................92
10.5.
Appendix 5:  Liver Safety:  Suggested Actions and Follow-up 
Assessments ...............................................................................................................96
10.6.
Appendix 6:  Protocol JVDU Restricted and Prohibited 
Concomitant Therapy .................................................................................................98
10.7.
Appendix 7:  Abbreviations ......................................................................................100
10.8.
Appendix 8:  Protocol Amendment History ..............................................................105
11.
References...............................................................................................................110








CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
15
Data Monitoring Committee: No
1.2.
Schema
Abbreviations: LD = loading dose; MD = maintenance dose; N = number of participants; PK = pharmacokinetic; 
QW = weekly; SC = subcutaneous.
a Refer to Section 4.1.1 for total enrollment, based on safety and PK data.
b Refer to Section 4.1.2 for additional details.
c Maximal proposed weekly doses are indicated. This dose will be administered once per week, with the LD given 
on Cycle 1 Day 1, except in Cohort B1 that will start with 875 mg SC QW MD without LD.
d Refer to Sections 4.3.2 and 6.1 for the dosing regimen.
e Sample size in Sub-Cohorts B2 and B3 (if opened) determined by PK and safety data, per Sections 4.1.2 and 9.2.




















CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
25
2.
Introduction
2.1.
Study Rationale
Ramucirumab, as a single agent or in combination with different chemotherapy regimens, has 
been approved in the US in the following second-line indications: 

gastric or gastroesophageal junction (GEJ) adenocarcinoma, 

non-small cell lung cancer (NSCLC), 

colorectal carcinoma (CRC), and 

hepatocellular carcinoma (HCC).
These approvals were based on 5 global, randomized Phase 3 studies which demonstrated overall 
survival (OS) benefit.  The approved ramucirumab dose and schedule by intravenous (IV)
infusion is 8 mg/kg every 2 weeks (Q2W) for gastric or GEJ adenocarcinoma, CRC, and HCC, 
and 10 mg/kg every 3 weeks (Q3W) for NSCLC (Fuchs et al. 2014; Wilke et al. 2014; Tabernero 
et al. 2015; Reck et al. 2017; Zhu et al. 2019). 
Most recently, RELAY, which evaluated ramucirumab 10 mg/kg Q2W IV in combination with 
an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), erlotinib, 
demonstrated a statistically significant and clinically meaningful improvement in the primary 
endpoint of progression-free survival (PFS) in first-line treatment in patients with metastatic 
EGFR-mutated NSCLC.  The application was approved by Food and Drug Administration 
(FDA) (Nakagawa et al. 2019).
The safety profile of IV ramucirumab is well established based on an exposure of more than 
6400 patients who have received ramucirumab in the development program and more than 
125,000 patients who have been treated with ramucirumab worldwide across 5 licensed 
second-line indications in the post-marketing setting.
For most drugs, the concentration at the site of the receptor determines the intensity of a drug’s 
effect, and one can see that there is a concentration below which no effect is observed, and a 
concentration above which no greater effect is achieved. Ramucirumab most closely aligns with 
this mode of activity, being an antibody that targets a receptor (vascular endothelial growth 
factor [VEGF] Receptor 2).  As such, it is common to associate drug effect with Ctrough
(FDA 2003).  Exposure‐response (ER) analyses across Phase 3 ramucirumab studies, where 
ramucirumab was dosed intravenously at the currently-approved doses of 8 mg/kg Q2W and 
10 mg/kg Q3W, showed that after the first dose administration, patients in the lowest 
ramucirumab Ctrough quartile and in some studies, in the lowest 2 Ctrough quartiles (25% or 50% of 
the overall patient population, respectively) demonstrated less treatment benefit (lower OS and 
PFS) than patients in the highest Ctrough quartiles.  These studies demonstrated a greater benefit 
for patients in the highest exposure quartile who achieved, after the first dose administration, a 
Ctrough of approximately 50 g/ml.  The lower ramucirumab Ctrough values were likely due to a 
faster ramucirumab clearance in those patients.
In attempts to improve efficacy outcomes in those patients with a lower Ctrough, efforts were 
made in 2 postmarketing Phase 2 studies to increase area under the plasma concentration versus 
time curve (AUC) and Ctrough at a population level.  Various IV doses and dosing regimens were 
tested in an attempt to produce higher measures of these criteria than what has been achieved 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
26
with the approved ramucirumab IV dosing regimens (8 mg/kg Q2W and 10 mg/kg Q3W).  While
increasing the ramucirumab dose in the second-line gastric cancer population from 8- to 12-
mg/kg Q2W IV did not identify new safety concerns, there was no statistical improvement in the 
PFS with the higher dose other than a modest upward trend (data on file).  In these studies, while 
ramucirumab AUC and Ctrough were increased by about 50% at 12 mg/kg Q2W compared with 8 
mg/kg Q2W, there continued to be a significant overlap in ramucirumab AUC and Ctrough, and 
patients with higher clearance were still not able to achieve substantial improvements in Ctrough.  
This may explain why substantial improvements in efficacy were not observed.  It takes about 8 
weeks of treatment with ramucirumab at 12 mg/kg Q2W IV for the majority (95%) of patients to 
achieve ramucirumab Ctrough above 50 g/mL.  Thus, increasing the dose of the IV formulation 
does not appear be an effective way to rapidly increase Ctrough for an entire population, which is 
needed to optimize efficacy.
Therefore, in contrast to the above strategy, based on the literature and knowledge of the 
pharmacokinetics (PK) of monoclonal antibodies (mAbs) following a subcutaneous (SC)
administration (Viola et al. 2018), it is hypothesized that introduction of a ramucirumab SC 
formulation would allow additional optimization of the ramucirumab PK profile. A SC dosing 
regimen for ramucirumab, with an initial loading dose, has the potential to achieve in almost all 
patients (including patients with higher clearance) a target Ctrough equivalent to the fourth quartile 
of the IV Ctrough observed across the Phase 3 studies (i.e., Ctrough above 50 g/mL after the first 
dose) and produce an AUC comparable to the approved IV formulation of ramucirumab, which 
may result in improved efficacy.
For ramucirumab, a more frequent dosing regimen (than Q2W) would produce a less variable
exposure over the dosing interval and may provide a new opportunity to further optimize
ramucirumab exposure (beyond the exposure following an IV administration).  Following a SC
administration, ramucirumab would be absorbed over a longer period compared to an IV
infusion, leading to a more constant ramucirumab concentration over the dosing interval.  This
would result in a lower Cmax and a higher Ctrough, with a lower peak-to-trough ratio compared 
with the 10 mg/kg Q2W IV administration.  The evidence of any ER relationship for treatment-
emergent adverse events (TEAEs) across the Phase 3 studies is minimal.  Increased exposure of 
ramucirumab was associated with Grade ≥3 hypertension and neutropenia observed in some of 
the second-line studies. A lower Cmax could result in potentially lower adverse events (AEs) 
related to severe hypertension and neutropenia that could further improve the benefit-risk profile.
The ramucirumab AUC following 10 mg/kg Q2W IV dosing regimen will be used as the 
reference exposure for the SC ramucirumab development because it is the highest ramucirumab 
exposure (tested in the Phase 3 RELAY study) with demonstrated efficacy and manageable 
safety. In addition, SC ramucirumab clinical investigation is supported by data from the ongoing 
study I4T-MC-JVDT (JVDT).  Study JVDT is a Phase 1, dose-escalation study evaluating the 
PK profile and safety of single-dose IV and single-dose SC ramucirumab in healthy participants.  
The results from JVDT led to prediction of similar mean ramucirumab AUC and similar 
variability (CV%) of exposure following either flat SC dosing (875 mg QW dosing) or weight-
based dosing (10 mg/kg Q2W IV).  The large clinical safety and PK data base from IV 
ramucirumab and the data from study JVDT support the dosing regimens to be tested (refer to
Section 4.3.2 for further details).


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
27
In summary, the development of a SC dosing regimen for ramucirumab has the potential to
improve patient outcomes by changing the PK profile, relative to IV dosing, by:

enabling the majority of patients to more rapidly achieve target Ctrough
(>50 g/mL) after the first dose,

achieving an AUC at a steady state at least comparable to a current IV dosing 
regimen which has demonstrated efficacy and safety, and

minimizing peak-to-trough fluctuations and high Cmax, potentially limiting some 
Cmax-related toxicities.
The JVDU study is a Phase 1, nonrandomized, open-label, multicohort, multiple-dose study and 
will evaluate the PK and safety of SC ramucirumab in participants with cancer, alone or in 
combination with additional anti-cancer therapy.
2.2.
Background
Ramucirumab is a human receptor-targeted 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; Lu et al. 2003; Zhu et al. 2003).  As a result, ramucirumab 
inhibits ligand-stimulated activation of VEGF Receptor 2 and its downstream intracellular 
signaling components, including extracellular signal-regulated protein kinases 1 and 2 
(Erk1/Erk2), neutralizing ligand-induced proliferation, and migration of human endothelial cells 
(Lu et al. 2003; Zhu et al. 2003; Jimenez et al. 2005; Miao et al. 2006; Goldman et al. 2007; 
Tvorogov et al. 2010).
Ramucirumab has shown clinical efficacy in terms of PFS and OS for second-line gastric cancer 
in 2 randomized Phase 3 trials:  REGARD (Study I4T-IE-JVBD [Study JVBD] [Fuchs et al. 
2014]; ramucirumab monotherapy with best supportive care [BSC]) and RAINBOW (Study I4T-
IE-JVBE [Study JVBE] [Wilke et al. 2014]; ramucirumab in combination with paclitaxel).  
Ramucirumab also demonstrated a statistically significant improvement in investigator-assessed 
PFS compared with placebo in a controlled Phase 3 study (I4T-MC-JVCU, RAINFALL) in first-
line patients with metastatic gastric or GEJ adenocarcinoma, although an OS benefit was not 
demonstrated. 
Ramucirumab has shown efficacy in terms of PFS and OS in randomized Phase 3 trials for 
NSCLC (Study I4T-MC-JVBA [Study JVBA]; REVEL [Reck et al. 2017]; ramucirumab in 
combination with docetaxel), CRC (Study I4T-MC-JVBB [Study JVBB]; RAISE [Tabernero et 
al. 2015]; ramucirumab in combination with FOLFIRI), and HCC (selected patients with an 
alpha-fetoprotein [AFP] ≥400 ng/mL) ([Study I4T-MC-JVDE]; REACH-2 [Zhu et al. 2019]; 
ramucirumab monotherapy). 
Another Phase 3, placebo-controlled study (I4T-MC-JVDC [Study JVDC], RANGE) (Petrylak et 
al. 2020) examining ramucirumab plus docetaxel versus placebo plus docetaxel as second-line 
therapy in locally advanced, unresectable, or metastatic urothelial carcinoma, met its primary 
endpoint of PFS, demonstrating a statistically significant improvement in the ramucirumab arm 
compared with the placebo arm.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
28
Most recently, RELAY, which evaluated ramucirumab 10 mg/kg Q2W IV in combination with 
an oral EGFR TKI, erlotinib, demonstrated a statistically significant and clinically meaningful 
improvement in the primary endpoint of PFS in first-line treatment in patients with metastatic 
EGFR-mutated NSCLC (Nakagawa et al. 2019).  The application was approved by FDA.
Ramucirumab is currently approved in the US:

as a single agent or in combination with paclitaxel, for treatment of advanced or 
metastatic gastric or GEJ adenocarcinoma with disease progression on or after prior 
fluoropyrimidine- or platinum-containing chemotherapy. 

in combination with docetaxel, for treatment of metastatic NSCLC with disease 
progression on or after platinum-based chemotherapy.  Patients with EGFR or anaplastic 
large-cell lymphoma kinase (ALK) genomic tumor aberrations should have disease 
progression on FDA-approved therapy for these aberrations prior to receiving 
ramucirumab.

in combination with FOLFIRI, for the treatment of metastatic CRC with disease 
progression on or after prior therapy with bevacizumab, oxaliplatin, and a 
fluoropyrimidine.

as a single agent, for the treatment of HCC in patients who have an AFP of ≥400 ng/mL 
and have been treated with sorafenib.
Details on the safety profile of ramucirumab is available in the Investigator’s Brochure (IB).
An SC formulation of ramucirumab is being developed with the goal of optimizing drug 
exposures based on insights from the prior development program.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ramucirumab may be found in the IB, Participant Information Leaflet, Package 
Insert, Development Safety Update Report, or Summary of Product Characteristics.
2.3.1.
Risk Assessment
The safety profile of IV ramucirumab is well established based on an exposure of more than 
6400 patients who received ramucirumab in the development program and more than 
125,000 patients who have been treated with ramucirumab worldwide across 5 licensed 
second-line indications in the post-marketing setting.
The AEs associated with IV ramucirumab across approved indications include specific effects of 
mAbs (including infusion-related reactions), and class-specific effects related to the mechanism 
of antiangiogenic agents which inhibit the VEGF/VEGF Receptor 2 signaling pathway 
(including hypertension, proteinuria, and bleeding/hemorrhage events).
Across the approved indications and in the RELAY study, the safety profile of IV ramucirumab, 
as a single agent or in combination with chemotherapy or erlotinib, was well tolerated with 
manageable toxicities.  


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
29
The key risks for IV ramucirumab either as a single agent or in combination with anti-cancer 
therapy across currently approved indications of advanced gastric cancer, metastatic CRC, 
metastatic NSCLC, and HCC with AFP of 400 ng/mL are as follows:
a.
Gastric cancer: Gastrointestinal (GI) perforation and severe (Grade ≥3) bleeding 
including GI hemorrhage
b. NSCLC: Grade ≥3 bleeding (including Grade ≥3 pulmonary hemorrhage)
c.
HCC: Grade ≥3 bleeding (including GI hemorrhage) and liver failure/liver injury 
(including hepatic encephalopathy)
The risks associated with ramucirumab are mitigated in the protocol by clearly defined eligibility 
criteria for enrollment and close monitoring of study participants following ramucirumab dosing 
and initiation of appropriate treatment as necessary.
Ramucirumab administered intravenously either as monotherapy or in combination with 
chemotherapy or erlotinib in Phase 3 studies has demonstrated a favorable benefit-risk profile in 
the treatment of various tumor types.
Results of a single-dose safety study in monkeys indicate that SC administration of ramucirumab 
has a low potential for injection site irritation.  The SC formulation may, by reducing Cmax, limit 
toxicities that are Cmax-driven. Interim results (Section 2.1) from JVDT, to date have shown SC 
ramucirumab to be safe and tolerable. The AEs observed were transient, monitorable, reversible,
and consistent with the known safety profile of IV ramucirumab.  In addition, injection site 
reactions were not reported.
Because ramucirumab is a biotherapeutic, no genotoxicity studies have been conducted.  No 
genotoxicity is expected based on the mechanism of action.  No reproductive toxicity studies 
have been conducted.  Based on the mechanism of action, fetal harm would be expected and 
ramucirumab should not be administered to pregnant women or women planning to become 
pregnant.
2.3.2.
Benefit Assessment
Ramucirumab, as a single agent or in combination with different chemotherapy regimens has 
been approved in the US in the following second-line indications: 

gastric or GEJ adenocarcinoma, 

NSCLC, 

CRC, and 

HCC. 
Since the ramucirumab SC formulation involves the same drug-product as that mentioned in 
Section 2.1, an SC dosing regimen for ramucirumab has the potential to optimize ramucirumab 
exposure by changing the ramucirumab PK profile, and thereby may further improve patient 
outcomes compared with an IV dosing regimen.  This would be achieved by raising 
ramucirumab Ctrough and lowering ramucirumab Cmax while achieving similar ramucirumab AUC 
and decreasing the time to achieve sustained therapeutic levels compared to IV administration.  


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
30
2.3.3.
Overall Benefit: Risk Conclusion
Ramucirumab IV has demonstrated a favorable benefit-risk profile in a variety of human cancers 
as a single agent or in combination with other anti-cancer therapies as demonstrated in 
Sections 2.2 and 2.3.  Considering the measures taken to minimize risk to participants 
participating in this study and for a lower potential for Cmax-associated toxicities, the potential 
risks identified in association with SC regimen for ramucirumab are justified by the anticipated 
benefits that may be afforded to participants with cancer.




CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
32
4.
Study Design
4.1.
Overall Design
Protocol I4T-MC-JVDU (JVDU) is a Phase 1, non-randomized, open-label investigation of 
multiple, repeated-weekly SC ramucirumab administrations in participants with cancer.  The 
injection site for the SC administration will be the abdomen.
The study comprises sequential dose-escalating cohorts with a third dose-expansion cohort (see 
Section 1.2 for study schema): Cohorts A, B (Sub-Cohorts B1, B2, and B3), and C (dose-
expansion cohort).
4.1.1.
Cohort A
Cohort A will recruit 3 participants with refractory/relapsed solid tumors with measurable 
disease and who have exhausted all treatments with proven clinical benefit.  Participants will 
receive an initial ramucirumab SC loading dose of 700 mg followed by a weekly ramucirumab 
SC injection maintenance dose of 350 mg (see Section 4.3.1 for more details).  Cohort A 
participants will be followed for a minimum of 3 weeks following initiation of ramucirumab SC 
treatment prior to opening enrollment in the subsequent Cohort B.  The study team will review 
the totality of available safety data from Cohort A and study JVDT, and based on this, will make 
a recommendation to open enrollment to Cohort B (please refer to Section 9.2.2). If new or 
unexpected safety findings are identified relative to the large database of IV ramucirumab, or one 
or more participants in Cohort A do not have sufficient PK data to inform dose for Cohort B, up 
to an additional 3 participants may be enrolled into Cohort A. Participants in Cohort A may have 
the opportunity to adjust their weekly maintenance dose to the maintenance dose selected for 
Cohort C, based on investigator’s discretion.
4.1.2.
Cohort B
Cohort B participants must fulfill all inclusion criteria requirements that apply to Cohort A. In 
addition, Cohort B participants with disease indications where ramucirumab is approved as either 
monotherapy or in combination with additional anti-cancer therapy are also eligible provided the 
initiation of the combination partner can be delayed for 3 weeks from the initiation of 
ramucirumab dosing.
The dose regimen for Cohort B will be selected to achieve a steady state Ctrough concentration 
higher than 50 µg/mL in the majority of the population with associated AUC similar to the 
approved ramucirumab IV regimen (e.g., 10 mg/kg Q2W IV). Initial Cohort B dosing will be 
determined based on bioavailability calculated using available PK data as shown in Sections 2.1
and 4.3.2.
Cohort B will be comprised of 3 sub-cohorts: B1, B2, and if required B3.  Additional details for 
each sub-cohort will be discussed below.
4.1.2.1.
Sub-Cohort B1
The goal of Sub-Cohort B1 is to obtain PK data by investigating a weekly SC ramucirumab 
maintenance dose (MD) predicted to achieve the desired PK endpoints of Ctrough and AUC 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
33
discussed above. The target Ctrough and steady-state exposure are predicted to be reached after 
two to three weeks, respectively following weekly SC ramucirumab. Thus, steady state is 
reached earlier as compared to the standard IV Q2W ramucirumab dosing which takes six to 
eight weeks.
Sub-Cohort B1 will open following a review of all available data from Cohort A, as discussed in 
Section 4.1.1. Initially, 3 participants will be recruited at a proposed maximum dose of 875 mg 
SC QW. For additional details, refer to Section 4.3.2. Up to an additional 3 participants may be 
enrolled into Sub-Cohort B1 if warranted by safety or PK data assessed at the interim analysis
(please refer to Section 9.2.2 for more details).
The PK data from a minimum of 6 participants treated in both Sub-Cohort B1 and Cohort A 
along with the data from Study JVDT will be used to determine the dosing regimen for Sub-
Cohort B2.
4.1.2.2.
Sub-Cohort B2
The goal of Sub-Cohort B2 is to identify a SC ramucirumab dosing regimen that will deliver the 
safety and PK objectives of the study.  Only one dosing regimen will be investigated in Sub-
Cohort B2, that will open following Sub-Cohort B1.
Initially, 3 participants will be recruited in Sub-Cohort B2 and receive SC ramucirumab as a LD 
on Day 1 of the first week (maximum 1750 mg), followed by a weekly MD (maximum 875 mg).  
For additional details, refer to Section 4.3.2. If a minimum of 3 weeks of PK and safety data 
reveal that there are no unexpected safety issues and adequate exposure is achieved, an 
additional 3 participants will be enrolled at the same dose.
This will be followed by an interim analysis of data from all 6 participants before opening 
Cohort C, at that dose.
If the initial dose for Sub-Cohort B2 does not meet the study objectives, an alternate dose may 
be explored in Sub-Cohort B3, if deemed feasible.
4.1.2.3.
Sub-Cohort B3
The goal of the optional Sub-Cohort B3 is the same as Sub-Cohort B2, that is, to identify a SC 
ramucirumab dosing regimen that will deliver the safety and PK objectives of the study if not 
achieved in Sub-Cohort B2. 
Only one dosing regimen will be investigated with 6 participants enrolled in Sub-Cohort B3 that 
may open if greater than anticipated target exposure is determined in Sub-Cohort B2 and/or 
unexpected safety findings warrant a dose reduction.  A reduced dose for unexpected safety 
findings will only be explored if it is predicted to reach target exposure as explained in Section 
4.3.2.
A review of the data from Sub-Cohort B3 will be performed as described above for Sub-Cohort 
B2.  If the study objectives are achieved, Cohort C will open at the dosing regimen investigated 
in Sub-Cohort B3.
Once the dose for Cohort C has been confirmed, if applicable, participants in Cohort B may have 
the opportunity to adjust their weekly maintenance dose to the maintenance dose selected for 
Cohort C, based on investigator’s discretion.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
34
4.1.3.
Cohort C
Cohort C will initiate recruitment of 6 participants once 3 weeks of dosing safety data from 
Cohort B (in at least 6 participants) and initial PK data support pursuing further enrollment at the 
same dosing regimen.  The study population will be the same as Cohort B.  The dose regimen for 
Cohort C is anticipated to be the same as the preceding 6 participants in Cohort B. This 
expanded number of participants will provide additional PK and safety data to inform potential 
further development of SC ramucirumab.
4.2.
Scientific Rationale for Study Design
See Section 2.1.
4.3.
Justification for Dose
4.3.1.
Rationale for Initial Cohort A Dose Selection
The ramucirumab SC dose for the initial Cohort A (n=3 to 6 participants) has been chosen with 
the intent to match the steady state AUC of the 8 mg/kg Q2W IV regimen, assuming a 
bioavailability of 80%.  The initial ramucirumab SC loading dose will be 700 mg followed by a 
weekly ramucirumab SC injection maintenance dose of 350 mg.
Ramucirumab IV has demonstrated an acceptable risk/benefit profile at the approved dose 
regimens of 8 mg/kg Q2W, 10 mg/kg Q2W, and 10 mg/kg Q3W as monotherapy or in 
combination with anti-cancer treatments.  Furthermore, ramucirumab IV at 13 mg/kg every week 
(QW) (equivalent to 26 mg/kg over two weeks) has been determined to be the maximum 
tolerated dose under weekly dosing (Study I4T-MC-JVBM).  Consequently, the proposed 
starting dose for JVDU is well below that dose/exposure intensity.
The planned starting dose of ramucirumab is 700 mg loading dose (LD) followed, a week later,
by 350 mg maintenance dose (MD) administered once a week.  This dosing regimen has been 
selected to ensure that, in the unlikely event of a bioavailability as high as 80%, the maximum 
ramucirumab AUC achieved in Cohort A participants will not exceed AUC following IV 
ramucirumab 8 mg/kg Q2W.
4.3.2.
Rationale for Cohort B (Sub-Cohorts B1, B2, and B3) Dose Selection
Cohort B dose selection is intended to deliver a Ctrough >50 µg/mL and a steady-state AUC 
similar to the approved IV ramucirumab dose regimen of 10 mg/kg Q2W. This will be 
accomplished by investigating a loading dose and maintenance dose paradigm, which will 
deliver target Ctrough and steady-state concentration rapidly.
The table below indicates the anticipated ramucirumab SC dosing regimen for Cohort B, as a 
function of estimated bioavailability. 
Bioavailability
(Mean F)
AUC at steady 
state eq to
(Q2W IV)
SC LD one dose 
(mg)a
SC MD (mg)
QW
40% to 50%
10 mg/kg 
1750
875
50% to 65%
10 mg/kg 
1400
700 
65% to 80%
10 mg/kg 
1120
560 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
35
80% to 100%
10 mg/kg 
880
440 
Abbreviations:  AUC = area under the plasma concentration versus time curve; eq = equivalent; F = bioavailability; 
IV = intravenous; LD = loading dose; MD = maintenance dose; SC = subcutaneous; Q2W = every 2 weeks; QW 
= every week.
a
In Sub-Cohort B1, the loading dose will not be given.
Interim data from Study JVDT indicates a bioavailability of 40% and peak concentration 
occurring at 4 days post administration for SC ramucirumab (consistent with a 0.3 day-1
absorption rate constant). With a bioavailability of 40%, a starting regimen of ramucirumab SC 
LD of 1750 mg and MD of 875 mg in Cohort B is proposed. The proposed maximum 
ramucirumab SC LD of 1750 mg will deliver exposure equivalent to 10 mg/kg/week and 
13 mg/kg/week for participants with body weights of 70 kg and 55 kg, respectively.  Assuming 
the same bioavailability, the proposed maximum ramucirumab SC MD of 875 mg will deliver 
exposure equivalent to 5 mg/kg/week and 6 mg/kg/week for participants with body weights of 
70 kg and 55 kg, respectively.  Consequently, the exposure achieved following both proposed 
LD and MD will be lower than the highest investigated ramucirumab IV doses of 20 mg/kg Q3W 
IV (Study JVBN) and 13 mg/kg QW IV (maximum tolerated dose in Study JVBM).
The bioavailability in single-dose healthy participants may vary from cancer patients who will 
receive multiple doses of ramucirumab SC, hence periodic PK and safety analysis will be 
planned as described in Section 4.1.
The combined PK and safety data from Cohort A and Sub-Cohort B1 will inform the starting 
dose selection for Sub-Cohort B2 (maximum planned dose ramucirumab SC LD of 1750 mg 
followed by 875 mg SC MD QW).  Subsequent need for Sub-Cohort B3 with an alternate dosing 
regimen is described in Section 4.1.2.3. The table below shows the proposed dosing regimen for 
each Sub-Cohort as well as possible alternate dose decisions that could be made based on either 
bioavailability and/or safety as described in Section 4.1.2.
Sub-
Cohort
Proposed LDa
Proposed MDb
Possible Dose Decision Based on Either 
Bioavailability and/or Safety
B1
Not Applicable
875 mg SC QW
e.g., MD 700 mg SC QW
e.g., MD 560 mg SC QW 
e.g., MD 440 mg SC QW
B2c
1750 mg SC infusion
875 mg SC QW
e.g., LD 1400 mg SC; MD 700 mg SC QW
e.g., LD 1120 mg SC; MD 560 mg SC QW
e.g., LD 880 mg SC; MD 440 mg SC QW
B3c
(Optional)
<1750 mg SC infusion
< 875 mg SC QW
e.g., LD 1400 mg SC; MD 700 mg SC QW
e.g., LD 1120 mg SC; MD 560 mg SC QW
e.g., LD 880 mg SC; MD 440 mg SC QW
Abbreviations:  LD = loading dose; MD = maintenance dose; QW = every week; SC = subcutaneous.
a
LD: During Week 1 administered as one dose on Day 1.
b MD: Weekly dosing starting on Week 2 (Cycle 1 Day 8) except for B1 when it will be starting on Week 1 (Cycle
1, Day 1).
c Only 1 dosing regimen (one LD - MD level) will be investigated in Sub-Cohort B2 and Sub-Cohort B3.  Dose will 
be selected based on PK and safety data as described in Section 4.1.2.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
36
4.3.3.
Rationale for Cohort C Dose Selection 
Cohort C will evaluate, in six participants, the dose regimen identified in Cohort B which 
answers the safety and PK objective of the study.  Cohort C may open if 3-week-dosing safety 
data from Cohort B (in at least 6 participants) and initial PK data support pursuing enrollment at 
the same dosing regimen.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the Schedule of Activities (SoA) for the last participant in the 
trial globally.






CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
39
a
Gastrointestinal-GEJ and NSCLC participants are allowed to be on therapeutic-dose anticoagulation if they are 
on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin.  If receiving 
warfarin, the participant must have an INR ≤3.0 and no active bleeding (i.e., no bleeding within 14 days prior to 
enrollment) nor a pathological condition present that carries a high risk of bleeding (e.g., tumor involving major 
vessels or known varices).  Participants on anticoagulation therapy with an underlying medical condition that 
increases the risk for bleeding (e.g., local tumor recurrence following resection) are not eligible.  Hepatocellular 
carcinoma participants are only allowed to be on prophylactic treatment with anticoagulants, not therapeutic 
doses, and their PT, PTT, and INR values must be consistent with the criteria listed in the table above.
Sex
9. Male or female
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
a.
Male participants:
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 84 days/12 weeks following completion of study drug 
administration:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual or homosexual intercourse, as their preferred and 
usual lifestyle (abstinent on a long-term and persistent basis), and agree to remain 
abstinent 
OR

Must agree to use contraception/barrier as detailed below:
o
Agree to use a male condom AND
female partner use of an additional highly effective contraceptive method 
with a failure rate of <1% per year as described in Appendix 4, when 
having sexual intercourse with a woman of childbearing potential
(WOCBP) who is not currently pregnant.
o
Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
b. Female participants:

A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies:
o
Is not a WOCBP 
OR
o
Is a WOCBP and using a contraceptive method that is highly effective 
(with a failure rate of <1% per year), preferably with low user 
dependency, as described in Appendix 4 during the intervention period 
and for at least 84 days/12 weeks, corresponding to the time needed to 
eliminate any study intervention(s) (e.g., 5 terminal half-lives) plus 30 
days (a menstrual cycle) after the last dose of study intervention, and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
40
during this period.  The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study 
intervention.
o
A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum as required by local regulations) within 24 hours before the first 
dose of study intervention.
o
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), 
a serum pregnancy test is required.  In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
Informed Consent
10. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
11. Have uncontrolled hypertension defined as systolic blood pressure (BP) >150 mmHg or 
diastolic BP >90 mmHg despite standard medical management.
12. Have significant bleeding disorders or experienced Grade 3/4 GI bleeding within 
3 months prior to enrollment.
13. Have hepatic impairment (such as severe liver cirrhosis Child-Pugh B [or worse], 
cirrhosis with a history of hepatic encephalopathy, clinically meaningful ascites requiring 
ongoing treatment with diuretics and/or paracentesis, or history of hepatorenal 
syndrome).
14. Have experienced any arterial thromboembolic events (ATEs), including but not limited
to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable 
angina, ≤6 months prior to randomization.
15. The participant has clinically relevant congestive heart failure (CHF; New York Heart 
Association [NYHA] Grade ≥2) or symptomatic or poorly controlled cardiac arrhythmia.
16. Have a serious concomitant systemic disorder that, in the opinion of the investigator, 
would preclude participation in the study.
17. Have active infection requiring systemic therapy (e.g., bacterial infection requiring 
intravenous antibiotics at time of initiating study treatment, systemic fungal infection, or 
detectable viral infection requiring systemic therapy).


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
41
18. Human immunodeficiency virus (HIV) positive participants (HIV 1 and/or 2; screening 
not required) are excluded unless they are well controlled on highly active antiretroviral 
therapy with:
a.
No evidence of acquired immunodeficiency syndrome (AIDS)-defining 
opportunistic infections within the last 2 years, and
b. CD4 count >350 cells/μl.
19. Have chronic active hepatitis B or C virus infection (screening not required).
20. Have prior or second concurrent primary malignancies that, in the judgment of the 
investigator and the Lilly clinical research physician (CRP)/clinical research scientist
(CRS), may affect the interpretation of results.  Participants with carcinoma in situ of any 
origin and participants with prior malignancies who are in remission and whose 
likelihood of recurrence is very low (such as basal cell carcinoma), as judged by the Lilly 
CRP/CRS, are eligible for this study.
21. Have symptomatic central nervous system (CNS) malignancy or metastasis (screening 
not required).  Participants with treated CNS metastases are eligible for this study if they 
are not currently receiving corticosteroids (exceeding 10 mg/day prednisone or 
equivalent) and/or anticonvulsants to treat CNS metastases, and their disease is 
asymptomatic and radiographically stable for at least 30 days.
22. Have a history of GI perforation and/or fistula within 6 months prior to enrollment.
23. Serious or non-healing wound, ulcer, or bone fracture within 4 weeks prior to enrollment.
Prior/Concomitant Therapy
24. Are receiving chronic therapy with nonsteroidal anti-inflammatory agents (e.g., 
indomethacin, naproxen, or similar agents) or other antiplatelet agents (e.g., clopidogrel 
or dipyridamole) within 7 days prior to first dose of study treatment.  Aspirin use at doses 
up to 325 mg/day is permitted (see Section 10.6, Appendix 6).
25. Participants with prior treatment with IV ramucirumab as monotherapy or in 
combination with chemotherapy or targeted/biological agents on or outside of a 
clinical trial.
Prior/Concurrent Clinical Study Experience
26. have participated, within the last 30 days, in a clinical study involving an investigational 
product.  If the previous investigational product has a long half-life, 5 half-lives or 
30 days (whichever is longer) should have passed.  Exceptions will be considered on a 
case by case basis by the sponsor CRP/CRS.
Other Exclusions
27. Have tattoos or scars over the abdomen, or other factors (e.g., rash, excessive folds of 
skin) that, in the investigator's opinion, would interfere with injection site assessments.
28. Have an elective or a planned major surgery during the course of the trial, or have 
undergone major surgery within 28 days prior to enrollment.
Note:  Central venous access device placement must occur at least 7 days prior to 
enrollment.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
42
Note:  If participant received major surgery, the participant must have recovered 
adequately from the toxicity and/or complications from the intervention prior to starting 
therapy.
Additional Key Exclusion Criteria specific to NSCLC
29. Have radiologically documented evidence of major blood vessel invasion or encasement 
by cancer.
30. Have radiographic evidence of intratumor cavitation, regardless of tumor histology.
31. Have a history of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon) within 
2 months prior to enrollment.
5.3.
Lifestyle Considerations
There are no specific lifestyle restrictions for this protocol.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number.  When 
rescreening, some screening tests and procedures may be repeated at the investigator’s 
discretion.  Individuals may be re-screened once only.  The interval between re-screenings 
should be at least 2 weeks.  Each time re-screening is performed, the individual must sign a new 
ICF.  Repeating of laboratory tests during the screening period or repeating screening tests to 
comply with the protocol designated screening period does not constitute rescreening.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
43
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.




CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
45
For participants on combination IV interventions, on days ramucirumab is to be administered 
with the combination intervention, ramucirumab is to be administered first.  The combination 
intervention will be administered per local guidelines, following the one-hour ramucirumab 
observation period. 
A delay of a treatment up to 7 days due to administrative reasons, including holidays, weekends, 
bad weather, or other unforeseen circumstances, will be permitted and not be counted as a 
protocol deviation.
After the SC administration, a 1-hour observation period will be completed.  Any premedication 
for combination therapy must be administered after the ramucirumab one-hour observation 
period.  All premedication administered must be adequately documented in the case report form 
(CRF).  
Ramucirumab will be initiated with a loading dose of 700 mg SC followed, a week later, by a 
maintenance dose of 350 mg SC QW (Cohort A), administered in the abdomen.  Ramucirumab 
dose will be escalated in Sub-Cohort B1 to investigate a weekly maintenance SC ramucirumab
dose (maximum of 875 mg SC weekly) and thereafter in Sub-Cohort B2 to investigate up to a 
maximum loading dose of 1750 mg SC followed, a week later, by a maximum weekly 
maintenance dose of 875 mg SC.  For loading doses greater than 700 mg, SC administration will 
be a SC infusion using a SC infusion pump where ramucirumab is infused at a rate of 
approximately 0.25 ml/min and duration of infusion will be based on dose and volume of 
infusion.  Interim analysis is planned after the Sub-Cohorts B1 and B2 are enrolled, and 
ramucirumab dose may be adjusted in the optional Sub-Cohort B3 to further explore whether the 
safety and PK objective of the study can be achieved (see Section 4.1.2).  The ramucirumab 
dosing regimen in Cohort C will be the same as in Cohort B which answers the safety and PK 
objective of the study (see Section 4.1.3).  The site of administration of each injection will be 
recorded, and when more than one injection is administered, the same site will not be used but 
another quadrant utilized. Ideally the site of SC ramucirumab injection should be the abdomen;
however, in case of contraindication to abdominal SC injection, such as clinical conditions with 
dermatitis, cellulitis, or surgical wound, the participant is allowed to rotate the injection site to 
thigh or upper arms.  If the loading dose causes an injection site reaction (>Grade 2), then the 
sponsor may determine an alternate administration of loading dose for subsequent participants.
6.1.1.
Treatment Requirements for Each Treatment Visit and Treatment Delays
Treatment Requirements for each New Cycle
The timing of starting a new cycle of protocol therapy will be as follows:

Those getting single-agent ramucirumab SC: Each cycle will be 21 days with weekly 
ramucirumab SC administration.  Each new cycle will start 7 days (±3 days) from the last 
ramucirumab SC.

Those getting ramucirumab SC with combination anti-cancer treatments: Ramucirumab 
SC will be given weekly within each cycle.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
46
a.
Ramucirumab SC with paclitaxel: Each cycle will be 28 days with paclitaxel 
administered on Days 1, 8, and 15 and start 14 days (±3 days) from the previous 
Day 15 paclitaxel administration. 
b. Ramucirumab SC with FOLFIRI: Each cycle will be 28 days and start 14 days 
(±3 days) from the last administration of FOLFIRI. 
c.
Ramucirumab SC with erlotinib: Each cycle will be 28 days with daily oral erlotinib 
and start 7 days (±3 days) from the last administration of ramucirumab SC in the 
previous cycle.
d. Ramucirumab SC with docetaxel: Each cycle will be 21 days with docetaxel 
administered on Day 1 and start 21 days (±3 days) from the last administration of 
docetaxel.
Note: For each weekly dose in Cycle 1, the following criteria must be fulfilled to administer 
ramucirumab SC:

Total bilirubin ≤1.5x upper limit of normal (ULN) or baseline (whichever is greater)

ALT and AST ≤3x ULN, if baseline <1.5x ULN 

ALT and AST ≤2x baseline, if baseline ≥1.5x ULN 
For each new cycle and every 3 weeks for those in Cohort B and C where combination therapies 
have been held or discontinued, the following criteria must be fulfilled to administer 
ramucirumab SC:

Total bilirubin ≤1.5x upper limit of normal (ULN) or baseline (whichever is greater)

ALT and AST ≤3x ULN, if baseline <1.5x ULN 

ALT and AST ≤2x baseline, if baseline ≥1.5x ULN 

Absolute neutrophil count (ANC) ≥1.5x 103/μL (≥1.5x 109/L), platelets ≥100x 103/μL 
(≥100x 109/L)

Ramucirumab-related AEs that are National Cancer Institute (NCI) common terminology 
criteria for adverse events, version 5.0 (CTCAE, v5.0) Grade <2 or equivalent severity to 
baseline (except for alopecia; for hypertension and proteinuria, see Section 6.5.1.8).
Participants not meeting the criterion for total bilirubin may be allowed to continue treatment 
with ramucirumab or placebo in specific cases (e.g., Gilbert’s syndrome) after the Lilly 
CRP/CRS and investigator agree that it is medically appropriate for these participants.  The 
decisions and supporting rationale must be documented in writing.  For participant and study site 
convenience and safety, treatment decisions will be based upon results of tests performed locally.  
For dosing decisions, bilirubin, AST, and ALT will be required to be collected locally and 
centrally; ANC and platelets will be collected locally.  The duplicate test results obtained locally 
will not be collected on the CRF, unless it impacts treatment decision, in which case the critical 
finding should be documented in the appropriate CRF as part of the rationale for dose 
modification.  Discrepancies between the local and central laboratory that may have an impact 
on treatment decisions will not be considered protocol violations.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
47
6.1.2.
Treatment Delays and Omissions
If the criteria to start a subsequent new cycle listed above are not met, the next ramucirumab SC 
dosing may be delayed for up to a maximum of 4 weekly doses to allow for recovery.  If the 
participant is on a combination anti-cancer treatment regimen, it should be continued during the 
delay of ramucirumab SC if the participant does not meet the criteria of delay and/or 
discontinuation for that regimen per its prescribing information.  If a delay of greater than 
4 weekly doses is necessary due to ramucirumab-related, unresolved toxicity, ramucirumab SC 
should be discontinued.  The combination anti-cancer treatment may be continued at 
investigator’s discretion with the participant remaining in the study, if clinically indicated.  If 
ramucirumab dose modification is warranted, refer to Section 6.6 for further details.
If participants have discontinued combination anti-cancer therapy, ramucirumab SC may be 
continued as monotherapy until progressive disease, at the discretion of the investigator.
Treatment delays and omissions due to anti-cancer therapies other than SC ramucirumab are 
addressed as follows:

If a participant has an AE found related to chemotherapy/TKI at the start of a new cycle, 
then the cycle is postponed and re-started once the AE has resolved and can be re-aligned
with the weekly ramucirumab SC administration.

If a participant has an AE found related to chemotherapy/TKI “within” a cycle, that dose 
is omitted, then the next planned dose is administered once the AE has resolved and can 
be re-aligned with the weekly ramucirumab SC administration.
Ramucirumab SC can only be administered at investigational site, at-home administration is not 
permitted in this study.  In the event of treatment delays of ramucirumab SC unrelated to AEs but 
due to unforeseeable circumstances (e.g., COVID-19 pandemic resurgence) and in the principal 
investigator’s discretion the participant has experienced clinical benefit, re-administration of 
loading dose is required only if ≥30 days has elapsed since the last ramucirumab SC dose.  In 
such a scenario, a discussion with Lilly CRP/CRS should be done before resuming ramucirumab 
SC.  In addition, all on-treatment SoA as in Section 1.3 must resume.  On resuming ramucirumab 
SC the combination anti-cancer treatment can be re-aligned with ramucirumab SC 
administration.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
48
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.
5. Investigators should consult the study drug information provided in the Pharmacy 
Manual or label for the specific administration information (including warnings, 
precautions, contraindications, adverse reactions, and dose modifications).
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label non-randomized study. 
6.4.
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study-site staff. 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the time 
of dosing by a member of the study-site staff other than the person administering the study 
intervention.  
When participants self-administer oral study intervention at home, compliance with oral study 
intervention will be assessed at each visit.  Compliance will be assessed by direct questioning 
and/or counting returned tablets/capsules during the site visits and documented in the source 
documents and CRF.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with:
●
Reason for use
●
Dates of administration including start and end dates
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1.
Palliative Medicine and Supportive Care
Palliative radiation therapy is permitted after discussion with and agreement of the Lilly 
CRP/CRS or designee for irradiating small areas of painful metastases that cannot be managed 
adequately using systemic or local analgesics.  Such areas must not be an identified target lesion 
and must not constitute progressive disease or meet RECIST criteria for progressive disease.  
Any symptomatic deterioration or clinical disease progression requiring, in the opinion of the 
investigator, other forms of specific antitumor systemic therapy, will be cause for discontinuation 
of study therapy.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
49
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study. Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the CRF.
Participants should receive full supportive care as appropriate (see Section 10.6, Appendix 6).  
Prophylactic antibiotic treatment should be consistent with American Society of Clinical 
Oncology (ASCO) guidelines (Taplitz et al. 2018).
6.5.1.1.
Injection Site Reactions
Local reactions at the injection site(s) will be evaluated for erythema, induration, pain, pruritus, 
and edema.  Symptomatic treatment would include acetaminophen, non-sedating antihistamines, 
and topical emollients, as appropriate.
6.5.1.2.
Transfusions
Transfusions of red blood cells, platelets, or other blood products are permitted at the 
investigator’s discretion.
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Bohlius et al. 2019).
6.5.1.3.
Antiemetic Agents
The use of antiemetic agents is permitted at the discretion of the investigator. 
6.5.1.4.
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 (Section 10.6).
6.5.1.5.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.
6.5.1.6.
Growth Factors
Growth factors should not be administered to enable a participant to satisfy study inclusion 
criteria.  
The use of granulocyte-colony stimulating factor (G-CSF) is permitted at the discretion of the 
investigator based on ASCO guidelines (Smith et al. 2015). 
In the event of Grade 3 or 4 neutropenia >7 days, initiate G-CSF in subsequent cycles, unless 
determined to be inappropriate for the participant per the investigator.
The as-needed use of erythroid-stimulating factors (e.g., erythropoietin) is permitted at the 
discretion of the investigator based on ASCO guidelines (Bohlius et al. 2019) (Section 10.6).
6.5.1.7.
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 
Section 10.6.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
50
6.5.1.8.
Supportive Care by Adverse Event of Special Interest
Refer to Section 6.6.1 for adverse event of special interest (AESI) dose-modification guidelines.
6.5.1.8.1.
Hypersensitivity Reactions, Including Anaphylaxis
Administration of mAbs such as ramucirumab can result in HSRs, including immediate reactions 
like anaphylactic reactions or infusion-related reactions and delayed reactions such as those 
involving the muco-cutaneous system. Monitor participants for symptoms and signs of HSRs
during the loading dose SC injection and maintenance SC injection followed by a 1-hour 
observation period post administration, with resuscitation equipment readily available.
Symptoms and signs that may occur as part of HSRs include, but are not limited to: 

fever, 

chills, 

nausea, 

headache, 

bronchospasm, 

hypotension, 

angioedema, 

throat irritation, 

rash, 

pruritus, 

myalgia, and 

dizziness.
Supportive care should be employed in accordance with the symptoms/signs.  Participants should 
be treated appropriately by the investigator.  If a severe (Grades 3 or 4) HSR occurs, discontinue 
ramucirumab permanently.
In the event of an HSR, a blood sample should be collected for immunogenicity 
(anti-ramucirumab antibody) and PK (ramucirumab serum concentration) at the following time 
points: (1) as close to the onset of the reaction as possible, (2) at the resolution of the event, and 
(3) 30 days following the onset of the event.  In addition, blood and urine samples should be 
collected as described in Section 10.2, Appendix 2 (Hypersensitivity tests).
6.5.1.8.2. Hypertension
An increased incidence of severe hypertension was reported in patients receiving ramucirumab 
as compared to placebo.  In most cases, hypertension was controlled using standard 
antihypertensive treatment.
Pre-existing hypertension should be controlled before starting ramucirumab treatment.  
Monitoring of BP is recommended during therapy.
Temporarily suspend ramucirumab for severe hypertension until controlled with medical 
management.  Permanently discontinue ramucirumab if medically significant hypertension 
cannot be controlled with antihypertensive therapy. 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
51
6.5.1.8.3. Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGF Receptor 2 pathway.  
Proteinuria has been associated with ramucirumab in clinical studies.  The majority of events 
were of Grades 1 and 2.
Monitoring for the development or worsening of proteinuria during ramucirumab therapy is 
required.  Prior to each dose of study treatment, the participant's urine protein must be 2+ on 
dipstick or routine urinalysis, <2 (or <200 mg/mmol) on urine protein-to-creatinine ratio 
(UPCR), or <2 g on 24-hour urine collection (Section 6.6.1).
Dose-modification guidelines for participants experiencing proteinuria are provided in 
Section 6.6.1.
6.5.1.8.4. Thromboembolic Events
6.5.1.8.4.1.
Arterial Thromboembolic Events
Serious ATEs, including myocardial infarction, cardiac arrest, cerebrovascular accident, and 
cerebral ischemia, have been reported in clinical trials.  Permanently discontinue ramucirumab in 
participants who experience a severe ATE.
6.5.1.8.4.2.
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 
incidence varies depending on the type of therapy, use of concomitant chemotherapy agents, and 
specific disease state.  Venous thromboembolic events have been reported from clinical studies 
investigating ramucirumab, particularly in the context of metastatic disease or in regions adjacent 
to implanted venous access devices.
Most VTEs lack early warning signs; therefore, awareness and prompt treatment are important, 
especially in those patients with risk factors and/or previous history of VTEs (Chen and Cleck 
2009; Suter and Ewer 2013).
Ramucirumab therapy should be discontinued in the event of any Grade 3 or 4 VTE that is 
considered by the investigator to be symptomatic and not adequately treated by anticoagulation 
therapy.  In some study protocols, at the investigator’s discretion, ramucirumab therapy may be 
continued in the setting of an incidentally diagnosed, asymptomatic deep vein thrombosis or 
pulmonary embolism or following a symptomatic deep vein thrombosis or pulmonary embolism 
when symptoms have resolved with the institution of anticoagulation therapy.  
Ramucirumab should also be discontinued in the setting of a deep vein thrombosis or pulmonary 
embolism that occurs or intensifies while the participant is receiving therapeutic anticoagulation 
therapy.
6.5.1.8.5. Bleeding/Hemorrhage
Ramucirumab is an antiangiogenic therapy and may increase the risk of severe bleeding.  Severe 
GI hemorrhage was reported in patients with gastric cancer treated with ramucirumab in


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
52
combination with paclitaxel and in patients with CRC treated with ramucirumab in combination 
with FOLFIRI.
Permanently discontinue ramucirumab in participants who experience Grade 3 or 4 bleeding.
6.5.1.8.6. Gastrointestinal Perforation
Ramucirumab is an antiangiogenic therapy and may increase the risk of GI perforations.  Cases 
of GI perforation have been reported in patients treated with ramucirumab.
Permanently discontinue ramucirumab in participants who experience GI perforations.
6.5.1.8.7. Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome (PRES) 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 
careful control of BP, withdrawal of potentially causative medication, and administration of anti-
convulsant agents to those experiencing seizures (Stott et al. 2005). 
Permanently discontinue ramucirumab in participants who experience PRES.
6.5.1.8.8. 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 or 
with other risk factors for CHF, including prior radiotherapy to the left chest wall.  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.
While the mechanism of action is currently unknown, based on the safety data received to date, it 
is likely that treatment with ramucirumab enhances the cardiotoxicity associated with 
mitoxantrone and has the potential to enhance cardiotoxicity of other agents within the 
anthracycline/anthracenedione class of chemotherapy medications. 
Participants with risk factors should be closely monitored for signs and symptoms of CHF.  
Caution should be exercised when treating participants with clinically significant cardiovascular 
disease, such as pre-existing coronary artery disease or CHF.  Participants with symptomatic 
CHF, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia should 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
53
not be enrolled in clinical trials with ramucirumab.  Ramucirumab should be discontinued in the 
event of any Grade 3 and 4 events consistent with CHF.
6.5.1.8.9. Fistula Formation
Gastrointestinal and non-GI fistula formation has been associated with antiangiogenic agents 
including bevacizumab and sunitinib (Kamba and McDonald 2007). Some fistulas can be 
resolved with surgery 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).  A small number of fistula events have been reported in ramucirumab 
clinical trials.  
Ramucirumab treatment should be discontinued in participants who develop fistulas.
6.5.1.8.10. Surgery and Impaired Wound Healing
The impact of ramucirumab has not been evaluated in patients with serious or nonhealing 
wounds.  In a study conducted in animals, ramucirumab did not impair wound healing. 
However, since ramucirumab is an antiangiogenic therapy and may have the potential to 
adversely affect wound healing, ramucirumab treatment should be withheld prior to scheduled 
surgery.  The decision to resume ramucirumab following surgical intervention should be based 
on clinical judgment of adequate wound healing.
If a participant develops wound-healing complications during therapy, discontinue ramucirumab 
until the wound is fully healed. 
6.5.1.8.11. Liver Failure and Other Hepatic Impairment
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  In HCC patients with liver cirrhosis, hepatic 
encephalopathy was reported at a higher rate in the ramucirumab-treated patients compared to 
the placebo-treated patients.  Use ramucirumab with caution in participants with severe liver 
cirrhosis (Child-Pugh B or C), cirrhosis with hepatic encephalopathy, clinically significant 
ascites due to cirrhosis, or hepatorenal syndrome. “Clinically significant ascites” is defined as 
ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or 
paracentesis.  Use only if the potential benefits of treatment are judged to outweigh the potential 
risk of progressive hepatic failure in these participants.
Ramucirumab should be discontinued in the event of any new occurrence of hepatic 
encephalopathy and/or hepatorenal syndrome resulting from liver cirrhosis.  
Refer to the appropriate section of each study protocol for detailed information regarding 
participant eligibility and criteria for discontinuation.
6.6.
Dose Modification
Ramucirumab loading dose modification is not allowed as it is a one-time dose.  
Dose modifications are permitted only for ramucirumab maintenance dose in the setting of non-
life-threatening and reversible Grade 3 clinical AEs (e.g., fever) considered to be at least 
possibly related to ramucirumab that resolve to Grade ≤1 or pretreatment baseline within 21 to 
28 days, based on cycle length.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
54
If a Grade 4 AE occurs and is deemed at least possibly related to ramucirumab, then 
ramucirumab should be discontinued except in the specific case of Grade 4 fever or Grade 4
laboratory abnormalities (please refer to Section 10.3 for additional details regarding severity 
grading of laboratory abnormalities).If Grade 4 fever or laboratory abnormalities resolve to 
Grade ≤1 or pretreatment baseline within 1 treatment cycle for that specific regimen 
(monotherapy or combination), treatment with ramucirumab may be continued at the discretion 
of the investigator.
In these settings, ramucirumab may be re-administered at the maintenance dose.  If a second 
instance of such an event occurs, ramucirumab should be subsequently re-administered at the 
next lower dose level as shown in the table below.  A second dose reduction is not permitted for 
this level of event (Grade 3 or 4 event).  If the dose of ramucirumab is reduced because of 
potentially related AEs, subsequent dose increases are not permitted.
Participants who enter the study with symptoms or laboratory values equivalent to NCI-CTCAE,
v5.0 Grade 1 or 2 AEs should not have dose reductions related to the persistence or mild 
worsening of those symptoms or laboratory values; dose reductions may be warranted if 
worsening of symptoms or laboratory values is clinically significant in the opinion of the 
investigator.  Except in the case of proteinuria, as described in Section 6.6.1, asymptomatic 
laboratory abnormalities should not result in dose interruptions, modifications, or discontinuation 
of study therapy unless determined by the investigator to be clinically significant or 
life-threatening.  Ramucirumab will be permanently discontinued in case of any 
ramucirumab-related event that is deemed life-threatening, regardless of grade.
In case a dose reduction is necessary, the study intervention will be administered as follows: 
In case of AEs that require dose reduction, reduction of the SC ramucirumab dosing regimen 
should occur as indicated in the table below, according to the dose regimen on which the toxicity 
was observed.




CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
56
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 Section 6.5.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Section 6.6.
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
1.
Hypersensitivity reaction
1.a.
Hypersensitivity reaction
2
Prior to all future injections of ramucirumab, premedicate with:

histamine H1 antagonist, such as diphenhydramine hydrochloride

dexamethasone or equivalent

acetaminophen/paracetamol
1.b.
Hypersensitivity reaction
3-4
Immediately and permanently discontinue ramucirumab.
2.
Hypertension
2.a.
Hypertension (non-life-threatening and associated 
with symptoms)
NOTE:  Hypertension should be monitored prior to 
each SC ramucirumab dose administration.
3

Omit 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., 21-28 days), discontinue ramucirumab at 
investigator’s discretion.
2.b.
Uncontrolled hypertension, hypertensive crisis, or 
hypertensive encephalopathy
4
Immediately and permanently discontinue ramucirumab.
3.
Proteinuria 
3.a.
Proteinuria ≤2+ (dipstick or routine urinalysis)

Administer ramucirumab at the current dose if clinically indicated.

Obtain spot UPCR on first morning urine sample within 3 days prior to the 
next dose.
o
If UPCR <2 (or <200 mg/mmol), administer study treatment at the 
participant's current dose.
o
If UPCR ≥2 (or ≥200 mg/mmol), modify the dose.  See 
Proteinuria ≥2 (or ≥200 mg/mmol) (UPCR), line 3.c.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
57
Adverse Event
NOTE:  All specific adverse events listed are 
defined as AESIs in Section 6.5.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Section 6.6.
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
3.b.
Proteinuria >2+ (dipstick or routine urinalysis)

Delay study treatment for up to 14 days (omit 2 doses).

Obtain spot UPCR on first morning urine sample within 3 days prior to the 
next dose.
o
If UPCR <2 (or <200 mg/mmol), no further dose delay or dose 
reduction is required.
o
If UPCR ≥2 (or ≥200 mg/mmol), modify the dose.  See 
Proteinuria ≥2 (or ≥200 mg/mmol) (UPCR), line 3.c.
3.c.
Proteinuria 2 (or ≥200 mg/mmol) (UPCR)
Omit ramucirumab dose until UPCR returns to <2 (or <200 mg/mmol).  Resume 
ramucirumab at reduced dose as shown in Section 6.6.
If UPCR remains 2 (or ≥200 mg/mmol) after 14 days, discontinue study 
treatment.

Second occurrence:  Discontinue study treatment.
3.d.
Proteinuria UPCR >3 (or >300 mg/mmol) or in the 
setting of nephrotic syndrome
Discontinue study treatment.
4.
Arterial thromboembolic events, venous 
thromboembolic events
3 or 4
Immediately and permanently discontinue ramucirumab.
5.
Bleeding/Hemorrhage
Bleeding/Hemorrhage
2
Continue with treatment unless investigator-considered related. 
Bleeding/Hemorrhage
3 or 4
Immediately and permanently discontinue ramucirumab.
6.
Gastrointestinal perforation
Immediately and permanently discontinue ramucirumab.
7.
Posterior reversible encephalopathy syndrome
Immediately and permanently discontinue ramucirumab.
8.
Congestive heart failure
Congestive heart failure
2
Continue with treatment unless investigator-considered related.  
Congestive heart failure
3 or 4
Immediately and permanently discontinue ramucirumab.
9.
Fistula formation
Immediately and permanently discontinue ramucirumab.
10.
Impaired wound healing
10.a.
Prior to planned surgery
Withhold ramucirumab at least 4 weeks (28 days) prior to scheduled surgery.
10.b
After surgery
Resume ramucirumab based on clinical judgment.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
58
Adverse Event
NOTE:  All specific adverse events listed are 
defined as AESIs in Section 6.5.1.8.
CTCAE 
Grade
Dose-Modification Guidelines
NOTES: 
Dose reductions to occur as defined in Section 6.6.
Treating physicians can modify or discontinue ramucirumab more 
conservatively than in the guidance below.
10.c.
Wound-healing complications developed during 
study treatment
Delay ramucirumab dosing until the wound is fully healed.
11.
Hypothyroidism
Hypothyroidism
2 or 3
Therapy with ramucirumab can be continued while treatment for the thyroid 
disorder is instituted.
Hypothyroidism
4
Immediately and permanently discontinue ramucirumab.
12.
Hepatic encephalopathy and/or hepatorenal 
syndrome resulting from liver cirrhosis
Immediately and permanently discontinue ramucirumab.
Abbreviations:  AESI = adverse event of special interest; CTCAE = common terminology criteria for adverse events; NCI = National Cancer Institute;
SC = subcutaneous; UPCR = urine protein-to-creatinine ratio.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
59
6.7.
Intervention after the End of the Study
The end of study definition is defined in Section 4.4.  Investigators will continue to follow the 
SoA provided in Section 1.3 until notified by sponsor that end of study has occurred.
6.7.1.
Intervention after Study Completion
Subcutaneous ramucirumab may be made available after conclusion of the study to participants 
who are still receiving and benefitting from study treatment in countries where the drug cannot 
be lawfully prescribed.
6.7.1.1.
Continued Access
Participants who are still on study intervention at the time of study completion may continue to 
receive study intervention if they are experiencing clinical benefit and no undue risks.
The continued access period will apply to this study only if at least 1 participant is still on study 
treatment when study completion occurs. Sponsor will notify investigators when the continued 
access period begins.
Participants are not required to sign a new ICF before treatment is provided during the continued 
access period; the initial ICF for this study includes continued access under this protocol.
The participant’s continued access to study intervention will end when a criterion for 
discontinuation is met (Section 7). Continued access follow-up will begin the day after the 
participant and the investigator agree to discontinue study intervention and lasts approximately 
30 days. Follow-up procedures will be performed as shown in the Continued Access SoA.
Participants who are in short-term follow-up when the continued access period begins will 
continue in short䢯term follow-up until the 30-day short-term follow-up visit is completed.
In all cases, no follow-up procedures will be performed for a participant who withdraws 
informed consent unless he or she has explicitly provided permission and consent.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
60
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
Participants will remain on treatment until a discontinuation criterion is met, at which point study 
intervention is permanently discontinued and the participant will enter the short-term follow-up 
period. See the SoA for data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed.  Short-term follow-up 
that includes safety follow-up begins when the participant and the investigator agree that the 
participant will no longer continue study treatment and will last for a minimum of 30 days 
following the last dose of study drug.
The discontinuation values required below pertain to participants enrolled with normal or near 
normal hepatic biochemical tests (ALT <2x ULN, total bilirubin level (TBL) <1.5x ULN, 
alkaline phosphatase [ALP] <1.5x ULN).  In participants with abnormal hepatic biochemical 
tests at baseline, the discontinuation values may need to be adjusted on a case-by-case basis.  For 
example, in participants enrolled with baseline ALT >1.5x ULN (for example, nonalcoholic fatty 
liver disease), the discontinuation value may need to be ALT >2x baseline plus symptoms 
instead of ALT >3x ULN plus symptoms.  Similarly, in participants with elevated TBL (for 
example, Gilbert’s syndrome) or elevated ALP (for example, underlying bone disease) at 
baseline, the discontinuation values will increase and will be based on direct bilirubin levels and 
hepatic ALP-isoenzyme levels respectively.  Consult with the GI & Liver Safety Committee if 
necessary.  If an adjustment is needed, follow the process for changing required language.
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention.  If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for safety.  See the SoA for data to be 
collected at the time of discontinuation of study intervention and follow-up and for any further 
evaluations that need to be completed.
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula (QTcF) after enrollment, the investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed.  This review of the electrocardiogram (ECG) printed at the 
time of collection must be documented.  Any new clinically relevant finding should be reported 
as an AE.
Possible reasons leading to permanent discontinuation of investigational product:
o
Subject Decision

the participant or the participant’s designee, requests to discontinue investigational 
product.
In addition, participants will be discontinued from the investigational product in the following 
circumstances:

the participant becomes pregnant during the study.

The participant has evidence of progressive disease.  


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
61

The participant experiences unacceptable toxicity.

The participant is noncompliant with study procedures and/or treatment.

The investigator decides that the participant should be discontinued from study 
intervention.

The participant, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication.  Discontinuation 
from study invention will occur prior to introduction of the new agent.

The participant has had 1 dose reduction and experiences an AE that would cause a 
second dose reduction.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:

at any time at his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

if the participant becomes pregnant during the study.  See Section 8.3.5 regarding 
regulatory reporting requirements on fetal outcome

if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study

if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent
Discontinuation is expected to be uncommon.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment.  If the investigator and the sponsor CRP/CRS agree it is medically 
appropriate to continue, the investigator must obtain documented approval from the sponsor 
CRP/CRS to allow the inadvertently enrolled participant to continue in the study with or without 
treatment with investigational product. Safety follow up is as outlined in Section 1.3 (SoA), 
Section 8.2 (Safety Assessments), and Section 8.3 (AEs and SAEs) of the protocol.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
62
7.3.
Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
63
8.
Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA.  Protocol waivers 
or exemptions are not allowed.
●
Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.
●
Adherence to the study-design requirements, including those specified in the SoA, 
is essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
8.1.
Efficacy Assessments
Tumor assessments will be performed for each participant at the times shown in the SoA 
(Section 1.3).
Computed tomography (CT) scans, including spiral CT, are the preferred methods of assessment 
(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 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 intravenous 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 scan of the thorax, abdomen, and pelvis is required.
In the event of unforeseeable circumstances where participant visits are not able to happen per 
SoA (e.g., travel restrictions due to Covid-19 pandemic resurgence), participant may opt to have 
scans done at a local imaging center that is more conveniently located to them. This will need to 
be orchestrated by the investigator to make sure the participant will remain evaluable per 
RECIST (contacting the local imaging center and ordering the correct scan/details, as well as 
thorough documentation of the imaging center location and copies of scans retained as source 
data at the investigator’s site.)
See Section 9.4 for definitions of efficacy endpoints.
8.2.
Safety Assessments
For each participant, ECGs, vital signs, laboratory tests, and other tests should be collected as 
shown in the SoA (Section 1.3).


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
64
In the event of unforeseeable circumstances where participant visits are not able to happen per 
SoA (e.g., travel restrictions due to Covid-19 pandemic resurgence), alternative options for 
safety assessments need to be performed as given below. 

If delayed visits occur, to ensure participants’ safety, the assessments and data collection 
should continue by remote methods, with the frequency specified in the protocol, 
including but not limited to AEs/SAEs, concomitant medications, ECOG PS.  Serious AE 
criteria, reporting, and follow-up requirements and procedures remain the same. 

Ensure that all delayed visits and remote-based assessments are documented. 

Labs and other procedures (e.g., imaging, ECG) can be performed locally if a participant
is unable to get to their scheduled visit where they were to be collected.  The name and 
address of the performing laboratory or clinic, certification status, and reference ranges 
also need to be maintained in the participant’s files by the site (see Section 8.2.1). 
Results from any clinical laboratory test analyzed by a central laboratory (refer to Section 10.2) 
will be provided to investigative sites by Lilly or its designee.
Refer to Section 8.3 for details on the recording of AEs.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
8.2.1.
Clinical Safety Laboratory Assessments
●
See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
●
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF.  The laboratory reports must be filed with the source 
documents.  Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.
●
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or until the completion of Visit 801 should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
○
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the 
sponsor notified.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
65
○
All protocol-required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the laboratory manual and the SoA. In the 
event of unforeseeable circumstances when this is not feasible (e.g., restricted 
travel due to Covid-19 pandemic resurgence), local or off-site laboratory 
testing is permissible.  In this case, the investigator must review the laboratory 
report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF.  The laboratory 
reports must be filed with the source documents.  The name and address of the 
performing off-site laboratory or clinic, certification status, and reference 
ranges also need to be maintained in the participant’s files by the site.
○
If there is an abnormal laboratory value or abnormal value for any other 
diagnostic or screening test (for example, BP increased, neutrophils decreased, 
etc.) and it is known to be related to a disease diagnosis (for example, 
hypertension, neutropenia, etc.) this should be reported in the CRF as an AE.  
Do not enter the test abnormality, enter the disease diagnosis or categorical 
term.  If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE, AE, or dose modification), then the event(s) must be reported in the 
CRF as AE(s).
8.2.2.
Safety Surveillance
The sponsor has robust safety surveillance processes based on recommendation made by Council
for International Organizations of Medical Sciences (CIOMS) Working Group VI - Management 
of Safety Information from Clinical Trials Report.  These processes are in line with FDA’s 
expectations for Safety Assessment Committees and European Medicines Agency expectations 
for monitoring safety in clinical trials. 
Each investigational drug has a Developmental Safety Surveillance Team (DSST) which is 
responsible for monitoring the safety of participants and overseeing the evolving safety profile of 
investigational drugs.  The DSST will review all available data including but not limited to 
clinical trial data (cumulative AE and SAE data and laboratory data), non-clinical data 
(toxicology studies), epidemiology studies and literature.  The team will conduct real time 
review of all SAEs and other incoming expedited safety reports.  The DSST is also responsible 
for review of accumulating safety data across all trials for the investigational drug.  The DSST 
will meet on a timely manner at pre-defined intervals or on an ad-hoc basis as required. 
The DSST is a multidisciplinary team which includes a physician/scientist who are well versed 
in Pharmacovigilance and with the therapeutic area for which the investigational drug is being 
developed.  The roles and responsibilities of this team and the processes are clearly defined in 
Lilly’s internal standard operating procedures.
Each investigational drug has a Developmental Safety Management Team (DSMT) which is a 
cross-functional, multidisciplinary team and includes DSST members, study team physicians and 
other members depending on the necessity such as epidemiologist, clinical pharmacologist, 
toxicologist, and statistician.  The DSST and DSMT work together to review clinical data from 
the clinical trial. 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
66
The DSST can make recommendations to the DSMT in order to minimize risk to participants in 
clinical trials.  Such recommendations will include (but are not limited to) changes to conduct of 
the trial, determination of new adverse drug reactions (ADRs), and determining if event(s) meets 
the criteria for expedited reporting to regulators (such as investigational new drug [IND] safety 
reports) and investigators.
In addition, each individual clinical trial study team has clearly defined processes to review all 
relevant safety data at cohort level and trial level in order to monitor safety of participants in 
clinical trials and enable trial level decisions such as dose escalation.  
Lilly Global Patient Safety (GPS) has a robust process, for expedited communication of SAEs 
and suspected unexpected serious adverse reactions (SUSARs) per regulatory requirements and 
other important study information as needed.  The protocol gives detailed information to study 
sites for collection and reporting of AEs and SAEs.
8.2.3.
Safety Monitoring
The Lilly CRP/CRS will monitor safety data throughout the course of the study.  This will 
include monitoring and recording all AEs, including all CTCAE v5.0 grades and SAEs.  The 
sponsor will review SAEs within the time frames mandated by company procedures.  The Lilly 
CRP/CRS will periodically review the following data:

trends in safety data

review of vital signs, physical exam findings, laboratory analytes including 
proteinuria, blood chemistry, and hematology labs.

adverse events, including monitoring of AESIs of ramucirumab (HSRs, 
hypertension, proteinuria, ATEs, VTEs, bleeding/hemorrhagic events, GI 
perforation, CHF, wound healing complications, fistula, liver failure/liver 
injury, and PRES). In addition, injection site reactions (ISRs) related to SC 
ramucirumab will be evaluated for pain, erythema, induration, swelling, and 
pruritus.
When appropriate, the sponsor CRP/CRS will consult with the functionally independent GPS 
therapeutic area physician or CRS.
8.2.4.
Hepatic Safety Monitoring
Close hepatic monitoring and evaluation
Liver testing (Section 10.5), including ALT, AST, ALP, TBL, direct bilirubin (D. Bil), gamma-
glutamyltransferase (GGT), and creatine kinase (CK), should be repeated within 2 to 4 days to 
confirm the abnormality and to determine if it is increasing or decreasing, if one or more of these 
conditions occur:
If a participant with baseline 
results of ... 
develops the following elevations:


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
67
ALT or AST <1.5x ULN
ALT or AST ≥5x ULN or
ALT or AST ≥3x ULN concurrent with 
TBL ≥2x ULN
ALT or AST ≥1.5x ULN
ALT or AST ≥3x baseline or
ALT or AST ≥2x baseline concurrent with 
TBL ≥2x ULN
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin level; 
ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), history of concomitant medications 
(including over-the-counter, herbal and dietary supplements, and history of alcohol drinking and 
other substance abuse).  In addition, the evaluation should include a blood test for prothrombin 
time, international normalized ratio (PT-INR); serological tests for viral hepatitis A, B, C, E;
autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 
Additional blood test for glutamate dehydrogenase (GLDH), an exploratory biomarker of drug 
induced liver injury will be collected for future exploratory analyses.
Based on the participant’s history and initial evaluation results, further testing should be 
considered, in consultation with the Lilly-designated medical monitor, including tests for 
hepatitis D virus (HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen 
levels, acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol 
levels, urinary ethyl glucuronide, and serum phosphatidylethanol.  Based on the circumstances 
and the investigator’s assessment of the participant’s clinical condition, the investigator should 
consider referring the participant for a hepatologist or gastroenterologist consultation, magnetic 
resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography 
(ERCP), cardiac echocardiogram, and/or a liver biopsy.  
Additional Hepatic Safety Data Collection
Additional safety data should be collected via the CRF if 1 or more of the following conditions 
occur: 
In participants enrolled with baseline ALT or AST <1.5 ULN

Elevation of serum ALT or AST to ≥5x ULN on 2 or more consecutive blood tests

The combination of elevated ALT or AST ≥3x ULN and elevated TBL ≥2x ULN
In participants enrolled with baseline ALT or AST ≥1.5x ULN

Elevated ALT or AST ≥3x baseline on 2 or more consecutive tests

The combination of elevated ALT or AST ≥2x baseline and elevated TBL ≥2x ULN


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
68
In all study participants 

Discontinuation from study treatment due to a hepatic event or abnormality of liver tests

Occurrence of a hepatic event considered to be an SAE
8.2.5.
Injection Site Reactions

Injection site assessments using the ISR questionnaire at times specified in the SoA (Section 
1.3).  If there are ≥2 injection sites, an ISR questionnaire will be filled out separately for each 
site.

Symptoms of a local ISR may include erythema, induration, pain, pruritus, and edema that 
will be assessed at the site by the study team using visual and palpation assessments as 
appropriate.  Injection site findings will be captured on an ISR questionnaire.  If any of the 
symptoms are present, the investigator will characterize using a categorical scale (e.g., 
intensity and diameter of erythema, diameter of induration, analgesic level requirements for 
pain, impact of pruritus on sleep, and degree of edema).

Injection site reactions, whether recorded as a result of the prespecified (or solicited) 
assessment or spontaneously reported reactions, will be recorded as AEs only if they qualify 
as SAEs.

If an unsolicited ISR is reported by a participant or investigator, the ISR questionnaire will be 
used to capture additional information about this reaction (for example, degree and area of 
erythema) at additional visits until resolution of the event.

Participants will be asked to assess injection site(s) daily and record any symptoms in a diary.  
The diary will be returned to the investigator at each clinic visit.  Participants should contact 
the investigator if any symptoms occur between clinic visits.
8.2.5.1.
Injection Site Pain Assessments

Injection site pain assessments using a 100-mm visual analogue scale (VAS) will be 
performed at times specified in the SoA (Section 1.3).  If there are ≥2 injection sites, VAS 
pain assessments will be filled out separately for each site.

The VAS will only be completed by participants if they indicate the presence of pain as 
investigators complete the ISR questionnaire for solicited/scheduled assessments using the 
ISR questionnaire.  The VAS will not be completed when the ISR questionnaire is used for 
spontaneous assessments.  

The VAS is a well-validated tool (Williamson and Hoggart 2005) to assess injection site 
pain.  It is presented as a 100-mm line anchored by verbal descriptors of “no pain” and 
“worst imaginable pain.” Participants will be provided with translations in which they are 
fluent. 
8.2.6.
Hypersensitivity Reactions, Including Anaphylaxis
In the event of a suspected systemic HSR, an AE CRF should be completed.  

Each clinical sign or symptom associated with the HSR (e.g. mucocutaneous, cardiovascular, 
respiratory, GI, CNS, or other) should be entered as a separate AE on the AE CRF form.

The investigator should indicate whether the event constituted an HSR.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
69

To fully characterize the HSR, additional information about each event will be captured on 
the AE CRF form.
o
Each symptom of the event should be assessed.  Symptoms may include rash/urticaria, 
tachycardia, chest pain, fever, flushing, dyspnea, and in severe cases, bronchospasm, 
angioedema, and hypotension.
o
Timing of the event occurrence is important.  The investigator should indicate the timing 
category that is appropriate.

In the event of an HSR, blood samples for immunogenicity and PK should be drawn and 
additional laboratory tests conducted as described in Section 6.5.1.8.1.
8.3.
Adverse Events and Serious Adverse Events
The investigator will use CTCAE v5.0 (NCI 2018) to assign AE-severity grades.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be collected from the signing of the ICF.
All AEs will be collected from the signing of the ICF until the follow-up visit.  
Adverse events that begin before the start of study intervention but after signing of the ICF will 
be recorded on the AE CRF.
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to sponsor begins after the participant has signed the ICF and has received study 
drug.  However, if an SAE occurs after signing the ICF, but prior to receiving ramucirumab, it 
needs to be reported ONLY if it is considered reasonably possibly related to study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3.  The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.  Serious AEs, 
including death, caused by disease progression should not be reported unless the investigator 
deems them to be possibly related to study treatment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
70
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE
occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs, and AESIs (as defined in Section 8.3.6), will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.3).  Further information on follow-up procedures is 
provided in Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs
●
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention under clinical investigation are met.
●
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation.  The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs), and investigators.
●
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements.
8.3.5.
Pregnancy
●
Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and until at least 
12 weeks after the last dose.
●
If a pregnancy is reported, the investigator should inform the sponsor within 
24 hours of learning of the pregnancy and should follow the procedures outlined 
in Appendix 4.
●
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, or ectopic pregnancy) are considered SAEs.
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements, any pregnancy should be reported 
following the SAE process described in Appendix 4 to collect data on the outcome for both 
mother and fetus.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
71
8.3.6. Adverse Events of Special Interest 
Adverse events of special interest for this program include:
a.
Hypersensitivity reactions
b. Hypertension
c.
Proteinuria
d. Thromboembolic events (ATEs and VTEs)
e.
Bleeding/hemorrhage events
f.
Gastrointestinal perforation
g. Posterior reversible encephalopathy syndrome
h. Congestive Heart Failure
i.
Fistula
j.
Wound-healing complications
k. Liver failure/liver injury 
Section 6.5.1.8 describes supportive care measures for each ramucirumab AESI.  Section 6.6.1
presents the dose-modification guidelines for ramucirumab AESIs.  Contact the Lilly CRP/CRS
if questions arise concerning AESIs.
8.3.7. Product Complaints
A product complaint is any written, electronic, or oral communication that alleges a deficiency 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
Lilly product after it is released for distribution. When the ability to use the product safely is 
impacted, the following are also product complaints: 

Deficiencies in labeling information, and

Use errors for device or combination products due to ergonomic design elements of the 
product.
Sponsor collects product complaints on investigational products, medical devices, and drug 
delivery systems used in clinical studies in order to ensure the safety of study participants, 
monitor quality, and to facilitate process and product improvements.
Complaints are also collected on comparators and other materials supplied, as required and 
instructed for the study.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product, medical device, or delivery system, so 
that the situation can be assessed.
Product complaints will be reported by the investigator to the sponsor per instructions provided 
on the study specific Product Complaint Form.
With each complaint related to a medical device or delivery system, the investigator will assess 
and indicate on the complaint form whether the product complaint, deficiency, or problem could 
have led to an SAE had precautions not been taken. As required by local regulations, the 
investigator will report to their IRB/IEC any unanticipated adverse device effect (UADE; 
unanticipated problem that resulted in an SAE), or any product complaint that could have led to 
an SAE had precautions not been taken.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
72
8.4.
Treatment of Overdose
In the event of an overdose, the investigator/treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities for at least
7 days).
3. Obtain a plasma sample for PK analysis within 2 days from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
●
Whole blood samples will be collected for measurement of serum concentrations 
of ramucirumab (LY3009806) as specified in the SoA (see Section 1.3.1 PK 
sampling schedule). 
●
A maximum of 5 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor.  The 
timing of sampling may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 
●
Instructions for the collection and handling of biological samples will be provided 
by the sponsor.  The actual date and time (24-hour clock time) of each sample will 
be recorded.
●
Genetic analyses will not be performed on these PK samples.  Participant 
confidentiality will be maintained. 
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last participant visit for the study. 
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected
and stored for analysis to determine antibody production against ramucirumab.  Antibodies may 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
73
be further characterized for their ability to neutralize the activity of ramucirumab.  To interpret 
the results of immunogenicity, a venous blood sample will be collected at the same time points to 
determine the plasma concentrations of ramucirumab (see Section 8.2.6).  All samples for 
immunogenicity should be taken predose when applicable and possible.  The detection and 
characterization of antibodies to ramucirumab will be performed using a validated assay method 
by or under the supervision of the sponsor.  Samples may be stored for a maximum of 15 years 
(or according to local regulations) following the last participant’s last visit for the study to enable 
further analysis of immune responses to ramucirumab.  Immunogenicity will be evaluated as 
described in Section 9.4.6.2.
8.10.
Health Economics
Not applicable.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
74
9.
Statistical Considerations
9.1.
Statistical Hypotheses
A projected registration dose (PRD) will be identified that is a safe ramucirumab SC dosing 
regimen leading to a PK profile with similar steady state exposure but higher Ctrough (>50 µg/mL) 
and lower Cmax relative to the PK profile of the approved IV ramucirumab dose of 10 mg/kg 
Q2W.
9.2.
Sample Size Determination
A maximum of approximately 30 participants will receive study intervention such that 
approximately 12 PK-evaluable participants complete the study at the PRD.
Participants who meet all criteria for enrollment will be assigned to receive ramucirumab in this 
study.  The sponsor will confirm the dose and identification number assignment (and cohort) for 
each participant.  No dose escalations (i.e., to the next cohort) can occur without prior discussion 
and agreement with the responsible sponsor CRP/CRS.
The primary objectives of this study are to assess the PK parameters of ramucirumab 
administered SC and to assess safety of ramucirumab administered SC.
9.2.1.
Cohort A
Three participants will be enrolled in Cohort A and followed for a minimum of 3 weeks prior to 
opening enrollment in Cohort B. If new or unexpected safety findings are identified relative to 
the large database of IV ramucirumab, or if 1 or more participant does not have sufficient PK
data to inform dose for Cohort B up to an additional 3 participants may be enrolled into Cohort 
A.
9.2.2.
Cohort B (Sub-Cohorts B1, B2, and B3)
The internal review committee will review the totality of available safety data from Cohort A
and Study JVDT, and based on this, will make a recommendation to open enrollment to Sub-
Cohort B1.
Sub-Cohort B1 will initially recruit 3 participants to receive the maintenance weekly regimen 
and based on the review of the first 3 weeks of safety and PK data, the following may be 
decided:

to enroll up to 3 additional participants in Sub-Cohort B1, if new or unexpected safety 
findings are identified relative to the large database of IV ramucirumab at an alternate 
dose, or

to enroll up to 3 additional participants in Sub-Cohort B1, if one or more participants in 
Cohort B1 does not have a sufficient PK data to inform dose for Cohort B2, or

to open Sub-Cohort B2 at the determined loading and maintenance dosing regimen based 
on the available data. 
Sub-Cohort B2 will recruit a minimum of 3 participants but will not exceed 6 participants. The
number of participants in Sub-Cohort B2 will depend on the dosing decisions made at the data 
reviews after the first 3 and 6 participants have completed 3 weeks of treatment in Sub-Cohort 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
75
B2. If either analysis reveals that the Sub-Cohort B2 dosing regimen is not optimal, then the 
optional Sub-Cohort B3 (N=6) may be opened to investigate an alternative dose, if deemed 
appropriate.
Overall, the maximum number of participants in Cohort B is approximately 18.
9.2.3.
Cohort C
Cohort C will recruit 6 participants.  Cohort C will initiate recruitment once 3-week dosing 
safety data from Cohort B (in at least 6 participants) and initial PK data support pursuing further 
enrollment at the same dosing regimen.  The study population will be the same as Cohort B.  The 
dose regimen for Cohort C is anticipated to be the same as the preceding 6 participants in 
Cohort B.  This expanded number of participants will provide additional PK and safety data to 
inform potential further development of SC ramucirumab.
If any participant of Cohorts A, B, or C discontinues the therapy prior to the assessment of safety 
and PK profile at Week 3, a new participant (up to 3) may be enrolled to make sure there will be 
sufficient data for safety and PK assessment.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF.
Enrolled/Intent-to-Treat
All participants who receive at least one dose of study treatment.
Efficacy Evaluable
All participants with evaluable disease per their baseline 
assessment and at least one complete post-baseline assessment.
Safety
All participants who take at least 1 dose of study intervention.
Pharmacokinetic Analysis
All treated participants who received at least 1 dose of study 
treatment and have at least one evaluable PK sample.
Abbreviations:  ICF = informed consent form; PK = pharmacokinetic. 
9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of sponsor or its designee.  The primary 
analysis will happen after all participants complete the PK and safety assessment at Week 3 or 
discontinue treatment prior to completing Week 3.
This is not a controlled study and statistical tests of clinical outcomes are not feasible.  
Summaries will be limited to descriptive statistics.  Unless otherwise stated, any confidence 
intervals (CIs) will be given at a 2-sided 95% level.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report.  Additional exploratory 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
76
analyses of the data will be conducted as deemed appropriate.  Principal features of the protocol 
include any analyses which are regarded critical to registration.
The initial statistical analysis plan will be finalized prior to first participant visit, and it will 
include a more technical and detailed description of the statistical analyses described in this 
section.  This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.
9.4.1. General Considerations
Any modifications or clarifications to the data analysis methods will be described and justified in 
the SAP before data analysis.  As this is an uncontrolled, open-label study, any modifications to 
analyses after the initial SAP will be considered post hoc.
The primary analysis of clinical data will occur after all participants have completed the PK 
evaluation period.  Additional updated analyses of efficacy and safety may be conducted at later 
times if deemed appropriate by the sponsor.
9.4.1.1.
Participant Disposition
A detailed description of participant disposition will be provided, according to CONSORT 
publishing requirements, including a summary of the number and percentage of participants 
entered into the study, enrolled in the study, and treated, as well as number and percentage of 
participants completing the study, as defined in the SAP, or discontinuing prior to study 
completion (overall and by reason for discontinuation).  A summary of all important protocol 
deviations will be provided.
9.4.1.2.
Participant Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target participant population considered for regulatory approval. 
A summary of baseline participant and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics.  
Other participant baseline characteristics will be summarized by cohort as deemed appropriate.
9.4.1.3.
Concomitant Medications
A summary of prior and concomitant medications and transfusions by cohort will be reported.
9.4.1.4.
Treatment Compliance
Study treatment compliance will be assessed as the proportion of treatment that is actually taken, 
relative to what is expected, after accounting for protocol-defined dose adjustments.  Study
treatment taken will be derived from the difference between the total number of doses dispensed 
and returned over the course of the participant’s treatment.
9.4.1.5.
Extent of Exposure
The duration on therapy, dose omissions, dose reductions, dose delays, and dose intensity for 
each drug will be summarized for all treated participants by arms.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
77
9.4.1.6.
Post-Study Treatment Therapy
The numbers and percentages of participants receiving post-study-treatment, anti-cancer 
therapies will be provided by type of therapy (surgery, radiotherapy, or systemic therapy), and by 
drug class and/or name, overall, and by line of therapy.
9.4.2.
Primary Endpoint
The primary clinical objective is to evaluate the safety and PK profile of ramucirumab 
administered SC.  The safety assessment will include, but not be limited to, summaries of 
TEAEs, SAEs, abnormal laboratory findings, and dose modifications.  See Section 9.4.5 for a 
detailed description of the safety analyses.
Serum concentration of ramucirumab will be summarized using descriptive statistics per dose 
and time point of collection.  Additional analysis utilizing the population PK approach will also 
be conducted if deemed appropriate.  See Section 9.4.6.1 for details.
9.4.3.
Secondary Endpoint(s)
Immunogenicity incidence will be tabulated, and correlation of immunogenicity to ramucirumab 
drug level, activity, and safety will be assessed as appropriate.  See Section 9.4.6.2 for details.
Injection site reactions will be summarized.  Details will be described in SAP.
9.4.4.
Tertiary/Exploratory Endpoint
Any evidence of clinical activity, including best overall response, will be noted for each 
participant.
9.4.5.
Other Safety Analyses
All safety analyses will be made on the Safety Population.  The most current version of MedDRA at the 
time of analysis will be used when reporting AEs by MedDRA terms and CTCAE (v5.0) will be utilized 
to assign AE-severity grades.
Safety analyses will include summaries of the following:

adverse events, including severity and possible relationship to study drug

serious AEs, including possible relationship to study drug

adverse events leading to dose adjustments

discontinuations from study treatment due to AEs or death

treatment-emergent abnormal changes in laboratory values

treatment-emergent abnormal changes in vital signs and ECGs.
All parameter estimates from the fitted dose-toxicity model used to guide the dose escalation will 
be provided along with the associated 95% CIs.
A summary overview of all AEs will be provided overall and by cohort. Treatment-emergent 
AEs, SAEs, and AESIs will be summarized and listed overall and by cohort.
All deaths that occur during the study, within 30 days of the study treatment discontinuation, as 
well as the cause of death, will be summarized and listed overall and by cohort.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
78
In addition, summary and listing of AEs leading to death, leading to study treatment 
discontinuation, and leading to study treatment dose modification will be produced overall and 
by cohort.
All relevant hematology and chemistry laboratory values will be graded according to 
CTCAE v5.0.  The shifts in CTCAE toxicity grading from baseline to worst grade postbaseline 
(first dose up to 30 days after study treatment discontinuation) will be produced overall and by 
cohort.
All vital signs including temperature, BP, heart rate, and weight will be listed overall and by 
cohort.
9.4.6.
Other Analyses 
9.4.6.1.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on all data from all participants who received at 
least 1 dose of investigational product and have sufficient evaluable PK samples.
Ramucirumab concentration will be summarized by standard summary statistic per dose level 
and collection time point.  Additionally, PK data may be added to the large IV ramucirumab PK 
database in cancer participant to estimate, using non-linear mixed effect modelling, the post-hoc 
individual PK-parameter estimate for Study JVDU participants.
9.4.6.2.
Immunogenicity Analyses
The frequency and percentage of participants with preexisting anti-drug antibody (ADAs) and 
with treatment-emergent (TE) ADA to ramucirumab will be tabulated.  Treatment-emergent 
ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimum required 
dilution if no ADAs were detected at baseline (treatment-induced ADAs) or those with a 4-fold 
(2 dilutions) increase in titer compared to baseline if ADAs were detected at baseline 
(treatment-boosted ADAs).  For the TE ADA+ participants the distribution of maximum titers 
will be described.  The frequency of neutralizing antibodies may also be tabulated in TE ADA+ 
participants if assessed.
The relationship between the presence of antibodies to ramucirumab, the PK parameters, and 
pharmacodynamic response, including safety and efficacy, to ramucirumab may be assessed.
In the event of an HSR, ADAs and ramucirumab serum concentrations will be tabulated (see 
Section 8.2.6).
9.5.
Interim Analyses 
An internal review committee will review the data on a cohort-by-cohort basis during the study
to identify the dose providing the appropriate PK profile, and to assess whether safety findings 
inconsistent with the IV ramucirumab profile are observed.  The investigators and the sponsor 
study team will make the determination regarding dose escalation based upon their review of the 
safety and tolerability data as described in this protocol.  Furthermore, access to PK data will be 
planned in the course of the study to inform on dose selection particularly prior to and during 
Cohort B.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
79
9.6.
Data Monitoring Committee (DMC)
Not applicable. 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
80
10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
●
This study will be conducted in accordance with the protocol and with the 
following:
○
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and CIOMS International Ethical Guidelines
○
Applicable International Council for Harmonization (ICH) good clinical 
practice (GCP) Guidelines
○
Applicable laws and regulations.
●
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
●
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.
●
The investigator will be responsible for the following:
○
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC
○
Notifying the IRB/IEC of SAEs (and/or UADEs) or other significant safety 
findings as required by IRB/IEC procedures
○
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations.
●
Investigator sites are compensated for participation in the study as detailed in the 
CTA.
10.1.2.
Financial Disclosure
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
81
10.1.3.
Informed Consent Process
●
The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study.
●
Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.
●
The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent 
must also sign the ICF.
●
Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study.
●
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection
●
Participants will be assigned a unique identifier by the sponsor.  Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred.
●
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law.  The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.
●
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
●
The sponsor has processes in place to ensure data protection, information security,
and data integrity.  These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.
10.1.5.
Committees Structure
Not applicable. 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
82
10.1.6.
Dissemination of Clinical Study Data
Communication of Suspended or Terminated Dosing
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by phone and/or email) 
as soon as possible.  It will be a requirement that investigators respond upon receipt to confirm 
that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention.  Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing.  If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified.
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.
Data 
The sponsor does not proactively share data from Phase 1 clinical trials.  Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected.
10.1.7.
Data Quality Assurance
●
All participant data relating to the study will be recorded on printed or electronic 
CRF (eCRF) unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.
●
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.
●
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.
●
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques are provided in the 
Monitoring Plan.
●
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.
●
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
83
●
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.
●
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
Clinical Trial Agreement (CTA) unless local regulations or institutional policies 
require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.
●
In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site.  The study 
may be audited by sponsor or its representatives, and/or regulatory agencies at 
any time.  Investigators will be given notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered sources and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment (COA) data (participant-focused outcome instrument) 
will be collected by the participant, via a paper source document and will be transcribed by the 
investigator site personnel into the EDC system.
Data collected via the sponsor-provided data capture system(s) will be stored at third parties.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention.  Data will subsequently be transferred from the central 
vendor to the sponsor-data warehouse.
Data from complaint forms submitted to sponsor will be encoded and stored in the global 
product complaint management system.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
84
10.1.8.
Source Documents
●
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator’s site.
●
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical 
records or transfer records, depending on the study.  Also, current medical records 
must be available.
●
Definition of what constitutes source data can be found in Section 10.1.7.
10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
●
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
●
Inadequate recruitment of participants by the investigator
●
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements.  The investigator shall promptly inform the participant and assure 
appropriate participant therapy and/or follow-up.
10.1.10.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.
10.1.11.
Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
















CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
92
10.4.
Appendix 4:  Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with:

12 months of amenorrhea for women >55, with no need for FSH

12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL and no 
other medical condition such as anorexia nervosa and not taking medications during 
the amenorrhea (e.g. oral contraceptives, hormones, gonadotropin releasing hormone, 
anti-estrogens, selective estrogen receptor modulators (SERMs), or chemotherapy 
that induced amenorrhea)


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
93
Contraception Guidance:
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner

(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed.  If not, an 
additional highly effective method of contraception should be used.  Spermatogenesis cycle is approximately 
90 days.)
Highly Effective Methodsb That Are User Dependent 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc
o
oral
o
intravaginal
o
transdermal
o
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
o
oral
o
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.)
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and correctly.  Typical use failure rates differ from those 
when used consistently and correctly.
c.) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action.
Note:  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom should not be used together (due to risk of failure with 
friction).


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
94
Collection of Pregnancy Information
Male participants with partners who become pregnant
●
The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study.  This applies only to male participants who receive study 
intervention.
●
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy.  The female partner will also be followed to determine the 
outcome of the pregnancy.  Information on the status of the mother and child will 
be forwarded to the sponsor.  Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date.  Any termination of the pregnancy 
will be reported including fetal status (presence or absence of anomalies) and
indication for the procedure. 
Female Participants who become pregnant
●
The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 
24 hours of learning of a participant's pregnancy. 
●
The participant will be followed to determine the outcome of the pregnancy.  The 
investigator will collect follow-up information on the participant and the neonate 
and the information will be forwarded to the sponsor.  Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date.  
Any termination of pregnancy will be reported, including fetal status (presence or 
absence of anomalies) or indication for the procedure.
●
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
●
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at >20 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 
●
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4.  While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
95
●
Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention.  If the participant is discontinued from the 
study intervention, follow the standard discontinuation process and continue 
directly to the follow-up phase.  






CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
98
10.6.
Appendix 6:  Protocol JVDU 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).  Participants 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.  Participants may receive other supportive therapy or vaccinations that the 
investigator deems to be medically necessary.




CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
100
10.7.
Appendix 7:  Abbreviations
Term
Definition
2L
Second line
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
AFP
alpha-fetoprotein
AIDS
acquired immunodeficiency syndrome
ALK
anaplastic large-cell lymphoma kinase
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
AUC
area under the plasma concentration versus time curve
BP
blood pressure
BSC
best supportive care
CHF
congestive heart failure
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CMV
cytomegalovirus
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, GCP, and applicable regulatory requirements.
CONSORT
Consolidated Standards of Reporting Trials
CRC
colorectal cancer
CRF
case report form


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
101
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
Cmax
maximum blood plasma concentration
CK
creatine kinase
CT
computed tomography
CTA
Clinical Trial Agreement
CTCAE
common terminology criteria for adverse events
Ctrough
lowest concentration of a drug just before the next dose
CV
Pharmacokinetic variability
D. Bil
direct bilirubin
DMC
data monitoring committee
DSMT
Developmental Safety Management Team
DSST
Developmental Safety Surveillance Team
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Score
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
enroll
The act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ER
exposure-response
ERCP
endoscopic retrograde cholangiopancreatography
Erk1/Erk2
extracellular signal-regulated protein kinases 1 and 2
FDA
Food and Drug Administration


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
102
FOLFIRI
fluorouracil and irinotecan
FSH
follicle-stimulating hormone
GCP
good clinical practice
G-CSF
granulocyte-colony stimulating factor
GEJ
gastroesophageal junction
GGT
gamma-glutamyltransferase
GI
gastrointestinal
GPS
Global Patient Safety
HCC
hepatocellular carcinoma
HDV
hepatitis D virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HSR
hypersensitivity reaction
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
Informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate.  Informed consent is 
documented by means of a written, signed and dated informed consent form.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
Institutional Review Board
ISP
injection site pain


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
103
ISR
injection site reaction
IV
intravenous
IWRS
interactive web-response system
LD
Loading dose
mAbs
monoclonal antibodies
MD
maintenance dose
MRI
magnetic resonance imaging
MRCP
magnetic resonance cholangiopancreatography
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
NSAID
nonsteroidal anti-inflammatory drug
ORR
overall response rate
OS
overall survival
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PD-1
programmed cell death-1
PET
positron emission tomography
PET-CT
positron emission tomography-CT
PFS
progression-free survival
PK
pharmacokinetic
PO
orally
PRD
projected registration dose
PRES
posterior reversible encephalopathy syndrome
PT
prothrombin time
QW
every week
Q2W
every 2 weeks
Q3W
every 3 weeks
QTcF
QT interval corrected using Fridericia’s formula


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
104
QW
every week
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SoA
Schedule of Activities
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin level
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TE ADA
treatment-emergent anti-drug antibody
TKI
tyrosine kinase inhibitor
UADE
unanticipated adverse device effect
ULN
upper limit of normal
VAS
visual analogue scale
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event
WOCBP
woman of childbearing potential


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
105
10.8.
Appendix 8:  Protocol Amendment History
Amendment d: 14-Jan-2021
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
The overall rationale for the amendment is to make changes based on preliminary data from 
Study JVDT, to remove hepatocellular carcinoma (HCC) and gastric cancer patients from 
inclusion in Cohort A and add to Cohorts B and C, and to correct an error in the contraceptive 
language.
Section # and Name
Description of Change
Brief Rationale
4.1. Overall Design
Introduced Study JVDT earlier in protocol.
Administrative change.
4.3.1. Rationale for Initial
Cohort A Dose Selection
Expanded number or participants from n = 3 
to n = 3 to 6.
Clarification of sample 
size for Cohort A.
5.1. Inclusion Criteria
Inclusion criterion 3:  Removed HCC and 
gastric cancer patients from inclusion in 
Cohort A and added to inclusion in 
Cohorts B and C.
Inclusion criterion 9:  Revised “Male 
participants are eligible to participate if they 
agree to the following during the 
intervention period and for at least the 
duration of the study or for 5 months 
following completion of study drug 
administration, whichever is longer:” to 
“ …for at least 84 days/12 weeks following 
completion of study drug administration:”
Ensure HCC and 
gastric cancer patients 
do not get sub-optimal 
dose on starting Cohort
A.
Correction of duration 
language for male 
participants related to 
contraceptive use, 
sperm donation, and 
sexual abstinence.
6.1.1 Treatment 
Requirements for Each 
Treatment Visit and 
Treatment Delays
Corrected start of each new cycle to ±3 days
Clarification
8.2.5. Injection Site 
Reactions
Added language to explain how injection site 
reactions will be assessed.
Clarification.
9.2.1. Cohort A
Added language to be able to expand sample 
size from 3 to up to 6 in Cohort A based on 
safety findings from Study JVDT.
Clarification of sample 
size for Cohort A.
10.6. Appendix 6:  Protocol 
JVDU Restricted and 
Prohibited Concomitant 
Therapy
Cytochrome P450 metabolizers allowed as 
needed or chronic use with exceptions.
Clarification related to 
use of concomitant 
therapy.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
106
Amendment c: 05-Nov-2020
Overall Rationale for the Amendment:
The overall rationale for the amendment is to incorporate updates for hepatic safety and to allow 
participants to adjust their weekly maintenance dose to the maintenance dose of Cohort C once 
the dose has been confirmed.
Section # and Name
Description of Change
Brief Rationale
4.1.1 Cohort A; 4.1.2 Cohort 
B
Allowance for participants to adjust weekly 
maintenance dose to the maintenance dose 
for Cohort C once the dose has been 
confirmed
Administrative
6.1.1 Treatment 
Requirements for Each 
Treatment Visit and Visit 
Delays; 8.2.4 Hepatic Safety 
Monitoring; Appendix 5: 
Liver Safety: Suggested 
Actions and Follow-up 
Assessments
Updated criteria for administering 
ramucirumab SC; added GLDH test for 
potential future analyses of biomarkers of 
drug-induced liver injury
Alignment with 
updated hepatic safety 
guidance
Amendment b: 02-Oct-2020
Overall Rationale for the Amendment:
The overall rationale for the amendment is to incorporate changes and provide additional 
clarifications according to regulatory agency interactions.
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities; 
2.3.1 Risk Assessment; 6.1 
Study Intervention(s) 
Administered; 6.5.1 
Palliative Medicine and 
Supportive Care
Removed premedication with antihistamines
Regulatory agency 
interaction
1.3 Schedule of 
Activities
Added coagulation collection on C2D1 and 
every other cycle afterwards
Regulatory agency 
interaction
1.3 Schedule of 
Activities; 7.1 
Discontinuation of 
Study Intervention
Clarified that short-term follow-up lasts a 
minimum of 30 days following the last dose 
of study drug
Clarification
Throughout
Minor editorial and document
formatting revisions.
These are minor 
changes; therefore, 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
107
Section # and Name
Description of Change
Brief Rationale
they have not been 
summarized.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
108
Amendment a: 14-Sep-2020
Overall Rationale for the Amendment:
The overall rationale for the amendment is to provide clarifications in the protocol related to 
schedule of activities, administration of the investigational product namely subcutaneous (SC)
ramucirumab and chemotherapy (FOLFIRI) as discussed below. There are no changes in the 
study-design, inclusion/exclusion criteria, or statistical analysis that would impact participant
safety and overall objectives of the study.
Section # and 
Name
Description of Change
Brief Rationale
1.3 Schedule 
of Activities
Changed D21 to D22 for C2 and 
C3-n.
Minor clarification.
1.3 Schedule 
of Activities
Clarified vital sign measurements 
will be obtained prior to the 
ramucirumab dose.
Minor clarification.
1.3 Schedule 
of Activities
Clarified no Pain VAS is 
required in the case of a positive 
response to pain question during 
spontaneous assessment of ISRs 
between scheduled visits.
Minor clarification.
Throughout
Updated RELAY approval 
throughout the protocol. 
Minor clarification. 
4.3.1 Rationale 
for Initial 
Cohort A Dose 
Selection
Clarified use of a syringe pump 
will not be used for Cohort A.
Minor clarification. 
4.3.2 Rationale 
for Initial 
Cohort B Dose 
Selection; 6.1 
Study 
Intervention(s) 
Administered
Clarified SC loading dose will be 
administered using a syringe 
pump.
Minor clarification.
6.1 Study 
Intervention(s) 
Administered
Clarified timing of premedication 
for combination therapy.
Minor clarification. 
6.1 Study 
Intervention(s) 
Administered
Added infusion rate for SC 
administration using a syringe 
pump.
Clarification.
6.1.1 
Treatment 
Requirements 
Changed ramucirumab SC with 
FOLFIRI timing from 28 to 
Rectifying error.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
109
Section # and 
Name
Description of Change
Brief Rationale
for Each 
Treatment 
Visit and 
Treatment 
Delays
14 days from the last 
administration of FOLFIRI. 
6.6 Dose 
Modification
Clarified an alternate 
administration of loading dose if 
an injection site reaction occurs.
Minor clarification.
Throughout
Minor editorial and document
formatting revisions.
These are minor changes;
therefore, they have not been
summarized.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
110
11.
References
Anderson KC, Landgren O, Arend RC, Chou J, Jacobs IA. Humanistic and economic impact of 
subcutaneous versus intravenous administration of oncology biologics. Future Oncol. 
2019;15(28):3267-3281.
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.
Bohlius J, Bohlke K, Castelli R, Djulbegovic B, Lustberg MB, Martino M, Mountzios G, 
Peswani N, Porter L, Tanaka TN, Trifirò G, Yang H, Lazo-Langner A. Management of cancer-
associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline 
update. J Clin Oncol. 2019;37(15):1336-1351. 
Chen HX, Cleck JC. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev 
Clin Oncol. 2009;6(8):465-477.
Dent S, Ammendolea C, Christofides A, Edwards S, Incekol D, Pourmirza B, Kfoury S, Poirier 
B. A multidisciplinary perspective on the subcutaneous administration of trastuzumab in HER2-
positive breast cancer. Curr Oncol. 2019;26(1):e70-e80.
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.
[FDA] US Food and Drug Administration. 2003. Guidance for Industry: Exposure-response 
relationships – study design, data analysis, and regulatory activities.  Available at:  
https://www.fda.gov/media/71277/download. Accessed on March 10, 2020.
Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol.
2017;264(8):1608-1616.
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, multicentre, 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. Erratum in: Lancet Neurol. 2015;14(9):847.
Goldman J, Rutkowski JM, Shields JD, Pasquier MC, Cui Y, Schmökel HG, Willey S, 
Hicklin DJ, Pytowski B, Swartz MA. Cooperative and redundant roles of VEGFR-2 and 
VEGFR-3 signaling in adult lymphangiogenesis. FASEB J. 2007;21(4):1003-1012. Erratum in: 
FASEB J. 2007;21(8):1942.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
111
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.
Jimenez X, Lu D, Brennan L, Persaud K, Liu M, Miao H, Witte L, Zhu Z. A recombinant, fully 
human, bispecific antibody neutralizes the biological activities mediated by both vascular 
endothelial growth factor receptors 2 and 3. Mol Cancer Ther. 2005;4(3):427-434.
Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J 
Cancer. 2007;96(12):1788-1795.
Lee VH, Wijdicks EFM, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior 
leukoencephalopathy syndrome. Arch Neurol. 2008;65(2):205-210.
Lu D, Shen J, Vil MD, Zhang H, Jimenez X, Bohlen P, Witte L, Zhu Z. Tailoring in vitro 
selection for a picomolar affinity human antibody directed against vascular endothelial growth 
factor receptor 2 for enhanced neutralizing activity. J Biol Chem. 2003;278(44):43496-43507.
Miao HQ, Hu K, Jimenez X, Navarro E, Zhang H, Lu D, Ludwig DL, Balderes P, Zhu Z. Potent 
neutralization of VEGF biological activities with a fully human antibody Fab fragment directed 
against VEGF receptor 2. Biochem Biophys Res Commun. 2006;345(1):438-445.
Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello 
S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, 
Frimodt-Moller B, Visseren-Grul C, Reck M; RELAY Study Investigators. Ramucirumab plus 
erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer 
(RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 
2019;20(12):1655-1669.
[NCI] National Cancer Institute. Common terminology criteria for adverse events (CTCAE) 
v5.0. Published January 5, 2018. Accessed October 07, 2019.
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
[NCI] National Cancer Institute. Common terminology criteria for adverse events (CTCAE) 
v4.03. Published June 14, 2010. Accessed February 10, 2021.
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:(6):649-655.
Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain 
SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, 
Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov 
A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, 
Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, 
Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, 
Powles T, RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus 
docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-
based therapy (RANGE): overall survival and updated results of a randomised, double-blind, 
phase 3 trial. Lancet Oncol. 2020;21(1):105-120. 


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
112
Reck M, Paz-Ares L, Bidoli P, Cappuzzo F, Dakhil S, Moro-Sibilot D, Borghaei H, Johnson M, 
Jotte R, Pennell NA, Shepherd FA, Tsao A, Thomas M, Carter GC, Chan-Diehl F, Alexandris E, 
Lee P, Zimmermann A, Sashegyi A, Pérol M. Outcomes in patients with aggressive or refractory 
disease from REVEL: A randomized phase III study of docetaxel with ramucirumab or placebo 
for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer. 2017;112:181-
187.
Rummel M, Kim TM, Aversa F, Brugger W, Capochiani E, Plenteda C, Re F, Trask P, Osborne 
S, Smith R, Grigg A. Preference for subcutaneous or intravenous administration of rituximab 
among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: 
results from a prospective, randomized, open-label, crossover study (PrefMab). Ann Oncol. 
2017;28(4):836-842.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Carwford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO; 
American Society of Clinical Oncology. Recommendations for the use of WBC growth factors: 
American Society of Clinical Oncology Clinical Practice guideline update. J Clin Oncol.
2015;33(28):3199-3122.
Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a 
misnomer reviewed. Intern Med J. 2005;35(2):83-90.
Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J. 
2013;34(15):1102-1111.
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. Erratum in: Lancet Oncol. 
2015;16(6):e262.
Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil 
LJ, Rajotte M, Rolston KV, Strasfeld L, Flowers CR. Antimicrobial prophylaxis for adult 
patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline 
update. J Clin Oncol. 2018;36(30):3043-3054.
Tvorogov D, Anisimov A, Zheng W, Leppänen VM, Tammela T, Laurinavicius S, 
Holnthoner W, Helotera H, Holopainen T, Jeltsch M, Kalkkinen N, Lankinen H, Ojala PM, 
Alitalo K. Effective suppression of vascular network formation by combination of antibodies 
blocking VEGFR ligand binding and receptor dimerization. Cancer Cell. 2010;18(6):630-640.
Viola M, Sequeira J, Seiça R, Francisco Veiga, João Serra, Ana C Santos, António J Ribeiro.  
Subcutaneous delivery of monoclonal antibodies: how do we get there? J Control Release. 
2018;286:301-314.
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs. 2005 ;14(7):798-804.


CONFIDENTIAL
Protocol I4T-MC-JVDU(e)
113
Wilke H, Muro K, Van Cutsem E, et al; 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):1224-35.
Zhu Z, Hattori K, Zhang H, et al. Inhibition of human leukemia in an animal model with human 
antibodies directed against vascular endothelial growth factor receptor 2. Correlation between 
antibody affinity and biological activity. Leukemia. 2003;17(3):604-611.
Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim 
HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart 
JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators. 
Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased 
α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 
3 trial. Lancet Oncol. 2019;20(2):282-296.


Leo Document ID = 31288c0a-fa3e-4ab9-b60f-1bc1f6101e72
Approver: 
Approval Date & Time: 26-Feb-2021 14:19:35 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 26-Feb-2021 14:24:35 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
I4T-MC-JVDU Statistical Analysis Plan Version 2 
 
 
A Phase 1, Nonrandomized, Open-Label Investigation of Subcutaneous Ramucirumab 
Administration in Participants with Advanced Solid Tumors 
 
NCT04557384  
 
Approval Date: 2-Jun-2021 
 
 
 


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 1
LY3009806
1.
Statistical Analysis Plan: 
I4T-MC-JVDU: A Phase 1, Nonrandomized, Open-Label 
Investigation of Subcutaneous Ramucirumab 
Administration in Participants with Advanced Solid 
Tumors
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Subcutaneous Ramucirumab (LY3009806)
Phase 1, nonrandomized, open-label study of subcutaneous ramucirumab administration in 
participants with advanced solid tumors.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4T-MC-JVDU
Phase 1
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:
02-September-2020
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 02-Jun-2021 GMT


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 2
LY3009806
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  I4T-MC-JVDU: A Phase 1, 
Nonrandomized, Open-Label Investigation of Subcutaneous 
Ramucirumab Administration in Participants with Advanced Solid 
Tumors ...............................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Exploratory Objectives...................................................................................................6
5.
Study Design.......................................................................................................................7
5.1.
Summary of Study Design..............................................................................................7
5.2.
Determination of Sample Size ........................................................................................7
5.2.1.
Cohort A................................................................................................................7
5.2.2.
Cohort B (Sub-Cohorts B1, B2, and B3).................................................................7
5.2.3.
Cohort C ................................................................................................................8
5.3.
Method of Assignment to Treatment ..............................................................................8
5.3.1.
Cohort A Dose Selection........................................................................................8
5.3.2.
Cohort B (Sub-Cohorts B1, B2, and B3) Dose Selection ........................................8
5.3.3.
Cohort C Dose Selection ......................................................................................10
6.
A Priori Statistical Methods ..............................................................................................11
6.1.
General Considerations ................................................................................................11
6.2.
Handling of Dropouts or Missing Data.........................................................................11
6.3.
Participant Disposition .................................................................................................12
6.4.
Participant Characteristics ............................................................................................12
6.5.
Treatment Compliance .................................................................................................13
6.6.
Concomitant Therapy...................................................................................................13
6.7.
Efficacy Analyses ........................................................................................................13
6.8.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................13
6.8.1.
Pharmacokinetic Analyses....................................................................................14
6.8.2.
Immunogenicity Analyses....................................................................................14
6.9.
Safety Analyses............................................................................................................14
6.9.1.
Extent of Exposure...............................................................................................14
6.9.2.
Adverse Events ....................................................................................................15


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 3
LY3009806
6.9.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................16
6.9.4.
Clinical Laboratory Evaluation.............................................................................17
6.9.5.
Vital Signs and Other Physical Findings...............................................................17
6.9.6.
Electrocardiograms ..............................................................................................17
6.10. Protocol Violations.......................................................................................................17
6.11. Interim Analyses and Data Monitoring.........................................................................17
6.12. Planned Exploratory Analyses......................................................................................17
6.13. Annual Report Analyses...............................................................................................18
6.14. Clinical Trial Registry Analyses...................................................................................18


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 4
LY3009806
Table of Contents
Table
Page
Table 5.1.
Initial Dose Level Options for Cohort B ..........................................................9
Table 5.2.
Dose Options for Cohort B ..............................................................................9


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 5
LY3009806
3.
Revision History
Statistical analysis plan (SAP) Version 1 was approved prior to the first visit when a subject 
receives study drug.
Statistical analysis plan Version 2 was approved after the internal review of Cohort A. Sample 
size in Cohort B was changed to reflect the safety and PK information collected from Cohort A.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 6
LY3009806
4.
Study Objectives
4.1.
Primary Objective
The primary objective of the study is to determine a recommended ramucirumab subcutaneous 
(SC) dosing regimen for future studies by assessing the pharmacokinetic (PK) parameters and 
safety of ramucirumab after SC administration.
4.2.
Secondary Objectives
The secondary objectives are as follows:

to assess the immunogenicity of ramucirumab after SC administration

to assess injection site reactions (ISRs) following SC administration of ramucirumab 
using ISR questionnaire.
4.3.
Exploratory Objectives
The exploratory objective of the study is to explore the antitumor activity of ramucirumab 
following SC administration.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 7
LY3009806
5.
Study Design 
5.1.
Summary of Study Design
The study comprises 3 sequential dose cohorts: Cohorts A, B, and C. Participants with 
refractory/relapsed solid tumors with evaluable disease and who have exhausted all treatments 
with proven clinical benefit, as well as participants with a diagnosis where ramucirumab is 
clinically acceptable treatment as a monotherapy (all cohorts) or in combination with additional 
anti-cancer therapy (Cohorts B and C only), are eligible for Study I4T-MC-JVDU (JVDU). Each 
treatment cycle is either 21 days or 28 days based on the treatment regimen, with SC 
ramucirumab administered weekly for 3 doses or 4 doses, respectively, within each cycle. 
Participants in Cohorts B and C who are planned to receive ramucirumab in combination with 
additional anti-cancer therapy will receive weekly SC ramucirumab as monotherapy for at least 
3 weeks for safety assessment, prior to initiation of the combination agent.  
5.2.
Determination of Sample Size
A maximum of approximately 30 participants will be treated in this study.
5.2.1.
Cohort A
Three participants will be enrolled in Cohort A and followed for a minimum of 3 weeks prior to 
opening enrollment to Cohort B. If new or unexpected safety findings are identified relative to
the large database of intravenous (IV) ramucirumab, or if 1 or more participants do not have 
sufficient PK data to inform dose for Cohort B, up to an additional 3 participants may be enrolled 
into Cohort A.
5.2.2.
Cohort B (Sub-Cohorts B1, B2, and B3)
The internal review committee will review the totality of available safety data from Cohort A 
and Study I4T-MC-JVDT (JVDT), and based on this, will make a recommendation to open 
enrollment to Sub-Cohort B1.
Sub-Cohort B1 will initially recruit 3 participants to receive the maintenance weekly regimen,
and based on the review of the first 3 weeks of safety and PK data, the following may be 
decided:

to enroll up to 3 additional participants in Sub-Cohort B1, if new or unexpected safety 
findings are identified relative to the large database of IV ramucirumab at an alternate 
dose

to enroll up to 3 additional participants in Sub-Cohort B1, if 1 or more participants in 
Cohort B1 do not have a sufficient PK data to inform dose for Cohort B2, or 

to open Sub-Cohort B2 at the determined loading and maintenance dosing regimen based 
on the available data. 
Sub-Cohort B2 will recruit a minimum of 3 participants but will not exceed 6 participants. The 
number of participants in Sub-Cohort B2 will depend on the dosing decisions made at the data 
reviews after the first 3 and 6 participants have completed 3 weeks of treatment in 


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 8
LY3009806
Sub-Cohort B2. If either analysis reveals that the Sub-Cohort B2 dosing regimen is not optimal, 
then the optional Sub-Cohort B3 (N=6) may be opened to investigate an alternative dose, if 
deemed appropriate.
Overall, the maximum number of participants in Cohort B is approximately 18.
5.2.3.
Cohort C
Cohort C will initiate recruitment of 6 participants once 3 weeks of dosing safety data from 
Cohort B (in at least 6 participants) and initial PK data support pursuing further enrollment at the 
same dosing regimen. The study population will be the same as Cohort B. The dose regimen for 
Cohort C is anticipated to be the same as the preceding 6 participants in Cohort B. This expanded 
number of participants will provide additional PK and safety data to inform potential further 
development of SC ramucirumab.
5.3.
Method of Assignment to Treatment
5.3.1.
Cohort A Dose Selection
The ramucirumab SC dose for the initial Cohort A (n=3 to 6 participants) has been chosen with 
the intent to match the steady-state area under the plasma concentration versus time curve (AUC)
of the 8-mg/kg every 2 weeks IV regimen, assuming a bioavailability of 80%. The initial 
ramucirumab SC loading dose will be 700 mg followed by a weekly ramucirumab SC injection 
maintenance dose of 350 mg.
5.3.2.
Cohort B (Sub-Cohorts B1, B2, and B3) Dose Selection
Cohort B dose selection is intended to deliver a trough concentration (Ctrough) >50 µg/mL and a 
steady-state AUC similar to the approved IV ramucirumab dose regimen of 10 mg/kg every 
2 weeks. This will be accomplished by investigating a loading dose and maintenance dose 
paradigm, which will deliver target Ctrough and steady-state concentration rapidly.
Table 5.1 below indicates the anticipated ramucirumab SC dosing regimen for Cohort B, as a 
function of estimated bioavailability.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 9
LY3009806
Table 5.1.
Initial Dose Level Options for Cohort B
Bioavailability
(Mean F)
AUC at steady state eq to (Q2W IV)
SC LD one dose (mg)a
SC MD (mg)
QW
40% to 50%
10 mg/kg
1750
875
50% to 65%
10 mg/kg
1400
700
65% to 80%
10 mg/kg
1120
560
80% to 100%
10 mg/kg
880
440
Abbreviations: AUC = area under the plasma concentration versus time curve; eq = equivalent; F = bioavailability; 
IV = intravenous; LD = loading dose; MD = maintenance dose; SC = subcutaneous; Q2W = every 2 weeks; 
QW = every week.
a
In Sub-Cohort B1, no loading dose will be given.
Interim data from Study JVDT indicates a bioavailability of 40% and peak concentration 
occurring at 4 days postadministration for SC ramucirumab. With a bioavailability of 40%, a 
starting regimen of ramucirumab SC loading dose (LD) of 1750 mg and maintenance dose (MD)
of 875 mg in Cohort B is proposed. The proposed maximum ramucirumab SC LD of 1750 mg 
will deliver exposure equivalent to 10 mg/kg/week and 13 mg/kg/week for participants with 
body weights of 70 kg and 55 kg, respectively. Assuming the same bioavailability, the proposed 
maximum ramucirumab SC MD of 875 mg will deliver exposure equivalent to 5 mg/kg/week 
and 6 mg/kg/week for participants with body weights of 70 kg and 55 kg, respectively. 
Consequently, the exposure achieved following both proposed LD and MD will be lower than 
the highest investigated ramucirumab IV doses of 20 mg/kg every 3 weeks IV 
(Study I4T-IE-JVBN [IMCL CP12-0402]) as well as the maximum tolerated dose exposure of 
13 mg/kg once weekly IV (as determined in Study I4T-IE-JVBM [IMCL CP12-0401]).
The combined PK and safety data from Cohort A and Sub-Cohort B1 will inform the starting 
dose selection for Sub-Cohort B2 (maximum planned dose ramucirumab SC LD of 1750 mg 
followed by 875 mg SC MD once weekly). Table 5.2 shows the proposed dosing regimen for 
each sub-cohort as well as possible alternate dose decisions that could be made based on either 
bioavailability and/or safety as described in Section 5.2.
Table 5.2.
Dose Options for Cohort B
Sub-
Cohort
Proposed LDa
Proposed MDb 
Possible Dose Decision Based on Either 
Bioavailability and/or Safety
B1
Not Applicable
875 mg SC QW
e.g., MD 700 mg SC QW
e.g., MD 560 mg SC QW 
e.g., MD 440 mg SC QW
B2c
1750 mg SC infusion
875 mg SC QW
e.g., LD 1400 mg SC; MD 700 mg SC QW
e.g., LD 1120 mg SC; MD 560 mg SC QW
e.g., LD 880 mg SC; MD 440 mg SC QW
B3c
(Optional)
<1750 mg SC infusion
<875 mg SC QW
e.g., LD 1400 mg SC; MD 700 mg SC QW
e.g., LD 1120 mg SC; MD 560 mg SC QW
e.g., LD 880 mg SC; MD 440 mg SC QW


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 10
LY3009806
Dose Options for Cohort B
Abbreviations: LD = loading dose; MD = maintenance dose; PK = pharmacokinetic; QW = every week; 
SC = subcutaneous.
a
LD: During Week 1 administered as 1 dose on Day 1.
b MD: Weekly dosing starting on Week 2 (Cycle 1 Day 8) except for B1 when it will be starting on Week 1 
(Cycle 1 Day 1).
c
Only 1 dosing regimen (1 LD - MD level) will be investigated in Sub-Cohort B2 and Sub-Cohort B3. Dose will 
be selected based on PK and safety data as described in Section 5.2.
5.3.3.
Cohort C Dose Selection 
Cohort C will evaluate, in 6 participants, the dose regimen identified in Cohort B which answers 
the safety and PK objective of the study. Cohort C may open if 3-week dosing safety data from 
Cohort B (in at least 6 participants) and initial PK data support pursuing enrollment at the same 
dosing regimen.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 11
LY3009806
6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of sponsor or its designee. The study 
PK scientist will be responsible for designing, conducting, and interpreting the PK analysis and 
delivering PK parameters. The interpretation of final study results will be the responsibility of 
the clinical research physician (CRP), the study statistician, and PK scientist. The primary 
analysis will happen after all participants complete the PK and safety assessment at Week 3 or 
discontinue treatment prior to completing Week 3.
This is not a controlled study and statistical tests of clinical outcomes are not feasible. 
Summaries will be limited to summary statistics. Unless otherwise stated, any confidence 
intervals (CIs) will be given at a 2-sided 95% level. Exploratory statistical analysis procedures 
not specified in the present document will be executed if deemed appropriate. 
The following general terms will be used globally in the SAP:

Unless otherwise specified, summary statistics stand for the number of participants with 
an observation (n), mean, standard deviation, median, minimum, and maximum for 
continuous variables; and population size (N), the number of subjects with events (n) and 
the proportion of subjects with events (p=n/N) for categorical variables.

Entered population will consist of all participants who sign the informed consent form.

Enrolled/Intent-to-Treat population will consist of all participants who receive at least 
1 dose of study drug.

Efficacy population will consist of all participants with evaluable disease per their 
baseline assessment and at least 1 complete postbaseline assessment.

Safety population will consist of all participants who take at least 1 dose of study drug.
The safety population will be used for all analyses of dosing, exposure, and safety.

Pharmacokinetic analysis population will consist of all treated participants who receive 
at least 1 dose of study drug and have at least 1 evaluable PK sample.
6.2.
Handling of Dropouts or Missing Data
For patient data listings, observed data will be used and missing data will not be imputed.
General rules for imputing dates related to adverse events (AEs) or concomitant therapy:

Onset date of an AE or start date of a concomitant therapy:
o
If only the day is missing, the date will be set to:

First day of the month that the event occurred, if the onset yyyy-mm is 
after the yyyy-mm of first study treatment.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 12
LY3009806

The day of the first study treatment, if the onset yyyy-mm is the same 
as yyyy-mm of first study treatment.
o
If both the day and month are missing, the complete date will be set to:

January 1 of the year of onset, if the onset year is after the year of the 
first study treatment.

The date of the first dose, if the onset year is the same as the year of 
the first study treatment.

Resolution date of an AE or end date of a concomitant therapy:

If only the day is missing, the date will be set to the last day of the month of the 
occurrence, or to the date of death of the patient died in the same month.

If both the day and month are missing, the date will be set to December 31 of the year 
of occurrence, or to the date of death of the patient died in the same year.
If a date is completely missing, then the AE will be considered as treatment emergent. In case of 
additional therapies, the therapy will be considered concomitant.
General rule for imputing other dates: If a date variable is needed for an analysis, use the 
following general rule to impute incomplete date:

If the day of a date is missing, but not the month or year, then assign Day 1 of the month 
to the day.

If the month of a date is missing, but not the day or the year, then assign January to the 
month.
After imputation, the imputed date should be logically consistent with other relevant date 
variable(s). 
6.3.
Participant Disposition
All patient discontinuation data will be listed, including the extent of the patient participation in 
the study. If known, a reason for their discontinuation from treatment and from study will be 
listed and summarized overall and by dose level (if appropriate). All participants entered in the 
study will be included in the summary and listing.
6.4.
Participant Characteristics
The following patient demographic and other baseline characteristics will be summarized overall 
and by dose level (if appropriate):

patient demographics: age (years), gender, race, ethnicity, weight (kg), height (cm), 
Eastern Cooperation Oncology Group Performance Status (ECOG PS), alcohol use and 
tobacco use

baseline disease characteristics: pathological diagnosis type at initial diagnosis, duration 
of disease (months), disease stage and histopathological diagnosis grade at study entry


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 13
LY3009806

prior cancer therapies

historical illness by Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term (PT), including infusion-related reaction (IRR) and hypersensitivity, presented in 
decreasing frequency
Patient listings of demographic data and baseline characteristics will be provided. Patient listings 
of prior cancer therapies (surgery, radiotherapy, and systemic therapy) will be provided.
6.5.
Treatment Compliance
Ramucirumab SC and other intravenously administered study drugs will be administered at the 
investigational sites. As a result, patient compliance is ensured.
The number of tablets taken relative to the number expected to be taken may be summarized for 
other study drugs such as erlotinib, if appropriate.
6.6.
Concomitant Therapy
The following concomitant medications used in study treatment period or the 30-day 
postdiscontinuation follow-up period will be summarized by numbers and percentages overall 
and by dose level (if appropriate), presented in decreasing frequency of the World Health 
Organization (WHO) drug term:

All concomitant medications

Supportive care and select medications including growth factors
Note: such drugs to be used for programming will be identified through reviewing of the 
unique drug terms collected in the study

Premedication for study drug
Patient listing of all concomitant therapies and premedications will be provided.
The number and percentage of participants with blood transfusions experienced in study 
treatment period or the 30-day postdiscontinuation follow-up period will be summarized overall 
and by dose level (if appropriate).
6.7.
Efficacy Analyses
The efficacy of ramucirumab following SC administration is an exploratory objective of the 
study. The planned analyses of efficacy are detailed in Section 6.12.
6.8.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods 
All PK/pharmacodynamic (PD) analysis will be the responsibility of Lilly Global PK/PD and 
Pharmacometrics group based on applicable Global PK/PD and Pharmacometrics Standard 
Operating Procedures and software approved by Global PK/PD and Pharmacometrics group’s 
management.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 14
LY3009806
6.8.1. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on all data from all participants who received at 
least 1 dose of investigational product and have sufficient evaluable PK samples.
Ramucirumab concentration will be summarized by standard summary statistic per dose level 
and collection time point. Additionally, PK data may be added to the large IV ramucirumab PK 
database in cancer participants to estimate, using non-linear mixed-effect modelling, the post-hoc 
individual PK-parameter estimate for Study JVDU participants.
6.8.2. Immunogenicity Analyses
Treatment-emergent antidrug antibody (TE ADA) evaluable: A patient is evaluable for TE ADA 
if there is at least 1 non-missing test result for ramucirumab ADA for each of the baseline period 
and the postbaseline period. All percentages are relative to the total number of subjects evaluable 
for TE ADA in each cohort.
TE ADA positive (+): A patient evaluable for TE ADA is considered to be TE ADA+ if the
subject has at least 1 postbaseline titer that is a 4-fold or greater increase in titer from baseline 
measurement (treatment-boosted). If baseline result is ADA Not Present, then the subject is TE 
ADA+ if there is at least 1 postbaseline result of ADA Present with titer >= 20 (treatment-
induced).
TE ADA inconclusive: A patient evaluable for TE ADA is considered TE ADA Inconclusive if 
20% of the subject’s postbaseline samples, drawn pre-dose, are ADA Inconclusive and all 
remaining postbaseline samples are ADA Not Present.
TE ADA negative (-): A patient evaluable for TE ADA is considered TE ADA- if not TE ADA+ 
and not TE ADA Inconclusive.
The frequency and percentage of participants with preexisting ADAs and with TE ADA to 
ramucirumab will be tabulated. For the TE ADA+ participants, the distribution of maximum 
titers will be described. The frequency of neutralizing antibodies may also be tabulated in TE 
ADA+ participants if assessed.
The relationship between the presence of antibodies to ramucirumab, the PK parameters, and PD
response, including safety and efficacy, to ramucirumab may be assessed.
In the event of a hypersensitivity, ADAs and ramucirumab serum concentrations will be 
tabulated.
6.9.
Safety Analyses
All participants who receive at least 1 dose of study drug will be summarized for exposure and 
safety.
6.9.1. Extent of Exposure
The following exposure-related variables will be reported using summary statistics overall and 
by dose level (if appropriate): 


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 15
LY3009806

Exposure: duration of treatment; number of cycles received; number of participants 
completing ≥1 cycle, ≥2 cycles, …, ≥6 cycles, and mean, standard deviation; number of 
participants with dose adjustments: dose reduction, dose delay, and dose omission;

Reasons for dose adjustments;

Dose intensity: cumulative dose; weekly dose intensity; relative dose intensity; overall 
weekly dose intensity; overall relative dose intensity. 
Details of study drug administration will be included in participants listings.
6.9.2. Adverse Events
The National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0
(NCI-CTCAE v5.0) will serve as the reference document for choosing appropriate terminology 
for, and grading the severity of, all AEs and other symptoms. For AEs without matching 
terminology within the NCI-CTCAE v5.0 criteria, the investigator will be responsible for 
selecting the appropriate system organ class (SOC) and assessing severity grade based on the 
intensity of the event.
Unless otherwise specified, when summarized by PT, AEs will be presented in decreasing 
frequency of PT; when summarized by SOC and PT, AEs will be presented in decreasing 
frequency of PT within SOC; and when summarized by NCI-CTCAE term, AEs will be 
presented in decreasing frequency of NCI-CTCAE term. If more than 1 AE is recorded for a 
patient within any SOC or PT term or NCI-CTCAE term, the patient will only be counted once 
on the most severe grade and the closest relationship to treatment.
Summary will be presented overall and by dose level (if appropriate).
6.9.2.1.
Overall Summary of Adverse Events
A treatment-emergent adverse event (TEAE) is defined as any untoward medical occurrence that 
either occurs or worsens at any time after treatment and that does not necessarily have to have a 
causal relationship with this treatment.
An overall summary of AEs will be provided to summarize the following categories using 
frequency counts and percentages overall and by dose level (if appropriate):

participants with at least 1 TEAE, serious adverse event (SAE), or NCI-CTCAE Grade 
≥3 TEAE

participants with AEs that led to death (on study treatment, within 30 days of 
discontinuation from study treatment) or discontinuation

participants with SAEs that led to discontinuation
The summary will be provided regardless of study drug causality, and repeated for events 
deemed by the investigator to be possibly related to study treatment.  
A participants listing of all AEs will be provided.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 16
LY3009806
6.9.2.2.
Treatment-Emergent Adverse Events
The following summaries of TEAEs will be provided overall and by dose level, if appropriate
(*repeat for events deemed by the investigator to be possibly related to study medication, 
Ъinclude 
consolidated summary):
•
by PT*Ъ
•
CTCAE Grade ≥3 TEAE by PT*Ъ
•
by SOC and by PT*
•
by maximum NCI-CTCAE grade and by PT*Ъ
6.9.2.3.
Injection Site Reactions (ISRs)
In addition to the typical AE analyses, the following analysis of the ISRs, which is of special 
interest in the study, will be provided overall and by dose level, if appropriate:
•
participants with at least 1 ISR
•
ISR details: anatomical location; directionality of the administration; injection site 
erythema; injection site induration; injection site pain; injection site pruritus; injection 
site edema
6.9.3. Deaths, Other Serious Adverse Events, and Other Notable
Adverse Events
Reasons for deaths (study disease, AE [any study drug-related, procedural-related]) will be 
summarized and listed separately for 1) all deaths, 2) deaths on therapy, 3) deaths within 30 days 
of treatment discontinuation, and 4) deaths on therapy or within 30 days of treatment 
discontinuation, 5) deaths after 30 days of treatment discontinuation.
Serious adverse events will be summarized by PT and repeated for events deemed by the 
investigator to be possibly related to study medication, with consolidated summary performed if 
needed. A listing of SAEs will be produced.
In addition, the following analyses will be performed (*repeated for events deemed by the 
investigator to be possibly related to study medication, 
Ъinclude consolidated summary):
•
AEs leading to death by PT
Ъ
•
AEs leading to study treatment discontinuation by PT
Ъ
•
AEs leading to study treatment dose adjustment by PT
Ъ
•
Adverse events of special interest (AESIs) by PT*
•
Listing of AESIs


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 17
LY3009806
6.9.4. Clinical Laboratory Evaluation
The severity of laboratory results will be classified according to CTCAE Version 5.0. The shifts
in CTCAE toxicity grading from baseline to worst grade postbaseline (first dose up to 30 days 
after the last dose of study treatment) will be produced. 
A participant listing of all laboratory data will be provided with a flag for values outside of the 
laboratory normal range as well as investigator site, patient identifier, age, gender, race, weight,
and visit.
6.9.5. Vital Signs and Other Physical Findings
Weight at baseline will be presented using summary statistics. Change from baseline to on-
treatment weight assessments will be presented. For systolic and diastolic blood pressure, shift 
from baseline will be provided. All vital signs including weight, temperature, blood pressure, 
heart rate, and respiratory rate will be listed for all enrolled participants. Hospitalizations during 
study or within 30 days of treatment discontinuation will be summarized and listed.
6.9.6. Electrocardiograms
Listing of ECG data will be provided.
6.10. Protocol Violations
All significant protocol violations will be listed by predetermined categories specified in the 
Trial Issue Management Plan.
6.11. Interim Analyses and Data Monitoring
An internal assessment committee will review the data on a cohort-by-cohort basis during the 
study to identify the dose providing the appropriate PK profile, and to assess whether safety 
findings inconsistent with the IV ramucirumab profile are observed. The investigators and the 
sponsor study team will make the determination regarding dose escalation based upon their 
review of the safety and tolerability data as described in this protocol. Furthermore, access to PK 
data will be planned in the course of the study to inform on dose selection particularly prior and 
during Cohort B (after the initial 3 participants in Cohort B complete 3-week sampling). 
6.12. Planned Exploratory Analyses
The exploratory objective of the study is to explore the efficacy of ramucirumab following SC 
administration, specifically the best overall response. Best overall response is the best response 
recorded from the start of treatment until disease progression, in the order of complete response, 
partial response, stable disease, and progressive disease. Best overall response will be 
summarized for all participants evaluable for efficacy whose disease is assessable by Response 
Evaluation Criteria in Solid Tumours (RECIST) v1.1.
If appropriate, best overall response will be estimated and reported overall and by dose level.


I4T-MC-JVDU Statistical Analysis Plan Version 2
Page 18
LY3009806
6.13. Annual Report Analyses
The following reports are needed for a Development Update Safety Report (DSUR):

estimated cumulative subject exposure

cumulative exposure to investigational drug, by demographic characteristics for ongoing 
unblinded clinical trials and completed clinical trials

exposure information for ongoing clinical trials and clinical trials that completed during 
the reporting period

listing of subjects who died during the DSUR reporting period

discontinuations due to AEs during the DSUR reporting period
6.14. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file. Both 
SAEs and ‘Other’ AEs are summarized: by treatment group, by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious. For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of participants in every treatment group may not be included if a 5% threshold is 
chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures (for example, the clinical 
study report, manuscripts, and so forth). 


Leo Document ID = 24eb869f-1f15-4409-8831-9ccef1b2e03f
Approver: 
Approval Date & Time: 02-Jun-2021 17:30:32 GMT
Signature meaning: Approved
PPD