Conditions: Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma
Keywords: stomach cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 245
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the efficacy of an alternative dose of ramucirumab in combination with paclitaxel in participants with second-line metastatic or locally advanced, unresectable gastric or gastroesophageal junction adenocarcinoma (GEJ).

Detailed description:

Arms:
arm 1: 12 milligram per kilogram (mg/kg) ramucirumab administered intravenously (IV) on day 1 and day 15 (28 day cycles) in combination with 80 milligram per square meter (mg/m²) paclitaxel administered IV on day 1, day 8 and day 15. arm 2: 8 mg/kg ramucirumab administered IV on day 1 and day 15 (28 day cycles) in combination with 80 mg/m² paclitaxel administered IV on day 1, day 8 and day 15.

Interventions: intervention 1: Ramucirumab intervention 2: Paclitaxel
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol document:
Prot_000.pdf: 
Protocol 05 I4T-MC-JVCZ 
 
Randomized Phase 2 Trial Evaluating Alternative Ramucirumab Doses in Combination with 
Paclitaxel in Second-Line Metastatic or Locally Advanced, Unresectable 
Gastric or Gastroesophageal Junction Adenocarcinoma 
 
NCT02514551 
 
Approval Date: 07-May-2015 
 


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Protocol I4T-MC-JVCZ
Randomized Phase 2 Trial Evaluating Alternative
Ramucirumab Doses in Combination with Paclitaxel in 
Second-Line Metastatic or Locally Advanced, Unresectable 
Gastric or Gastroesophageal Junction Adenocarcinoma
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
ramucirumab (LY3009806), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments are subject to United States Freedom of Information Act Exemption 4.
Ramucirumab (LY3009806)
An open-label, randomized Phase 2 study comparing alternative ramucirumab dose in 
combination with paclitaxel in approximately 240 patients with metastatic or locally 
advanced gastric or gastroesophageal junction adenocarcinoma with disease progression 
during or following prior combination chemotherapy.  Treatment will continue until a 
discontinuation criterion is met.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 07-May-2015 GMT


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Table of Contents
Randomized Phase 2 Trial Evaluating Alternative
Ramucirumab Doses in Combination with Paclitaxel in 
Second-Line Metastatic or Locally Advanced, Unresectable 
Gastric or Gastroesophageal Junction Adenocarcinoma
Section
Page
1.
Synopsis .............................................................................................................................9
2.
Introduction ......................................................................................................................12
3.
Objectives and Endpoints..................................................................................................13
4.
Study Design.....................................................................................................................14
4.1.
Overview of Study Design ...........................................................................................14
4.2.
Rationale for Study Design...........................................................................................17
4.3.
Benefit/Risk Assessment..............................................................................................18
4.4.
Study Completion and End of Trial ..............................................................................19
5.
Study Population...............................................................................................................20
5.1.
Inclusion Criteria..........................................................................................................20
5.2.
Exclusion Criteria ........................................................................................................22
5.2.1.
Re-Screening........................................................................................................24
6.
Treatment..........................................................................................................................25
6.1.
Treatments Administered .............................................................................................25
6.1.1.
Selection and Timing of Doses.............................................................................25
6.1.1.1.
Premedication.................................................................................................26
6.1.1.1.1.
Premedication Prior to Administration of 
Ramucirumab ...........................................................................................26
6.1.1.1.2.
Premedication Prior to Administration of Paclitaxel..................................26
6.1.1.2.
Administration of Ramucirumab.....................................................................26
6.1.1.3.
Administration of Paclitaxel ...........................................................................27
6.1.2.
Investigator Responsibilities.................................................................................28
6.2.
Treatment Assignment .................................................................................................29
6.3.
Blinding .......................................................................................................................29
6.4.
Packaging and Labeling ...............................................................................................29
6.5.
Preparation/Handling/Storage.......................................................................................29
6.6.
Dose Modification........................................................................................................29
6.6.1.
Ramucirumab Dose Modifications .......................................................................29
6.6.1.1.
Ramucirumab Dose Modifications for AESIs .................................................30
6.6.1.2.
Ramucirumab Dose Modifications for Non-AESIs .........................................32


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6.6.2.
Paclitaxel Dose Modifications..............................................................................33
6.7.
Treatment Compliance .................................................................................................33
6.8.
Concomitant Therapy...................................................................................................33
6.9.
Treatment After Study Completion (Continued Access Period) ....................................34
7.
Discontinuation Criteria ....................................................................................................35
7.1.
Discontinuation From Study Treatment........................................................................35
7.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................36
7.2.
Discontinuation from the Study....................................................................................37
7.2.1.
Patients Who Are Lost to Follow-Up....................................................................37
8.
Study Assessments and Procedures ...................................................................................38
8.1.
Efficacy........................................................................................................................38
8.1.1.
Efficacy Assessments at Baseline and During Study 
Treatment.............................................................................................................38
8.1.2.
Efficacy Assessments During Postdiscontinuation Follow-
Up........................................................................................................................38
8.1.3.
Efficacy Measures................................................................................................39
8.1.4.
Appropriateness of Measurements........................................................................39
8.2.
Safety...........................................................................................................................39
8.2.1.
Adverse Events ....................................................................................................40
8.2.1.1.
Adverse Events of Special Interest for Ramucirumab......................................42
8.2.1.1.1.
Infusion-Related Reactions .......................................................................42
8.2.1.1.1.1.
Guidelines for Reporting IRRs ............................................................42
8.2.1.1.2.
Hypertension ............................................................................................42
8.2.1.1.3.
Proteinuria ................................................................................................43
8.2.1.1.4.
Thromboembolic Events...........................................................................43
8.2.1.1.4.1.
Arterial Thromboembolic Events ........................................................43
8.2.1.1.4.2.
Venous Thromboembolic Events.........................................................43
8.2.1.1.5.
Bleeding/Hemorrhage...............................................................................43
8.2.1.1.6.
Gastrointestinal Perforation.......................................................................43
8.2.1.1.7.
Reversible Posterior Leukoencephalopathy Syndrome ..............................44
8.2.1.1.8.
Congestive Heart Failure ..........................................................................44
8.2.1.1.9.
Fistula Formation......................................................................................44
8.2.1.1.10.
Surgery and Impaired Wound Healing ......................................................45
8.2.1.1.11.
Liver Failure and Other Significant Liver Injury .......................................45
8.2.1.2.
Serious Adverse Events ..................................................................................45
8.2.1.3.
Suspected Unexpected Serious Adverse Reactions..........................................46
8.2.2.
Other Safety Measures .........................................................................................46
8.2.2.1.
Electrocardiograms.........................................................................................46


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8.2.2.2.
Echocardiogram or Multiple-Gated Acquisition Scan .....................................47
8.2.3.
Safety Monitoring ................................................................................................47
8.3.
Sample Collection and Testing.....................................................................................47
8.3.1.
Samples for Study Qualification and Health Monitoring.......................................48
8.3.2.
Biomarkers...........................................................................................................48
8.3.2.1.
Whole Blood for DNA Collection...................................................................48
8.3.2.2.
Plasma for Biomarkers ...................................................................................49
8.3.3.
Samples for Immunogenicity Research.................................................................49
8.3.4.
Pharmacokinetics .................................................................................................49
9.
Statistical Considerations and Data Analysis.....................................................................50
9.1.
Determination of Sample Size ......................................................................................50
9.2.
General Statistical Considerations ................................................................................51
9.3.
Treatment Group Comparability...................................................................................51
9.3.1.
Patient Disposition...............................................................................................51
9.3.2.
Patient Characteristics..........................................................................................52
9.3.3.
Concomitant Therapy...........................................................................................52
9.3.3.1.
Postdiscontinuation Therapy...........................................................................52
9.3.4.
Treatment Compliance .........................................................................................52
9.4.
Efficacy Analysis .........................................................................................................52
9.4.1.
Progression-Free Survival ....................................................................................52
9.4.2.
Objective Response Rate and Disease Control Rate..............................................53
9.4.3.
Overall Survival...................................................................................................53
9.5.
Safety Analyses............................................................................................................53
9.6.
Pharmacokinetic Analyses............................................................................................54
9.6.1.
Biomarker Analyses.............................................................................................54
9.7.
Other Analysis .............................................................................................................54
9.7.1.
Immunogenicity Analyses....................................................................................54
9.8.
Interim Analyses ..........................................................................................................54
10.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process................................................................................................................56
10.1. Informed Consent.........................................................................................................56
10.2. Ethical Review.............................................................................................................56
10.2.1.
Subgroup Analyses ..............................................................................................56
10.3. Regulatory Considerations ...........................................................................................56
10.4. Investigator Information...............................................................................................57
10.5. Protocol Signatures ......................................................................................................57
10.6. Final Report Signature..................................................................................................57
10.7. Complaint Handling.....................................................................................................57


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10.8. Data Quality Assurance................................................................................................57
10.8.1.
Data Capture System............................................................................................58
10.9. Study and Site Closure .................................................................................................58
10.9.1.
Discontinuation of Study Sites .............................................................................58
10.9.2.
Discontinuation of the Study................................................................................58
11.
References ........................................................................................................................59


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List of Tables
Table
Page
Table JVCZ.1.
Treatment Regimens/Dosing Schedule ...................................................25
Table JVCZ.2.
Criteria to Be Met Prior to Each Ramucirumab Administration ..............27
Table JVCZ.3.
Criteria to Be Met Prior to Paclitaxel Administration
On Day 1 of Each Cycle .........................................................................28
Table JVCZ.4.
Criteria to Be Met Prior to Paclitaxel Administration
On Day 8 and Day 15 of Each Cycle ......................................................28
Table JVCZ.5.
Ramucirumab Dose Reductionsa ............................................................30
Table JVCZ.6.
Dose-Modifications for Ramucirumab Adverse Events of Special 
Interest ...................................................................................................30
Table JVCZ.7.
Criteria for Discontinuation from Study Treatment With 
Ramucirumab and/or Paclitaxel ..............................................................36
Table JVCZ.8.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........40


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List of Figures
Figure
Page
Figure JVCZ.1.
Illustration of study design......................................................................15
Figure JVCZ.2.
Study period and continued access diagram. ...........................................17
Figure JVCZ.3.
Predicted Cmin,ss following different dose regimens. ................................18


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List of Attachments
Attachment
Page
Attachment 1.
Protocol JVCZ Time and Events Table...................................................61
Attachment 2.
Protocol JVCZ Clinical Laboratory Tests ...............................................66
Attachment 3.
Protocol JVCZ Sampling Schedule for Pharmacokinetics, 
Immunogenicity, and Biomarkers ...........................................................67
Attachment 4.
Protocol JVCZ Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................69
Attachment 5.
Protocol JVCZ Dosing Scenarios for Ramucirumab and Paclitaxel.........70
Attachment 6.
Protocol JVCZ ECOG Performance Status .............................................73
Attachment 7.
Protocol JVCZ Creatinine Clearance Formula ........................................74
Attachment 8.
Protocol JVCZ RECIST 1.1....................................................................75
Attachment 9.
Protocol JVCZ Permitted and Prohibited Concomitant Therapy..............81
Attachment 10.
Protocol JVCZ Abbreviations and Definitions ........................................82


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1.
Synopsis
Title of Study:
Randomized Phase 2 Trial Evaluating Alternative Ramucirumab Doses in Combination with Paclitaxel in 
Second-Line Metastatic or Locally Advanced, Unresectable Gastric or Gastroesophageal Junction Adenocarcinoma
Summary of Study Design:
Study I4T-MC-JVCZ is a multicenter, open-label, randomized Phase 2 study comparing alternative ramucirumab 
doses in combination with paclitaxel in patients with metastatic or locally advanced unresectable gastric or 
gastroesophageal junction (GEJ) adenocarcinoma with disease progression during or after prior platinum and/or 
fluoropyrimidine-containing combination chemotherapy.
Objectives/Endpoints:
Objectives
Endpoints
Primary

Evaluate the efficacy of ramucirumab 
12 mg/kg versus placebo, both in 
combination with paclitaxel, in terms of 
PFS

PFS, as determined by investigator assessment per 
RECIST 1.1
Secondary

Evaluate the efficacy of ramucirumab 
12 mg/kg versus ramucirumab 8 mg/kg, 
both in combination with paclitaxel, in 
terms of PFS

PFS, as determined by investigator assessment per 
RECIST 1.1

PK of ramucirumab in combination with 
paclitaxel

Minimum ramucirumab concentration in serum

Safety and tolerability
The safety endpoints evaluated will include but are not limited to 
the following:

TEAEs, AESIs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and physical 
examinations

ORR

ORR

DCR

DCR

Immunogenicity

Blood samples for immunogenicity testing will be collected to 
determine antibody production against ramucirumab.
Exploratory

OS

OS

Assess the relationship between 
biomarkers and clinical outcome

Biomarker research on genetic and circulating factors may be 
assessed from whole blood and plasma samples, unless 
precluded by local regulations.
Abbreviations:  AESIs = adverse events of special interest; DCR = disease control rate; ORR = objective response 
rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAEs = serious adverse events; TEAEs = treatment-emergent adverse 
events.


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Treatment Arms and Duration:
Dose and Schedule (q 28 Days)
Arm
N
Ramucirumab D1 and D15
Paclitaxel D1, D8, and D15
Number of Cycles
1
120
8 mg/kg
80 mg/m2
Treatment will continue until 
a discontinuation criterion is 
met.
2
120
12 mg/kg
80 mg/m2
Abbreviations:  D = day; N = number of randomized patients; q = every.
If, at any time during the study, Lilly determines that the safety profile of ramucirumab 12 mg/kg 
is unacceptable, enrollment in Arms 1 and 2 will be stopped, and 30 additional patients will be 
enrolled in a new treatment arm (Arm 3).  Patients enrolled in Arm 3 will receive ramucirumab 
10 mg/kg on Days 1 and 15 in combination with paclitaxel 80 mg/m2 on Days 1, 8, and 15, every 
28 days.  For ongoing patients receiving ramucirumab 12 mg/kg, dose reduction to ramucirumab 
10 mg/kg is recommended; however, if the patient is receiving ramucirumab without 
unacceptable toxicity, the patient may continue to receive ramucirumab 12 mg/kg at the 
discretion of the investigator.
Analysis:
Efficacy

Median progression-free survival (PFS) with the 95% confidence interval (CI) and PFS 
curves will be provided using the Kaplan-Meier method (Kaplan and Meier 1958).

The objective response rate (ORR) with 95% CI will be summarized for each treatment arm.

Median overall survival (OS) with the 95% CI and OS curves for each treatment arm will be 
provided using the Kaplan-Meier method.
Pharmacokinetics

All concentrations will be summarized by descriptive statistics.  Additional analysis utilizing 
the population pharmacokinetic approach may also be conducted if deemed appropriate.

The relationship between ramucirumab exposure and selected efficacy and safety outcomes 
may be explored.
Safety

Adverse events (AEs) will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class/Preferred Term (PT), classified from verbatim terms.  The 
incidence and percentage of patients with at least one occurrence of a PT will be included in 
the summaries, according to the most severe Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 grade (NCI 2009).  Causality (relationship to study treatment), 
action taken, and outcome will be summarized separately. Duration of AEs will be 
determined and included in the listings.


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
Exposure to study treatment will be summarized for each treatment arm with the following 
variables: number of infusions, number of cycles, duration of therapy, cumulative dose, dose 
intensity, and relative dose intensity.

Laboratory results will be classified according to CTCAE Version 4.0 grade.  The incidence 
of laboratory abnormalities will be summarized.
Immunogenicity

The number and percentage of patients with positive anti-ramucirumab antibodies will be 
summarized. Any relationship with the occurrence of an infusion-related reaction and 
positive anti-ramucirumab antibodies may be explored.


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2.
Introduction
Ramucirumab (Cyramza®), a human immunoglobulin, subclass 1 anti-vascular endothelial 
growth factor (VEGF) Receptor 2 monoclonal antibody, obtained marketing authorization in the 
United States and in the European Union for the treatment of adult patients with advanced gastric 
cancer or gastroesophageal junction (GEJ) adenocarcinoma with disease progression after prior 
platinum and/or fluoropyrimidine chemotherapy.  The approvals were based on the clinical 
efficacy and safety demonstrated in 2 global, randomized, double-blind and placebo-controlled 
Phase 3 studies, RAINBOW (Wilke et al. 2014) and REGARD (Fuchs et al. 2014).  RAINBOW 
evaluated ramucirumab in combination with paclitaxel for advanced gastric or GEJ 
adenocarcinoma after prior chemotherapy; REGARD evaluated ramucirumab as a single agent in 
the same setting.

FDA approval was granted in April 2014 for ramucirumab as a single agent and in 
November 2014 in combination with paclitaxel.

European Commission marketing authorisation was granted in December 2014 for 
ramucirumab in combination with paclitaxel and as monotherapy for adult patients for 
whom treatment in combination with paclitaxel is not appropriate.
In the Phase 1 dose-escalation study, Study I4T-IE-JVBM, weekly doses of ramucirumab 
ranging from 2 to 16 mg/kg were evaluated, and the maximum-tolerated dose was identified as 
13 mg/kg when given once weekly (Spratlin et al. 2010).  The dosing regimen of 8 mg/kg 
administered once every 2 weeks was suggested for evaluation in further trials because clearance 
at this dose seemed to be saturated, and trough levels were >18 µg/mL, the level at which 
activity was seen in mouse xenograft models treated with a ramucirumab surrogate antibody.  
This dosing regimen of ramucirumab 8 mg/kg every 2 weeks was used in REGARD and 
RAINBOW.
Both REGARD and RAINBOW confirmed that the ramucirumab dosing regimen of 8 mg/kg 
administered once every 2 weeks (hereafter referred to as the standard dose regimen) is a 
pharmacologically and clinically effective and safe dose for the treatment of patients with 
advanced gastric cancer and offers a favorable benefit-risk profile for these patients.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

Evaluate the efficacy of ramucirumab 
12 mg/kg versus placebo, both in 
combination with paclitaxel, in terms of 
PFS

PFS, as determined by investigator assessment per 
RECIST 1.1
Secondary

Evaluate the efficacy of ramucirumab 
12 mg/kg versus ramucirumab 8 mg/kg, 
both in combination with paclitaxel, in 
terms of PFS

PFS, as determined by investigator assessment per 
RECIST 1.1

PK of ramucirumab in combination with 
paclitaxel

Minimum ramucirumab concentration in serum

Safety and tolerability
The safety endpoints evaluated will include but are not limited to 
the following:

TEAEs, AESIs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and physical 
examinations

ORR

ORR

DCR

DCR

Immunogenicity

Blood samples for immunogenicity testing will be collected to 
determine antibody production against ramucirumab.
Exploratory

OS

OS

Assess the relationship between 
biomarkers and clinical outcome

Biomarker research on genetic and circulating factors may be 
assessed from whole blood and plasma samples, unless 
precluded by local regulations.
Abbreviations:  AESIs = adverse events of special interest; DCR = disease control rate; ORR = objective response 
rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAEs = serious adverse events; TEAEs = treatment-emergent adverse 
events.


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4.
Study Design
4.1.
Overview of Study Design
Study I4T-MC-JVCZ (JVCZ) is a multicenter, randomized, open-label, parallel trial in patients 
with metastatic or locally advanced gastric cancer or GEJ adenocarcinoma (hereafter referred to 
as gastric cancer) whose disease has progressed during or following prior combination 
chemotherapy.  The study will randomize (1:1) approximately 240 patients to the 2 treatment 
arms (Table JVCZ.1).  Randomization will be stratified by Eastern Cooperative Oncology Group 
(ECOG) performance status (0 versus 1).
The primary objective of the study is to evaluate the efficacy of ramucirumab 12 mg/kg in 
combination with paclitaxel as determined by improvement in progression-free survival (PFS) 
compared with placebo in combination with paclitaxel.  A key secondary objective is to evaluate 
the efficacy of ramucirumab 12 mg/kg versus ramucirumab 8 mg/kg, both in combination with 
paclitaxel, in terms of PFS. In order to perform the network analysis to compare ramucirumab
12 mg/kg versus placebo, additional data on placebo and ramucirumab 8 mg/kg, in combination 
with paclitaxel, from the RAINBOW study will be utilized.
If, at any time during the study, Lilly determines that the safety profile of ramucirumab 12 mg/kg
(Arm 2) is unacceptable, enrollment in Arms 1 and 2 will be stopped, and 30 additional patients 
will be enrolled to a new treatment arm (Arm 3).  For additional details, see Section 6.1.
Figure JVCZ.1 illustrates the study design.


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Abbreviations:  D = day; ECOG PS = Eastern Cooperative Oncology Group performance status; GEJ = gastroesophageal junction; 
iv = intravenous; N = number of randomized patients.
Figure JVCZ.1.
Illustration of study design.
Arm 1 (28-day cycles)
Ramucirumab 8 mg/kg iv
D1, D15
Paclitaxel 80 mg/m2 iv
D1, D8, D15
Arm 2 (28-day cycles)
Ramucirumab 12 mg/kg iv
D1, D15
Paclitaxel 80 mg/m2 iv
D1, D8, D15
Enroll
Patients with 
gastric or GEJ 
adenocarcinoma
Stratify
ECOG PS (0 vs 1)
Randomize
N=240
(1:1)
•
Discontinue enrollment in Arms 1 and 2
•
Enroll 30 patients in Arm 3 to assess safety
Arm 3 (28-day cycles)
Ramucirumab 10 mg/kg iv
D1, D15
Paclitaxel 80 mg/m2 iv
D1, D8, D15
If safety profile of Arm 2 is unacceptable:
Study
Completion
Postdiscontinuation
Follow-Up
Study
Completion
Postdiscontinuation
Follow-Up
If safety profile of Arm 2 is acceptable:


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Terms used to describe the periods during the study are defined below:

Baseline:  begins when the informed consent form (ICF) is signed and ends on the day 
before the first dose of study treatment (or at discontinuation, if no treatment is given).  
Patients must be randomized to treatment within 21 days after signing the ICF, and the 
first treatment will be administered within 7 days after randomization.

Study Period:  includes the Study Treatment Period and Postdiscontinuation Follow-Up.  
The study period does not include the continued access period.
o
Study Treatment Period:  begins on the date of the first dose of study treatment 
(within 7 days after randomization) and ends on the date the patient and the 
investigator agree that the patient will no longer continue study treatment.  The 
date of this agreement is to be reported on the case report form (CRF) as the Date 
of Discontinuation from study treatment.
o
Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.
Short-term follow-up begins the day after the patient and the investigator agree 
that the patient will no longer continue study treatment and lasts until the 
short-term follow-up visit is completed, approximately 30 days (±7 days) after the 
date of discontinuation.
Long-term follow-up begins the day after short-term follow-up is completed and 
continues until the patient's death or overall study completion, whichever is 
earlier.

Continued Access Period:  begins after study completion and ends at the end of trial 
(see Section 4.4).  During the continued access period, patients on study treatment who 
continue to experience clinical benefit and no undue risks may continue to receive study 
treatment until one of the criteria for discontinuation is met.  The continued access period 
includes continued access follow-up.
o
Continued access follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 30 days (±7 days).
Figure JVCZ.2 presents a diagram of the study period and the continued access period.


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Abbreviations:  PFS = progression-free survival; PK =pharmacokinetics.
Figure JVCZ.2.
Study period and continued access diagram.
4.2.
Rationale for Study Design
Study JVCZ is a postmarketing commitment to FDA to determine whether a higher dose of 
ramucirumab, in combination with paclitaxel, provides superior PFS as compared with the 
recommended ramucirumab dose (8 mg/kg) in combination with paclitaxel, in patients with 
previously treated gastric cancer.
This study is designed to evaluate efficacy and safety of a higher ramucirumab dose, 12 mg/kg 
administered on Days 1 and 15, in combination with paclitaxel (80 mg/m2) administered on 
Days 1, 8, and 15, of a 28-day cycle.
The exposure-efficacy analyses from REGARD and RAINBOW indicated an association 
between efficacy and ramucirumab exposure. Although exposure-safety analyses in RAINBOW 
also suggested that increasing exposure of ramucirumab (when given in combination with 
paclitaxel) is associated with increased risk of Grade 3 hypertension, neutropenia, and 
leukopenia, the association of neutropenia with ramucirumab exposure does not appear to 
translate to an increased risk of febrile neutropenia.
2nd interim analysis
of safety and PK
End of 
Trial
Study 
Completion
Study Period
Continued 
Access Period
(Lilly will notify sites when the Continued 
Access Period  begins and ends.)  
Last visit/
scheduled procedure for 
last patient
1st interim analysis
of safety and PK
Patient 
continues 
on Study 
Treatment
Continued 
Access 
Period 
Follow-Up
Patient 
Discontinues 
Study 
Treatment
Study Treatment
Individual patients continue on study treatment until a 
discontinuation criterion is met.
If a discontinuation criterion occurs
Long-term 
follow-up
Short-term 
follow-up 
The patient 
discontinues 
study 
treatment
Final analysis of the 
primary endpoint 
(191 PFS events)


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Additionally, the overall favorable safety profile of ramucirumab and the exposure-efficacy 
relationship observed in REGARD and RAINBOW suggested that there may be an opportunity 
to further improve efficacy while maintaining an acceptable safety profile in this combination 
therapy setting.
Study JVCZ will compare the standard ramucirumab dose (8 mg/kg) and a new, higher
ramucirumab dose (12 mg/kg), both administered on Days 1 and 15, in combination with 
paclitaxel (80 mg/m2) administered on Days 1, 8, and 15, of a 28-day cycle (see Table JVCZ.1) 
in order to examine the potential improvement in efficacy as measured by PFS.
The new ramucirumab dosing regimen (12 mg/kg) is predicted to produce approximately 50% 
higher exposure relative to the 8-mg/kg standard dose based on linear pharmacokinetic (PK)
assumption (Figure JVCZ.3) and therefore is expected to improve PFS. However, it is unknown 
whether doses leading to exposures higher than the standard ramucirumab 8-mg/kg 
every-2-week regimen will have an acceptable toxicity profile.  This study will also evaluate the 
safety and tolerability of the higher ramucirumab dose and assess whether higher ramucirumab 
exposure can still maintain an acceptable toxicity profile when given in combination with 
paclitaxel.
Abbreviations:  Cmin,ss = minimum concentration at steady state; Q = every; W = week.
Box plots depict the 5th, 25th, 50th, 75th, and 95th percentiles calculated from 
1000 simulation iterations.
Figure JVCZ.3.
Predicted Cmin,ss following different dose regimens.
4.3.
Benefit/Risk Assessment
Information about the known and expected benefits, risks, and reasonably anticipated adverse 
events (AEs) of ramucirumab, including in ramucirumab administered in combination with 
paclitaxel, may be found in the Investigator's Brochure (IB).  Information on AEs expected to be 
related to ramucirumab may be found in Section 7 (Development Core Safety Information) of the 
0
50
100
150
200
250
8 mg/kg Q2W
12 mg/kg Q2W
Predicted Minimum Steady-State
Ramucirumab Concentration (µg/mL)


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IB.  Information on serious adverse events (SAEs) expected in the study population independent 
of drug exposure and that will be assessed by Lilly in aggregate, periodically during the course 
of the study, may be found in Section 6 (Effects in Humans) of the IB.
See Section 8.2.1.1 for information about adverse events of special interest (AESIs) for 
ramucirumab.
In countries where ramucirumab is approved, refer to the package insert for more detailed 
information about the known and expected benefits and risks of ramucirumab.
Refer to the paclitaxel package insert for more detailed information about the known and 
expected safety and risks of paclitaxel.
4.4.
Study Completion and End of Trial
Study completion will occur following the final analysis of PFS, as determined by Lilly.  If the 
study is stopped early because of safety concerns, study completion will occur following the 
final analysis of safety.  Investigators will continue to follow the Time and Events Table
(Attachment 1) for all patients until notified by Lilly that study completion has occurred.   If 
Arm 3 is initiated, the study will be considered complete when patients on Arm 3 complete at 
least 3 cycles of therapy or discontinue treatment, whichever comes first.
“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient 
(including patients participating in the continued access period).  The end of trial occurs after 
study completion and after the last patient has discontinued study treatment and completed the 
final follow-up visit (including the final follow-up visit for the continued access period, if 
applicable) or has been declared lost to follow-up.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
5.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
The patient has a histopathologically or cytologically confirmed diagnosis of 
gastric or GEJ (Siewert Types I-III) adenocarcinoma.
[2]
The patient has documented disease progression during or within 4 months 
after the last dose of first-line chemotherapy for metastatic disease, or during 
or within 6 months after the last dose of neoadjuvant or adjuvant therapy.
a.
Elevations in carcinoembryonic antigen or other tumor markers without 
radiographic evidence of progression do not constitute satisfactory 
evidence of progression on prior therapy.
b.
Patients who are intolerant to first-line chemotherapy regimens are 
eligible, provided disease progression was assessed within 4 months after 
the last dose of first-line therapy.
[3]
The patient received combination chemotherapy prior to disease progression.
a.
Prior chemotherapy regimens must include a platinum and/or a 
fluoropyrimidine component and must not include a taxane or 
antiangiogenic agent (either approved or experimental treatment).  
Exposure to antineoplastic therapy, in addition to platinums and/or
fluoropyrimidines, is acceptable if the agents were used in the first-line 
metastatic or neoadjuvant/adjuvant setting.
b.
Patients who have had one or more components of first-line 
chemotherapy discontinued because of toxicity, but continued to receive 
the other component(s), are eligible following disease progression.
[4]
The patient has metastatic disease or locally advanced disease that is 
measurable, or nonmeasurable but evaluable, by radiological imaging per 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) 
(Eisenhauer et al. 2009 [Attachment 8]).  Baseline tumor assessment should 
be performed using a high resolution computed tomography (CT) scan using 
intravenous and oral contrast unless clinically contraindicated.  Magnetic 
resonance imaging (MRI) is acceptable if a CT cannot be performed.
[5]
The patient has an ECOG performance status of 0 or 1 (see Attachment 6).


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[6]
The patient has adequate organ function, including:
a.
Total bilirubin 1.5 × the upper limit of institutional normal (ULN) and 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
3 × ULN.  If the liver has tumor involvement, AST and ALT <5 × ULN 
are acceptable.
b. Serum creatinine 1.5 × ULN or calculated creatinine clearance (per the 
Cockcroft-Gault formula or equivalent and/or 24-hour urine collection) 
50 mL/min (Attachment 7).
c.
Urinary protein is <2+ on dipstick or routine urinalysis.
If urine dipstick or routine urinalysis indicates proteinuria 2+, then a 
24-hour urine collection must be performed and must demonstrate urine 
protein <2 g to allow the patient to participate in the study.
d. Absolute neutrophil count 1.5 × 109/L, platelets 100 × 109/L, and 
hemoglobin 9 g/dL (5.58 mmol/L).  Packed red blood cell transfusions 
are not allowed within 1 week prior to baseline hematology profile.
e.
International normalized ratio (INR) 1.5 × ULN and partial 
thromboplastin time 5 seconds above ULN, unless the patient is 
receiving anticoagulation therapy. Patients receiving warfarin must be 
switched to low molecular weight heparin and have achieved stable 
coagulation profile prior to randomization.
[7]
The patient is at least 18 years old (or of an acceptable age according to local 
regulations, whichever is older).
[8]
The patient has provided written informed consent prior to any study-specific 
procedures and is amenable to compliance with protocol schedules and 
testing.
[9]
The patient has an estimated life expectancy of 12 weeks in the judgment of 
the investigator.
[10] The patient has resolution to Grade 1 by Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 (NCI 2009), of all clinically significant 
toxic effects of previous anticancer therapy.  Patients with nonserious and 
nonlife-threatening toxicities, such as alopecia, altered taste, or nail changes, 
can be considered. Stable Grade 2 neuropathy is permitted.
[11] The patient, if male, is sterile (including vasectomy confirmed by 
post-vasectomy semen analysis) or agrees to use a reliable method of birth 
control and to not donate sperm during the study and for at least 12 weeks 
following the last dose of study treatment.
[12] The patient, if female, is surgically sterile, is postmenopausal, or agrees to use 
a highly effective method of birth control during the study and for 12 weeks 
following the last dose of study treatment.


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A "highly effective method of birth control" is defined as one that results in a 
low failure rate (that is, <1% per year) when used consistently and correctly.
[13] The patient, if female and of child-bearing potential, must have a negative 
serum or urine pregnancy test within 7 days prior to randomization.
5.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] The patient has cancer with histology other than adenocarcinoma.
[15] The patient is receiving chronic therapy with any of the following within 
7 days prior to randomization:
a.
nonsteroidal anti-inflammatory agents (NSAIDs; such as 
indomethacin, ibuprofen, naproxen, or similar agents)
b.
other anti-platelet agents (such as clopidogrel, ticlopidine, 
dipyridamole, or anagrelide)
Aspirin use at doses up to 325 mg/day is permitted.
[16] The patient received radiotherapy within 14 days prior to randomization.  
Palliative radiotherapy during the study, if clinically indicated, can be 
considered after consultation with the Lilly clinical research physician (CRP).  
Any lesion requiring palliative radiotherapy or which has been previously 
irradiated cannot be considered for response assessment.
[17] The patient received >1 line of prior therapy for the treatment of locally 
advanced and unresectable or metastatic gastric or GEJ (Siewert Types I-III) 
adenocarcinoma.
[18] The patient received previous systemic chemotherapy with a cumulative dose 
of >900 mg/m2 of epirubicin or >400 mg/m2 of doxorubicin.
[19] The patient received previous treatment with agents targeting the 
VEGF/VEGF Receptor 2 signaling pathway, including previous exposure to 
ramucirumab.
[20] The patient has documented brain metastases, leptomeningeal disease, or 
uncontrolled spinal cord compression.  Screening of asymptomatic patients is 
not required.
[21] The patient has a significant bleeding disorder or vasculitis or had a Grade 3 
bleeding episode within 12 weeks prior to randomization.
[22] The patient experienced any arterial thromboembolic event (ATE), including 
myocardial infarction, unstable angina, cerebrovascular accident, or transient 
ischemic attack, within 6 months prior to randomization.
[23] The patient has symptomatic congestive heart failure (CHF; New York Heart 
Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia.


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[24] The patient has uncontrolled hypertension, as defined in CTCAE Version 4.0,
prior to initiating study treatment, despite antihypertensive intervention.
CTCAE Version 4.0 defines uncontrolled hypertension as Grade >2 
hypertension; clinically, the patient continues to experience elevated blood 
pressure (systolic >160 mmHg and/or diastolic >100 mmHg) despite 
medications).
[25] The patient underwent major surgery within 28 days prior to randomization or 
central venous access device placement within 7 days prior to randomization.
[26] The patient plans to undergo elective major surgery during the course of the 
trial.
[27] The patient has a history of gastrointestinal (GI) perforation or fistula within 
6 months prior to randomization.
[28] The patient has a history of inflammatory bowel disease or Crohn’s disease 
requiring medical intervention (immunomodulatory or immunosuppressive 
medications or surgery) 12 months prior to randomization.
[29] The patient has an acute or subacute bowel obstruction or history of chronic 
diarrhea that is considered clinically significant in the opinion of the 
investigator.
[30] The patient has either of the following:
a.
cirrhosis at a level of Child-Pugh B (or worse)
b.
cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis.  Clinically 
meaningful ascites is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.
[31] The patient has known allergy or hypersensitivity to any components of study 
treatment.
[32] The patient is currently enrolled in a clinical trial involving an investigational 
product or nonapproved use of a drug or is concurrently enrolled in any other 
type of medical research judged not to be scientifically or medically 
compatible with this study.  Patients participating in surveys or observational 
studies are eligible to participate in this study.
[33] The patient received any previous investigational therapy within 4 half-lives 
of the investigational agent prior to randomization.
[34] The patient has a serious illness or medical condition including, but not 
limited to, the following:
a.
known human immunodeficiency virus infection or acquired 
immunodeficiency syndrome-related illness
b.
active or uncontrolled clinically serious infection


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[35] The patient is pregnant or breastfeeding.
[36] The patient has a concurrent active malignancy other than the following:
a.
adequately treated nonmelanomatous skin cancer
b.
curatively treated in situ carcinoma of the cervix or other noninvasive 
carcinoma or in situ neoplasm
A patient with a history of prior malignancy is eligible if he or she has been 
disease free for 3 years prior to randomization.
[37] The patient has a serious nonhealing:  (a) wound, (b) peptic ulcer, or (c) bone 
fracture, within 28 days prior to randomization.
[38] The patient experienced any Grade 3 or 4 venous thromboembolic event 
(VTE) that is considered by the investigator to be life-threatening or that is 
symptomatic and not adequately treated by anticoagulation therapy, within 
6 months prior to randomization.
[39] The patient has any condition (for example, psychological, geographical, or 
medical) that does not permit compliance with the study and follow-up 
procedures or suggests that the patient is, in the investigator’s opinion, not an 
appropriate candidate for the study.
5.2.1. Re-Screening
Individuals who do not meet the criteria for participation in this study (screen failure) may be
re-screened, only after discussion with and permission from the Lilly CRP or designee.
Repeating laboratory tests during the screening period does not constitute re-screening.
Screening laboratory tests may not be repeated more than twice in order to meet eligibility 
during the screening period.


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6.
Treatment
6.1.
Treatments Administered
Treatment for the first cycle should begin only if all inclusion and exclusion criteria are met and 
patient has been randomized to an arm of treatment via interactive web-response system (IWRS).  
For subsequent cycles, dose delay/modification is permitted. Missed doses will not be replaced.
Table JVCZ.1 shows the treatment regimens. The first dose of study treatment should be 
administered within 7 days after randomization.
Administer ramucirumab prior to paclitaxel.
Table JVCZ.1.
Treatment Regimens/Dosing Schedule
Dose and Schedule (q 28 Days)
Arm
N
Ramucirumab D1 and D15
Paclitaxel D1, D8, and D15
Route of Administration
1
120
8 mg/kg
80 mg/m2
Intravenous
2
120
12 mg/kg
80 mg/m2
Intravenous
Abbreviations:  D = day; N = number of randomized patients; q = every.
If, at any time during the study, Lilly determines that the safety profile of ramucirumab 12 mg/kg 
is unacceptable, enrollment in Arms 1 and 2 will be stopped, and 30 additional patients will be 
enrolled in a new treatment arm (Arm 3).  Patients enrolled in Arm 3 will receive ramucirumab 
10 mg/kg on Days 1 and 15 in combination with paclitaxel 80 mg/m2 on Days 1, 8, and 15, every 
28 days.  For ongoing patients receiving ramucirumab 12 mg/kg, dose reduction to ramucirumab 
10 mg/kg is recommended; however, if the patient is receiving ramucirumab without 
unacceptable toxicity, the patient may continue to receive ramucirumab 12 mg/kg at the 
discretion of the investigator.
If a patient cannot be treated with 1 component of the study therapy (ramucirumab or paclitaxel) 
for more than 28 days from the last administered dose, that component will be permanently 
discontinued.  The other component should be continued, with the patient remaining on study, if 
clinically indicated.
6.1.1. Selection and Timing of Doses
A cycle is defined as an interval of 28 days.  Initiation of a new treatment cycle will be defined 
by administration of paclitaxel.  If paclitaxel cannot be administered on the planned Day 1 of the 
next cycle, ramucirumab will be administered within the current cycle.  Once paclitaxel can be 
administered, the new treatment cycle will start, and ramucirumab and paclitaxel administration 
should be synchronized.  Refer to Attachment 5 for example dosing scenarios.
A delay of a dose due to holiday, weekend, bad weather, or other unforeseen circumstance will 
be permitted for up to 3 days and will not be counted as a protocol deviation.
The patient’s actual dose of ramucirumab will be determined by measuring the patient’s weight 
at the beginning of each cycle.  If the patient’s weight fluctuates by more than 10% from the 


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weight used to calculate the prior dose, the ramucirumab dose must be recalculated.  
Recalculation of the ramucirumab dose for weight fluctuations of <10% is permitted but not 
required.
The patient’s first dose of paclitaxel is dependent upon the patient’s baseline body surface area 
(BSA). Subsequent doses of paclitaxel must be recalculated if the patient’s BSA changes by 
10% from his or her baseline BSA.
For patients undergoing repeated palliative drainage procedures to remove pleural or peritoneal 
fluid, dry weight will be defined as weight obtained after the drainage procedure and before fluid 
reaccumulation.  In such circumstances, dry weight will be used for dose calculation, if obtained 
30 days prior to dose.  If no recent dry weight is available, actual weight will be used.
A 5% variance in the calculated total dose will be allowed for ease of dose administration.
6.1.1.1.
Premedication
6.1.1.1.1. Premedication Prior to Administration of Ramucirumab
Prior to each infusion of ramucirumab, premedicate all patients with an intravenous histamine 
H1 antagonist, such as diphenhydramine hydrochloride.
Additional premedication may be provided at investigator discretion.
See Table JVCZ.6 for ramucirumab dose modifications and additional premedication 
requirements for patients who have experienced a prior ramucirumab infusion-related reaction 
(IRR).
6.1.1.1.2. Premedication Prior to Administration of Paclitaxel
Premedication is required prior to infusion of paclitaxel according to the manufacturer’s 
instructions and local standards.  Premedication will consist of:

dexamethasone 8 to 20 mg (or equivalent) administered:
o
orally 12 hours and 6 hours prior to paclitaxel, or
o
intravenously 30 to 60 minutes prior to paclitaxel

an antihistamine (H1 antagonist) such as diphenhydramine hydrochloride (or equivalent) 
50 mg administered intravenously

cimetidine (H2 antagonist) (or equivalent) 300 mg administered intravenously
An antiemetic, such as ondansetron 8 mg administered orally or intravenously (or equivalent)
30 to 120 minutes before paclitaxel, is recommended.
6.1.1.2.
Administration of Ramucirumab
Prior to each infusion of ramucirumab, the patient must meet the criteria shown in Table JVCZ.2.


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Table JVCZ.2.
Criteria to Be Met Prior to Each Ramucirumab Administration
Urine protein

<2+ on dipstick or routine urinalysis for C1D1;
2+ on dipstick or routine urinalysis for subsequent infusionsa
-or-

<2 g on 24-hour urine collection
Hypertension

Hypertension is controlled
Wound healing

Any wound is fully healed
Ramucirumab-related toxicities and AEs 
(other than AESIs [see Section 6.6.1.2])

CTCAE (Version 4.0) Grade <2 or the patient’s baseline level, 
except for clinically insignificant AEs (such as alopecia), as 
determined by the investigator.
Abbreviations:  AE = adverse event; AESI = adverse event of special interest; C1D1 = Cycle 1 Day 1; 
CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009).
a
If urine protein =2+ on dipstick or routine urinalysis, refer to Table JVCZ.6.
If the first dose of ramucirumab cannot be administered within 7 days after the randomization 
date, ramucirumab must be delayed until laboratory tests are repeated (see Laboratory 
Assessments in Attachment 1).
Ramucirumab infusions should be delivered in approximately 60 minutes.  The infusion rate 
should not exceed 25 mg/min.  Infusions >60 minutes are permitted in the following situations:
1. if needed in order to maintain an infusion rate 25 mg/min, or
2. if the patient previously experienced a ramucirumab IRR. See Section 8.2.1.1.1 for dose 
modifications and premedication requirements.
6.1.1.3.
Administration of Paclitaxel
On Day 1 of each cycle, the patient must meet the criteria shown in Table JVCZ.3 prior to 
administration of paclitaxel. On Day 8 and Day 15, the patient must meet the criteria shown in 
Table JVCZ.4.
Paclitaxel infusions should be delivered in approximately 60 minutes.  Refer to the 
manufacturer’s instructions for complete prescribing information and follow institutional 
procedures for administration of paclitaxel.


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Table JVCZ.3. 
Criteria to Be Met Prior to Paclitaxel Administration 
On Day 1 of Each Cycle 
Laboratory Test 
Required Value 
Neutrophils 
1.5 × 109/L 
Platelets 
100 × 109/L 
Hemoglobin 
8.0 g/dL 
Serum creatinine or CrCl 
1.5 × ULN or CrCl 50 mL/min 
Bilirubin 
1.5 × ULN 
AST/ALT 
 
 
if the patient has liver metastases 
5 × ULN 
 
if the patient does not have liver metastases 
3 × ULN 
Paclitaxel-related toxicities/AEs (except for clinically 
insignificant events, as determined by the investigator) 
CTCAE Grade <2 or the patient's baseline level 
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CrCl = creatinine clearance; CTCAE = Common Toxicity Criteria for Adverse Events; ULN = upper limit of 
normal. 
 
Table JVCZ.4. 
Criteria to Be Met Prior to Paclitaxel Administration 
On Day 8 and Day 15 of Each Cycle 
Laboratory Test 
Required Value 
Neutrophils 
1.0 × 109/L 
Platelets 
75 × 109/L 
Hemoglobin 
8.0 g/dL 
Bilirubin 
1.5 × ULN 
AST/ALT 
 
 
if the patient has liver metastases 
5 × ULN 
 
if the patient does not have liver metastases 
3 × ULN 
Paclitaxel-related toxicities/AEs (except for clinically 
insignificant events, as determined by the investigator) 
CTCAE Grade <2 or the patient's baseline level 
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = Common Toxicity Criteria for Adverse Events; ULN = upper limit of normal. 
6.1.2. Investigator Responsibilities 
The investigator or his/her designee is responsible for the following: 
 explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the site personnel, 
 verifying that instructions are followed properly, 
 maintaining accurate records of ramucirumab and paclitaxel dispensing and collection, 
 and returning all unused medication to Lilly or its designee at the end of the study. 
Note:  In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials. 


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Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study treatment so that the situation can be assessed.
6.2.
Treatment Assignment
Patients who meet all criteria for enrollment will be randomly assigned to Arm 1 or Arm 2.
The study will randomize (1:1) approximately 240 patients to the 2 treatment arms.  
Randomization will be stratified by ECOG performance status (0 versus 1).
Assignment to treatment arms will be determined by a computer-generated random sequence 
using an IWRS.
If, at any time during the study, Lilly determines that the safety profile of ramucirumab 12 mg/kg 
is unacceptable, 30 additional patients will be enrolled to a new treatment arm (Arm 3).  For 
additional details, see Section 6.1.
Patients in all arms will be treated until disease progression, toxicity requiring cessation of 
treatment, withdrawal of consent, or other withdrawal criteria are met.
6.3.
Blinding
This is an open-label study.
6.4.
Packaging and Labeling
Ramucirumab will be provided by Lilly and will be labeled according to the country’s regulatory 
requirements.  In the United States, paclitaxel will be provided by the study sites.  Outside of the 
United States, paclitaxel will be provided by Lilly and will be labeled according to the country's 
regulatory requirements.
6.5.
Preparation/Handling/Storage
Refer to the IB for detailed information about preparation, handling, and storage of 
ramucirumab.  Additional information is provided in the study pharmacy manual.
Refer to the manufacturer’s instructions for instructions on preparation, handling, and storage of 
paclitaxel.  Additional information for dosing is provided in the study pharmacy manual.
6.6.
Dose Modification
6.6.1. Ramucirumab Dose Modifications
This section provides instructions for ramucirumab dose modifications applicable to all treatment 
arms.  The ramucirumab dose may need to be delayed and/or reduced if the patient experiences 
an adverse event, including AESIs and non-AESIs.
Table JVCZ.5 presents the specific ramucirumab dose reductions applicable to each treatment 
arm.


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Table JVCZ.5.
Ramucirumab Dose Reductionsa
Abbreviation:  D = day.
a
Ramucirumab dose reductions are allowed between cycles and within a given cycle.
If enrollment in Arm 3 is initiated (see Section 4.1), the following ramucirumab dose reductions 
will apply:  (1) first dose reduction, 8 mg/kg; and (2) second dose reduction, 6 mg/kg.
Any patient who requires a ramucirumab dose reduction will continue to receive a reduced dose 
until discontinuation from ramucirumab or discontinuation from the study.
Any patient who has had 2 ramucirumab dose reductions and who experiences an event that 
would cause a third dose reduction must be discontinued from ramucirumab.
6.6.1.1.
Ramucirumab Dose Modifications for AESIs
Table JVCZ.6 presents the criteria for ramucirumab dose modifications applicable if the patient 
experiences an AESI.  A list of the AESIs for ramucirumab is provided below:
Infusion-related reactions (IRRs)
Hypertension
Proteinuria
Arterial thromboembolic events (ATEs)
Venous thromboembolic events (VTEs)
Bleeding/hemorrhage
Gastrointestinal perforation 
Congestive heart failure
Wound healing complications
Fistula
Liver failure/liver injury
Reversible posterior leukoencephalopathy syndrome (RPLS)
Table JVCZ.6.
Dose-Modifications for Ramucirumab Adverse Events of Special 
Interest
Adverse Event of Special Interest
Dose Modification
1.
Infusion-related reaction (Section 8.2.1.1.1)
1.a.

Infusion-related reaction - Grade 1 or 2
Reduce the infusion rate by 50% for the duration of the 
infusion and for all future infusions.
Prior to all future infusions of ramucirumab, premedicate 
with:

an intravenous histamine H1 antagonist, such as 
diphenhydramine hydrochloride,

dexamethasone or equivalent, and

acetaminophen
1.b.

Infusion-related reaction - Grade 3 or 4
Discontinue ramucirumab.
2.
Hypertension (Section 8.2.1.1.2)
Dose
Arm 1
Arm 2
Starting dose
8 mg/kg
on D1, D15
12 mg/kg
on D1, D15
First dose reduction
6 mg/kg
on D1, D15
10 mg/kg
on D1, D15
Second dose reduction
5 mg/kg
on D1, D15
8 mg/kg
on D1, D15


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Adverse Event of Special Interest
Dose Modification
2.a.

Hypertension (non-life-threatening and 
associated with symptoms) -
Grade 2 or 3
Delay ramucirumab until the hypertension is controlled with 
medication and is resolved to Grade <2.

If controlled with medication and resolved to Grade <2 
within 14 days, then resume ramucirumab at current 
dose.

If controlled with medication and resolved to Grade <2 
within 28 days, then resume ramucirumab at a reduced 
dose as shown in Table JVCZ.5.

If not controlled with medication and not resolved to 
Grade <2 within 28 days, then discontinue 
ramucirumab.

Investigators have the discretion to consider the clinical 
circumstances of individual patients, especially 
involving borderline hypertension, and administer 
unchanged dose of ramucirumab for blood pressure up 
to systolic 160 mm Hg and diastolic 100 mm Hg, if 
clinically appropriate.
2.b.

Uncontrolled hypertension, hypertensive 
crisis, or hypertensive encephalopathy -
Grade 4
Discontinue ramucirumab.
3.
Proteinuria (Section 8.2.1.1.3)
3.a.

Proteinuria =2+ (dipstick or routine 
urinalysis)a

Administer ramucirumab at the patient's current dose if 
clinically indicated.

Obtain 24-hour urine protein results within 3 days prior 
to the next ramucirumab dose.
o
If urine protein is <2 g/24 h, administer 
ramucirumab at the patient's current dose.
o
If urine protein is 2 g/24 h, modify the 
ramucirumab dose based on 24-hour collection.  
See Proteinuria 2 g/24 h (24-hour urine 
collection), Line 3.c in this table.
3.b.

Proteinuria >2+ (dipstick or routine 
urinalysis)a

Delay ramucirumab dose for up to 28 days.

Obtain 24-hour urine protein results within 3 days prior 
to the next ramucirumab dose.
o
If urine protein is <2 g/24 h, no further dose delay 
or dose reduction is required.
o
If urine protein is 2 g/24 h, modify the 
ramucirumab dose based on 24-hour collection.  
See Proteinuria 2 g/24 h (24-hour urine 
collection), Line 3.c in this table.
3.c.

Proteinuria 2 g/24 h (24-hour urine 
collection)a
First or second occurrence:  delay ramucirumab until urine 
protein returns to <2 g/24 h.  Reduce ramucirumab dose, as 
shown in Table JVCZ.5.
If urine protein remains 2 g/24 h after holding ramucirumab 
for 28 days, discontinue ramucirumab. 
Third occurrence:  discontinue ramucirumab.


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Adverse Event of Special Interest
Dose Modification
3.d.

Proteinuria >3 g/24 h or in the setting of 
nephrotic syndromea
Discontinue ramucirumab.
4.
Arterial thromboembolic events, venous 
thromboembolic events (Section 8.2.1.1.4) -
Grade 3 or 4
Discontinue ramucirumab.
5.
Bleeding/hemorrhage (Section 8.2.1.1.5) -
Grade 3 or 4
Discontinue ramucirumab.
6.
Gastrointestinal perforation 
(Section 8.2.1.1.6)
Discontinue ramucirumab.
7.
Reversible posterior leukoencephalopathy 
syndrome (Section 8.2.1.1.7)
Discontinue ramucirumab.
8.
Congestive heart failure (Section 8.2.1.1.8) –
Grade 3 or 4
Discontinue ramucirumab.
9.
Fistula formation (Section 8.2.1.1.9)
Discontinue ramucirumab.
10.
Impaired wound healing (Section 8.2.1.1.10)
10.a.

Prior to planned surgery

Withhold ramucirumab.
10.b

After surgery

Resume ramucirumab based on clinical judgment 
(maximum delay is 28 days after the patient's previous 
dose).
10.c.

Wound-healing complications developed 
during study treatment

Delay ramucirumab dosing (for up to 28 days) until the 
wound is fully healed.
11.
Liver injury/liver failure (Section 8.2.1.1.11)
11.a.

Hepatic encephalopathy and/or 
hepatorenal syndrome resulting from 
liver cirrhosis
Discontinue ramucirumab.
a
Perform dipstick or routine urinalysis within 3 days prior to each infusion of ramucirumab (see Table JVCZ.2).  
If 24-hour urine collection is also performed, the results of 24-hour urine collection should be used for clinical 
decision-making.
Refer to Section 8.2.1.1 for detailed information about AESIs for ramucirumab.
6.6.1.2.
Ramucirumab Dose Modifications for Non-AESIs
The ramucirumab dose may be modified if the patient experiences a Grade 3 clinical AE that 
meets all of the following conditions:

the AE is reversible and non-life-threatening

the AE is not an AESI

the AE is considered to be at least possibly related to ramucirumab

the AE resolves to Grade 1 or to the patient's pretreatment baseline level within 28 days
If the patient experiences Grade 4 fever or a Grade 4 laboratory abnormality, ramucirumab may 
be continued at the discretion of the investigator if the fever or laboratory abnormality resolves
to Grade 1 or to the patient's pretreatment baseline level within 28 days.
If a second instance of Grade 4 fever or Grade 4 laboratory abnormality occurs, resume 
ramucirumab at a lower dose as shown in Table JVCZ.5.


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Patients who enter the study with symptoms or laboratory values equivalent to 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. Asymptomatic laboratory 
abnormalities should not result in dose delays, modifications, or discontinuation of ramucirumab
unless determined by the investigator to be clinically significant or life-threatening.
6.6.2. Paclitaxel Dose Modifications
This section provides instructions for paclitaxel dose modifications applicable if the patient 
experiences AEs or laboratory toxicities.
On Days 8 and 15 of each cycle, the patient must meet the criteria shown in Table JVCZ.4.  If 
the patient does not meet these criteria, omit the paclitaxel dose.  Refer to Attachment 5 for 
example dosing scenarios.
If the patient experiences any of the following CTCAE toxicities, reduce the paclitaxel dose by 
10 mg/m2 beginning at the next cycle:

Grade 4 hematological toxicity

Grade 3 paclitaxel-related nonhematological toxicity that is clinically significant (as 
determined by the investigator)
Discontinue paclitaxel if the patient experiences Grade 4 nonhematological toxicity that is 
related to paclitaxel.
No reductions of the paclitaxel dose are allowed within a given cycle.  Any patient who requires 
a paclitaxel dose reduction will continue to receive a reduced dose.
Any patient who has had 2 paclitaxel dose reductions and who experiences a toxicity that would 
cause a third dose reduction must be discontinued from paclitaxel.
6.7.
Treatment Compliance
The study medication will be administered only at the investigational sites by the authorized 
study personnel.  As a result, treatment compliance is ensured.
6.8.
Concomitant Therapy
A list of restricted and excluded concomitant therapies is provided in Attachment 9.  All 
premedication, supportive care, and concomitant medication must be reported on the CRF at 
each visit.
The use of analgesic agents during the conduct of the study is permitted at the discretion of the 
investigator.  The chronic use of NSAIDs with a high risk of bleeding (for example, 
indomethacin, ibuprofen, naproxen, or similar agents) is strongly discouraged except at the 
discretion and responsibility of the investigator after careful assessment of the individual 
bleeding risk of the patient.  Chronic use of aspirin up to 325 mg/day is permitted.


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Chronic use of analgesic agents with no or low bleeding risk (for example, 
paracetamol/acetaminophen, metamizole, dipyrone, or propyphenazone) is acceptable.
6.9.
Treatment After Study Completion (Continued Access Period)
Patients receiving study treatment and experiencing ongoing clinical benefit and no undue risks 
may continue to receive study treatment in the continued access period until one of the criteria 
for discontinuation is met (Section 7.1).  Crossover from 1 treatment arm to another will not be 
permitted.  Lilly will notify investigators when the continued access period begins.  The 
continued access period will apply to this study only if at least 1 patient is still on study treatment 
when study completion occurs.
For patients who are in short-term follow-up when the continued access period begins, follow-up 
will end when the short-term follow-up visit is completed.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
Procedures will be performed as shown in the Time and Events Table for the Continued Access 
Period provided in Attachment 1.  During the continued access period, all AEs, SAEs, and 
ramucirumab exposure data will be reported on the CRF.  Serious adverse events will also be 
reported to Lilly Global Patient Safety (see Section 8.2.1.2).  In the event that an SAE occurs, 
Lilly may request additional information (such as local laboratory results, concomitant 
medications, and hospitalizations) in order to evaluate the reported SAE.
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly 
will not routinely collect the results of these assessments.


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7.
Discontinuation Criteria
The reason for discontinuation from ramucirumab, paclitaxel, or study participation and the date 
of discontinuation will be collected for all randomized patients.  All randomized patients who 
discontinue, regardless of whether or not they received ramucirumab and/or paclitaxel, will have 
procedures performed as shown in the Time and Events Table (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.1.
Discontinuation From Study Treatment
Table JVCZ.7 presents the criteria for discontinuation of the patient from ramucirumab and/or 
paclitaxel.  Refer to Section 6.6 for information about discontinuation from study treatment due 
to AEs.


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Table JVCZ.7.
Criteria for Discontinuation from Study Treatment With 
Ramucirumab and/or Paclitaxel
Criterion
Discontinue
Ramucirumab
Discontinue
Paclitaxel
1.
The patient enrolls in any other clinical trial involving an investigational 
product or enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
X
X
2.
The patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study 
indication; discontinuation from study treatment occurs prior to introduction 
of the new agent.
X
X
3.
The patient experiences disease progression (assessed radiologically or 
clinically).
X
X
4.
The patient is significantly noncompliant with study procedures and/or 
treatment.
X
X
5.
The investigator decides the patient should be discontinued from:
a.
ramucirumab
X
b.
paclitaxel
X
6.
The patient requests to be withdrawn from:
a.
ramucirumab
X
b.
paclitaxel
X
7.
The patient experiences any Grade 4 AE, other than fever or laboratory 
abnormality, that is considered to be at least possibly related to 
ramucirumab.
X
8.
The patient experiences any life-threatening AE or other unacceptable 
toxicity that, in the opinion of the investigator:
a.
is related to ramucirumab
X
b.
is related to paclitaxel
X
c.
cannot be attributed to ramucirumab or paclitaxel
X
X
9.
The patient has had 2 ramucirumab dose reductions and experiences an 
adverse event that would require a third ramucirumab dose reduction.
X
10. The patient has had 2 paclitaxel dose reductions and experiences an adverse 
event that would require a third paclitaxel dose reduction.
X
Abbreviation:  AE = adverse event.
If the patient is discontinued from one study drug (ramucirumab or paclitaxel) because of 
toxicity, the patient may continue to receive the other study drug until progressive disease (PD)
or until another criterion for discontinuation is met.
After discontinuation of all study treatment, the patient will be treated as clinically indicated by 
the investigator or referring physician.  All patients will be followed until resolution or 
stabilization of any SAE or study-related toxicity.
7.1.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, Lilly must be notified.  


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If Lilly identifies a patient who did not meet enrollment criteria and who was inadvertently 
enrolled, the investigator site will be notified.  A discussion must occur between the Lilly CRP 
and the investigator to determine whether the patient may continue in the study, with or without 
ramucirumab.  Inadvertently enrolled patients may be maintained in the study and on 
ramucirumab when the Lilly CRP agrees with the investigator that it is medically appropriate for 
that patient.  The patient may not continue in the study with or without ramucirumab if the Lilly 
CRP does not agree with the investigator’s determination it is medically appropriate for the 
patient to continue.  The investigator must obtain documented approval from the Lilly CRP to 
allow the inadvertently enrolled patient to continue in the study with or without ramucirumab.
7.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

the investigator decides that the patient should be discontinued from the study

the patient requests that the patient be withdrawn from the study

the patient becomes pregnant during the study.  See Section 8.2.1 regarding regulatory 
reporting requirements on fetal outcome and breast-feeding.

Lilly stops the study or stops the patient’s participation in the study for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and good 
clinical practice (GCP).
7.2.1. Patients Who Are Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow.
Site personnel, or an independent third party, will attempt to collect the vital status (that is, alive 
or dead) for all randomized patients who are lost to follow-up, including randomized patients 
who do not receive any dose of ramucirumab or paclitaxel, within legal and ethical boundaries.  
Site personnel, or an independent third party, may search public sources for vital status 
information.  If the patient's vital status is determined, the vital status will be documented and the 
patient will not be considered lost to follow-up.  Lilly will notify site personnel or the 
independent third party when to stop efforts to collect vital status.
Lilly personnel will not be involved in any attempts to collect vital status information.


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8.
Study Assessments and Procedures
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.
Physical examinations and radiological assessments performed as part of routine clinical care 
may be used as baseline assessments if performed within 21 days prior to randomization.
Patients may be enrolled on study with measurable or nonmeasurable but evaluable disease 
based on RECIST v.1.1 (Attachment 8).  If feasible, the primary gastric tumor should not be used 
as a target lesion for RECIST purposes.
8.1.
Efficacy
Because radiographic imaging scans may be needed for future regulatory purposes or an 
independent review of all or a representative sample of scans may be considered following the 
completion of the study, copies of all scans will be collected throughout the study and stored 
centrally by a coordinating vendor designated by Lilly.
8.1.1. Efficacy Assessments at Baseline and During Study Treatment
Study procedures, assessments, and their timing are described in the sections below and shown in 
the Time and Events Table (Attachment 1).
Within 21 days prior to randomization, baseline tumor measurements will be performed on each 
patient.  Computed tomography scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, MRI is also acceptable 
in certain situations, such as when body scans are indicated or if there is a concern about 
radiation exposure associated with CT.  Intravenous and oral contrast are 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 v.1.1.
During study treatment, perform tumor assessment and imaging every 8 weeks (±7 days) from 
the date of the first dose of study treatment until the patient has objective PD or dies, whichever 
occurs first.
Except when deemed not feasible in the opinion of the investigator because of the patient’s 
clinical status, imaging studies and tumor assessments will be performed as scheduled, even if 
therapy is delayed.  The method of tumor assessment used at baseline must be used consistently 
throughout the study.  Radiological scan of the thorax, abdomen, and pelvis is required.
8.1.2. Efficacy Assessments During Postdiscontinuation Follow-Up
Postdiscontinuation follow-up will be conducted as described in the Time and Events Table
(Attachment 1).


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For patients who discontinue ramucirumab without objectively measured PD, continue to 
perform tumor assessment and imaging as follows:

every 8 weeks (±7 days) until the patient has objective PD or dies, or until study 
completion, whichever occurs first
8.1.3. Efficacy Measures
Progression-free survival (PFS) is measured from the date of randomization to the date of 
radiographic documentation of progression (as defined by RECIST v1.1) or the date of death due 
to any cause, whichever is earlier.  The censoring is taken in the following order:

if a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the enrollment date, regardless of whether or not radiographically 
determined disease progression or death has been observed for the patient.  Otherwise, 

if a patient is not known to have died or have radiographically documented progression as 
of the data inclusion cutoff date for the analysis, the PFS time will be censored at date of 
the last complete radiographically documented progression-free disease assessment.
Best response will be derived to encompass all tumor assessments from baseline until the earliest 
assessment of radiographically documented progression or start of new anticancer therapy.  Any 
responses observed after radiographically documented progression or the start of new anticancer 
therapy are excluded from the determination of best respo nse.
The objective response rate (ORR) is the proportion of randomized patients achieving a best 
overall response of complete response (CR) or partial response (PR).
The disease control rate (DCR) is the proportion of randomized patients achieving a best overall 
response of CR, PR, or stable disease (SD).
Overall survival (OS) is the time from the date of randomization to the date of death from any 
cause.  If the patient was alive at the data inclusion cutoff date for the analysis (or was lost to 
follow-up), OS will be censored on the last date the patient was known to be alive.
8.1.4. Appropriateness of Measurements
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials.
8.2.
Safety
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or study procedures, or that caused 
the patient to discontinue before completing the study.  The patient should be followed until the 


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event is resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Time and Events Table (Attachment 1).
Laboratory assessments performed at baseline may also be used for treatment decisions on Day 1 
of Cycle 1 if both of the following conditions are met:

The baseline assessments were performed within 7 days before Day 1 of Cycle 1.

The results are deemed still clinically valid by the treating investigator.
Table JVCZ.8 presents a summary of AE and SAE reporting guidelines.  Table JVCZ.8 also 
shows which database or system is used to store AE and SAE data.
Table JVCZ.8.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
X
All AEs
X
SAEs related to protocol procedures
X
X
Study treatment period
All AEs 
X
All SAEs
X
X
Short-term postdiscontinuation 
follow-up 
All AEs 
X
All SAEs
X
X
Long-term postdiscontinuation 
follow-up
All SAEs related to study treatment or 
protocol procedures
X
X
Continued access period
All AEs
X
All SAEs
X
X
Continued access follow-up
All AEs
X
All SAEs
X
X
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment and 
no longer in follow-up)
All SAEs related to study treatment or 
protocol procedures that the 
investigator becomes aware of
X
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
8.2.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from electrocardiograms (ECGs), laboratory tests, vital sign 
measurements, other procedures, and so on that result in a diagnosis should be reported to Lilly 
or its designee.


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Cases of pregnancy during maternal or paternal exposures to ramucirumab that occur up to 
12 weeks after the last dose of study treatment should be reported.  Data on fetal outcome and 
breast-feeding are collected for regulatory reporting and drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting conditions.  All AEs related to protocol procedures are reported to Lilly
or its designee.
In addition, all AEs occurring after the patient receives the first dose of ramucirumab must be 
reported to Lilly or its designee via CRF.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to study procedure or study treatment via the CRF.
The investigator will decide whether he or she interprets the observed AEs as related to study 
treatment or study procedure.  To assess the relationship of the AE to study treatment or study 
procedure, the following terminologies are defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible.

Does not know:  the investigator cannot determine the causal relationship.

Not related:  without question, the AE is definitely not associated with the study 
treatment.
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study treatment or study procedure.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
CTCAE (Version 4.0) will serve as the reference document for choosing appropriate terminology 
for, and grading the severity of, all AEs and other symptoms.  For AEs without matching 
CTCAE terminology, the investigator will be responsible for selecting the appropriate system 
organ class and assessing severity grade based on the intensity of the event.
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within Medical Dictionary 
for Regulatory Activities (MedDRA™).
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.


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8.2.1.1.
Adverse Events of Special Interest for Ramucirumab
Table JVCZ.6 presents the criteria for dose modifications applicable if the patient experiences an 
AESI.  Contact the Lilly CRP if questions arise concerning AESIs.
8.2.1.1.1. Infusion-Related Reactions
As with other monoclonal antibodies, IRRs may occur during or following 
ramucirumab administration.  Patients should be closely monitored for signs and symptoms 
indicative of an IRR from the initiation of the infusion in an area where resuscitation equipment 
and other agents (such as epinephrine and corticosteroids) are readily available.
A 1-hour observation period following the ramucirumab infusion is mandatory for the first 
2 infusions.  If the patient shows no evidence of an IRR with the first 2 infusions of 
ramucirumab, no observation period is required for subsequent infusions.  In the event an IRR 
occurs thereafter, the 1-hour observation should be reinstituted.
Symptoms of IRRs include rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, 
flushing, dyspnea, wheezing, hypoxia, and paresthesia.  In severe cases, symptoms include 
bronchospasm, supraventricular tachycardia, and hypotension.
If the patient experiences a Grade 2 IRR, interrupt the infusion and treat the patient with 
anti-allergic medication.  If symptoms resolve, resume the infusion at a reduced rate (50%).
In the event of an IRR, blood samples will be collected for both PK and immunogenicity analysis 
at the following time points:  (i) as close as possible to the onset of the IRR, (ii) at the resolution 
of the IRR, and (iii) 30 days following the IRR.
8.2.1.1.1.1.
Guidelines for Reporting IRRs
Any treatment-related IRRs are defined according to the CTCAE Version 4.0 definition (General 
Disorders and Administration Site Conditions).  Symptoms occurring during or following 
infusion of investigational therapy may also be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome (Immune System Disorders).  In the 
setting of symptoms occurring during or following infusion of investigational t herapy, 
investigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.
8.2.1.1.2. Hypertension
An increased incidence of severe hypertension (CTCAE Grade 3) has been reported in patients 
receiving ramucirumab as compared with placebo.  In most cases, hypertension was controlled 
using standard antihypertensive treatment.  Preexisting hypertension should be controlled before 
starting ramucirumab treatment.
Monitoring of blood pressure is required during ramucirumab therapy.  Every attempt should be 
made to control blood pressure to systolic <140 mm Hg and diastolic <90 mm Hg prior to 
starting treatment with ramucirumab.  Routine clinical and laboratory monitoring is required in 
patients who again develop hypertension or experience a deterioration in previous hypertension.


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8.2.1.1.3.
Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGF Receptor 2 pathway, 
including ramucirumab.  Proteinuria has been associated with ramucirumab in clinical studies.  
The majority of events were Grade 1 or 2.  Monitoring for the development or worsening of 
proteinuria during ramucirumab therapy is required.  Discontinue ramucirumab if the patient 
experiences proteinuria >3 g/24 hours or nephrotic syndrome.
8.2.1.1.4. Thromboembolic Events
8.2.1.1.4.1.
Arterial Thromboembolic Events
Serious, sometimes fatal ATEs, including myocardial infarction, cardiac arrest, cerebrovascular 
accident, and cerebral ischemia, have been reported in clinical trials.
8.2.1.1.4.2.
Venous Thromboembolic Events
Venous thromboembolic events 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.  VTEs have been reported from clinical studies investigating ramucirumab, particularly in 
the context of metastatic disease or in regions adjacent to implanted venous access devices.
8.2.1.1.5. Bleeding/Hemorrhage
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding.  Severe GI hemorrhages, including fatal events, have been reported in patients with 
gastric cancer treated with ramucirumab in combination with paclitaxel.
Serious hemorrhagic AEs have been reported from clinical studies investigating ramucirumab.  
Hemorrhagic complications are associated with some malignancies (that is, variceal bleeding 
from portal hypertension in hepatocellular carcinoma, lower GI hemorrhage from bowel 
metastases in ovarian carcinoma), although the rate of these complications varies considerably.  
As detailed in the ramucirumab IB, the incidences of hemorrhagic events to date, significant 
background incidence of bleeding in some malignancies, and use of concomitant antiplatelet 
therapy in some of the reported cases preclude any definitive association between bleeding and 
ramucirumab, although ongoing surveillance and identification (and exclusion) of patients with 
high bleeding risk remain essential and are detailed in the inclusion/exclusion criteria.
8.2.1.1.6. Gastrointestinal Perforation
Patients with unresected (or recurrent) primary tumors or mesenteric or peritoneal disease who 
participate in this clinical study may be at increased risk for GI perforation due to the nature of 
the disease (metastatic gastric cancer).
An infrequent incidence of GI perforations has been associated with some antiangiogenic
therapeutic agents, most specifically in the context of colorectal cancer (treated with combination 
regimens, including anti-VEGF antibodies and cytotoxic chemotherapy) and in advanced ovarian 
cancer.  These events may be associated with extensive abdominal/peritoneal disease burden.  


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Gastrointestinal perforation has been reported from clinical studies investigating ramucirumab. 
The incidences of these events to date and presence of significant comorbidities and risk factors 
preclude any definitive association with ramucirumab, although ongoing surveillance remains 
essential. More information about GI perforation may be found in the IB.
8.2.1.1.7. Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome is a clinical and radiologic syndrome 
typically consisting of reversible cortical neurological dysfunction and brain-imaging findings of 
subcortical edema involving the posterior circulation, particularly the occipital lobes (Hinchey et 
al. 1996).  The symptoms of RPLS most often include generalized seizures, headache, delirium, 
and cortical blindness, although these may vary significantly and occasionally include focal 
neurological deficits (Hinchey et al. 1996; Garg 2001; Lee et al. 2008).  MRI represents the most 
reliable method for diagnosis (Lee et al. 2008).  Clinical symptoms and MRI abnormalities 
usually recover within days to weeks with proper management, although permanent neurologic 
dysfunction has been reported (Hinchey et al. 1996; Tajima et al. 1999; Garg 2001; Lee et al. 
2008).
Across the clinical program to date, 2 cases of RPLS have been reported.  Both cases occurred in 
the recently completed double-blind, randomized, placebo-controlled Phase 3 Study 
I4T-MC-JVBB evaluating ramucirumab in combination with irinotecan, 5-fluorouracil, and 
folinic acid (FOLFIRI) versus FOLFIRI in combination with placebo for patients with metastatic 
colorectal cancer.
Reversible posterior leukoencephalopathy syndrome should be identified and treated promptly in 
order to minimize potential for permanent neurological damage.  Treatment encompasses careful 
control of blood pressure, withdrawal of potentially causative medication, and administration of 
anticonvulsant agents to those experiencing seizures (Stott et al. 2005).
8.2.1.1.8. Congestive Heart Failure
An increased risk of CHF has been associated with some antiangiogenic therapeutic agents, 
particularly in patients with metastatic breast cancer previously treated with anthracyclines.  A 
small number of CHF events (including fatal) were also reported in patients who had received 
ramucirumab after prior treatment with anthracyclines in the Phase 2 and Phase 3 studies.
Treatment with ramucirumab has the potential to enhance cardiotoxicity of agents within the 
anthracycline/anthracenedione class of chemotherapy medications.
Patients with risk factors should be closely monitored for signs and symptoms of CHF.
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease, such as preexisting coronary artery disease or CHF.  Ramucirumab should be 
discontinued in the event of any Grade 3 or 4 events consistent with CHF.
8.2.1.1.9. Fistula Formation
Because fistula formation has been associated with antiangiogenic agents, patients may be at 
increased risk for the development of fistula when treated with ramucirumab.  Some fistulas can 


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be resolved with surgical procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and Cleck 
2009).
8.2.1.1.10.Surgery and Impaired Wound Healing
Because ramucirumab is an antiangiogenic therapy, it may have the potential to adversely affect 
wound healing.  Ramucirumab did not impair wound healing in a study conducted in animals; 
however, the impact of ramucirumab on serious or nonhealing wounds has not been evaluated in 
humans.
8.2.1.1.11.Liver Failure and Other Significant Liver Injury
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  Patients with 1) cirrhosis at a level of Child-Pugh 
Class B (or worse) or 2) cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis should not be enrolled in clinical trials with 
ramucirumab.  “Clinically meaningful ascites” is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.
8.2.1.2.
Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed the ICF and has received 
study treatment.  If a patient experiences an SAE after signing the ICF, but prior to receiving 
study treatment, the event will not be reported as serious unless the investigator feels the event 
may have been caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly-approved method.  If study site personnel contact Lilly or its 
designee by telephone regarding an SAE, study site personnel must also immediately provide 
official notification on study-specific SAE forms.


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This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to study treatment.
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, if an investigator becomes aware of an SAE 
occurring after the patient’s participation in the trial has ended, and the investigator believes that 
the SAE is related to a protocol procedure or study treatment, the investigator should report the 
SAE to Lilly, and the SAE will be entered in the Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by Lilly in aggregate periodically during the course of the trial may be found in 
the IB.
8.2.1.3.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information in the IB and that the investigator identifies as 
related to study treatment or study procedure.  United States 21 CFR 312.32 and European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and associated detailed guidances.
8.2.2. Other Safety Measures
8.2.2.1.
Electrocardiograms
For each patient, a single 12-lead digital ECG will be obtained according to the Time and Events 
Table (Attachment 1) as single ECG.  The patient must be supine for approximately 5 to
10 minutes before ECG collection and remain supine but awake during ECG collection.  ECGs 
are recommended to be recorded before collecting any blood for safety or PK tests.  ECGs may 
be obtained at additional times, when deemed clinically necessary.  All ECGs recorded should be 
stored at the investigational site.
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the patient is still 


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present, to determine whether the patient meets entry criteria and for immediate patient
management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant finding is identified (including but not limited to 
changes in QT/corrected QT interval from baseline), the investigator will determine if the patient 
can continue in the study. The investigator or qualified designee is responsible for determining if 
any change in patient management is needed and must document his/her review of the ECG 
printed at the time of collection. Any new clinically relevant finding should be reported as an
AE.
8.2.2.2.
Echocardiogram or Multiple-Gated Acquisition Scan
An echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan will be performed 
according to the Time and Events Table (Attachment 1).  Additional evaluations are not required 
but should be performed in the setting of cardiac symptoms, at the discretion of the investigator.
Patients will undergo baseline left ventricular ejection fraction determination by ECHO or 
MUGA scan. This evaluation may be repeated at any time during the study if clinically 
indicated.
8.2.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP 
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review:

trends in safety data

laboratory analytes

adverse events, including monitoring of AESIs

If a patient experiences elevated ALT ≥5 × ULN and elevated total bilirubin ≥2 × ULN, 
clinical and laboratory monitoring should be initiated by the investigator. For patients 
entering the study with ALT ≥3× ULN, monitoring should be triggered at ALT ≥2 × 
baseline.

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests.  See Attachment 4.
Additional reviews of safety data will be performed during the interim analyses as described in 
Section 9.8.
8.3.
Sample Collection and Testing
Samples collected for this study will be coded with the patient number.  The samples and any 
data generated from them can be linked back to the patient only by investigator site personnel.


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Attachment 2 lists the specific laboratory tests that will be performed for this study and whether 
these will be performed at a central or local laboratory.
Attachment 3 lists the schedule for collection of PK, immunogenicity, and biomarker samples.
8.3.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.3.2. Biomarkers
Collection of samples for biomarker research is also part of this study.  Plasma and whole blood 
samples will be collected.
8.3.2.1.
Whole Blood for DNA Collection
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ethical review boards (ERBs) allow, a blood sample will be collected for 
pharmacogenetic analysis.
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to ramucirumab.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum of 15 years, 
where allowed by local regulations, after the last patient visit for the study at a facility selected 
by Lilly.  The samples and any data generated from them can only be linked back to the patient 
by investigator site personnel.  The duration allows Lilly to respond to regulatory requests 
related to ramucirumab.
Samples will be destroyed according to a process consistent with local regulation.


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8.3.2.2.
Plasma for Biomarkers
Plasma (from whole blood) will be used for the analyses of various biomarkers related to 
pathways associated with gastric cancer and the mechanism of ramucirumab, and/or 
angiogenesis; and for related research methods or validation of diagnostic tools or assays.  
Potential pharmacodynamics and/or circulating markers may include, but are not limited to, 
VEGF-A, VEGF-C, VEGF-D, placental growth factor, soluble VEGF Receptor 1, soluble VEGF 
Receptor 2, and soluble VEGF Receptor 3.
The plasma samples will be stored for up to a maximum 15 years after the last patient visit for 
the study at a facility selected by Lilly or its designee.  The duration allows Lilly to respond to 
regulatory requests related to the study treatment.
8.3.3. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine antibody production 
against ramucirumab.  The schedule for collection of these blood samples is provided in
Attachment 3.
Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies in 
the presence of ramucirumab.  Antibodies may be further characterized and/or evaluated for their 
ability to neutralize the activity of ramucirumab.
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by Lilly to enable further analysis of immune responses to ramucirumab.  The 
duration allows Lilly to respond to regulatory requests related to ramucirumab
8.3.4. Pharmacokinetics
Blood samples will be collected from all randomized patients to assess ramucirumab 
concentrations in serum.  The schedule for collection of these blood samples is provided in
Attachment 3.
Bioanalytical samples collected to measure ramucirumab concentration will be retained for a 
maximum of 1 year following last patient visit for the study .


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9. Statistical Considerations and Data Analysis 
9.1. Determination of Sample Size 
Estimation of the sample size for this study was performed to ensure adequate statistical power 
for both a conventional analysis of PFS, with a log-rank test for ramucirumab doses of 12 mg/kg 
versus 8 mg/kg using data from Study JVCZ alone, and a network meta-analysis with 
RAINBOW for comparing ramucirumab dose of 12 mg/kg with placebo. 
The sample size to test PFS for the comparison of ramucirumab doses of 12 mg/kg and 8 mg/kg 
using data from Study JVCZ alone was determined based on the following assumptions: 
• α = 0.05 (2-sided) 
• statistical power = 80% 
• randomization 1:1 
• hazard ratio (HR)=0.667, targeting a 2-month increase in median PFS from 4 months 
(ramucirumab 8 mg/kg) to 6 months (ramucirumab 12 mg/kg) 
• Accrual rate:  0-1m:  2 pts; 1-2m:  4 pts; 2-3m:  5 pts; >3m:  7.5 pts/m 
Under these assumptions, approximately 191 PFS events from 228 patients will be needed.  
Assuming 5% early drop outs (such as patients withdrawing consent or lost to follow-up), 
240 patients will be randomized in this study.  With the assumed accrual rate, the estimated study 
duration is 36 months. 
The sample size to test PFS for the comparison of the ramucirumab dose of 12 mg/kg in 
Study JVCZ with placebo in RAINBOW using meta-analysis with RAINBOW was determined 
based on the following assumptions: 
• α = 0.05 (2-sided) 
• statistical power = 90% 
• HR=0.635*0.667=0.424, where: 
o 0.635 is the observed HR (ramucirumab 8 mg/kg compared with placebo) in 
RAINBOW, and 
o 0.667 is the assumed HR (ramucirumab 12 mg/kg compared with 8 mg/kg) in 
Study JVCZ. 
Denote: 
• HR1 = HR from RAINBOW (8 mg/kg compared with placebo), and Z1 = -ln(HR1) 
• HR2= HR from this study (12 mg/kg compared with 8 mg/kg), and Z2 = -ln(HR2) 
then, the sample size can be determined based on the test statistic Z = Z1 + Z2 with variance 
Var(Z) = Var(Z1) + Var(Z2).  Specifically, given a true HR (new ramucirumab dose compared 
with placebo) ϖ, the sample size is determined by: 
 =  ln 
 
 + 


 


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Given Var(Z1) = 0.007 from RAINBOW and Var(Z2) = 4/(number of events), 64 PFS events are 
required for this study. Therefore, the sample size of 191 events, as determined by the test for 
ramucirumab 12 mg/kg compared with ramucirumab 8 mg/kg, is also sufficient for the 
meta-analysis.
This sample size is also adequate for safety and PK analysis.
9.2.
General Statistical Considerations
Statistical analysis of this study will be the responsibilit y of Lilly.
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is 
defined as all patients randomized to study treatment.  Patients will be grouped according to 
randomized treatment.
Safety analyses will be based on the safety population, defined as all enrolled patients receiving 
at least a partial dose of ramucirumab or paclitaxel.  Patients will be grouped according to 
treatment received in Cycle 1.  Pharmacodynamic and/or tailoring biomarker analyses will be 
based on the subset of patients from the above populations from whom a valid assay result 
(according to laboratory guideline) has been obtained.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all 
confidence intervals (CIs) will be 2-sided, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.
Any other change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
9.3.
Treatment Group Comparability
9.3.1. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  A summary of all important protocol deviations will be pr ovided.


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9.3.2. Patient Characteristics
Description of patient characteristics at baseline, such as patient demographics, baseline disease 
characteristics, preexisting conditions, and prior therapies , will be reported using descriptive 
statistics.
9.3.3. Concomitant Therapy
Concomitant medications will be summarized for the safety population.
9.3.3.1.
Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, o r systemic therapy), and by drug 
name.
9.3.4. Treatment Compliance
The number of dose omissions, reductions, and delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients per treatment arm.
9.4.
Efficacy Analysis
9.4.1. Progression-Free Survival
Two PFS analyses will be performed utilizing gatekeeping strategy to control the overall α=0.05:
o
first, test ramucirumab 12 mg/kg compared with placebo, in combination with paclitaxel,
and
o
then, test ramucirumab 12 mg/kg compared with ramucirumab 8 mg/kg, in combination 
with paclitaxel.
The primary analysis (PFS Analysis 1) is the comparison of ramucirumab 12 mg/kg plus 
paclitaxel in this study and placebo plus paclitaxel in RAINBOW.  PFS Analysis 1 will be 
performed using a simple network meta-analysis anchoring on the 8-mg/kg ramucirumab plus 
paclitaxel arm common to Study JVCZ and RAINBOW.
Denote:

HR1 = HR from RAINBOW (8 mg/kg compared with placebo), and Z1 = -ln(HR1)

HR2= HR from this study (12 mg/kg compared with 8 mg/kg), and Z 2 = -ln(HR2)


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then:
o
the test statistic Z = Z1+Z2 with variance Var(Z) = Var(Z1) + Var(Z2). The Zi and its 
variance will be estimated from Cox model in each study.
o
the HR of ramucirumab 12 mg/kg compared with placebo will be estimated as 
HR=HR1*HR2, with CI derived as exponential of the CI of -Z(= -ln(HR)).
The key assumption for PFS Analysis 1 is that, as in any meta-analysis, the populations in this 
study and RAINBOW are similar with respect to any predictive factors, especially that patients 
receiving ramucirumab 8 mg/kg in the 2 studies will perform similarly.
PFS Analysis 2 is the comparison of ramucirumab 8 mg/kg (Arm 1) and ramucirumab 12 mg/kg
(Arm 2) using data from Study JVCZ alone. A stratified log-rank test will be conducted to 
compare the 2 arms. The HR will be estimated using a stratified Cox regression model.
Survival curves and median with 95% CIs will be given using Kaplan-Meier method.
Additional sensitivity analyses taking into account clinical progression or stratification -factor 
data reported on the CRF or using alternative censoring rules will be specified in the statistical 
analysis plan. Univariate and multivariate Cox regression models will be used to explore 
potential prognostic and/or predictive factors.
9.4.2. Objective Response Rate and Disease Control Rate
The best overall response will be determined using the RECIST v.1.1 guidelines.
The ORR will be calculated as the number of randomized patients who achieve a best overall 
response of CR or PR, divided by the total number of patients randomized to the corresponding 
treatment arm (the ITT population).  Additionally, a subgroup analysis will be performed for 
patients with measureable disease and for patients with nonmeasurable disease.  Patients who do 
not have a tumor response assessment for any reason will be considered as nonresponders and 
are included in the denominator when calculating the response rate.  The ORR with 95% CI 
observed in each treatment group will be summarized and compared using the Cochran-Mantel-
Haenszel test adjusting for the randomization strata. The DCR will be calculated as the number 
of patients who achieve a best overall response of CR, PR, or SD, divided by the total number of 
patients randomized to the corresponding treatment group. DCR will be analyzed similarly to 
ORR.
9.4.3. Overall Survival
Overall survival will be analyzed similarly to PFS Analysis 1 and Analysis 2. Univariate and 
multivariate Cox regression model may be used to explore potential prognostic and/or predictive 
factors.
9.5.
Safety Analyses
All safety summaries and analyses will be based on the safety population as defined in 
Section 9.2.


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Adverse events will be summarized by MedDRA System Organ Class/Preferred Term (PT), 
classified from verbatim terms.  The incidence and percentage of patients with at least 
1 occurrence of a PT will be included, according to the most severe CTCAE Version 4.0 grade 
(NCI 2009).  Causality (relationship to ramucirumab), action taken, and outcome will be 
summarized separately.  Duration of AEs will be determined and included in the listings.
Exposure to study treatment will be summarized for each treatment arm with the following 
variables:  number of infusions, number of cycles, duration of therapy, cumulative dose, dose 
intensity, and relative dose intensity. The number of patients with any dose adjustment will be 
presented for entire treatment period as well as for each cycle.
Laboratory results will be classified according to CTCAE Version 4.0 grade.  The incidence of 
laboratory abnormalities will be summarized.
Hospitalizations due to AEs, transfusions, and vital signs will be summarized.
9.6.
Pharmacokinetic Analyses
Serum concentrations of ramucirumab prior to infusion (minimum concentration) and at 1 hour 
after the end of the ramucirumab infusion (approximately maximum concentration) will be 
summarized using descriptive statistics.  Additional analyses utilizing the population PK 
approach may also be conducted if deemed appropriate.
The relationship between ramucirumab exposure and selected efficacy and safety outcomes may
be explored.
9.6.1. Biomarker Analyses
Biomarkers will be analyzed for associations with clinical outcomes.
9.7.
Other Analysis
9.7.1. Immunogenicity Analyses
The number and percentage of patients with positive anti-ramucirumab antibodies will be 
summarized. Any relationship with the occurrence of an IRR and positive anti-ramucirumab 
antibodies may be explored.
9.8.
Interim Analyses
Interim analyses of safety and PK will be conducted at the following time points:
1. after approximately a total of 80 patients complete 6 weeks of therapy, or discontinue 
treatment due to other reasons, whichever comes first, and
2. after approximately a total of 160 patients complete 6 weeks of therapy, or discontinue 
treatment due to other reasons, whichever comes first.
An assessment committee internal to Lilly will review AE profiles, AESIs, dose modifications, 
reasons for patient discontinuations, and other safety data at each interim analysis to determine 


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whether there are sufficient safety concerns to justify the termination of study treatment and/or 
enrollment.  There will be no prespecified rules for stopping the trial due to safety concerns.
No efficacy data will be included in the interim analyses.
Unplanned interim analyses for safety may be performed during the course of the study should 
safety concerns arise.  If an unplanned interim analysis is deemed necessary for reasons other 
than a safety concern, the protocol must be amended.


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10.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
10.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study 
treatment.
10.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline on 
GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites.  The ERBs will review the protocol as required.
The study sites' ERBs should be provided with the following:

the current IB or package labeling and updates during the course of the study

the ICF

relevant curricula vitae
10.2.1. Subgroup Analyses
Subgroup analysis may be performed as deemed appropriate.  A prespecified list of subgroups, 
which are based on important characteristics, will be identified in the statistical analysis plan.
10.3. Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines

ICH GCP Guideline (E6)

applicable laws and regulations


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The investigator or designee will promptly submit the protocol to applicable ERBs.
Some of the obligations of Lilly will be assigned to a third-party organization.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data.
10.4. Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
10.5. Protocol Signatures
Lilly’s responsible medical officer will approve the protocol, confirming that, to the best of his 
or her knowledge, the protocol accurately describes the planned design and conduct of the study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
10.6. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
Lilly will select an investigator to serve as the clinical study report coordinating investigator.
The Lilly responsible medical officer and statistician will approve the final clinical study report 
for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
10.7. Complaint Handling
Lilly collects product complaints on investigational products used in clinical studies in order to 
ensure the safety of study participants, monitor qualit y, and facilitate process and product 
improvements.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.8. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate


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
sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and study 
procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.
10.8.1. Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the Lilly-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data or ECG data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly generic labs system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
10.9. Study and Site Closure
10.9.1. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges discontinuation of study site participation necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.
10.9.2. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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11. References
Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev 
Clin Oncol. 2009;6(8):465-477.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
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.
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos 
Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, 
Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, 
Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated 
advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an 
international, randomised, multicenter, placebo-controlled, phase 3 trial. Lancet. 
2014;383(9911):31-39.
Garg RK. Posterior leukoencephalopathy syndrome. Postgrad Med J. 2001;77(903):24-28.
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.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53(282):457-481.
Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior 
leukoencephalopathy syndrome. Arch Neurol. 2008;65(2):205-210.
[NCI] National Cancer Institute. Common terminology criteria for adverse events. Version 4.0, 
2009. 
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.
Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C,
Chow LQ, Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, 
Rowinsky EK, Eckhardt SG. Phase I pharmacologic and biologic study of ramucirumab 
(IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular 
endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780-787.
Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a 
misnomer reviewed. Intern Med J. 2005;35(2):83-90.
Tajima Y, Isonishi K, Kashiwaba T, Tashiro K. Two similar cases of encephalopathy, possibly a 
reversible posterior leukoencephalopathy syndrome: serial findings of magnetic resonance 
imaging, SPECT, and angiography. Intern Med. 1999;38(1):54-58.


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Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, 
Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, 
Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab 
plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced 
gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, 
randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235.


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Attachment 1.
Protocol JVCZ Time and Events Table


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Time and Events Table, Protocol I4T-MC-JVCZ
Baseline
(within 21 days prior to 
randomization)
All Treatment Cyclesa
(28-day cycles)
Postdiscontinuation Follow-Upb,c
21
7
Day
1
Day
8
Day
15
Short-Term 
Follow-Up Visitd
Visit 801
Long-Term
Follow-Up
Visit 802-8XX
Procedures
Prot. Ref.
Informed consente
Sec. 8
X
Inclusion/exclusion criteria review
Sec. 5
X
Medical historyf
Sec. 8.2.1.2
X
ECG
Sec. 8.2.2.1
X
X
Echocardiogram or MUGA scan
Sec. 8.2.2.2
X
ECOG PS
Sec. 5, Att. 6
X
Xg
X
Concomitant therapyh
Sec. 6.8
X
X
X
Physical exam
X
Xu
X
Height, weight, and BSAi
Sec. 6.1.1
X
X
Vital signsj
X
X
X
X
X
AE collection; CTCAE grading
Sec. 8.2
X
X
X
X
Xk
Xl
Laboratory Assessmentsm
Hematology profilen
Sec. 8.2, 
Att. 2
X
X
X
X
X
Coagulation profileo
Att. 2
X
X
ALT, AST, total bilirubin
Att. 2
X
X
Full chemistry profilep
Sec. 8.2, 
Att. 2
X
X
X
TSH and Free T4
Att. 2
X
X
Urinalysisq
Sec. 6.1.1.2, 
Att. 2
X
X
X
Pregnancy testr
Att. 2
X
X
Efficacy Assessments
Survival information
Sec. 8.1.3
Xs
Xs
Tumor assessment and imagingt
Sec. 8, Att. 8
Xu
Xv
Xw
Xw


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Baseline
(within 21 days prior to 
randomization)
All Treatment Cyclesa
(28-day cycles)
Postdiscontinuation Follow-Upb,c
21
7
Day
1
Day
8
Day
15
Short-Term 
Follow-Up Visitd
Visit 801
Long-Term
Follow-Up
Visit 802-8XX
Procedures
Prot. Ref.
Additional Analyses
Biomarkers
Pharmacokinetics
Immunogenicity
Sec. 8.3, 
Att. 3
Treatment Administrationx
Sec. 6.1
Administer ramucirumab
X
X
Administer paclitaxel
X
X
X
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; Att. = attachment; BSA = body surface area; 
CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance 
status; ERB = ethical review board; ICF = informed consent form; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; 
PD = progressive disease; Prot. Ref. = protocol reference; SAE = serious adverse event; Sec. = Section; TSH = thyroid-stimulating hormone.
a
Day 1, Day 8, and Day 15 assessments are performed only if dosing is scheduled to occur on that day.
b
No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent.
c
Postdiscontinuation follow-up begins on the day after the patient and the investigator agree that the patient will no longer continue study treatment.
d
The short-term follow-up visit occurs approximately 30 days (±7 days) after the day the patient and the investigator agree that the patient will discontinue 
from all study treatment.
e
Obtain prior to any study-specific procedures.  If the ICF is revised during the course of the study, re-consenting of patients may be required if deemed 
necessary by Lilly or the ERB.
f
Including preexisting conditions, historical illnesses, and prior treatment.
g
A time window of -3 days is permitted for the Cycle 1 Day 1 assessment.
h
Concomitant medications will be recorded, including any taken within 30 days prior to randomization and those taken during the 30 days after the last dose of 
study treatment.
i
Measure height at baseline only.  During all treatment cycles, measure weight at the beginning of each cycle; recalculate the ramucirumab and/or paclitaxel 
dose if needed.
j
Vital signs include temperature, pulse rate, and blood pressure.  For the patient's first 2 doses of ramucirumab, measure all vital signs at the following time 
points:  (i) within 15 minutes prior to the infusion, (ii) after completion of the infusion, and (iii) at the end of the postinfusion observation period.  For all 
infusions of paclitaxel and all subsequent infusions of ramucirumab, measure blood pressure and pulse prior to the infusion and measure other vital signs as 
clinically indicated.


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k
All AEs/SAEs will be followed for up to 30 days after the patient and investigator agree that the patient will no longer continue study treatment.
l
During long-term follow-up, only SAEs that are related to ramucirumab, paclitaxel, or protocol procedures will be collected.  Follow-up should be attempted 
at regularly scheduled intervals (every 90 days [±7 days]) until death or for up to 1 year after the date the last patient was randomized (whichever occurs first). 
This follow-up might be a phone call to the patient, her/his family, or local doctor.
m All treatment decisions will be based on local laboratory reports.
n
Hematology profile:  (1) Baseline assessments can be used for treatment decisions for Cycle 1 Day 1 if the baseline assessments were performed within 
7 days prior to Cycle 1 Day 1 and the results are deemed still clinically valid by the treating investigator.
(2) For subsequent infusions, perform within 3 days prior to each infusion of ramucirumab and/or paclitaxel. 
(3) In the event a patient permanently discontinues paclitaxel and continues on ramucirumab monotherapy, perform within 3 days prior to Day 1 of each
cycle; thereafter, a hematology profile is not required prior to infusion of ramucirumab on Day 15, unless clinically indicated.
o
Coagulation profile:  Baseline assessments can be used for treatment decisions for Cycle 1 Day 1 if the baseline assessments were performed within 7 days 
prior to Cycle 1 Day 1 and the results are deemed still clinically valid by the treating investigator.  Thereafter, perform within 3 days prior to Day 1 of every 
odd-numbered cycle.
p
Chemistry profile: Baseline assessments can be used for treatment decisions for Cycle 1 Day 1 if the baseline assessments were performed within 7 days 
prior to Cycle 1 Day 1 and the results are deemed still clinically valid by the treating investigator.  Thereafter, perform within 3 days prior to Day 1 of each 
cycle.
q
Urinalysis:  Perform dipstick or routine urinalysis at baseline and within 3 days prior to Day 1 of each cycle. Baseline assessments can be used for treatment 
decisions for Cycle 1 Day 1 if the baseline assessments were performed within 7 days prior to Cycle 1 Day 1 and the results are deemed still clinically valid 
by the treating investigator.  If baseline urine protein ≥2+ on dipstick or routine urinalysis, 24-hour urine protein results must be obtained prior to the first 
infusion.  See Table JVCZ.6 for information about dose modifications required for proteinuria.
r
Pregnancy test:  Required for women of child-bearing potential.  If required per local regulations and/or institutional guidelines, pregnancy testing can also 
be performed at other times during the study treatment period.
s
Follow-up for the collection of survival data and subsequent anticancer treatments should be attempted at regularly scheduled intervals (every 90 days 
[±7 days]) until death or overall study completion, whichever is earlier. This follow-up might be a phone call to the patient, her/his family, or local doctor.
t
Radiological scan of thorax, abdomen, and pelvis is required; MRI may be used as a complementary method for assessment of the abdomen and pelvis.
u
Assessments previously obtained as part of routine clinical care may be used as the baseline assessment if performed within 21 days prior to randomization.
v
Perform tumor assessment and imaging every 8 weeks (±7 days) until the patient has objective PD or dies, whichever occurs first.  Perform as scheduled even 
if study treatment is delayed, except when tumor assessment and imaging are not feasible in the opinion of the investigator because of the patient’s clinical 
status.  Imaging is not required on Cycle 1 Day 1.  The method of tumor assessment used at baseline must be used consistently throughout the study.
w For patients who discontinue all study treatment without objectively measured PD, continue to perform tumor assessment and imaging every
8 weeks (±7 days) until the patient has objective PD or dies or until study completion, whichever comes first.
Tumor assessments and imaging should be performed, except when tumor assessment and imaging are not feasible in the opinion of the investigator because 
of the patient’s clinical status.  After the patient has objective disease progression, tumor assessments and imaging are no longer required.
x
The first treatment will be administered within 7 days following randomization.  In the event of a medication error, sites must inform Lilly within 24 hours of 
becoming aware of the error.
y
ALT, AST, and total bilirubin:  Perform with 3 days prior to infusion of paclitaxel on Day 8 and Day 15 of each cycle.


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Time and Events Table for the Continued Access Period only, Protocol I4T-MC-JVCZ
Patients on Study Treatment
Continued Access
Cycle
X-Y
Follow-Upa,b
Visit
501-5XX
901
Relative day within a cycle
1
8
15
Procedure 
Protocol Reference
Adverse Events Collection/CTCAE Gradingc
Sec. 8.2
X
X
Immunogenicity:  Anti-ramucirumab antibodiesd
Sec. 8.3.3, Att. 3
X
Administer ramucirumab
Sec. 6.1
X
X
Administer paclitaxel
Sec. 6.1
X
X
X
Abbreviations:  Att. = Attachment; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction; PK = pharmacokinetics; 
SAEs = serious adverse events; Sec. = Section.
a
No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent.
b
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 30 days (±7 days).
c
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly Safety System.
d
If a patient experiences an IRR to ramucirumab, blood samples for immunogenicity and PK analysis will be taken at the following time points:  (1) as soon as 
possible after the onset of the IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
Note:  Efficacy assessments will be done at the investigator’s discretion based on the standard of care.


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Attachment 2.
Protocol JVCZ Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology - local laboratory only:
Clinical Chemistry - local and central laboratories:a
Whole Blood Concentrations of the following:
Serum Concentrations of the following:
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total bilirubin
Mean cell volume 
Direct bilirubin
Mean cell hemoglobin concentration 
Alkaline phosphatase
Leukocytes (WBC)
Alanine aminotransferase (ALT)
Neutrophilsb
Aspartate aminotransferase (AST)
Lymphocytes
Blood urea nitrogen (BUN) or blood urea
Monocytes
Creatinine
Eosinophils
Urate
Basophils
Calcium
Platelets
Glucose, random
Albumin
Coagulation Tests - local laboratory only:
Prothrombin time (PT or INR)
Urinalysis - local laboratory only:
Dipstick or routine urinalysis.
If urine dipstick or routine urinalysis indicates 
proteinuria 2+, a 24-hour urine collection (to assess 
protein) must be obtained.
Partial thromboplastin time (PTT or aPTT)
Pregnancy Test (applies only to women of child-
bearing potential) - local laboratory only:   Serum 
or urine
Thyroid Tests - central laboratory only:
TSH/Free T4 (to be collected at baseline and 
short-term follow-up)
Abbreviations:  aPTT = activated partial prothrombin time; CRF = case report form; INR = international normalized 
ratio; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells; 
TSH = thyroid-stimulating hormone; WBC = white blood cells.
a
Treatment decisions will be based on local laboratory results.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band forms.  
Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.


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Attachment 3.
Protocol JVCZ Sampling Schedule for 
Pharmacokinetics, Immunogenicity, and Biomarkers
It is essential that the exact infusion start and stop times (actual clock readings) are recorded in 
the source document.  The exact time of collection of each venous blood sample will be based on 
the clock used to record infusion times.  It is essential that the PK blood samples not be 
withdrawn from the same site as the drug infusion.


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Table ATT.3.1.
Pharmacokinetic, Immunogenicity, and Biomarker Collection Timepoints
Biomarker Collection
Visit
Study Day
Time
PKa
IKa
Plasma
Whole Blood
Cycle 1 Day 1
Day 1
Prior to infusion
X
X
X
Xb
Cycle 1 Day 1
Day 1
Within 1 to 1.5 hours after the end of the 
infusion
X
Cycle 1 Day 15
Day 15
Within 3 days prior to infusion
X
Cycle 2 Day 1
Day 29
Within 3 days prior to infusion
X
Cycle 2 Day 15
Day 43
Within 3 days prior to infusion
X
Cycle 2 Day 15
Day 43
Within 1 to 1.5 hours after the end of the 
infusione
X
Cycle 3 Day 1
Day 57
Within 3 days prior to infusion
X
X
X
Cycle 3 Day 15
Day 71
Within 3 days prior to infusion
X
Cycle 4 Day 1
Day 85
Within 3 days prior to infusion
X
Cycle 4 Day 1
Day 85
Within 1 to 1.5 hours after the end of the 
infusion
X
Short-term follow-up
Any
Anytime during the follow-up visit
X
X
X
Abbreviations:  IK = immunogenicity; IRR = infusion-related reaction; PK = pharmacokinetics.
a
In the event of an IRR, blood samples will be collected for both PK and IK analysis at the following timepoints:  (i) as soon as possible after the onset of the 
IRR, (ii) at the resolution of the IRR, and (iii) 30 days following the IRR.
b
It is highly recommended to draw the whole blood sample prior to the first infusion of ramucirumab.  However, it can be collected later during the study if 
necessary.


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Attachment 4.
Protocol JVCZ Hepatic Monitoring Tests 
for Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly clinical research physician.  
Additional tests, not specified below, may also be required under specific circumstances to 
investigate the hepatic abnormality.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK 
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; IgM = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 5.
Protocol JVCZ Dosing Scenarios for 
Ramucirumab and Paclitaxel


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Dosing Scenarios for Ramucirumab and Paclitaxel
Cyclea
Day
Administer Ramucirumab?
Administer Paclitaxel?
Scenario 1:  Planned Dosing for Ramucirumab and Paclitaxel
n
1
Yes
Yes
8
No
Yes
15
Yes
Yes
n+1
1
Yes
Yes
8
No
Yes
15
Yes
Yes
Scenario 2:  Ramucirumab Delay on Day 1
n
1
Delay
Yes
8
Yes
Yes
15
Yes
Yes
Scenario 3:  Ramucirumab Delay on Days 1 and 8
n
1
Delay
Yes
8
Delay
Yes
15
Yes
Yes
Scenario 4:  Ramucirumab Delay on Days 1, 8, and 15
n
1
Delay
Yes
8
Delay
Yes
15
Delay until Day 1 of Cycle n+1
Yes
Scenario 5:  Ramucirumab Delay of up to 28 Days After the Planned Treatment Date
n
1
Delay
Yes
8
Delay
Yes
15
Delay until Day 1 of Cycle n+1
Yes
Scenario 6:  Ramucirumab Delay on Day 15
n
1
Yes
Yes
8
No
Yes
15
Delay until Day 1 of Cycle n+1
Yes
Scenario 7:  Paclitaxel Delay on Planned Day 1 (Actual Day 29)
n
Planned Day 1 of 
the next cycle 
(Actual Day 29
of the current 
cycle)
Yes
Delay the start of Cycle n+1 until the 
patient meets the dosing criteria 
shown in Table JVCZ.3.
Repeat blood counts and serum 
chemistry weekly to determine if 
paclitaxel can be administered.


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Cyclea
Day
Administer Ramucirumab?
Administer Paclitaxel?
Scenario 7.a:  Paclitaxel Can Be Administered on Planned Day 8 (Actual Day 1)
n
Planned Day 1 of 
the next cycle
(Actual Day 29
of the current 
cycle)
Yes
No
n+1
1
Yes
Yes
8
No
Yes
15
Yes
Yes
Scenario7.b: Paclitaxel Can Be Administered on Planned Day 15 (Actual Day 1)
n
Planned Day 1 of 
the next cycle 
(Actual Day 29
of the current 
cycle)
Yes
No
Planned Day 8 of 
the next cycle 
(Actual Day 36
of the current 
cycle)
No
No
n+1
1
Yes
Yes
8
No
Yes
15
Yes
Yes
Scenario 8:  Paclitaxel Omitted on Day 8
n
1
Yes
Yes
8
No
Omit
15
Yes
Yes
Scenario 9:  Paclitaxel Omitted on Day 15
n
1
Yes
Yes
8
No
Yes
15
Yes
Omit
a
n = any cycle; n+1 = the next cycle; n-1 = the previous cycle.


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


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Attachment 7.
Protocol JVCZ Creatinine Clearance 
Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.
For serum creatinine 
concentration in mg/dL:
CrCl =
(mL/min) 
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(mL/min)
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.


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Attachment 8.
Protocol JVCZ RECIST 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone Lesions:

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.


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


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


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Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete response (CR) in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease (PD).
PET Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan.
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  The appearance of 1 or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to make a 
reliable evaluation of response.
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).


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Non-CR/ non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The best overall response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table ATT.8.1 provides a summary of the overall response status calculation at 
each time point for patients who have measurable disease at baseline.
Table ATT.8.1.
Time Point Response: Patients with Target (Nontarget) Disease
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease.
Table ATT.8.2 is to be used when patients have nonmeasurable disease only.


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Table ATT.8.2.
Time Point Response:  Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations:  CR = complete response; NE = not evaluable; PD = progressive disease; SD = stable disease.
a
non-CR/non-PD is preferred over SD for nontarget disease.
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  Normally, all target and 
nontarget sites are evaluated at each assessment using the same method.  However, bone scans 
may need to be repeated only when CR is identified in target disease or when progression in 
bone is suspected.
Duration of Response
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD).


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Attachment 9.
Protocol JVCZ Permitted and Prohibited 
Concomitant Therapy
Below is a table of medications and drug classes that either have restricted use (see the 
Conditions for Use column and referenced guidelines) or are not permissible for use while the 
patient is on study.
Therapy
As 
Needed
Chronic 
Use
Conditions for Use
Anticoagulants other 
than warfarin
yes
yes
Careful evaluation is required if patients need to be administered 
anticoagulation during study treatment.  Note that increased risk 
of hemorrhage is a boxed warning in the ramucirumab package 
insert.
Use of warfarin is prohibited. Refer to Inclusion Criterion [6] e.
Biologic response 
modifiers
no
no
Chemotherapy
no
no
Colony-stimulating 
factors
yes
no
Follow local guidelines.
Erythroid growth 
factors
yes
no
Follow local guidelines.
Experimental 
medicines
no
no
Investigational agents
no
no
NSAIDs
yes
no
Chronic use of aspirin up to 325 mg/day is permitted.
Radiotherapy
yes
no
Palliative radiotherapy during the study, if clinically indicated, 
can be considered after consultation with the Lilly CRP.
Abbreviations:  CRP = clinical research physician; NSAIDs = nonsteroidal anti-inflammatory drugs.


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Attachment 10. Protocol JVCZ Abbreviations and 
Definitions


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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.
AESI
adverse event of special interest
ALT
alanine aminotransferase
aPTT/PTT
activated partial prothrombin time / partial thromboplastin time
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
audit
A systematic and independent examination of the trial-related activities and documents to 
determine whether the evaluated trial-related activities were conducted, and the data were 
recorded, analyzed, and accurately reported according to the protocol, applicable standard 
operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory 
requirement(s).
BSA
body surface area
CHF
congestive heart failure
CI
confidence interval
collection database
A computer database where clinical trial data are entered and validated.
CR
complete response
CRF
case report form:  Sometimes referred to as clinical report form:  A printed or electronic 
form for recording study participants’ data during a clinical study, as required by the 
protocol.
CRP
clinical research physician:  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.
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 the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
continued access 
period
The period between study completion and end of trial during which patients on study 
treatment who continue to experience clinical benefit and no undue risks may continue to 
receive study treatment until one of the criteria for discontinuation is met. 


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Term
Definition
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form (ICF) directly or 
through their legally acceptable representatives.
ERB
ethical review board:  A board or committee (institutional, regional, or national) 
composed of medical and nonmedical members whose responsibility is to verify that the 
safety, welfare, and human rights of the patients participating in a clinical trial are 
protected.
FOLFIRI
irinotecan, 5-fluorouracil, and folinic acid
GCP
good clinical practice
GEJ
gastroesophageal junction
GI
gastrointestinal 
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial that are relevant to the 
patient’s decision to participate.  Informed consent is documented by means of a written, 
signed, and dated informed consent form.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible leader 
of the team and may be called the principal investigator.


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Term
Definition
IRR
infusion-related reaction
ITT
intention-to-treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the consequence 
that patients allocated to a treatment group should be followed up, assessed, and analyzed 
as members of that group irrespective of their compliance to the planned course of 
treatment.
IWRS
interactive web-response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition
NSAIDs
nonsteroidal anti-inflammatory drugs
ORR
objective response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational product 
is targeted.
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
PT
preferred term
PTT
partial thromboplastin time
randomize
the process of assigning patients to an experimental group on a random basis
RBC
red blood cells
RECIST
Response Evaluation Criteria in Solid Tumors


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Term
Definition
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  In this study, screening 
involves invasive or diagnostic procedures and/or tests (for example, diagnostic 
psychological tests, x-rays, blood draws).  For this type of screening, informed consent for 
these screening procedures and/or tests shall be obtained; this consent may be separate 
from obtaining consent for the study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to have 
a causal relationship with this treatment.
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event
WBC
white blood cells


Leo Document ID = 04f07f92-5aa1-4302-9d84-cf7fec10d2be
Approver: 
Approval Date & Time: 07-May-2015 17:27:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 07-May-2015 17:51:05 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I4T-MC-JVCZ (b) 
 
Randomized Phase 2 Trial Evaluating Alternative Ramucirumab Doses in Combination with 
Paclitaxel in Second-Line Metastatic or Locally Advanced, Unresectable 
Gastric or Gastroesophageal Junction Adenocarcinoma 
 
NCT02514551 
 
Approval Date: 15-Nov-2017 
 


I4T-MC-JVCZ Statistical Analysis Plan Version 2
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1.
Statistical Analysis Plan
I4T-MC-JVCZ:  Randomized Phase 2 Trial Evaluating 
Alternative Ramucirumab Doses in Combination with 
Paclitaxel in Second-Line Metastatic or Locally Advanced, 
Unresectable Gastric or Gastroesophageal Junction 
Adenocarcinoma
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
Ramucirumab (LY3009806 ) Gastric or Gastroesophageal Junction Adenocarcinoma
An open-label, randomized Phase 2 study comparing alternative ramucirumab dose levels 
in combination with paclitaxel in approximately 240 patients with advanced gastric or 
gastroesophageal junction adenocarcinoma with disease progression during or following 
prior combination chemotherapy.  Treatment will continue until a discontinuation criterion is 
met.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
[Protocol I4T-MC-JVCZ]
[Phase 2]
Statistical Analysis Plan V1 electronically signed and approved by Lilly:  26 September 
2015
Statistical Analysis Plan V2 electronically signed and approved by Lilly on date provided 
below
Approval Date: 15-Nov-2017 GMT


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LY3009806
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan  I4T-MC-JVCZ:  Randomized Phase 2 Trial 
Evaluating Alternative Ramucirumab Doses in Combination with 
Paclitaxel in Second-Line Metastatic or Locally Advanced, 
Unresectable Gastric or Gastroesophageal Junction Adenocarcinoma..................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
5.
A Priori Statistical Methods ................................................................................................7
5.1.
Determination of Sample Size ........................................................................................7
5.2.
General Considerations ..................................................................................................8
5.2.1.
Definitions of Analysis Variables...........................................................................8
5.2.1.1.
Efficacy Analysis Variables..............................................................................9
5.2.1.2.
Safety Analysis Variables...............................................................................12
5.2.1.3.
PK Analysis Variables....................................................................................14
5.3.
Adjustments for Covariates ..........................................................................................14
5.4.
Handling of Dropouts or Missing Data.........................................................................15
5.5.
Multicenter Studies ......................................................................................................16
5.6.
Study Patients ..............................................................................................................16
5.6.1.
Analysis Populations............................................................................................17
5.6.2.
Important Protocol Violations ..............................................................................17
5.7.
Demographic and Other Baseline Characteristics .........................................................18
5.8.
Concomitant Medications.............................................................................................19
5.9.
Treatment Compliance .................................................................................................19
5.10. Efficacy Analyses ........................................................................................................19
5.10.1.
Primary and key Secondary Efficacy Analyses.....................................................20
5.10.2.
Secondary Efficacy Analyses ...............................................................................20
5.10.2.1.
Supportive Analyses of PFS Analysis 1 and 2.................................................20
5.10.2.2.
Analyses of Other Secondary Efficacy Endpoints ...........................................21
5.10.2.3.
Analyses of Exploratory Efficacy Endpoints...................................................21
5.10.3.
Subgroup Analyses ..............................................................................................21
5.11. Post-Discontinuation Therapy ......................................................................................21
5.12. Safety Evaluation.........................................................................................................22
5.12.1.
Exposure..............................................................................................................22
5.12.2.
Adverse Events ....................................................................................................22
5.12.2.1.
Overall Summary of Adverse Events ..............................................................22


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5.12.2.2.
Treatment-Emergent Adverse Events (TEAEs)...............................................23
5.12.3.
Deaths, SAEs, and Other Significant AEs ............................................................23
5.12.4.
Clinical Laboratory Evaluation.............................................................................23
5.12.5.
Hospitalizations and Transfusions ........................................................................24
5.12.6.
Vital Signs, Physical Findings, and Other Observations 
Related to Safety..................................................................................................24
5.13. Pharmacokinetics and Immunogenicity ........................................................................24
5.14. Translational Research .................................................................................................25
5.15. Interim Analysis...........................................................................................................25
5.16. Clinical Trial Registry Analyses...................................................................................26
6.
References ........................................................................................................................27


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Table of Contents
Table
Page
Table JVCZ.5.1. Censoring Rule of Progression-Free Survival Analysis ..................................10
Table JVCZ.5.2. Censoring Rules for Progression-Free Survival Sensitivity Analysis 
Definitions.....................................................................................................10
Table JVCZ.5.3. Analysis Populations .....................................................................................17


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3.
Revision History
Statistical Analysis Plan Version 1 was approved prior to the first patient visit.
Version 2 was approved prior to the primary progression-free survival (PFS) analysis to update 
the components listed below:

Revised censoring rules to match with the censoring rules in RAINBOW study.

Revised PFS sensitivity analysis criteria in Table 5.2 due to the censoring rules changes. 

Modified the definition and analysis of important protocol deviations prior to database 
lock. 

Changed the wording “30-day post 30-day post treatment follow-up visit” to “30-day post 
treatment discontinuation.

Modified Section 5.6.2 Important Protocol Violation to match with the criteria team 
discussed.

Added two additional exploratory analyses for the PFS and OS data in Section 5.10.2.3.

Modified Section 5.12.3. The summary will be provided separately for 1) all deaths, 2) 
deaths up to 30 days after treatment discontinuation, and 3) deaths after 30-day post 
treatment discontinuation. 


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4.
Study Objectives
Objectives
Endpoints
Primary

Evaluate the efficacy of ramucirumab 12 
mg/kg versus placebo, both in combination 
with paclitaxel, in terms of PFS

PFS, as determined by investigator assessment per 
RECIST 1.1
Secondary

Evaluate the efficacy of ramucirumab 
12 mg/kg versus ramucirumab 8 mg/kg, 
both in combination with paclitaxel, in 
terms of PFS

ORR

DCR

PFS, as determined by investigator assessment per 
RECIST 1.1

ORR

DCR

PK of ramucirumab in combination with 
paclitaxel

Minimum ramucirumab concentration in serum (Cmin)

Safety and tolerability
The safety endpoints evaluated will include but are not limited to 
the following:

TEAEs, AESIs, SAEs, and hospitalizations

Clinical laboratory tests, vital signs, and physical 
examinations

Immunogenicity

Blood samples for immunogenicity testing will be collected to 
determine antibody production against ramucirumab.

Exploratory


OS

OS
Assess the relationship between biomarkers 
with clinical outcome
Biomarker research on genetic and circulating factors may be 
assessed from whole blood and plasma samples, unless precluded 
by local regulations.
Abbreviations:  AESIs = adverse events of special interest; DCR = disease control rate; ERB = ethical review board; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; 
RECIST = Response Evaluation Criteria In Solid Tumors; SAEs = serious adverse events; TEAEs = treatment-
emergent adverse events.


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5.
A Priori Statistical Methods
5.1.
Determination of Sample Size
Estimation of the sample size for this study was performed to ensure adequate statistical power 
for both a conventional analysis of PFS, with a log-rank test for ramucirumab doses of 12 mg/kg 
versus 8 mg/kg using data from Study JVCZ alone (denoted as PFS analysis 2), and a network 
meta-analysis with RAINBOW for comparing ramucirumab dose of 12 mg/kg with placebo
(denoted as PFS analysis 1).
The sample size to test PFS for the comparison of ramucirumab doses of 12 mg/kg and 8 mg/kg 
using data from Study JVCZ alone was determined based on the following assumptions:

α = 0.05 (2-sided)

statistical power = 80%

randomization 1:1

hazard ratio (HR)=0.667, targeting a 2-month increase in median PFS from 4 months 
(ramucirumab 8 mg/kg) to 6 months (ramucirumab 12 mg/kg)

Accrual rate:  0-1m: 2 pts; 1-2m: 4pts; 2-3m: 5pts; >3m: 7.5pts/m
Under these assumptions, approximately 191 PFS events from 228 patients will be needed.  
Assuming 5% early drop outs (such as patients withdrawing consent or lost to follow-up), 
240 patients will be randomized in this study.  With the assumed accrual rate, the estimated study 
duration is 36 months.
The sample size to test PFS for the comparison of the ramucirumab dose of 12 mg/kg in 
Study JVCZ with placebo in RAINBOW using meta-analysis with RAINBOW was determined 
based on the following assumptions:

α = 0.05 (2-sided)

statistical power = 90%

HR=0.635*0.667=0.424, where:
o
0.635 is the observed HR (ramucirumab 8 mg/kg compared with placebo) in 
RAINBOW, and
o
0.667 is the assumed HR (ramucirumab 12 mg/kg compared with 8 mg/kg) in 
Study JVCZ.
Denote:

HR1 = hazard ratio from RAINBOW (8 mg/kg compared with placebo), and 
Z1 = -ln(HR1)

HR2= hazard ratio from this study (12 mg/kg compared with 8 mg/kg), and 
Z2 = -ln(HR2)
then, the number of events can be determined based on the test statistic Z = Z1 + Z2 with 
variance Var(Z) = Var(Z1) + Var(Z2).  Specifically, given a true HR ω (new ramucirumab dose 
compared with placebo), the number of events is determined by:


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Given Var(Z1)= 0.007 from RAINBOW and Var(Z2) = 4/(number of events), 64 PFS events 
from JVCZ are required to compare the ramucirumab 12 mg/kg with placebo based on network 
meta-analysis.  Therefore, the 191 events, as determined by the test for ramucirumab 12 mg/kg 
compared with ramucirumab 8 mg/kg, is also sufficient for the meta-analysis. 
This number of events is also adequate for safety and PK analysis. 
5.2. General Considerations 
This document describes the statistical analyses planned prior to final treatment assignment 
unblinding of the aggregate database.  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 CSR.  Additional exploratory analyses of the data 
will be conducted as deemed appropriate. 
All tests of treatment effects will be conducted at a two-sided alpha level of 0.05, and all 
confidence intervals (CIs) will be given at a two-sided 95% level, unless otherwise stated.  
Statistical analysis will be performed using SAS software (SAS, Version 9.1.2 or higher).  
The following general terms will be used globally in the SAP: 
 Unless otherwise specified, summary statistics stand for n, mean, standard 
deviation, median, minimum, and maximum for continuous variables; and 
frequency and percentage for categorical variables.  
 Study Treatment Period:  begins on the day the first dose of study treatment 
is administered and ends when the patient and the investigator agree that the 
patient will no longer continue study treatment.  The date of this agreement is 
to be reported on the case report form (CRF) as the Date of Discontinuation 
from study treatment. 
 Postdiscontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment. 
Short-term follow-up begins the day after the patient and the investigator agree that 
the patient will no longer continue study treatment and lasts approximately 30 days 
(±7 days) (until the short-term 30-day safety follow-up visit is completed). 
Long-term follow-up begins the day after short-term follow-up is completed and 
continues until the patient’s death or overall study completion (whichever is earlier).   
5.2.1. Definitions of Analysis Variables 
Definitions of efficacy and safety analysis variables are listed in Section 5.2.1.1 and Section 
5.2.1.2, respectively.  Other variables are listed below alphabetically. 


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
Age (years): (Informed Consent Date – Date of Birth + 1)/365.25.
Note:  Average days in a year = 365.25, reflecting the Julian Year of three 
years with 365 days each and one leap year of 366 days.  Birth month and day 
are imputed to be 01 July because only birth year is collected through CRF. 

Baseline measurement is the last non-missing measurement prior to first 
dose for safety analyses; and the last non-missing measurement prior to 
randomization for demographic and efficacy analyses.

Duration is calculated as:
o
Duration (days):  (End Date – Start Date + 1)
o
Duration (weeks):  (End Date – Start Date + 1)/7
o
Duration (months):  (End Date – Start Date + 1)/30.4375
Note. Days in months = (1/12)*average number of days in a year
o
Duration (years):  (End Date – Start Date + 1)/365.25

Duration of disease is defined as months from first diagnosis of cancer to 
randomization.

Measurable disease (Yes/No) is defined as yes for patients with at least one 
target lesion and no otherwise, based on radiographic assessment data 
collected at baseline.

Study Day indicates the number of days the patient has been receiving study 
treatment.  It is calculated as assessment date – randomization date + 1 day, if 
the assessment is done on or after the randomization day.  If the assessment is 
done prior to the randomization day, the study day will be calculated as 
assessment date – randomization date.  Date of randomization is defined as 
Study Day 1.
5.2.1.1.
Efficacy Analysis Variables
Definition of efficacy analysis variables are listed below.
Progression-free survival (PFS) is defined as the time measured from the date of randomization 
to the date of radiographic documentation of progression (as defined by RECIST v.1.1) or the 
date of death due to any cause, whichever is earlier.  The detailed censoring rule is provided in 
Table JVCZ.5.1.
PFS (day) = Date of progression / censor - Date of randomization + 1


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Table JVCZ.5.1.
Censoring Rule of Progression-Free Survival Analysis 
Situation
Event / Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate radiological assessment 
or date of randomization (whichever is later)
unless
No baseline radiological tumor assessment 
available
Censored
Date of randomization
No adequate post baseline radiological tumor 
assessment available and no death reported
Censored
Date of randomization
No tumor progression or death prior to new 
anticancer therapy
Censored
Date of adequate radiological assessment 
prior to (start of new therapy) or date of 
randomization
(whichever is later)
Tumor progression or death documented
immediately after 2 or more consecutive
missing scan intervals following last adequate 
radiological tumor assessment or randomization 
(whichever is later)
Censored
Date of last adequate radiological assessment 
prior to the missing assessment or date of 
randomization
(whichever is later)
Abbreviation:  CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
Note:
Adequate radiological tumor assessment refers to an assessment with one of the following responses: CR, PR, SD or 
PD.
If there are multiple dates associated with one assessment, the assessment date will be set to the first date when the 
overall response is PD and the last date otherwise. 
Table JVCZ.5.2 lists censoring rules for sensitivity analysis (SA) definitions.
Table JVCZ.5.2.
Censoring Rules for Progression-Free Survival Sensitivity Analysis 
Definitions
Sensitivity 
Analysis (SA)
Definition #
Situation
Date of
Progression or
Censor
Progressed / 
Censored 
SA 1: Count 
symptomatic 
deterioration as 
progression
Radiographic documented 
progression or symptomatic 
deterioration 
Date of documented progression or date 
of symptomatic deterioration,
whichever occurred first.
Progressed
SA 2: Ignore new 
anticancer 
treatment
New anticancer treatment (systemic 
therapy) started before 
radiographicdomumented 
progression or death
last adequate radiological assessment 
prior to new anticancer treatment or date 
of randomization whichever is later
Progressed
SA 3: Ignore 
missing tumor 
assessment
Radiographic documented  
progression or death
occur immediately after 2 or more 
scan intervals
last adequate radiological assessment 
prior to missed tumor assessment or date 
of randomization whichever is later
Progressed


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Sensitivity 
Analysis (SA)
Definition #
Situation
Date of
Progression or
Censor
Progressed / 
Censored 
SA 4: Treat lost to 
follow up as 
progression
Patient is lost to follow-up without 
radiographic documented 
progression or death
Date of next scheduled post baseline 
radiological assessment at or after 
becoming lost to follow-up 
Progressed


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Objective response rate (ORR) is defined as the proportion of randomized patients achieving a 
best overall response of PR or CR per RECIST v.1.1.  Patients who do not have any post 
baseline tumor response assessments are considered non-responders and are included in the 
denominator when calculating the response rate. 
Note: Tumor assessments performed after initiation of new anticancer treatment (systemic 
therapy) will be excluded from evaluating the best overall response.
Disease control rate (DCR) is defined as the proportion of randomized patients achieving a best 
overall response of CR, PR, or SD per RECIST v.1.1.  Patients who do not have any post 
baseline tumor response assessments for any reason are considered non-responders and are 
included in the denominator when calculating the response rate.
Note:  Best overall response is the best response recorded from randomization until disease 
progression, in the order of CR, PR, and SD. Refer to Attachment 5 of the protocol for 
definitions of CR, PR, and SD.
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
from any cause.  If the patient was alive at the cutoff for analysis (or was lost to follow-up), OS 
data will be censored for analysis on the last date the patient was known to be alive.
5.2.1.2.
Safety Analysis Variables
Definitions of variables for safety analysis are listed by category and alphabetically within 
category.
Adverse event (AE)-related variables are listed below:

Adverse event (AE) is defined as any untoward medical occurrence in a patient 
administered a pharmaceutical product, without regard to the possibility of a causal 
relationship. 

AEs of special interest (AESIs) include arterial thromboembolic events (ATE)*, 
bleeding/hemorrhage (also gastrointestinal [GI] hemorrhage as a subcategory)*, 
congestive heart failure (CHF)*, fistula (GI* and non-GI), gastrointestinal perforation 
(non-fistula)*, healing complication, hypertension*, infusion related reaction (IRR), liver 
injury/failure*, proteinuria*, renal failure*, reversible posterior leukoencephalopathy 
syndrome (RPLS), thrombotic microangiopathy and venous thromboembolic events 
(VTE)*.
Notes:  Categories of AESI may be modified as the understanding of the safety of the 
investigational drug increases.  The final list of categories will be maintained at both the 
compound and study level and reported in the CSR.  

Consolidated AEs are composite AE terms consisting of synonymous preferred terms 
(PTs) to allow meaningful interpretation of the AE data.  Consolidated AE categories and 
PTs will be maintained at compound and/or study level and reported in the CSR. 

Serious adverse event (SAE) is any AE that results in one of the following outcomes:
-
death


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a life-threatening experience (that is, immediate risk of dying)
-
persistent or significant disability/incapacity
-
initial or prolonged inpatient hospitalization
-
congenital anomaly/birth defect
-
considered significant by the investigator for any other reason.

Treatment-emergent adverse event (TEAE) is defined as any untoward medical 
occurrence that either occurs or worsens at any time after treatment baseline and that does 
not necessarily have to have a causal relationship with this treatment.
Exposure-related variables are listed below:

Number of dose level reductions: Sum of the number of dose level reductions as 
reported in the eCRF

Dose delays: As reported in the eCRF

Dose withheld (Not Administered): As reported in the eCRF.
Ramucirumab or placebo treatment:

Duration of treatment (weeks; 14 days added to duration of treatment because 
administration is every 2 weeks [on day 1, 15 of each 4-week cycle]) = [(Date of last dose
−date of first dose) + 14] ÷ 7

Cumulative dose, dose intensity, relative dose intensity:
-
Cumulative dose (mg/kg) = Sum of (Dose administered at each infusion [mg] ÷
Last available weight [kg])
-
Weekly dose intensity (mg/kg/week) = (Cumulative dose) ÷ (Duration of 
Treatment[week])
-
Planned weekly dose intensity (mg/kg/week) = 2 x 8mg/kg / 3 weeks = 
5.3 mg/kg/week
-
Relative dose intensity (%) = (Weekly dose intensity) ÷ (Planned weekly dose 
intensity) x 100
Paclitaxel treatment:

Duration of treatment (weeks; 14 days added to duration of treatment because last 
administration of each cycle is for 2 weeks [on day 1, 8, 15 of each 4-week cycle]) = 
[(Date of last dose date of first dose) + 14] ÷ 7

Cumulative dose, dose intensity, relative dose intensity:
-
Cumulative dose  (mg/m2) = Sum of all (total dose administered [mg] ÷ BSA 
using last available weight [m²])
-
Weekly dose intensity  (mg/m2/week) = (Cumulative dose) ÷ (Duration of 
treatment)
-
Planned weekly dose intensity (mg/m²/week) = 3x 80mg/m2 / 4 weeks = 60 
mg/m2/week


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Relative dose intensity (%) = (Weekly dose intensity) ÷ (Planned weekly dose 
intensity) x 100
5.2.1.3.
PK Analysis Variables
Definition of PK analysis variables are listed below:

Minimum concentration (Cmin):  Serum concentrations of ramucirumab prior to infusion

Approximate maximum concentration (Cmax):  Serum concentrations of ramucirumab at 
1-hour post-end of ramucirumab infusion
5.3.
Adjustments for Covariates
As supportive analysis, the primary and secondary efficacy endpoints will also be analyzed 
adjusting for pre-specified potential prognostic factors chosen from the variables listed below.  
Detailed description as for which factors to be used will be provided for relevant analyses in later 
sections.

Randomization stratification factors:
o
ECOG performance status (0 versus 1)

Other factors of interest: 
o
Sex (males versus females)
o
Age (< 65 versus ≥65 years)
o
Race (White versus Asian versus all others)
o
Geographic region
o
primary tumor location (gastric versus GEJ) 
o
disease measurability (measurable versus nonmeasurable)
o
Prior first-line treatment (doublet versus triplet)
o
Time to progression on first-line therapy
o
Previous gastrectomy (Y/N)
o
Histologic subtype (diffuse versus intestinal versus mixed/unknown)
o
Peritoneal metastases (Y/N)
o
Weight loss (≥10% over the 3 months prior to study entry versus 
<10%)
o
Number of metastatic sites (≤2 versus ≥3)
o
Liver metastasis (Yes versus No)
o
Presence of ascites (Yes versus No) 


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o
Tumor differentiation (Well, Moderately, Poorly, Unknown1)
o
Primary tumor present (Y/N)
5.4.
Handling of Dropouts or Missing Data
Rules for handling dropouts or missing data are listed by type of analysis alphabetically.  Unless 
otherwise specified, observed data will be used and missing data will not be imputed or carried 
forward.
General rules for imputing dates related to AE or concomitant therapy:

Onset date of an AE or start date of a concomitant therapy:
o
If only the day is missing, the date will be set to:

First day of the month that the event occurred, if the onset yyyy-mm is 
after the yyyy-mm of first study treatment.

The day of the first study treatment, if the onset yyyy-mm is the same as 
yyyy-mm of the first study treatment.
o
If both the day and month are missing, the complete date will be set to:

01 January 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:
o
If only the day is missing, the date will be set to the last day of the month of the 
occurrence, or to the date of death if the patient died in the same month.
o
If both the day and month are missing, the date will be set to 31 December of the 
year of occurrence or to the date of death if the patient died in the same year.
If a date is completely missing, then the AE will be considered treatment emergent.  In case of 
additional therapies, if the start date is completely missing, 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 date has no missing year and month but the day is missing, then assign Day 1 to the 
day.
                                               
1 In Cox PH model, the grouping of tumor differentiation is Well/Moderately versus 
Poorly/Unknown.


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
If the date has no missing year, but has missing month, then assign January to the month.
After imputation, the imputed date should be logically consistent with other relevant date 
variable(s).  For example, if a visit start date was 10 May 2008 and a tumor assessment date was 
xx May 2008 (missing day) but it was known that it occurred after that visit, then after 
imputation, the tumor assessment date became 01 May 2008.  In this case, the imputed tumor 
assessment date should be compared to the visit start date and then corrected to be the visit start 
date, 10 May 2008.
Safety analysis:  The following rule for missing data processing will apply for safety analysis:

Missing classifications concerning study medication relationship will be considered as 
related to study medication.

If the AE onset date is missing or partial, the date will be compared as far as possible 
with the date of first dose of study medication when determining whether or not the AE is 
present at baseline.  In this case, the AE will be assumed to be treatment emergent, unless 
there is clear evidence (through comparison of partial dates) to suggest that the AE 
started prior to the first dose of study medication.
Time-to-event analysis:  All censored data will be accounted for using appropriate statistical 
methods.  See Section 5.2.1 and Section 5.10 for details.
5.5.
Multicenter Studies
This is a multicenter, randomized, open-label study.  Investigative center was not a stratification 
factor because the large number of investigative centers would breakdown the intended balance 
within each combined stratification level by the stratified randomization method.  It will not be 
included as a covariate in any covariate-adjusted analysis because the large number of 
investigative centers in this study cannot be practically incorporated into such analysis. 
5.6.
Study Patients
The following summaries (frequency and percentage) and listings for patient disposition will be 
performed: 

Patient disposition by investigator site and country and overall:  patients 
entered (i.e., signed informed consent), entered but not randomized, 
randomized (i.e., ITT population), randomized but not treated, treated (i.e., 
safety population), in Per-Protocol population (PPP).

Reasons for discontinuation for the following patients groups:
o
all treated patients as well as patients continuing on the study
o
randomized patients who did not receive any study treatment

Reason for screen failure for patients who entered but not randomized

Listings of
o
primary reason for discontinuation


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o
date of randomization, first dose administration, last dose 
administration, and treatment discontinuation.
5.6.1. Analysis Populations
Table JVCZ.5.3 lists analysis population definitions and associated data type for analysis.
Table JVCZ.5.3.
Analysis Populations
Population
Definition
Analysis Type / Variable
Note
Intention-to-treat 
(ITT) Population
All randomized patients 
Baseline characteristics, 
concomitant medication, 
all efficacy analyses
Patients will be grouped 
according to randomized 
treatment.
Safety Population 
(SP)
All randomized patients who 
received any quantity of study 
drug
Safety, e.g. 
dosing/exposure, AE and 
resource utilization 
Patients will be grouped 
according to treatment 
received as defined by the 
first dose received.
Per-Protocol 
Population (PPP) 
ITT patients who received at least 
one cycle of study therapy and 
did not have any major protocol 
violations that could potentially 
affect the efficacy conclusion. 
These major protocol violations 
are detailed in Section 5.6.2.
PFS analysis 2 on PPP as a 
sensitivity analysis of PFS; 
other efficacy endpoints 
may also be analyzed as 
needed
PPP will only be 
performed if there are 
significant numbers of 
patients with major 
protocol violations (≥5% 
of total ITT population). 
Abbreviations:  AE = adverse event; OS = overall survival; PFS = progression-free survival.
A patient listing of analysis population details will be provided.  This listing will be presented by 
treatment group and will include: investigator site, patient identifier, inclusion/exclusion flag for 
each population and reason for exclusion from each population.  All patients screened will 
appear on this listing.
5.6.2. Important Protocol Violations
The PPP is a subset of the ITT population and consists of the randomized and treated patients 
who do not have a major protocol violation (i.e. clinically important and potentially impact 
efficacy evaluations) as listed below:

Patient does not have histologically- or cytologically-confirmed gastric carcinoma, 
including gastric adenocarcinoma or GEJ adenocarcinoma. In particular, patients with 
only squamous histology, but without any adenocarcinoma components

No metastatic disease or locally recurrent, unresectable disease

Had not experienced disease progression during first-line therapy or within 4 months 
after the last dose of first-line therapy for metastatic disease, or during or within 6 months 
after the last dose of neoadjuvant or adjuvant therapy.

The patient did not receive combination chemotherapy prior to disease progression.


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
Baseline ECOG performance status (ECOG PS) score of 2 or above or incorrect 
stratification factor values used for randomization.

The patient has received more than one prior systemic chemotherapy regimen for the 
treatment of locally advanced and unresectable or metastatic gastric or GEJ (Siewert 
Types I-III) adenocarcinoma.

Have documented brain metastases, leptomeningeal disease or uncontrolled spinal cord 
compression.

Had received prior therapy with an agent that directly inhibits VEGF or VEGFR-2 
activity (including bevacizumab and ramucirumab).

Patient has received additional concurrent chemotherapy, biological response modifiers, 
other investigational agents and radiation therapy (except for palliation to symptomatic 
sites of disease) while receiving study treatment.

Patient received incorrect study medication at least 25% of the times (i.e.,  Number of 
incorrect medication infusions/Total number of infusions patient received > =25%).
The list of patients (except for patients with incorrect study medication) included in this 
population will be identified prior to database lock for the final analysis.   
The protocol violations described in this SAP are restricted to violations that can be assessed by 
analysis of data available in the clinical database.
5.7.
Demographic and Other Baseline Characteristics
The following patient demographic and other baseline characteristics will be summarized: 

Patient demographics:  age (years) and age group (<65versus ≥65), gender, 
race, ethnicity, height (cm), weight (kg), BSA (m2) 

Potential prognostic factors as listed in Section 5.3

Baseline disease characteristics:
o
at initial diagnosis only: disease stage
o
at study entry only: current disease stage, duration of disease (months)

Prior cancer therapies:  type of therapy (surgery, radiotherapy, systemic 
therapy), type of prior surgery, type of prior radiotherapy, type of prior 
systemic therapy 

Historical illness (no versus at least one diagnosis) by Medical Dictionary of 
Regulatory Activities (MedDRA) PT, presented in decreasing frequency 
Note: Subjects reporting more than one condition/diagnosis within a PT will 
be counted only once for that PT.

Comparison between the CRF and interactive voice response system (IVRS) 
values of the stratification factors


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Patient listings of demographic data and baseline characteristics will be provided. Patient listings 
of prior cancer therapies (surgery, radiotherapy, and systemic therapy) will be provided.
5.8.
Concomitant Medications
The following concomitant medications used in study treatment period or the 30-day post 
treatment discontinuation will be summarized by numbers and percentages by treatment group, 
presented in decreasing frequency of the World Health Organization (WHO) drug term across 
treatment arms: 

All concomitant medications

Best supportive care (BSC) and select medications including growth factors 
(erythropoietin, G-CSF, granulocyte-macrophage colony-stimulating factor 
[GM-CSF]) 
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.
The proportions of patients reporting use of concomitant medications will be compared between 
the treatment groups.  Patient listing of all concomitant therapies and premedications will be 
provided.
5.9.
Treatment Compliance
Ramucirumab/placebo and Paclitaxel will be intravenously administered only at the 
investigational sites.  As a result, patient compliance is ensured.
5.10. Efficacy Analyses
A gatekeeping approach to test primary objective and key secondary objective will be applied in 
order to protect the study-wise Type I error rate and to enable inferential statements; each 
hypothesis is inferentially tested only if each of the preceding hypotheses were rejected.  The 
sequential order of the confirmatory testing in the ITT population will be: 1) PFS analysis 1: PFS 
of ramucirumab 12 mg/kg plus Paclitaxel from JVCZ compared with placebo plus paclitaxel 
from RAINBOW using network meta-analysis; 2) PFS analysis 2: PFS of ramucirumab 12 
mg/kg plus Paclitaxel compared with ramucirumab 8 mg/kg plus paclitaxel from JVCZ.  Both 
PFS analyses 1 and 2 will be analyzed at the same level of significance 0.05.  


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5.10.1. Primary and key Secondary Efficacy Analyses
The PFS analysis 1 and 2 are described in Section 5.1. The hazard ratio of PFS analysis 1 
is equal to HR1*HR2, where HR1 is 0.635, the observed HR (ramucirumab 8 mg/kg 
compared with placebo) in RAINBOW; HR2 (12 mg/kg compared to 8 mg/kg) will be 
estimated HR using Cox proportional hazards (PH) model with assigned treatment as the 
only covariate. The stratification will be the same as that used for randomization. This 
Cox PH model will be referred to as the primary Cox PH model henceforth. The test 
statistic for PFS analysis 1 is Z = Z1 + Z2 with variance Var(Z) = Var(Z1) + Var(Z2), 
where Var(Z1)=0.007 from RAINBOW; Z2 and Var(Z2) will be estimated from the 
primary Cox PH model.
The following analyses of PFS will also be performed:

Summary of PFS events (number and percentage), censoring rate, and reasons 
for censoring

Restricted mean difference in PFS between the treatment groups and its 95% 
CI, with the area under the Kaplan-Meier survival curve calculated up to the 
minimum across treatment arms of the maximum observed (i.e., event or 
censored) time

Kaplan-Meier survival curve (Kaplan and Meier 1958) by treatment group 
will be provided

The Kaplan-Meier method will be used to estimate parameters (medians, 
quartiles, and percentages), as well as difference of percentage and associated 
95% CI and p-values for landmark analyses on each treatment group at 3, 6, 9, 
12, and 24 months.  Patients who did not have the event at the corresponding 
time point will be considered right-censored observations.   
5.10.2. Secondary Efficacy Analyses
5.10.2.1. Supportive Analyses of PFS Analysis 1 and 2
Since PFS analysis 1 is based on PFS analysis 2, the following supportive analyses will be 
performed for PFS analysis 2 only:

Hazard ratio for treatment effect will be estimated using an unstratified Cox PH model.

As a sensitivity analysis, the PFS analysis 2 will be repeated using stratification based on 
the CRF values.

Hazard ratio for treatment effect will be estimated using a multivariate Cox PH model to 
be constructed by selecting covariates among all the variables in Section 5.3 using 
stepwise selection method.  The stepwise selection will use an entry p-value 0.10 and exit 
p-value 0.15.  The treatment factor will not be used for stepwise selection, but be added 
to the final model. HR for treatment effect and corresponding 95% CI will be estimated 
from the final model.


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
As a sensitivity analysis, the PFS analysis 2 will be repeated for the per-protocol 
population.

As sensitivity analyses, the PFS analysis 2 will be repeated using different PFS censoring 
rule as defined in Table JVCZ.5.2, to evaluate whether and to what extent the conclusion 
of the PFS analysis under the primary definition would be affected under the different 
censoring rules.

As an exploratory analysis of primary endpoint, individual patient data from JVCZ and 
RAINBOW may be pooled together. The PFS analysis directly comparing ramucirumab 
12 mg/kg plus paxlitaxel from JVCZ and placebo plus paxlitaxel from RAINBOW may 
be performed using pooled individual patient data. If statistical significant difference 
exists between the two 8 mg/kg arms, additional adjusted analysis may be explored.
5.10.2.2. Analyses of Other Secondary Efficacy Endpoints
Tumor response (CR+PR) rate and disease control (CR+PR+SD) rate will be reported along with 
exact confidence bounds (CI: 95%) and compared using the Cochran-Mantel-Haenszel test 
adjusting for the stratification variables. 
5.10.2.3. Analyses of Exploratory Efficacy Endpoints
Overall survival will be analyzed similarly to PFS Analysis 1 and Analysis 2.  Univariate and 
multivariate Cox regression model may be used to explore potential prognostic and/or predictive 
factors.
It is expected that Asian patients tend to have noticeably longer OS than non-Asian patients. 
Since JVCZ does not enroll patients from Asia while RAINBOW enrolled significant number of 
Asian patients, two additional exploratory analyses will be performed in attempt to account for 
such regional difference in the analyses of pooled individual patient data to compare 12mg/kg 
plus paclitaxel from JVCZ with placebo arm from Rainbow study. One is to adjust region 
(Asian and non-Asian) in the Cox regression model and the other is to use only the subgroup of 
non-Asian patients. 
Patient listings of tumor assessments (target and non-target lesion assessments and tumor 
response), PFS, and OS will be provided.
5.10.3. Subgroup Analyses
Progression-Free Survival and OS HR for treatment effect and its 95% CI will be estimated 
using the unstratified Cox PH model for each of the subgroups listed in Section 5.3.  A forest 
plot of the estimated HRs and their 95% CIs will be provided.  If the number of events in a 
particular subgroup is less than 10 from any arm, this subgroup will excluded from subgroup 
analysis and will not be presented in forest plot.
5.11. Post-Discontinuation Therapy
The numbers and percent of patients reporting post-discontinuation therapies will be provided 
overall, and by type of therapy (surgery, radiotherapy, or systemic therapy).  Surgery and 


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radiotherapy will be further characterized by intent.  Systemic therapy will be further categorized 
by WHO drug terms.
Additional analysis may be explored for helping interpret OS results, for example time to PDT or 
censoring at the start of PDT in OS analysis.
5.12. Safety Evaluation
5.12.1. Exposure
The following exposure-related variables will be reported using summary statistics (number of 
patients, mean, and standard deviation) by treatment group: 

Exposure:  duration of treatment; number of cycles received; number of patients 
completing ≥ one cycle, ≥ two cycles, …, ≥ six cycles, and mean, standard deviation; 
number of patients with dose adjustments: dose reduction, dose delay, and dose omission;

Reasons for dose adjustments.
The following exposure-related variables will be reported using summary statistics (number of 
patients, mean, standard deviation, median, 1st and 3rd quartiles, minimum, and maximum) by 
treatment group: 

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 patient listings.
5.12.2. Adverse Events
The most current version of MedDRA at time of analysis will be used when reporting AEs by 
MedDRA terms.  Unless otherwise specified, when summarized by PT, AEs will be presented in 
decreasing frequency of PT across treatment arms; when summarized by SOC and PT, AEs will 
be presented in decreasing frequency of PT within system organ class (SOC) across treatment 
arms.  If more than one AE is recorded for a patient within any SOC or PT term, the patient will 
only be counted once on the most severe grade and the closest relationship to treatment.
5.12.2.1. Overall Summary of Adverse Events
An overall summary of AEs will be provided to summarize the following categories using 
frequency counts and percentages: 

patients with at least one TEAE, SAE, Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 3 or 4 TEAE

patients with AEs that led to death (all, on study therapy, up to 30 days after treatment 
discontinuation or )

patients with SAEs that led to discontinuation.


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The summary will be provided for regardless of study drug causality, and repeated for events 
deemed by the investigator to be related to study treatment.  Comparison between the treatment 
groups will be performed using Fisher’s exact test.
5.12.2.2. Treatment-Emergent Adverse Events (TEAEs)
The following summaries of TEAEs by treatment arm will be provided (*repeated for events 
deemed by the investigator to be possibly related to study medication):

by PT*

by SOC and PT*

by maximum CTCAE grade and by SOC and PT*
Consolidated AE may be summarized for TEAE and study treatment-related TEAE.  A patient 
listing of all AEs will be provided.
5.12.3. Deaths, SAEs, and Other Significant AEs
Reasons for deaths (study disease, AE [any AE, study treatment related AE, study procedural 
related AE]) will be summarized separately for 1) all deaths, 2) deaths up to 30 days after 
treatment discontinuation, and 3) deaths after 30-day post treatment discontinuation. 
Serious adverse events will be summarized by SOC and PT, 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, †include consolidated summary):

Adverse events leading to death by PT†

Adverse events leading to study treatment discontinuations by PT†

Adverse events leading to study treatment dose modification by PT†

Adverse events of Special Interests SIs by PT*

Liver injury/failure*
Note: Liver injury/failure is analyzed separately from other AESIs because its analysis 
requires a different format. 

Listing of AESIs.
5.12.4. Clinical Laboratory Evaluation
The severity of laboratory results will be classified according to CTCAE Version 4.0.  The shifts
in CTCAE toxicity grading from baseline to worst grade postbaseline (first dose up to 30 days 
after discontinuation of study treatment) will be produced. 


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A patient 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.
5.12.5. Hospitalizations and Transfusions 
The frequency and percentage of patients with any hospitalizations experienced during the study 
treatment period or 30-day post treatment discontinuation will be summarized by treatment 
group.  Hospitalization incidence rates will be compared between the treatment groups using 
Fisher’s exact test.  In addition, total number of days in hospital and admissions will be 
summarized and compared using the Wilcoxon rank sum test.  These will be further 
characterized by reason (study-drug-related, Lilly-study-drug-related, non-study-drug-related).
Note:  Discharge date will be imputed with last contact date for hospitalizations that are still 
ongoing at time of analysis. 
The frequency and percentage of patients with any blood transfusions experienced during the 
study treatment period or 30-day post treatment discontinuation will be summarized by treatment 
group.  Transfusions will be further characterized by transfused blood product (e.g., packed red 
blood cells, platelets, fresh frozen plasma, or whole blood).  The proportions of patients having 
blood transfusions will be compared between the treatment groups using Fisher’s exact test.
Details of hospitalizations and transfusions will be included in patient listings.
5.12.6. Vital Signs, Physical Findings, and Other Observations Related 
to Safety
A summary of ECOG PS at each scheduled time point will be provided.  Actual value and 
change from baseline for vital sign measurements will be summarized at each assessment time 
point using summary statistics.  electrocardiogram (ECG), echocardiogram, and multiple-gated 
acquisition (MUGA) measurements will be summarized at each assessment time point using 
summary statistics.  Listings of ECOG PS, vital signs, ECG, echocardiogram, and MUGA data 
will be provided.
5.13. Pharmacokinetics and Immunogenicity
Serum concentrations of ramucirumab prior to infusion (minimum [Cmin]) and at 1 hour post-end 
of ramucirumab infusion (approximately maximum [Cmax]) will be summarized using descriptive 
statistics.  Additional analysis utilizing the population PK approach based on an established 
population PK model may also be conducted if deemed appropriate.  Relationships between 
ramucirumab exposure and measures of efficacy and safety will be explored if deemed 
appropriate.
For immunogenicity, the number and percent of patients with positive ramucirumab antibody 
response will be summarized.  Additional efficacy or safety analyses may be performed in the 
subgroup of patients with positive ramucirumab antibody response.  The antibody response and 
any alteration in ramucirumab PK may also be explored, as well as any relationship with 


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experiencing an infusion reaction.  Further exploratory analyses may be performed as 
appropriate.
5.14. Translational Research
Translational research analyses will be performed according to a separate analysis plan. 
5.15. Interim Analysis
An Assessment Committee (AC) internal to Lilly will be established prior to first patient visit.  
Interim analyses of safety and PK will be conducted after approximately a total of 80 and 160
patients complete 6 weeks of therapy or discontinue treatment due to any reason, whichever 
comes first.  The AC will review interim analyses of safety and PK data.  Study sites will receive 
information about interim results ONLY if they need to know for the safety of their patients.  
There will be no prespecified rules for stopping the trial due to safety concerns.  The AC will 
determine whether there are sufficient safety concerns to justify a change in the conduct of the 
study or the termination of study treatment and/or enrollment.
The AC comprises at least one physician (oncologist), one safety physician, one statistician, and 
one PK specialist responsible for the evaluation and interpretation of the results from the interim 
analysis.  One of the AC members is designated as chairperson.
Since this is an open-label study, the study statistical team will be responsible for conducting the 
interim analysis and delivering the interim analysis reports.  The study clinical trial manager will 
serve as AC secretary and be responsible for organizing meetings, ensuring that meeting logistics 
are established and recording minutes.
The following analyses will be performed for safety interim analysis:
Demographic and Other Baseline Characteristics

Patient demographics
Patient Disposition

Reasons for treatment discontinuation as well as patients continuing on the study
Exposure

Summary statistics for exposure-related variables

Dose intensity of study drugs

Reasons for dose adjustments and dose delays
Adverse Events

Overview of AEs

TEAEs summarized by PT

CTCAE Grade 3 and 4 TEAEs

Treatment-related TEAEs summarized by PT

Treatment-related CTCAE Grade 3 and 4 AEs

SAEs summarized by PT

AESIs

Reasons for deaths


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
AEs leading to study treatment discontinuations

AEs leading to study treatment dose modification

Listing of SAEs

Listing of preexisting conditions and AEs
5.16. Clinical Trial Registry Analyses
For the purpose of fulfilling the Clinical Trial Registry (CTR) requirements, summary of SAEs 
(whether treatment emergent or not) and ‘Other’ AEs (i.e., non-serious TEAEs) by PT and 
treatment group will be performed.  For each PT, the number of patients at risk, patients who 
experienced the event, and events will be presented.  In addition, the summary will be provided 
as a dataset in XML format.  


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6.
References
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53(282):457-481.


Leo Document ID = e53de6a2-1807-4825-b284-2bb330b76c53
Approver: 
Approval Date & Time: 15-Nov-2017 15:55:12 GMT
Signature meaning: Approved
PPD