Conditions: Gastroesophageal Junction Adenocarcinoma Gastric Adenocarcinoma
Keywords: Second line Angiogenesis Vascular endothelial growth factor receptor 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 440
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of the study drug known as ramucirumab in participants with gastric and gastroesophageal cancer.

Detailed description:

Arms:
arm 1: 8 mg/kg ramucirumab was administered as an intravenous infusion (IV) on days 1 and 15, in combination with 80 mg/m² paclitaxel administered by IV on days 1, 8, and 15 of every 28-day cycle.

Participants may continue on treatment until discontinuation criteria were met. arm 2: Placebo was administered at a volume equivalent to a dose of 8 mg/kg by IV on Days 1 and 15, in combination with 80 mg/m² paclitaxel administered by IV on Days 1, 8, and 15 of a 28-day cycle.

Participants may continue on treatment until discontinuation criteria were met.

Interventions: intervention 1: Ramucirumab intervention 2: Paclitaxel intervention 3: Placebo
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV intervention 3: Administered IV

Protocol document:
Prot_000.pdf: 
Protocol I4T-CR-JVCR (c) 
A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase 3 Study of Weekly 
Paclitaxel with or without Ramucirumab (IMC-1121B) in Patients with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma, Refractory to or Progressive after First-Line 
Therapy with Platinum and Fluoropyrimidine 
NCT02898077
Approval Date: 14-Mar-2019 


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1.
Protocol I4T-CR-JVCR(c)
A Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, Phase 3 Study of Weekly Paclitaxel 
with or without Ramucirumab (IMC-1121B) in Patients 
with Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma, Refractory to or Progressive after 
First-Line Therapy with Platinum and Fluoropyrimidine
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 (IMC-1121B, LY3009806), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Ramucirumab (IMC-1121B, LY3009806)
This is a randomized, placebo-controlled, double-blind, multicenter, Phase 3 study of 
patients with advanced gastric or gastroesophageal junction adenocarcinoma, refractory to 
or progressive after first-line therapy with platinum and fluoropyrimidine. Patients will be 
randomized to receive either paclitaxel plus ramucirumab or paclitaxel plus placebo.
Treatment will continue until disease progression, unacceptable toxicity, or meeting other 
treatment discontinuation criteria.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on: 17 December 2015
Amendment (a) Signed and Approved by Lilly on: 20 March 2017
Amendment (b) Signed and Approved by Lilly on:  25 Aug 2017
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below:
Approval Date: 14-Mar-2019 GMT


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2.
Synopsis
Study Rationale
In China, gastric cancer is the second most common cancer and is the third leading cause of 
cancer death. In the first-line setting in advanced gastric cancer, platinum/fluoropyrimidine 
regimens form the backbone of chemotherapy. Meanwhile, in the second-line setting, there has 
been no standard regimen established for gastric cancer to date. The high incidence and 
mortality of gastric cancer and relatively limited chemotherapeutic options after first-line therapy 
underpin the need for research in second-line therapeutic options.
One promising approach to the treatment of cancer is inhibition of angiogenesis by targeting the 
vascular endothelial growth factor (VEGF) pathway. Ramucirumab (IMC-1121B, LY3009806) 
is a recombinant human monoclonal antibody that specifically binds to the extracellular domain 
of VEGF Receptor 2 (VEGFR-2) with high affinity as demonstrated in animal models. A Phase
3 global study (I4T-IE-JVBD [JVBD]) demonstrated that ramucirumab monotherapy plus best 
supportive care (BSC) following disease progression on initial therapy could improve overall 
survival (OS; median 5.2 months versus 3.8 months, hazard ratio [HR] = 0.776, 95% confidence 
interval [CI] = 0.603 to 0.998, p=.0473) and progression-free survival (PFS; median 2.1 months 
versus 1.3 months, HR = 0.483, 95% CI = 0.376 to 0.620, p<.0001) as compared with placebo 
plus BSC in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Furthermore, preclinical and clinical data have shown that the addition of agents targeting the 
VEGF pathway can improve the efficacy of chemotherapy, providing a rationale to investigate 
the efficacy and safety of adding ramucirumab to a commonly used second-line
chemotherapeutic drug such as paclitaxel in advanced gastric cancer. Accordingly, another
Phase 3 global study (I4T-IE-JVBE [JVBE]) was designed to demonstrate the superiority of
ramucirumab plus paclitaxel comparing with placebo plus paclitaxel in patients with advanced 
gastric or GEJ adenocarcinoma after failure of first-line therapy with platinum and 
fluoropyrimidine. Study JVBE demonstrated that ramucirumab plus paclitaxel as a combination 
therapy for patients improves OS (median 9.6 months versus 7.4 months, HR = 0.807, 95% CI =
0.678 to 0.962, p=.0169) and PFS (median 4.4 months versus 2.9 months, HR = 0.635, 95% CI =
0.536 to 0.752, p<.0001) as compared with paclitaxel monotherapy. Based on the results of 
these 2 Phase 3 studies, ramucirumab was approved by the United States Food and Drug 
Administration as a single agent, as well as in combination with paclitaxel, for the treatment of 
advanced or metastatic gastric or GEJ adenocarcinoma, with disease progression on or after prior 
fluoropyrimidine- or platinum-containing chemotherapy.
To further confirm the results of Study JVBE in a predominantly East Asian population, this
multicenter randomized study is designed to evaluate the efficacy and safety of paclitaxel plus 
ramucirumab versus paclitaxel plus placebo in patients with advanced gastric or GEJ 
adenocarcinoma, refractory to or progressive after first-line therapy with platinum and 
fluoropyrimidine.


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Clinical Protocol Synopsis:  Study I4T-CR-JVCR
Name of Investigational Product:  Ramucirumab (IMC-1121B, LY3009806)
Title of Study:  A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase 3 Study of Weekly 
Paclitaxel with or without Ramucirumab (IMC-1121B) in Patients with Advanced Gastric or Gastroesophageal 
Junction Adenocarcinoma, Refractory to or Progressive after First-Line Therapy with Platinum and 
Fluoropyrimidine
Number of Planned Patients:
   Entered:  500
   Randomized:  450
Phase of Development:  3
Length of Study:  
Planned first patient visit:  November 2016
Planned last patient visit:  July 2020
Planned interim analysis: An interim analysis is planned with a total of 256 PFS events.
Objectives:  The co-primary objective of this study is to evaluate PFS and OS in patients treated with paclitaxel 
plus ramucirumab (IMC 1121B) versus paclitaxel plus placebo as second-line treatment in patients with advanced
gastric or GEJ adenocarcinoma after failure of any platinum and fluoropyrimidine doublet with or without 
anthracycline (epirubicin or doxorubicin).
The secondary objectives of the study are to evaluate:

Time to progression

Objective response rate

Duration of objective response

Safety profile

Patient-reported outcome measures
In addition, exploratory objectives include:

To explore biomarkers relevant to gastric or GEJ adenocarcinoma or safety, efficacy, and mechanism of
action of ramucirumab.
Study Design:  This is a multicenter, randomized study evaluating the efficacy and safety of paclitaxel plus 
ramucirumab using a double-blind, placebo-controlled design. Approximately 450 patients will be randomized on 
a 2:1 ratio to receive either Arm A (paclitaxel plus ramucirumab) or Arm B (paclitaxel plus placebo) to observe at 
least 336 deaths. Randomization will be stratified by Eastern Cooperative Oncology Group performance status 
(ECOG PS) (0 versus 1) and peritoneal metastases (yes versus no).
Patients will continue to receive all treatments until there is radiographic or symptomatic progression of disease, 
toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Patients will undergo radiographic 
assessment of disease status according to the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1, every 6 weeks (±5 days), following the first dose of study therapy for the first 6 months and every 
9 weeks (±5 days) thereafter, until documentation of radiographic progressive disease (PD). During 
postdiscontinuation follow-up, all patients will be followed for survival at regularly scheduled intervals (every 8 
weeks [+0 to 7 days]) for as long as the patient is alive, or until the study completion.
Diagnosis and Main Criteria for Inclusion and Exclusion:  Male and female patients (age ≥18 years) with 
histologically or cytologically confirmed advanced gastric or GEJ adenocarcinoma who have received at least 1
cycle of therapy with any platinum and fluoropyrimidine as first-line treatment of their gastric adenocarcinoma, 
and who have experienced documented disease progression during first-line therapy, or within 4 months after the 
last dose of first-line therapy prior to study entry, will be randomized and treated at the investigational centers.  
Test Product, Dosage, and Mode of Administration:  
Ramucirumab drug product (DP), injection for intravenous (IV) use, supplied in sterile, preservative-free,
single-use vials containing 500 mg/50-mL product, at a final concentration of 10 mg/mL in a histidine-buffered 
formulation, administered as an IV infusion at a dose of 8 mg/kg on Days 1 and 15 of a 4-week cycle.  The 
infusion should be delivered over approximately 60 minutes.  The infusion rate should not exceed 25 mg/minute.


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Reference Therapy, Dose, and Mode of Administration:  
Ramucirumab DP placebo injection for IV use, supplied in single-use 50-mL vials containing histidine buffer only.  
Because investigators and ancillary medical personnel will be blinded as to assignment to active therapy versus 
placebo, the volume of placebo to be administered will be calculated as if it were active product formulated at 10 
mg/mL (at a volume equivalent to a dose of 8 mg/kg) on Days 1 and 15 of a 4-week cycle.
Paclitaxel, administered over approximately 60 minutes according to manufacturer standards, at a dose of
80 mg/m2 on Days 1, 8, and 15 of a 4-week cycle.
Note:  Premedication is required prior to infusion of paclitaxel according to the manufacturer’s instructions and 
local standards.  Premedication may consist of dexamethasone 20 mg orally administered approximately 12 and 6 
hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and
cimetidine 300 mg or ranitidine 50 mg IV 30 to 60 minutes before paclitaxel.  An antiemetic (such as ondansetron 
8 mg IV or equivalent) administered 30 to 120 minutes before paclitaxel is recommended.
Planned Duration of Treatment:  
Study treatment period: A treatment cycle will be defined as 28 days (4 weeks) in each arm and include the period 
of treatment with paclitaxel given on Days 1, 8, and 15, in combination with either ramucirumab or ramucirumab 
placebo given on Days 1 and 15.  The period during which no treatment will be administered is required for 
patients to recover from toxicities to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE), Version 4.03 Grade <2 or baseline (with the exception of alopecia), and is expected to last 
for 14 days.  Patients will continue to receive all treatments until there is radiographic or symptomatic progression 
of disease, toxicity requiring cessation, protocol noncompliance, or withdrawal of consent.
Short-term follow-up period (postdiscontinuation):  Approximately 30 days (no more than 37 days).
Long-term follow-up period (postdiscontinuation):  After the decision is made to discontinue study treatment, 
follow-up information regarding further anticancer treatment and survival status will be collected at least every 
8 weeks (+0 to 7 days).  For patients who discontinue treatment for any reason other than radiographically 
documented PD (for example, symptomatic deterioration), information on disease progression (radiographic 
assessment) will also be collected until PD is documented by imaging.  Follow-up will continue as long as the 
patient is alive, or until study completion, whichever is first.


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Criteria for Evaluation:  
Efficacy: 
Progression-free survival is defined as the time from the date of randomization to the date of the first 
radiographically documented PD as defined by RECIST, Version 1.1, or death due to any cause,
whichever is first.
Overall survival is defined as the time from the date of randomization to the date of death from any 
cause.
Time to progression is defined as the time from the date of randomization to the date of the first 
radiographically documented PD as defined by RECIST, Version 1.1.
Objective response rate is defined as the proportion of randomized patients achieving a best overall 
response of partial response (PR) or complete response (CR).  
Duration of objective response is measured from the time measurement criteria first met for CR or PR 
(whichever is first recorded) to the date of the first radiographically documented PD as defined by 
RECIST, Version 1.1, or death due to any cause, whichever is first.
Assessment for response, according to RECIST, Version 1.1, will be performed every 6 weeks (±5 days) following 
the first dose of study therapy for the first 6 months, and every 9 weeks (±5 days) thereafter, until documentation of 
radiographic PD.
Safety:  
Safety will be evaluated based on reported adverse events (AEs), clinical laboratory assessments, vital signs, and 
physical examinations. Adverse events will be coded using the Medical Dictionary for Regulatory Activities.
Clinical laboratory toxicity and AEs will be graded using the NCI-CTCAE, Version 4.03.
Health Outcomes:
The assessment of quality of life and health status will be conducted using the European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30), and EuroQol-5 Dimension-3 Level 
(EQ-5D-3L), respectively.
Translational Research: 
Whole blood samples may be used for DNA/genotype analysis and may include an examination of genes 
associated with angiogenesis, the mechanism of ramucirumab, and/or cancer, including but not limited to, 
VEGFR-2 and VEGF-A. Plasma samples may be analyzed for potential pharmacodynamic markers, including, but 
not necessarily limited to, placental growth factor, VEGF-A, VEGF-C, VEGF-D, soluble VEGFR-1, and soluble 
VEGFR-2. In addition, collection of tumor tissue samples will be strongly recommended for potential evaluation 
of tumor-specific mutations, VEGFR-2 expression, VEGFR-2 copy number variability, and other cancer-
associated biomarkers.


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Statistical Methods:  
Statistical:  
Approximately 450 patients will be randomized to the 2 treatment arms in a 2:1 ratio (300 patients in Arm A 
[paclitaxel plus ramucirumab] and 150 patients in Arm B [paclitaxel plus placebo]) in order to obtain at least 336 
deaths. Assuming an exponential distribution in each arm and a true underlying HR of 0.81 as observed in the 
global study, 336 deaths will provide at least 80% probability to assure that the effect size observed in this study is 
consistent with the global study. Also assuming a constant accrual rate of 12 patients/month, a median OS of 10.5 
months in Arm B and a median OS of 13 months in Arm A, the study will take approximately 44 months to obtain 
the required 336 deaths (37 months for accrual and 7 months for the follow-up). The primary PFS analysis and an 
interim OS analysis will be performed when at least 256 PFS events have occurred.
Efficacy:
The analysis of PFS/OS in this study is to estimate the HR and its 2-sided 95% CIs in a stratified Cox’s 
proportional hazards model using treatment arm as a single covariate.  The stratification factors included in the 
Cox model are ECOG PS (0 versus 1) and peritoneal metastases (yes versus no). A sensitivity analysis with an 
unstratified Cox proportional hazards model will be employed.  Stratified (using the same stratification factor) and 
unstratified log-rank tests will also be conducted. The survival curves for each randomized arm will be estimated 
using the Kaplan-Meier (KM) product-limit method.  Two-sided, 95% CIs for median PFS/OS will be computed 
by the Brookmeyer and Crowley method.  Landmark survival rates will also be estimated using KM estimates on 
the survival curve for each randomized arm.  Associated 2-sided 95% CIs will also be calculated.
Safety:
Safety analyses will be performed on all randomized patients who receive at least 1 dose of study treatment. 
Safety analyses will include summaries of the incidence of AEs by maximum CTCAE grade (Version 4.03) that 
occur during the study treatment period or within 30 days after the decision is made to discontinue study treatment. 
Health Outcomes:
QLQ-C30 and EQ-5D-3L analyses will be performed on all randomized patients with 1 baseline assessment and ≥1 
postbaseline assessment. They will be analyzed descriptively by treatment arm.  
Translational Research:
Translational research will be performed to analyze relevant biomarkers and their correlation to clinical outcomes.


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3.
Table of Contents
A Randomized, Multicenter, Double-Blind, 
Placebo-Controlled Phase 3 Study of Weekly Paclitaxel with 
or without Ramucirumab (IMC-1121B) in Patients with 
Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma, Refractory to or Progressive after
First-Line Therapy with Platinum and Fluoropyrimidine
Section
Page
1.
Protocol I4T-CR-JVCR(c) A Randomized, Multicenter, Double-
Blind, Placebo-Controlled, Phase 3 Study of Weekly Paclitaxel with 
or without Ramucirumab (IMC-1121B) in Patients with Advanced 
Gastric or Gastroesophageal Junction Adenocarcinoma, Refractory to 
or Progressive after First-Line Therapy with Platinum and 
Fluoropyrimidine ................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................14
5.
Introduction ......................................................................................................................19
6.
Objectives.........................................................................................................................22
6.1.
Primary Objective ........................................................................................................22
6.2.
Secondary Objectives...................................................................................................22
6.3.
Exploratory Objectives.................................................................................................22
7.
Study Population...............................................................................................................23
7.1.
Inclusion Criteria..........................................................................................................23
7.2.
Exclusion Criteria ........................................................................................................25
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................27
7.3.
Discontinuations ..........................................................................................................27
7.3.1.
Discontinuation of Patients...................................................................................28
7.3.1.1.
Discontinuation from All Study-Related Therapy ...........................................28
7.3.1.2.
Discontinuation from Ramucirumab/Placebo Therapy....................................29
7.3.1.3.
Discontinuation from Paclitaxel Therapy........................................................30
7.3.1.4.
Continuation of Therapy On-Study in the Setting of 
Discontinuation of One Component of Therapy..............................................30
7.3.2.
Discontinuation of Study Sites .............................................................................31
7.3.3.
Discontinuation of the Study................................................................................31
8.
Investigational Plan...........................................................................................................32


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8.1.
Summary of Study Design............................................................................................32
8.1.1.
Baseline and Study Period Assessments ...............................................................34
8.1.1.1.
Screening/Baseline .........................................................................................34
8.1.1.2.
Treatment Period............................................................................................35
8.1.2.
Postdiscontinuation Follow-Up ............................................................................36
8.1.2.1.
Short-Term Follow-Up ...................................................................................37
8.1.2.2.
Long-Term Follow-Up ...................................................................................37
8.1.3.
Study Completion and End of Trial......................................................................38
8.1.4.
Extension Period..................................................................................................39
8.2.
Discussion of Design and Control ................................................................................40
9.
Treatment..........................................................................................................................41
9.1.
Treatments Administered .............................................................................................41
9.1.1.
Premedication ......................................................................................................41
9.1.2.
Ramucirumab Drug Product or Placebo................................................................42
9.1.3.
Paclitaxel .............................................................................................................43
9.2.
Materials and Supplies .................................................................................................43
9.2.1.
Ramucirumab Drug Product.................................................................................43
9.2.2.
Ramucirumab Drug Product Placebo....................................................................44
9.2.3.
Paclitaxel .............................................................................................................44
9.3.
Method of Assignment to Treatment ............................................................................44
9.4.
Selection and Timing of Doses.....................................................................................44
9.4.1.
Special Treatment Considerations ........................................................................44
9.4.1.1.
Treatment Requirements and Delays...............................................................44
9.4.1.1.1.
Requirements Prior to Day 1 of Each Treatment 
Cycle ........................................................................................................44
9.4.1.1.2.
Requirements Prior to Days 8 and 15 of Each 
Treatment Cycle .......................................................................................46
9.4.2.
General Dose Modifications:  Ramucirumab ........................................................47
9.4.2.1.
Treatment Guideline and Dose modification for Specific 
Adverse Events of Ramucirumab....................................................................47
9.4.2.1.1.
Ramucirumab Infusion-Related Reactions ................................................48
9.4.2.1.2.
Hypertension ............................................................................................51
9.4.2.1.3.
Thromboembolic Events...........................................................................52
9.4.2.1.4.
Bleeding (Hemorrhagic) Events................................................................53
9.4.2.1.5.
Proteinuria ................................................................................................53
9.4.2.1.6.
Gastrointestinal Perforation.......................................................................53
9.4.2.1.7.
Fistula Formation......................................................................................54


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9.4.2.1.8.
Congestive Heart Failure in Patients Who Received 
Ramucirumab in Combination with Mitoxantrone or 
Following Prior Anthracycline Therapy ....................................................54
9.4.2.1.9.
Surgery and Impaired Wound Healing ......................................................54
9.4.2.1.10.
Liver Injury/Liver Failure .........................................................................54
9.4.2.1.11.
Reversible Posterior Leukoencephalopathy Syndrome ..............................55
9.4.3.
General Dose Modifications:  Paclitaxel...............................................................56
9.4.3.1.
Treatment Guideline and Dose Modification for Specific 
Adverse Events of Paclitaxel ..........................................................................56
9.4.3.1.1.
Paclitaxel Hypersensitivity Reactions .......................................................56
9.5.
Blinding .......................................................................................................................57
9.5.1.
Emergency Unblinding ........................................................................................57
9.5.2.
Inadvertent Unblinding ........................................................................................57
9.6.
Concomitant Therapy...................................................................................................57
9.6.1.
Antidiarrheal Agents............................................................................................58
9.6.2.
Antiemetic Agents................................................................................................58
9.6.3.
Analgesic Agents .................................................................................................58
9.6.4.
Appetite Stimulants..............................................................................................58
9.6.5.
Granulocyte-Colony Stimulating Factors..............................................................58
9.6.6.
Erythroid Growth Factors.....................................................................................59
9.7.
Treatment Compliance .................................................................................................59
10.
Efficacy, Patient-Reported Outcomes, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of Measurements .........................................60
10.1. Efficacy Measures........................................................................................................60
10.1.1.
Efficacy Assessments at Baseline and During Study 
Treatment.............................................................................................................60
10.1.2.
Efficacy Assessments During the Study Period 
Postdiscontinuation Follow-Up ............................................................................60
10.1.3.
Primary Efficacy Measure....................................................................................60
10.1.4.
Secondary Efficacy Measures...............................................................................61
10.2. Health Outcome/Quality of Life Measures ...................................................................62
10.2.1.
Patient-Reported Outcomes..................................................................................62
10.2.1.1.
EORTC QLQ-C30..........................................................................................62
10.2.1.2.
EQ-5D-3L ......................................................................................................62
10.3. Safety Evaluations........................................................................................................62
10.3.1.
Adverse Events ....................................................................................................63
10.3.1.1.
Serious Adverse Events ..................................................................................64
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................65
10.3.2.
Safety Monitoring ................................................................................................65


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10.3.3.
Complaint Handling.............................................................................................66
10.4. Sample Collection and Testing.....................................................................................66
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................66
10.4.2.
Samples for Translational Research......................................................................67
10.5. Appropriateness of Measurements................................................................................69
11.
Data Quality Assurance.....................................................................................................70
11.1. Data Capture System....................................................................................................70
12.
Sample Size and Statistical Methods .................................................................................71
12.1. Determination of Sample Size ......................................................................................71
12.2. Statistical and Analytical Plans.....................................................................................71
12.2.1.
General Considerations ........................................................................................71
12.2.2.
Patient Disposition...............................................................................................72
12.2.3.
Patient Characteristics..........................................................................................72
12.2.4.
Concomitant Therapy...........................................................................................72
12.2.5.
Treatment Compliance .........................................................................................72
12.2.6.
Primary Outcome and Methodology.....................................................................72
12.2.6.1.
Progression-free Survival................................................................................72
12.2.6.2.
Overall Survival .............................................................................................73
12.2.7.
Secondary Efficacy Analyses ...............................................................................73
12.2.8.
Health Outcome/Quality of Life Analyses............................................................74
12.2.9.
Safety Analyses....................................................................................................75
12.2.10. Subgroup Analyses ..............................................................................................75
12.2.11. Statistical Analysis for Translational Research .....................................................76
12.2.12. Interim Analyses and Data Monitoring.................................................................76
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................77
13.1. Informed Consent.........................................................................................................77
13.2. Ethical Review.............................................................................................................77
13.3. Regulatory Considerations ...........................................................................................77
13.3.1.
Investigator Information.......................................................................................78
13.3.2.
Protocol Signatures ..............................................................................................78
13.3.3.
Final Report Signature .........................................................................................78
14.
References ........................................................................................................................79


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List of Tables
Table
Page
Table JVCR 9.1.
Criteria for Paclitaxel Treatment on Day 1 of Each Cycle.......................45
Table JVCR 9.2.
Criteria for Ramucirumab Treatment on Day 1 of Each Cycle ................45
Table JVCR 9.3.
Criteria for Paclitaxel Treatment on Days 8 and 15 of Each Cycle ..........46
Table JVCR 9.4.
Criteria for Ramucirumab Treatment on Day 15 of Each Cycle ..............46
Table JVCR 9.5.
NCI-CTCAE, Version 4.03, Infusion-Related Reactions.........................49


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List of Figures
Figure
Page
Figure JVCR 8.1.
Illustration of study design for Study I4T-CR-JVCR...............................32
Figure JVCR 8.2.
Study completion, the extension period, and the end of trial....................39


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List of Attachments
Attachment
Page
Attachment 1.
Protocol JVCR Study Schedule – Study Period.......................................83
Attachment 2.
Protocol JVCR Study Schedule – Study Extension Period ......................87
Attachment 3.
Protocol JVCR Clinical Laboratory Tests ...............................................88
Attachment 4.
Protocol JVCR Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................89
Attachment 5.
Protocol JVCR Sampling Schedule for Translational Research...............90
Attachment 6.
Protocol JVCR Eastern Cooperative Oncology Group (ECOG) 
Performance Status.................................................................................91
Attachment 7.
Protocol JVCR Response Evaluation Criteria in Solid Tumors 
(RECIST) Criteria, Version 1.1 ..............................................................92
Attachment 8.
Protocol JVCR Creatinine Clearance Formula ........................................99
Attachment 9.
Protocol JVCR Amendment(c) Summary
A Randomized, Multicenter, Double-Blind, Placebo-Controlled, 
Phase 3 Study of Weekly Paclitaxel with or without Ramucirumab 
(IMC-1121B) in Patients with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma, Refractory to or 
Progressive after First-Line Therapy with Platinum and 
Fluoropyrimidine..................................................................................100


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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product 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.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and risks involved in participating 
in a study (required by some institutional review boards [IRBs]). 
AST
aspartate aminotransferase
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).
bFGF
basic fibroblast growth factor
blinding/masking
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.  
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
BOR
best overall response
BP
blood pressure
BSC
best supportive care
CHF
congestive heart failure
CI
confidence interval
companion diagnostic
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product


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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.
CR
complete response
CrCl
creatinine clearance
CRF/eCRF
case report form/electronic case report form (sometimes referred to as clinical report 
form):  A printed or electronic form for recording study participants’ data during a 
clinical study, as required by the protocol.
CRP
clinical research physician:  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.
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DC101
mouse antibody counterpart of ramucirumab
DCR
disease control rate
DOR
duration of objective response
DP
drug product
ECG
electrocardiogram
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 directly or 
through their legally acceptable representatives.
EORTC
European Organization for Research and Treatment of Cancer
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient 
(includes short-term follow-up).  
EQ-5D-3L
EuroQol-5 Dimension-3 Level Questionnaire
ERB/IRB
ethical review board/institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical and nonmedical members whose 
responsibility is to verify that the safety, welfare, and human rights of the patients 
participating in a clinical trial are protected.


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extension period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit may continue to receive study 
therapy until one of the criteria for discontinuation is met.
FDA
Food and Drug Administration
GCP
good clinical practice
GEJ
gastroesophageal junction
GI
gastrointestinal
GPS
Global Patient Safety
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IMC-1121B
ramucirumab, LY3009806
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
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
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.
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.


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IV
intravenous
IWRS
interactive web response system
KM
Kaplan-Meier product-limit method
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.
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MUGA
multi-gated acquisition scan
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
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
PlGF
placental growth factor
PPS
per protocol set:  The set of data generated by the subset of patients who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PR
partial response
PRO
patient-reported outcome
PS
performance status
PVC
polyvinyl chloride
QLQ-C30
Quality of Life Questionnaire Core 30
QoL
quality of life
randomize
The process of assigning patients to an experimental group on a random basis.
RECIST
Response Evaluation Criteria in Solid Tumors


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rescreen
To screen a patient who was previously declared a screen failure for the same study.
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, x-rays, 
CT/MRI, 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
SDF1a
stromal cell-derived factor 1a
study completion
This study will be considered complete after the final analyses of overall survival are
performed.  
SUSARs
suspected unexpected serious adverse reactions 
TTP
time to progression
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WOCBP
women of child-bearing potential


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A Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, Phase 3 Study of Weekly Paclitaxel with 
or without Ramucirumab (IMC-1121B) in Patients with 
Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma, Refractory to or Progressive after
First-Line Therapy with Platinum and Fluoropyrimidine
5.
Introduction
Gastric cancer is a common malignancy with significant mortality rates; two-thirds of patients 
present with advanced disease at diagnosis (Pozzo and Barone 2008). In China, gastric cancer is 
the second most common cancer and the third leading cause of cancer death (Chen et al. 2015).  
The National Central Cancer Registry reported that there were 420,489 new cases and 297,496
deaths in 2011 (Chen et al. 2015). Because of its significant mortality rates and poor prognosis, 
new treatments are urgently required.
In the past decade, cytotoxic chemotherapy remains the cornerstone of treatment for gastric 
cancer. In the first-line setting in advanced gastric cancer, platinum/fluoropyrimidine regimens 
form the backbone of chemotherapy. Triplet regimens, such as adding an anthracycline or 
taxane, result in better outcomes. However, triplet regimens are reserved only for selected 
patients due to toxicity. Meanwhile, in the second-line setting, there has been no standard 
regimen established for gastric cancer to date. Several Phase 3 trials have demonstrated that 
monotherapies in second-line, such as paclitaxel, docetaxel, and irinotecan, are superior to best 
supportive care (BSC), resulting in longer survival (Thuss-Patience et al. 2011; Kang et al. 2012; 
Hironaka et al. 2013; Ford et al. 2014). Weekly administration of paclitaxel (at a dose of 80 
mg/m2) has become a common practice for second-line treatment in gastric cancer. However, 
only marginal improvements in patient outcomes have been achieved.
The progress of targeted therapy in gastric cancer has been slow as compared with other
common cancers, such as breast, colorectal, and lung cancers. With the results of ToGA trial, 
trastuzumab in combination with chemotherapy has demonstrated a survival benefit as first-line 
therapy in human epidermal growth factor 2 positive gastric cancer patients (Bang et al. 2010).
Many other molecular targeted agents are still undergoing clinical trials.
Vascular endothelial growth factor (VEGF) is expressed in gastric cancer, and it has been 
associated with more aggressive clinical disease (Feng et al. 2002). Previous studies showed that 
VEGF inhibition was effective in inhibiting gastric cancer growth (Jung et al. 2002).  The 
AVAGAST trial, designed to evaluate the efficacy and safety of adding bevacizumab to 
fluoropyrimidine-cisplatin in the first-line treatment of advanced gastric cancer, was the first 
Phase 3 evaluation of an antiangiogenic agent with chemotherapy in advanced gastric cancer.  
However, this trial did not reach its primary objective; the median overall survival (OS) was 
12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo 
plus fluoropyrimidine-cisplatin (hazard ratio [HR] = 0.87; 95% confidence interval [CI] = 0.73 to 


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1.03; p=.1002) (Ohtsu et al. 2011). Regional analysis indicated that patients enrolled in North 
America and Latin America appeared to have a survival benefit with the addition of 
bevacizumab, whereas patients enrolled in Asia (90% from Japan and Korea) appeared to have 
no benefit. In Chinese patients with advanced gastric cancer, the results from the AVATAR trial 
also have demonstrated that bevacizumab plus capecitabine and cisplatin did not significantly 
improve outcomes (Shen et al. 2015). These results necessitate further investigation of agents 
targeting the VEGF pathway in gastric cancer by refining the selection of the patient population.
Ramucirumab (IMC-1121B, LY3009806) is a recombinant human immunoglobulin G, subclass 
1 (IgG1) receptor-targeted monoclonal antibody (mAb) that specifically binds to the extracellular 
domain of vascular endothelial growth factor receptor 2 (VEGFR-2) with high affinity.  
Preclinical studies showed that the mouse antibody counterpart of ramucirumab (DC101) therapy 
is associated with significant reductions in tumor vascularity (as measured by cluster of 
differentiation 31 expression) and increase in endothelial and tumor apoptosis, resulting in reduced 
tumor growth in gastric cancer xenografts (Jung et al. 2002). DC101 has conferred enhanced 
antitumor effect when combined with cytotoxic agents, such as paclitaxel in murine models of 
human prostate and bladder cancers (Inoue et al. 2000; Sweeney et al. 2002).
A Phase 1 clinical study (I4T-IE-JVBM [JVBM]) has demonstrated that ramucirumab monotherapy, 
administered at doses ranging from 2 to 16 mg/kg every week in patients with advanced cancer, 
achieved an objective response rate (ORR) of 10.8% and a disease control rate (DCR) of 64.9% 
(Spratlin et al. 2010). In particular, 1 patient with gastric cancer had confirmed partial response (PR)
lasting 103 weeks.  In a Phase 3 global study (I4T-IE-JVBD [JVBD]) in patients with advanced 
gastric or gastroesophageal junction (GEJ) adenocarcinoma, ramucirumab as a single agent plus BSC
versus placebo plus BSC, reduced the risk of death by 22% (HR = 0.776; 95% CI = 0.603 to 0.998; 
p=.0473), resulting in a 37% longer median survival in the ramucirumab arm (5.2 months versus
3.8 months, a difference of 1.4 months). Progression-free survival (PFS) was largely improved 
as well (median 2.1 months versus 1.3 months, HR = 0.483; 95% CI = 0.376 to 0.620; p<.0001). 
Additionally, ramucirumab was well tolerated in this patient population, as demonstrated by
similar rates between the ramucirumab and placebo arms for most adverse events (AEs). The 
most frequent AEs of Grade ≥3 were: hypertension (7.6% ramucirumab, 2.6% placebo); fatigue 
(6.4% ramucirumab, 10.0% placebo); anemia (6.4% ramucirumab, 7.8% placebo); abdominal pain 
(5.9% ramucirumab, 2.6% placebo); decreased appetite (3.4% ramucirumab, 3.5% placebo); and 
bleeding/haemorrhage (3.4% ramucirumab, 2.6% placebo) (Fuchs et al. 2014).
Furthermore, the possibility of combining ramucirumab with an active chemotherapeutic drug 
was also explored. Preclinical and clinical data have shown that the addition of agents targeting 
the VEGF pathway can improve the efficacy of taxane regimens (Enzinger et al. 2006; Shah et al. 
2011). A Phase 1b study (I4T-IE-JVBW [JVBW]) investigating weekly paclitaxel with
ramucirumab in 6 Japanese patients with advanced gastric adenocarcinomas demonstrated that 
the combination was safe and well-tolerated.  There were no dose-limiting toxicities in this 
study. The DCR and the ORR were 100% and 16.7%, respectively (Ueda et al. 2015). The
Phase 3 global study (I4T-IE-JVBE [JVBE]) was designed to demonstrate efficacy in patients
treated with paclitaxel plus ramucirumab compared to patients treated with paclitaxel plus 


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placebo as second-line treatment in metastatic gastric or GEJ adenocarcinoma after failure of any 
platinum and fluoropyrimidine doublet with or without anthracycline (epirubicin or 
doxorubicin). Study JVBE demonstrated that ramucirumab plus paclitaxel as a combination 
therapy for patients with advanced gastric cancer improves OS (median 9.6 months versus 7.4
months, HR = 0.807; 95% CI = 0.678 to 0.962; p=.0169) and PFS (median 4.4 months versus
2.9 months, HR = 0.635; 95% CI = 0.536 to 0.752; p<.0001) as compared with paclitaxel
monotherapy (Wilke et al. 2014). Based on these results, ramucirumab was approved by the 
United States Food and Drug Administration (FDA) as a single agent, as well as in combination 
with paclitaxel, for treatment of advanced or metastatic gastric or GEJ adenocarcinoma, with 
disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
Besides second-line treatment, there is another ongoing Phase 3 study (I4T-MC-JVCU [JVCU]) 
investigating efficacy and safety of capecitabine (or 5-fluorouracil) and cisplatin with or without 
ramucirumab in the first-line setting of metastatic gastric or GEJ adenocarcinoma. 
To investigate the same combination regimen in a predominantly East Asian population, this
confirmatory study is specifically designed to evaluate the efficacy and safety of ramucirumab in 
combination with paclitaxel in patients with advanced gastric or GEJ adenocarcinoma that have 
failed standard therapy with platinum and fluoropyrimidines.
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of ramucirumab may be found in the Investigator’s Brochure (IB).  Information on AEs expected 
to be related to the investigational product may be found in Section 7 (Development Core Safety 
Information) of the IB.  Information on serious adverse events (SAEs) expected in the study 
population independent of drug exposure and that will be assessed by the sponsor in aggregate, 
periodically during the course of the study, may be found in Section 6 (Effects in Humans) of the 
IB.


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6.
Objectives
6.1.
Primary Objective
The co-primary objective of this study is to evaluate PFS and OS in patients treated with 
paclitaxel plus ramucirumab (IMC-1121B, LY3009806) versus paclitaxel plus placebo as 
second-line treatment in patients with advanced gastric or GEJ adenocarcinoma after failure of 
any platinum and fluoropyrimidine doublet with or without anthracycline (epirubicin or 
doxorubicin).
6.2.
Secondary Objectives
Secondary objectives are to evaluate:

Time to progression (TTP)

ORR

Duration of objective response (DOR)

Safety profile

Patient-reported outcome (PRO) measures
6.3.
Exploratory Objectives
The exploratory objectives of the study include:

To explore biomarkers relevant to gastric or GEJ adenocarcinoma or safety, efficacy, and 
mechanism of action of ramucirumab.


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7.
Study Population
Male and female patients (age ≥18 years) with histologically or cytologically confirmed 
advanced gastric or GEJ adenocarcinoma who have received at least 1 cycle of therapy with any 
platinum and fluoropyrimidine as first-line treatment of their gastric adenocarcinoma, and who 
have experienced documented disease progression during first-line therapy, or within 4 months 
after the last dose of first-line therapy prior to study entry, will be randomized and treated at the 
investigational centers. A record of the most recent cancer- and noncancer-related 
screening/baseline evaluations will be reviewed to determine the eligibility of a patient for this 
study.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. If a patient is considered for rescreening, the investigator must contact the Lilly 
Medical Monitor or designee. Individuals may be rescreened up to 2 times. The interval 
between rescreenings should be at least 1 week.  Each time rescreening is performed, the 
individual must sign a new informed consent form (ICF) and will be assigned a new 
identification number.
Study participants should be instructed not to donate blood or blood products during the study or 
for 12 weeks following the last dose of study drugs.
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Have provided signed informed consent prior to any study-specific procedures
and are amenable to compliance with protocol schedules and testing.
[2]
Are at least 18 years of age (or of an acceptable age according to local 
regulations, whichever is older) at the time of randomization.
[3]
Have an Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) of 0 or 1 at study entry (see Attachment 6).
[4]
Have a histopathologically or cytologically confirmed diagnosis of gastric or 
GEJ adenocarcinoma.
[5]
Have metastatic disease or locally advanced, unresectable disease.
[6]
Have at least 1 measurable lesion based on Response Evaluation Criteria in Solid 
Tumors (RECIST), Version 1.1 (see Attachment 7).  Positron emission 
tomography (PET) scans and ultrasounds may not be used for diagnostic 
purposes.


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[7]
Have experienced documented objective radiographic or symptomatic disease 
progression (for example, any new or worsening malignant effusion 
documented by ultrasound examination) which may be confirmed by 
pathologic criteria (histology and/or cytology) if appropriate, during first-line 
therapy, or within 4 months after the last dose of first-line therapy with any 
platinum/fluoropyrimidine doublet (acceptable prior platinum agents are 
cisplatin, carboplatin, or oxaliplatin; acceptable prior fluoropyrimidine agents 
are 5-fluorouracil, capecitabine, or S-1) with or without anthracycline 
(epirubicin or doxorubicin) for unresectable or metastatic disease.
[8]
Have resolution to Grade ≤1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03, of all 
clinically significant toxic effects of chemotherapy, surgery, radiotherapy, or 
hormonal therapy (with the exception of alopecia), except where otherwise 
noted in this eligibility criteria.
[9]
Have adequate organ function, defined as:

Total bilirubin ≤1.5 times (×) the upper limit of normal (ULN), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤3× ULN for 
AST/ALT if no liver metastases, ≤5× ULN if liver metastases.

Serum creatinine ≤1.5× ULN or calculated creatinine clearance (CrCl; per 
the Cockcroft-Gault [1976] formula or equivalent and/or 24-hour urine 
collection) ≥50 mL/min (Cockcroft and Gault 1976; see Attachment 8).

Absolute neutrophil count (ANC) ≥1.5× 109/L, hemoglobin ≥9 g/dL 
(5.58 mmol/L; packed red blood cell transfusions are not allowed within 
1 week prior to baseline hematology profile), and platelets ≥100× 109/L.

International Normalized Ratio (INR) ≤1.5 or prothrombin time ≤1.5×
ULN.

Partial thromboplastin time/activated partial thromboplastin time
(PTT/aPTT) ≤1.5× ULN.
[10] Have urinary protein ≤1+ on dipstick or routine urinalysis. If urine dipstick or 
routine analysis indicates proteinuria ≥2+, then a 24-hour urine sample must 
be collected and must demonstrate <1000 mg of protein in 24 hours to allow 
participation in the study.


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[11] If female, are surgically sterile, postmenopausal, or compliant with a highly 
effective contraceptive method (failure rate <1%) during and for 12 weeks 
after the treatment period (oral hormonal contraception alone is not considered 
highly effective and must be used in combination with a barrier method).  If 
male, are surgically sterile or compliant with a highly effective contraceptive 
regimen during and for 6 months after the treatment period.  The label (for 
example, Summary of Product Characteristics, United States Package Insert, 
and so on) requirements with regard to the methods and duration of 
contraception during and after treatment with paclitaxel can differ between 
countries.  Country specific requirements will apply only if they are more 
stringent than those already stipulated in the protocol.
[12] Have an estimated life expectancy of at least 12 weeks, in the judgment of the 
investigator.
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[13] Have squamous cell or undifferentiated gastric cancer.
[14] Have undergone major surgery within 28 days prior to randomization, or have 
had a central venous access device placement within 7 days prior to 
randomization, except if the procedure is minimally invasive (for example, 
introduction of peripherally inserted central catheter [PICC] line) and the 
investigator does not anticipate any significant bleeding.
[15] Have received any first-line chemotherapy other than platinum and 
fluoropyrimidine with or without anthracycline for advanced gastric or GEJ 
adenocarcinoma.
[16] Have received previous systemic chemotherapy with a cumulative dose of 
>900 mg/m2 of epirubicin or >400 mg/m2 of doxorubicin.
[17] Have received any previous systemic therapy (including investigational 
agents) targeting VEGF or the VEGFR signaling pathways.  Other previous 
targeted therapies (for example, trastuzumab) are permitted, if stopped at least 
28 days prior to randomization.
[18] Have a history of deep vein thrombosis, pulmonary embolism, or any other 
significant thromboembolism (venous port or catheter thrombosis or 
superficial venous thrombosis are not considered “significant”) during the 
3 months prior to randomization. 
[19] Are receiving therapeutic anticoagulation with warfarin, low-
molecular-weight heparin, or similar agents. Patients receiving prophylactic, 
low-dose anticoagulation therapy are eligible provided that the coagulation 
parameters defined in the inclusion criteria (INR ≤1.5) are met.


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[20] Are receiving ongoing therapy with nonsteroidal anti-inflammatory agents 
(NSAIDs; for example, indomethacin, ibuprofen, naproxen, or similar agents) 
or other antiplatelet agents (for example, clopidogrel, ticlopidine, 
dipyridamole, and anagrelide). Aspirin (acetylsalicylic acid) at doses of 
≤325 mg/day is permitted.
[21] Have significant bleeding disorders, vasculitis, or had a significant bleeding 
episode from the gastrointestinal (GI) tract within 3 months prior to study 
entry.
[22] Have a history of GI perforation and/or fistulae within 6 months prior to 
randomization.
[23] Have symptomatic congestive heart failure (CHF; New York Heart 
Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
[24] Have experienced any arterial thromboembolic event, including myocardial 
infarction, unstable angina, cerebrovascular accident, or transient ischemic 
attack, within 6 months prior to randomization.
[25] Have uncontrolled arterial hypertension (systolic blood pressure ≥160 mmHg
or diastolic blood pressure ≥100 mmHg) despite standard medical 
management.
[26] Have a serious or nonhealing wound, peptic ulcer, or bone fracture within 
28 days prior to randomization.
[27] Have a bowel obstruction, history or presence of inflammatory enteropathy or 
extensive intestinal resection (hemicolectomy or extensive small intestine 
resection with chronic diarrhea), Crohn’s disease, ulcerative colitis, or chronic 
diarrhea. 
[28] Have a serious illness or medical condition(s) including, but not limited to the 
following:

Known human immunodeficiency virus infection or acquired 
immunodeficiency syndrome-related illness

Active or uncontrolled clinically serious infection

Previous or concurrent malignancy, except for basal or squamous cell skin 
cancer and/or in situ carcinoma of the cervix, or other solid tumors treated 
curatively and without evidence of recurrence for at least 3 years prior to 
the study

Uncontrolled metabolic disorders or other nonmalignant organ or systemic 
diseases or secondary effects of cancer that induce a high medical risk 
and/or make assessment of survival uncertain


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
Other severe acute or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with study 
participation or study drug administration, or may interfere with the 
interpretation of study results, and in the judgment of the investigator 
would make the patient ineligible for entry into this study

History or evidence of known central nervous system metastases or 
carcinomatous meningitis

Child-Pugh B cirrhosis (or worse)

Cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis

Known allergy or hypersensitivity to mAb treatment or any components 
used in the ramucirumab drug product (DP) preparation

Known allergy or hypersensitivity to paclitaxel or any components used in 
the paclitaxel preparation or other contraindication for taxane therapy.
[29] Are pregnant or breastfeeding.
[30] Are currently enrolled in, or have been discontinued within the last 28 days 
from, a clinical trial involving an investigational product or nonapproved use 
of a drug or device (other than the investigational drug/device used in this 
study), or 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.
7.2.1. Rationale for Exclusion of Certain Study Candidates
The exclusion criteria have been carefully selected by the sponsor to ensure their ethical and 
scientific acceptability, and to help establish specificity of the patient population for both 
efficacy and safety analyses.
Exclusion criteria [13] and [15] specify the patient population that is intended for enrollment. 
Exclusion criteria [14], [18] - [27] are for patient safety based on what is known about the side 
effect profile of an antiangiogenic agent such as ramucirumab. Exclusion criteria [17], [28], and 
[30] are to prevent previously administered systemic therapy targeting VEGF or the VEGFR 
signaling pathways, investigational therapy, or comorbidity, from confounding an assessment of 
safety/efficacy in this study.  Exclusion criterion [28] is also to prevent enrollment of patients 
whose prognosis may be particularly poor.  Exclusion criteria [16] and [29] are also written in 
the interest of patient safety.
7.3.
Discontinuations
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.


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7.3.1. Discontinuation of Patients
7.3.1.1.
Discontinuation from All Study-Related Therapy
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without investigational product.  Inadvertently 
enrolled patients may be maintained in the study and on investigational product 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 investigational product 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 investigational product.
In addition, the investigator should withdraw a patient from all study-related therapy for any of 
the following reasons:

Enrollment 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.

Investigator decision
o
The investigator decides that the patient should be discontinued from the study or 
study drugs.
o
If the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drugs occurs prior to introduction of the new 
agent.

Patient decision 
o
The patient or the patient’s designee (for example, parents or legal guardian) 
requests to be withdrawn from the study or study drug.  (If the patient withdraws 
consent to treatment, he or she may still enter long-term follow-up if follow-up 
consent is not withdrawn.)

Sponsor decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP).

Radiographic progression as defined in Attachment 7 or symptomatic progression of 
disease.

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient), which in the opinion of the investigator cannot be attributed to 
a specific study agent.


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
A Grade 3 to 4 infusion-related reaction (IRR) which in the opinion of the investigator 
cannot be attributed to a single study agent (considered at least possibly related to each 
study agent).

Any therapy-related event that is deemed life-threatening, regardless of grade.

Any event which would require study therapy to be modified by more than 2 dose 
reductions, or to be held for more than 28 days from the last administered dose, and is 
considered at least possibly related to both study agents (paclitaxel and 
ramucirumab/placebo).

An intercurrent illness or change in the patient’s condition that renders the patient 
unsuitable for further treatment, in the opinion of the investigator.

Protocol noncompliance with this study protocol.  Patients who miss appointments shall 
be contacted by site personnel to determine the reason for the missed appointment and to 
try to reschedule the appointment.  The date(s) the patient was contacted and the type of 
contact used should be recorded in the study documentation.
The reason and date for discontinuation will be collected for all patients.  All randomized 
patients who discontinue, regardless of whether they received study drug or not, will have 
procedures performed as shown in the Study Schedule (Attachment 1).
7.3.1.2.
Discontinuation from Ramucirumab/Placebo Therapy
The investigator may withdraw a patient from ramucirumab/placebo therapy for any of the 
following reasons:

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient) that is, in the opinion of the investigator, attributed to 
ramucirumab/placebo (and considered unrelated or unlikely related to paclitaxel).

A Grade 3 to 4 IRR that is attributed to ramucirumab (and unrelated or unlikely related to 
paclitaxel).

A Grade 3 to 4 arterial thromboembolic event.

Any Grade 3 to 4 venous thromboembolic event that is considered by the investigator to 
be life-threatening, or symptomatic and not adequately treated by anticoagulation 
therapy.

Any venous thromboembolic event occurring or intensifying during anticoagulant 
therapy.

A Grade 3 to 4 bleeding or hemorrhagic event.

Grade 4 hypertension or persistent/recurrent hypertension as detailed in Section 9.4.2.1.2.

Proteinuria >3 g/24-hours or persistent/recurrent proteinuria >2 g/24-hours, as detailed in 
Section 9.4.2.1.5.

Any Grade 4 (life-threatening) nonhematologic toxicity considered by the investigator to 
be possibly, probably, or definitely related to ramucirumab/placebo.

Gastrointestinal perforation.

Any Grade 3 to 4 events consistent with CHF.

Any event which would warrant ramucirumab/placebo therapy to be modified by more 
than 2 dose reductions or to be held for >28 days from the last administered dose, and is 


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clearly attributed to ramucirumab/placebo (that is, recurrent or persistent hypertension or 
proteinuria).

New occurrence of hepatic encephalopathy and/or hepatorenal syndrome resulting from 
liver cirrhosis.  
7.3.1.3.
Discontinuation from Paclitaxel Therapy
The investigator may withdraw a patient from paclitaxel therapy for any of the following 
reasons:

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient) and is, in the opinion of the investigator, clearly attributed to 
paclitaxel (and considered unrelated or unlikely related to ramucirumab/placebo)

A Grade 3 to 4 infusion reaction that is attributed to paclitaxel (and considered unrelated 
or unlikely related to ramucirumab/placebo).

Any event which would warrant paclitaxel therapy to be modified by more than 2 dose 
reductions or to be held for >28 days from the last administered dose, and is clearly 
attributed to paclitaxel (that is, recurrent or persistent neuropathy).
The Lilly Medical Monitor will be consulted before a patient is discontinued from the study due 
to paclitaxel intolerance.
7.3.1.4.
Continuation of Therapy On-Study in the Setting of Discontinuation of 
One Component of Therapy
If 1 therapeutic agent is permanently discontinued secondary to toxicity, then therapy with the 
other study agents should continue and the patient should remain on-study with full adherence to 
all protocol related requirements.  Patients who have paclitaxel discontinued may continue to 
receive ramucirumab/placebo on-study, provided they continue to meet entry criteria and do not 
have evidence of disease progression.  Patients who have ramucirumab/placebo discontinued 
(that is, in the setting of Grade 4 hypertension or proteinuria) may receive ongoing paclitaxel 
therapy on-study, provided they continue to meet entry criteria and do not have evidence of 
disease progression.
After termination of study therapy, 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.  If the reason for withdrawal from the trial is the death of 
the patient, the 2 options for categorizing withdrawal are either progressive disease (PD) or an 
AE (>1 AE may be documented as a reason for withdrawal).  Only 1 event will be recognized as 
the cause of death.  If a patient is discontinued from all study therapy:

The reasons for discontinuation should be documented in the patient’s medical record and 
electronic case report form (eCRF).

For patients who discontinue for reasons other than radiographic PD, radiographic 
assessment for tumor response should continue every 6 weeks (±5 days) following the 
first dose of study therapy for the first 6 months, and every 9 weeks (±5 days) thereafter, 
until documentation of radiographic PD.


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
A follow-up evaluation begins the day after the decision is made to discontinue study 
treatment and lasts approximately 30 days (no more than 37 days) as described in Section 
8.1.2.1.  The patient should be followed for survival at regularly scheduled intervals (at 
least every 8 weeks [+0 to 7 days]) for as long as he or she remains alive (until study 
completion as defined in Section 8.1.3); for additional details, please see Section 8.1.2.2. 
7.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.
7.3.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.




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Short-term follow-up begins 1 day after the patient and the investigator agree that 
the patient will no longer continue study treatment and lasts approximately 
30 days (no more than 37 days).  
Long-term follow-up begins 1 day after short-term follow-up is completed and 
continues until the patient’s death or overall study completion to collect additional 
data (for example, survival data).

Extension Period:  begins after study completion and ends at the end of trial.  During the 
extension period, patients on study therapy who continue to experience clinical benefit 
may continue to receive study therapy until one of the criteria for discontinuation is met.  
Crossover may be permitted to the control arm.  The extension period includes extension 
period follow-up.  
o
Extension Period Follow-Up:  begins 1 day after the patient and the investigator 
agree that the patient will no longer continue treatment in the extension period 
and lasts approximately 30 days (no more than 37 days).
Baseline radiographic assessment of disease will be performed within 21 days prior to 
randomization; first treatment will be administered within 7 days following randomization.
Patients in both arms will receive any necessary premedication (see Section 9.1.1) prior to the 
first infusion of study therapy at each treatment session.  Following necessary premedication, 
patients will receive the following treatments:

Experimental Arm A: 
o
Ramucirumab DP 8 mg/kg intravenous (IV) on Days 1 and 15 of every 28-day 
cycle
o
Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle

Placebo Arm B:
o
Ramucirumab DP placebo (administered at a volume equivalent to a dose of 
8 mg/kg) IV on Days 1 and 15 of every 28-day cycle
o
Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle
Administration of all therapeutic products will occur as described in Section 9.1.
A treatment cycle will be defined as 28 days (4 weeks) in each arm and includes the period of 
treatment with paclitaxel given on Days 1, 8, and 15, in combination with either ramucirumab or 
ramucirumab placebo given on Days 1 and 15.  The period during which no treatment will be 
administered is required for patients to recover from toxicities to NCI-CTCAE, Version 4.03 
criteria Grade <2 or baseline (with the exception of alopecia), and is expected to last 14 days.
Patients will undergo radiographic assessment of disease status every 6 weeks (±5 days) 
following the first dose of study therapy for the first 6 months, and every 9 weeks (±5 days) 
thereafter, until documentation of radiographic PD. Patients in both arms will continue to 
receive all treatments until there is radiographic or symptomatic progression of disease, toxicity 
requiring cessation, protocol noncompliance, or withdrawal of consent.  In case of treatment 
discontinuation for any reason other than radiographically confirmed PD, radiographic tumor 


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assessments will continue every 6 weeks (±5 days) following the first dose of study therapy for 
the first 6 months, and every 9 weeks (±5 days) thereafter, until documentation of radiographic 
PD.
Follow-up information regarding further anticancer treatment and survival status will be 
collected at least every 8 weeks (+0 to 7 days).  Long-term follow-up will continue as long as the 
patient is alive, or until study completion (as defined in Section 8.1.3), whichever is first.
Clinical assessments for safety will occur as described in Section 8.1 and Section 10.3.  Adverse 
event information will be collected approximately 30 days (no more than 37 days) after the 
decision is made to discontinue study treatment and until all SAEs and all therapy-related AEs 
have resolved, stabilized, returned to baseline, or been deemed irreversible.
Patients with evidence of sustained clinical benefit (that is, no disease progression) may continue 
to receive study drug(s) for long-term durations during the extension period.
Upon study completion (see Section 8.1.3), investigators and patients may be unblinded to study 
treatment assignment.
The Lilly CRP will notify investigators in the event of study closure.
8.1.1. Baseline and Study Period Assessments
8.1.1.1.
Screening/Baseline
Screening/baseline evaluations used to determine the patient’s study eligibility must be 
completed within 28 days prior to randomization unless otherwise specified.  Written informed 
consent must be obtained prior to any study-specific evaluations and prior to receiving treatment.  
All patients must undergo the following evaluations:

Demography (year of birth, sex, race/ethnicity)

Medical history (any preexisting toxicity within 28 days prior to randomization should be 
documented and recorded as part of the medical history)

Assessment of baseline toxicity/AEs and conditions (to be conducted within 14 days prior 
to randomization)

Physical examination (including height and weight measurements and calculation of body 
surface area; to be conducted within 14 days prior to randomization)

Vital signs (including temperature, pulse rate, respiratory rate, and blood pressure; within 
14 days prior to randomization)

ECOG PS evaluation (within 21 days prior to randomization)

Concomitant medication assessment, including all medications taken within 28 days prior 
to randomization (to be conducted within 14 days prior to randomization)

Hematology profile (within 7 days prior to randomization; packed red blood cell 
transfusions are not allowed within 1 week prior to baseline hematology profile)

Coagulation profile (within 7 days prior to randomization)

Full serum chemistry profile (within 7 days prior to randomization)

Urinalysis (within 14 days prior to randomization)


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
Serum β-human chorionic gonadotropin pregnancy test for women of child-bearing 
potential (WOCBP) (within 7 days prior to randomization)

Imaging studies (computed tomography [CT]/magnetic resonance imaging [MRI]) and 
tumor assessment as described in Section 10.1 (within 21 days prior to randomization)

Electrocardiogram (ECG; within 21 days prior to randomization)

Echocardiogram/multi-gated acquisition scan (MUGA; within 21 days prior to 
randomization)

Patient-reported outcomes assessment (within 14 days prior to randomization) using the 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) and the EuroQol-5 Dimension-3 Level (EQ-
5D-3L) questionnaire, to be completed at the beginning of the visit, before blood 
sampling or any extensive contact and consultation with the clinician/study investigator; 
such encounters may thereafter bias patient responses.  The instruments should be 
administered together and in sequence order, with the EORTC QLQ-C30 presented first, 
followed by presentation of the EQ-5D-3L.

Sampling for translational research as describe in Section 10.4.2.
Results of all screening/baseline evaluations must be reviewed by the principal investigator or 
his or her physician designee to ensure that all eligibility criteria have been satisfied prior to 
enrollment.  If a patient is not to be randomized, the reason for ineligibility must be recorded.
8.1.1.2.
Treatment Period
A series of clinical tests and procedures will be performed throughout the study as described 
below and in the Study Schedule (Attachment 1).
Evaluations/procedures to be performed prior to and at the completion of each infusion include:
Vital sign measurements, including temperature, pulse rate, respiration rate, and blood 
pressure, before and at the completion of each infusion of ramucirumab or placebo and 
before and at the completion of each infusion of paclitaxel.  If paclitaxel is administrated 
within 30 minutes after the completion of ramuciumab/placebo infusion, the 
measurement of vital signs before paclitaxel administration is optional.
Evaluations/procedures to be performed on Days 1, 8, and 15 of each cycle include:
Toxicity/AE assessment
Concomitant medication assessment
Hematology profile (within 36 hours prior to treatment [blood may be collected the 
morning of study therapy or the day before, results to be available and evaluated prior to 
start of infusion] on Days 1, 8, and 15 of each cycle until discontinuation of paclitaxel; 
thereafter, prior to the start [Day 1] of every 28-day cycle only. Baseline lab assessments 
can be used for dosing for Cycle 1 Day 1 if performed within 7 days prior to Cycle 1 Day 
1.)
Serum ALT, AST, and total bilirubin (within 36 hours prior to treatment [blood may be 
collected the morning of study therapy or the day before, results to be available and 
evaluated prior to start of infusion] on Days 1, 8, and 15 of each cycle until


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discontinuation of paclitaxel; thereafter, to be collected along with full serum chemistry 
profile prior to the start [Day 1] of every 28-day cycle only, Baseline lab assessments can 
be used for dosing for Cycle 1 Day 1 if performed within 7 days prior to Cycle 1 Day 1.)
Urinalysis (Days 1 and 15 only)
Sampling for plasma pharmacodynamic biomarker (before the fourth and seventh 
infusions of ramucirumab/placebo).
Evaluations/procedures to be performed prior to the start (Day 1) of each cycle only include:

Physical examination (to include weight; height does not need to be repeated beyond the 
initial evaluation)

ECOG PS evaluation

Full serum chemistry profile (within 36 hours prior to treatment).
Evaluations to be performed for WOCBP, Electrocardiogram, Echocardiogram/MUGA and 
Coagulation profile are scheduled as below:
Serum or urine pregnancy test for WOCBP (within 3 days prior to Day 1 of every odd-
numbered cycles or in accordance with local regulations, whichever is of shorter 
duration)
Electrocardiogram (within 3 days prior to the first infusion of Cycles 2, Cycle 3, and then
every odd-numbered cycles, thereafter, within 30 days after the discontinuation of 
ramucirumab/placebo and within 30 days after the discontinuation of paclitaxel)
Echocardiogram/MUGA (within 3 days prior to the first infusion of Cycle 3 only, within 
30 days after the discontinuation of ramucirumab/placebo, and within 30 days after the 
discontinuation of paclitaxel)
Coagulation profile (within 3 days prior to Day 1 of every odd-numbered cycles and can
be performed more frequently if clinically indicated)
Evaluations to be performed every 6 weeks (±5 days) following the first dose of study therapy 
include:
Imaging studies/tumor assessments, including CT/MRI of all known disease, as described 
in Section 10.1 and Attachment 7, will be performed every 6 weeks (±5 days) following 
the first dose of study therapy for the first 6 months, and every 9 weeks (±5 days) 
thereafter, until radiographic documentation of PD, even if therapy is delayed due to 
toxicity or for other reasons.
Evaluations to be performed prior to each cycle following the first dose of study therapy include:
Patient reported outcomes. This does not need to be completed prior to Cycle 1 if 
screening/baseline assessment was completed.
8.1.2. Postdiscontinuation Follow-Up
All patients should be followed and AEs reported for approximately 30 days during short-term 
follow-up.  Other follow-up assessments will be conducted as shown in the Study Schedule 
(Attachment 1).


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8.1.2.1.
Short-Term Follow-Up
End-of-therapy occurs after the decision is made to discontinue study therapy.  In all cases, the 
primary reason for discontinuation will be captured in the eCRF.
All AEs occurring after the patient receives the first dose of study treatment until 30 days after 
the decision is made to discontinue study treatment must be reported to the Sponsor or its 
designee via eCRF. The short-term follow-up begins the day after the decision is made to 
discontinue study treatment and lasts approximately 30 days (no more than 37 days):

Physical examination with weight measurement

Vital signs

ECOG PS evaluation

Toxicity/AE assessment

Serum or urine pregnancy test for WOCBP

Hematology

Full serum chemistry profile

Coagulation profile

Electrocardiogram

Echocardiogram/MUGA

Urinalysis

Concomitant medication assessment

Patient-reported outcomes (PROs)
All SAEs and AEs considered at least possibly-related to study therapy will be followed until 
resolved, stabilized, returned to baseline, or deemed irreversible.
For patients who discontinue treatment for reasons other than radiographic PD, imaging studies 
with tumor measurements/disease response assessments will continue to be performed every 
6 weeks (±5 days) following the first dose of study therapy for the first 6 months, and every 
9 weeks (±5 days) thereafter, until documentation of radiographic PD.
If it is deemed to be in the best interest of the patient to start a new anti-cancer treatment prior to 
the scheduled end of the short-term follow-up visit, the follow-up visit duration may be 
shortened. In this case, the short-term follow-up assessments should be completed prior to the 
initiation of the new therapy. 
8.1.2.2.
Long-Term Follow-Up
Patients will be contacted at least every 8 weeks (+0 to 7 days) to obtain information about 
survival status and detailed information on any subsequent systemic anticancer therapy and 
disease progression (for patients not having a radiographic progression).  Long-term follow-up 
will continue as long as the patient is alive, or until study completion (as defined in 
Section 8.1.3). 


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8.1.3. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the interim analysis (256 PFS events) if the study is stopped early, or 
following the final analysis of OS (336 deaths; see Section 12) if the study is not stopped early, 
as determined by Lilly.
Investigators will continue to follow the Study Schedule for all patients until notified otherwise 
by Lilly.  
“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed the 30-day short-term safety follow-up in the extension period.  If no 
patients enter the extension period, study completion will occur at the same time as the end of 
trial (that is, the date of the last visit of the last scheduled procedure shown in the Study Schedule 
for the last patient) in this study.
The study can be stopped at any time by the institutional review board/acting ethics committee or 
the Sponsor because of safety considerations or futility.
Figure JVCR 8.2 provides an illustration of study completion, the extension period, and the end 
of trial.




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During the extension period, the following information will be collected according to 
Attachment 2:

All AEs will be reported on the case report form (CRF).  Serious adverse events will also 
be reported on the CRF and to Lilly Global Patient Safety (GPS; see Section 10.3.1).  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.  

Drug administration information

Reason for study therapy discontinuation
During the extension period, routine safety and efficacy monitoring, including radiographic 
evaluation of disease and laboratory testing, such as pregnancy testing, should be continued as 
necessary, and documentation retained within the source files, to confirm patient eligibility to 
continue on treatment or the 30-day short-term follow-up visit.  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.
8.2.
Discussion of Design and Control
This study will be conducted since the prognosis for patients with advanced gastric cancer is 
generally poor, and there is a great unmet medical need for novel treatments.  Paclitaxel has been 
extensively studied as second-line chemotherapy in advanced gastric cancer patients, using a 
schedule consisting of 80 mg/m2 administered once a week for 3 weeks followed by a 1-week 
rest period (Hironaka et al. 2006; Kodera et al. 2007).  This treatment, with the addition of 
placebo, will act as the control arm of this study.  The study arm will add ramucirumab (8 mg/kg
IV on Days 1 and 15 of every 28-day cycle) to weekly paclitaxel, with the objective of 
evaluating the efficacy and safety of ramucirumab plus weekly paclitaxel as second-line therapy
among patients with advanced gastric cancer.  This ramucirumab dose is the same as that used in 
the global Phase 3 Study JVBE.
Investigational treatment administration in this study is double-blind; that is, patients, 
investigational sites, and the sponsor study team do not have immediate access to treatment 
assignments for any patients.  Randomization in this study will be stratified by ECOG PS (0 
versus 1) and peritoneal metastases (yes versus no).  Both factors were independent prognostic 
factors for OS in global Studies JVBD and JVBE. 


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9.
Treatment
9.1.
Treatments Administered
Following necessary premedication, patients will receive the following treatments:

Experimental Arm A: 
o
Ramucirumab DP 8 mg/kg IV on Days 1 and 15 of every 28-day cycle
o
Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle.

Placebo Arm B:
o
Ramucirumab DP placebo (administered at a volume equivalent to a dose of 
8 mg/kg) IV on Days 1 and 15 of every 28-day cycle
o
Paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle.
On Days 1 and 15 of each cycle, following premedication, ramucirumab/placebo will be 
administered over approximately 60 minutes.  Administration will be followed by a 1-hour 
observation period, and subsequently by administration of paclitaxel over approximately 
60 minutes.  The 1-hour observation period between administration of ramucirumab/placebo and 
paclitaxel is mandatory for the first 2 cycles, but may be omitted in Cycle 3 and beyond,
provided there has been no evidence of IRR.
Any measurements used to determine dose should be taken at each cycle, and dose should be 
recalculated for each cycle.  
The investigator or his or her designee is responsible for the following: 

Explaining the correct use of the drug(s) and planned duration of each individual’s 
treatment to the site personnel 

Verifying that protocol instructions are followed properly

Maintaining accurate records of study drug storage, dispensing, and collection

Returning all unused medication, if not already destroyed by the site, to Lilly or its 
designee at the end of the study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
9.1.1. Premedication
Premedication is recommended prior to infusion of ramucirumab DP or placebo.  Recommended 
premedication agents include histamine H1 antagonists such as diphenhydramine hydrochloride (or 
equivalent).  Additional premedication may be provided at investigator discretion.  Premedication 
must be provided in the setting of a prior Grade 1 to 2 IRR, as detailed in Section 9.4.2.1.1.  
All premedication administered must be adequately documented in patient’s source charts and on 
the eCRF.
Premedication is required prior to infusion of paclitaxel according to the manufacturer’s 
instructions and local standards.  Premedication may consist of dexamethasone 20 mg orally 
administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its 


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equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine 300 mg or ranitidine 50 
mg IV (or equivalent) 30 to 60 minutes before paclitaxel.  An antiemetic (such as ondansetron 8 
mg IV or equivalent) administered 30 to 120 minutes before paclitaxel is recommended.
When ramucirumab/placebo and paclitaxel are administered subsequently on the same day (that 
is, Days 1 and 15 of each cycle), it is sufficient to administer diphenhydramine hydrochloride 
and dexamethasone only once, prior to administration of ramucirumab/placebo.
9.1.2. Ramucirumab Drug Product or Placebo
Aseptic technique is to be used when preparing and handling ramucirumab or placebo.  Patients 
will receive ramucirumab or placebo by IV infusion over approximately 60 minutes at 8 mg/kg 
on Days 1 and 15 of every 28 days in the absence of disease progression or other withdrawal 
criteria.
Patients will receive ramucirumab/placebo via IV infusion over approximately 60 minutes.  The 
infusion rate should not exceed 25 mg/minute.  In the event that the infusion time takes longer 
than 60 minutes (based on the patient’s body weight), the infusion time should be accurately 
recorded on the eCRF.  The first dose of ramucirumab (or placebo) is dependent upon the 
patient’s screening/baseline body weight in kilograms.  Subsequent doses of ramucirumab (or 
placebo) must be recalculated if there is a ≥10% change (increase or decrease) in body weight 
from the time of the most recent dose calculation; subsequent doses may be recalculated if there 
is a <10% change (increase or decrease) in body weight from the time of the most recent dose 
calculation.  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 within 30 days prior to dose.  If no recent dry weight is available, actual 
weight will be used.
Ramucirumab is compatible with common infusion containers. The use of a low protein binding 
0.22 micron in–line filter is recommended. Based on the calculated volume of ramucirumab, add 
(or remove from pre-filled [with 0.9% normal saline] IV infusion container) a sufficient quantity 
of sterile normal saline (0.9% weight/volume) to the container to make the total volume 250 mL.  
For dose volumes greater than 250 mL, the addition of sterile normal saline is not required.  Do 
not use dextrose-containing solutions. The container should be gently inverted to ensure 
adequate mixing. The infusion should be delivered in approximately 60 minutes. The infusion 
rate should not exceed 25 mg/minute. Infusions of duration longer than 60 minutes are permitted 
in specific circumstances (that is, for larger patients in order to maintain an infusion rate that 
does not exceed 25 mg/minute, or in the setting of prior ramucirumab IRR); the infusion duration 
must always be accurately recorded.  The infusion set must be flushed post infusion with sterile 
0.9% normal saline equal to or greater than infusion set hold-up volume to ensure delivery of the 
calculated dose.
CAUTION:  Infusion-related reactions may occur during or following ramucirumab or placebo 
administration.


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9.1.3. Paclitaxel
Investigators should consult the manufacturer’s instructions for paclitaxel for complete 
prescribing information (including warnings, precautions, contraindications, and adverse 
reactions) and follow institutional procedures for the administration of paclitaxel.
Aseptic technique is to be used when preparing and handling paclitaxel.  Patients will receive 
paclitaxel by IV infusion over approximately 60 minutes at 80 mg/m2 on Days 1, 8, and 15 of 
every 28-day cycle.
The first dose of paclitaxel is dependent upon the patient’s baseline body surface area.  
Subsequent doses of paclitaxel must be recalculated if there is a ≥10% change (increase or 
decrease) in body surface area from baseline; subsequent doses may be recalculated if there is a 
<10% change (increase or decrease) in body surface area from baseline.
Paclitaxel must be diluted prior to infusion.  When reconstituting paclitaxel, please follow the 
current local product labeling instructions.  Paclitaxel should be diluted in 0.9% sodium chloride 
(normal saline) injection, United States Pharmacopeia (USP) or local equivalent; 5% dextrose 
injection, USP or local equivalent; 5% dextrose and 0.9% sodium chloride injection, USP or 
local equivalent; or 5% dextrose in Ringer’s injection, to a final concentration of 0.3 to 1.2 
mg/mL.  The solutions are physically and chemically stable for up to 27 hours at ambient 
temperature (approximately 25°C) and room lighting conditions.  Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to administration 
whenever solution and container permit.  Upon preparation, solutions may show haziness, which 
is attributed to the formulation vehicle.  No significant losses in potency have been noted 
following simulated delivery to the solution through IV tubing containing an in-line (0.22
micron) filter.
Data collected for the presence of the extractable plasticizer di-[2-ethyl-hexyl] phthalate show 
that levels increase with time and concentration when dilutions are prepared in polyvinyl 
chloride (PVC) containers.  Consequently, the use of plasticized PVC containers and 
administration sets is not recommended.  Paclitaxel solutions should be prepared and stored in 
glass, polypropylene, or polyolefin containers.  Non-PVC containing administration sets, such as 
those which are polyethylene-lined, should be used.
9.2.
Materials and Supplies
9.2.1. Ramucirumab Drug Product
Ramucirumab DP is a sterile, preservative-free solution for infusion formulated in histidine 
buffer at a ramucirumab drug substance concentration of 10 mg/mL (500 mg/50-mL vial).  The 
buffer contains 10 mM histidine, 75 mM sodium chloride, 133 mM glycine, and 
0.01% polysorbate 80, pH 6.0.
All excipients used for the manufacture of ramucirumab are of pharmacopeial grade.  No 
animal-derived components are used in the manufacture of ramucirumab.


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9.2.2. Ramucirumab Drug Product Placebo
Placebo is a sterile, preservative-free solution for infusion formulated in histidine buffer.  The 
buffer contains 10mM histidine, 75mM sodium chloride, 133mM glycine, and 
0.01% polysorbate 80, pH 6.0.
All excipients used for the manufacture of placebo are of pharmacopeial grade.  No 
animal-derived components are used in the manufacture of placebo.
9.2.3. Paclitaxel
Investigators should consult the provided paclitaxel package insert for complete packaging and 
labeling information.
9.3.
Method of Assignment to Treatment
Upon completion of all screening evaluations to confirm a patient’s eligibility, the site will
register the patient via the Interactive Web Response System (IWRS). The IWRS registration 
consists of assigning the patient a unique study identification number and randomizing the 
patient to 1 of the 2 treatment arms. Once the patient is registered through the IWRS, he/she is 
considered to be enrolled in the study.
Randomization will be stratified by ECOG PS (0 versus 1) and peritoneal metastases (yes versus 
no).  To balance the treatment allocation among the stratification factors, a stratified permuted 
block randomization will be utilized and incorporated into the IWRS.
9.4.
Selection and Timing of Doses
Patients will receive either paclitaxel plus ramucirumab or paclitaxel plus placebo (see Section
8.1).  Study drug will be administered as shown in Section 9.1.
A treatment cycle is defined as 28 days (4 weeks).  It is recognized that in the course of clinical 
cancer care, it is not always possible to schedule therapeutic infusions at precise intervals 
(because of holidays, travel difficulties, or other circumstances).  Accordingly, infusions 
administered within 3 days before or after the planned infusion time point will be considered 
acceptable.  Deviations beyond this window are strongly discouraged, and require Sponsor (or 
designee) approval.
9.4.1. Special Treatment Considerations 
9.4.1.1.
Treatment Requirements and Delays
9.4.1.1.1. Requirements Prior to Day 1 of Each Treatment Cycle
Prior to Day 1 of each administration of study therapy, hematology, urine protein (dipstick), liver, 
and renal function must be adequate as required in Table JVCR 9.1 and Table JVCR 9.2. 
Preinfusion laboratory data may not be older than 36 hours. For AE/toxicities not listed in Table 
JVCR 9.1 and Table JVCR 9.2, treatment delay is at investigator discretion.  


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Table JVCR 9.1.
Criteria for Paclitaxel Treatment on Day 1 of Each Cycle
Parameter
Criterion
Neutrophils
>1.5 × 109/L
Platelets
>100 × 109/L
Hemoglobin
≥8 g/dL
Serum Creatinine
<1.5× ULN or calculated creatinine clearance >50 ml/min
Bilirubin
<1.5× ULN
AST/ALT
≤3× ULN if no liver metastases, <5× ULN if liver metastases
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; min = 
minute; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; ULN = 
upper limit of normal.
Table JVCR 9.2.
Criteria for Ramucirumab Treatment on Day 1 of Each Cycle
Parameter
Criterion
Urine Protein
Dipstick <2+ or protein level <2 g/24-hr
Specific Adverse Event of 
Ramucirumab
Refer to 9.4.2.1
Abbreviations:  AE = adverse event; hr = hour; NCI-CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events.
If 1 or more criteria outlined in the tables above are not met at the time of a planned treatment, 
the following general rules for the management of treatment delays apply:

In the case of paclitaxel-related toxicity or abnormal laboratory values, blood counts and 
serum chemistry will be repeated weekly.  The start of the next cycle will be delayed 
until recovery to the values stated above.  However, ramucirumab/placebo therapy should 
continue as scheduled until the next cycle has resumed.  When the subsequent cycle of 
paclitaxel is initiated, administration of ramucirumab/placebo and paclitaxel will be 
resynchronized according to the study design described in this protocol (that is, the cycle 
will begin at Day 1 for both ramucirumab and paclitaxel, even if this requires 
ramucirumab to be administered on consecutive weeks).  In case of discontinuation of 
paclitaxel for any reason, a new cycle will be started on Day 29 (Day 1 of the new cycle) 
with the administration of ramucirumab monotherapy, provided the criteria outlined in 
Table JVCR 9.2 are met.

In the case of ramucirumab/placebo-related toxicity, ramucirumab/placebo will be 
delayed for 1 week and administered on Day 8 (and Day 15) of the treatment cycle 
provided that ramucirumab/placebo-related toxicities have resolved to Grade <2 or 
baseline (except for hypertension, venous thromboembolic events, and proteinuria).  If 
toxicities have not resolved on Day 8, ramucirumab/placebo will be delayed for another 
week and administered on Day 15 according to the schedule described in this protocol.  
In both cases, paclitaxel will continue according to the planned schedule.

If a patient cannot be treated with 1 component of the study therapy (paclitaxel or 
ramucirumab) for more than 28 days from the last administered dose, that component will 


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be permanently discontinued.  The other agent should be continued, with the patient 
remaining on-study, if clinically indicated.

If the start of a cycle is delayed due to toxicity, radiographic assessment of disease 
response should not be delayed, but should be performed every 6 weeks (±5 days) 
following the first dose of study therapy for the first 6 months, and every 9 weeks 
(±5 days) thereafter, until documentation of radiographic PD.
9.4.1.1.2. Requirements Prior to Days 8 and 15 of Each Treatment Cycle
Prior to Days 8 and 15 of each administration of study therapy, hematology, urine protein (dipstick), 
and liver function must be adequate (see Table JVCR 9.3 and Table JVCR 9.4).  Preinfusion 
laboratory data may not be older than 36 hours.  For AE/toxicities not listed in Table JVCR 9.3 and 
Table JVCR 9.4, treatment delay is at investigator discretion.
Table JVCR 9.3.
Criteria for Paclitaxel Treatment on Days 8 and 15 of Each Cycle
Parameter
Criterion
Absolute neutrophil count
≥1.0 × 109/L
Platelet count
≥75 × 109/L
Hemoglobin
≥8 g/dL
Bilirubin
≤1.5× ULN
AST/ALT
≤3× ULN if no liver metastases, <5× ULN if liver metastases
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; ULN = upper 
limit of normal.
Table JVCR 9.4.
Criteria for Ramucirumab Treatment on Day 15 of Each Cycle
Parameter
Criterion
Urine Protein
Dipstick <2+ or protein level <2 g/24-hr
Specific Adverse Event of 
Ramucirumab
Refer to 9.4.2.1
Abbreviations:  AE = adverse event; hr = hour; NCI-CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events.
If 1 or more criteria outlined in the tables above are not met at the time of a planned treatment, 
the following general rules for management of treatment delays apply:

In the case of paclitaxel-related toxicity or abnormal laboratory values (Table JVCR 9.3) 
on Days 8 or 15, paclitaxel will be skipped that day.  No dose reductions are allowed 
within a given cycle

In the case of ramucirumab-related toxicity on Day 15 (Table JVCR 9.4), paclitaxel will 
be administered according to the planned schedule, but ramucirumab will be delayed for 
1 week and administered on Day 22 of the treatment cycle, provided that 
ramucirumab-related toxicities have resolved to Grade <2 or baseline (except for 
hypertension, venous thromboembolic events, or proteinuria).  If toxicities have not 
resolved on Day 22, ramucirumab will be skipped for that cycle and administered on Day 


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1 of the following cycle, provided that ramucirumab-related toxicities have resolved to 
Grade <2 or baseline (except for hypertension, venous thromboembolic events, and 
proteinuria).  
9.4.2. General Dose Modifications:  Ramucirumab 
Dose modifications are permitted for ramucirumab/placebo in the setting of non-life-threatening 
and reversible Grade 3 clinical AEs (for example, fever) considered to be at least possibly related 
to ramucirumab/placebo and that resolve to Grade ≤1 or pretreatment baseline within 1 treatment 
cycle (approximately 28 days).  If a Grade 4 AE occurs and is deemed at least possibly related to 
ramucirumab/placebo, then ramucirumab/placebo should be discontinued except in the specific 
case of Grade 4 fever or Grade 4 laboratory abnormalities.  If Grade 4 fever or laboratory 
abnormalities resolve to Grade ≤1 or pretreatment baseline within 1 treatment cycle 
(approximately 28 days), treatment with investigational product may be continued at the 
discretion of the investigator.  In these settings, ramucirumab/placebo may be readministered.  If 
a second instance of such an event occurs, ramucirumab/placebo should be subsequently 
readministered at a dose of 6 mg/kg every other week.  A second dose reduction to 5 mg/kg 
every other week is permitted for this level of event (Grade 3 or 4 event).  If the dose of 
ramucirumab/placebo is reduced because of potentially related AEs, subsequent dose increases 
are not permitted.  Note that this section of the protocol pertains only to general dose 
modifications.  Criteria for dose reduction in the setting of various specific AEs may be found in 
Section 9.4.2.1.  Ramucirumab/placebo will be permanently discontinued in case of any 
ramucirumab/placebo-related event that is deemed life-threatening, regardless of grade.
Patients who enter the study with symptoms or laboratory values equivalent to NCI-CTCAE,
v 4.03, Grade 1 or 2 AEs should not have dose reductions related to the persistence or mild 
worsening of those symptoms or laboratory values; dose reductions may be warranted if 
worsening of symptoms or laboratory values is clinically significant in the opinion of the 
investigator.  Except in the case of proteinuria, as described in Section 9.4.2.1.5, asymptomatic 
laboratory abnormalities should not result in dose interruptions, modifications, or discontinuation 
of study therapy unless determined by the investigator to be clinically significant or 
life-threatening.
9.4.2.1.
Treatment Guideline and Dose modification for Specific Adverse Events 
of Ramucirumab
Ramucirumab should be administered to patients only according to the inclusion and exclusion 
criteria specified in the clinical study protocol.
Ramucirumab must not be administered to patients with previous severe (Grade 3 or 4) 
hypersensitivity reactions to ramucirumab.
Ramucirumab should not be administered to patients who have a known allergy to any of the 
ingredients used in the DP formulation.
Adverse events of concern, which may or may not be associated with ramucirumab therapy, may 
include IRRs, hypertension, arterial or venous thromboembolic events, bleeding (hemorrhagic) 


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events, GI perforation, proteinuria, CHF, surgery and impaired wound healing, liver injury/liver 
failure, and reversible posterior leukoencephalopathy syndrome (RPLS). 
9.4.2.1.1. Ramucirumab Infusion-Related Reactions
Any treatment-related IRRs are defined according to the NCI-CTCAE, Version 4.03, definition 
(general disorders and administration site conditions).  Symptoms occurring during or following 
infusion of investigational therapy may also be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome (immune system disorders).  In the 
setting of symptoms occurring during or following infusion of investigational therapy, 
investigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.  Those described above 
should be graded as shown in Table JVCR 9.5.


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Table JVCR 9.5.
NCI-CTCAE, Version 4.03, Infusion-Related Reactions
Adverse 
Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Infusion-
related 
reaction
Mild transient 
reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications indicated 
for ≤24 hr
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for clinical 
sequelae
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse reaction to the infusion of pharmacological or biological 
substances.
Allergic 
reaction
Transient 
flushing or 
rash, drug fever 
<38°C 
(<100.4°F); 
intervention not 
indicated
Intervention or 
infusion interruption 
indicated; responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics); 
prophylactic 
medications indicated 
for ≤24 hr
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for clinical 
sequelae (e.g., renal 
impairment, 
pulmonary infiltrates)
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; 
allergy-related 
edema/angioedema; 
hypotension
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine 
and histamine-like substances from mast cells, causing a hypersensitivity immune response.  Clinically, it 
presents with breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness, and may lead to 
death.


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NCI-CTCAE, Version 4.03, Infusion-Related Reactions
Adverse 
Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Cytokine-
release 
syndrome
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications indicated 
for ≤24 hr
Prolonged (eg, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for clinical 
sequelae (e.g., renal 
impairment, 
pulmonary infiltrates)
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of 
breath; it is caused by the release of cytokines from the cells.
Abbreviations:  e.g. = for example; hr = hour; IV = intravenous; NCI-CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events; NSAIDs = nonsteroidal anti-inflammatory drugs.
Consistent with usual medical practice, selected parenteral medications may be utilized for 
Grade 2 allergic/hypersensitivity reaction as detailed below.  The Lilly Medical Monitor or 
designee should be contacted immediately if questions arise concerning the grade of the reaction.
The following are treatment guidelines for IRRs:
Grade 1

Slow the infusion rate by 50%

Monitor the patient for worsening of condition

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV
(or equivalent); additional premedication may be administered at the investigator’s 
discretion
Grade 2

Stop the infusion

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), acetaminophen 
650 mg orally for fever, and oxygen

Resume the infusion at 50% of the prior rate once the IRR has resolved or decreased to 
Grade 1; the infusion duration should not exceed 2 hours.

Monitor for worsening of condition

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV
(or equivalent); additional premedication may be administered at the investigator’s 
discretion


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For a second Grade 1 or 2 IRR, administer dexamethasone 8 to 20 mg IV (or equivalent); then, 
for subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV (or 
equivalent), acetaminophen 650 mg orally, and dexamethasone 8 to 20 mg IV (or equivalent).  
When ramucirumab/placebo and paclitaxel are administered subsequently on the same day (that 
is, Days 1 and 15 of each cycle), it is sufficient to administer diphenhydramine hydrochloride 
and dexamethasone only once, prior to administration of ramucirumab/placebo.
Grade 3

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride IV (or equivalent, per institutional 
guidelines), dexamethasone IV (or equivalent, per institutional guidelines), 
bronchodilators for bronchospasm, and other medications/treatment as medically 
indicated.

Patients who have a Grade 3 IRR will not receive further ramucirumab (or placebo) 
treatment, but will continue to be followed on the protocol.
Grade 4

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride IV (or equivalent, per institutional 
guidelines), dexamethasone IV (or equivalent, per institutional guidelines), 
bronchodilators for bronchospasm, and other medications/treatment as medically 
indicated.

Give epinephrine or bronchodilators as indicated.

Hospital admission for observation may be indicated.

Patients who have a Grade 4 IRR will not receive further ramucirumab (or placebo) 
treatment, but will continue to be followed on the protocol.
If a patient should have an IRR to ramucirumab/placebo, all attempts should be made to obtain a 
blood sample for anti-ramucirumab antibody analysis as close to the onset of the event as 
possible, at the resolution of the event, and approximately 30 days following the event.  In 
addition, these same samples may be assessed for levels of ramucirumab and for 
pharmacodynamic markers to provide information on the nature of the IRR.  The procedure for 
sample collection and handling is described in a separate procedural manual.
9.4.2.1.2. Hypertension
The following are treatment guidelines for hypertension (an expected AE in patients receiving 
ramucirumab) that develops during the study:
Grade <3

If the hypertension is not associated with symptoms, continue ramucirumab (or placebo) 
therapy and initiate antihypertensive therapy.

If the hypertension is associated with symptoms, hold ramucirumab (or placebo) therapy 
until symptoms resolve and initiate antihypertensive therapy.


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
If ramucirumab (or placebo) therapy is held for hypertension (that is, symptomatic 
hypertension, markedly elevated blood pressure [BP] unresponsive to antihypertensive 
therapy), the dose of ramucirumab (or placebo) should be reduced upon retreatment to 
6 mg/kg every 2 weeks.  A second dose reduction to 5 mg/kg every 2 weeks should be 
undertaken if an additional postponement of therapy is required.
Grade 3 (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg; medical intervention indicated; 
more than 1 drug or more intensive therapy than previously used indicated)

For Grade 3 hypertension not associated with symptoms, continue ramucirumab (or 
placebo) therapy with more intensive antihypertensive therapy.  If systolic BP remains 
≥160 mmHg or diastolic BP ≥100 mmHg for >2 weeks after initiation of additional 
antihypertensive therapy, hold ramucirumab (or placebo) while continuing appropriate 
antihypertensive therapy.

If the hypertension is associated with symptoms, hold ramucirumab (or placebo) therapy 
until symptoms resolve and initiate antihypertensive therapy.

If ramucirumab (or placebo) therapy is held for hypertension (that is, symptomatic 
hypertension, markedly elevated BP unresponsive to antihypertensive therapy), the dose 
of ramucirumab (or placebo) should be reduced upon retreatment to 6 mg/kg every 
2 weeks.  A second dose reduction to 5 mg/kg every 2 weeks should be undertaken if an 
additional postponement of therapy is required
Grade 4 or refractory

Patients with Grade 4 hypertension (life-threatening consequences, for example,
malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis; 
or urgent intervention indicated) or patients whose hypertension is poorly controlled 
(systolic BP >160 mmHg or diastolic BP >100 mmHg for >4 weeks) despite 
appropriate oral medication (>2 oral agents at maximum tolerated dose) will be 
discontinued from ramucirumab.  Treatment with paclitaxel may be continued if 
appropriate in the opinion of the investigator
9.4.2.1.3. Thromboembolic Events
Investigators should perform all testing required to fully characterize arterial or venous 
thromboembolic/vascular events.  The incidence and type of thromboembolic/vascular events 
will be collected and reported.
Ramucirumab therapy should be discontinued in the event of any Grade 3/4 arterial 
thromboembolic event or any Grade 3/4 venous thromboembolic event that is considered by the 
investigator to be life-threatening, or symptomatic and not adequately treated by anticoagulation 
therapy.  At the investigator’s discretion, ramucirumab therapy may be continued in the setting 
of an incidentally diagnosed, asymptomatic deep vein thrombosis or pulmonary embolism, or 
following a symptomatic deep vein thrombosis or pulmonary embolism when symptoms have 
resolved with the institution of anticoagulation therapy.  Ramucirumab should also be 


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discontinued in the setting of a deep vein thrombosis or pulmonary embolism that occurs or 
intensifies while the patient is receiving therapeutic anticoagulation therapy.
9.4.2.1.4. Bleeding (Hemorrhagic) Events
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 (Version 10.0 and subsequent versions), 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 precludes 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 (Section 7).
9.4.2.1.5. Proteinuria
If, while on ramucirumab (or placebo) therapy, a patient has proteinuria ≥2+ per a dipstick or 
routine urinalysis test, a 24-hour urine collection will be conducted.  If the protein level is 
<2 g/24-hours, the patient will continue on ramucirumab (or placebo) therapy at the same dose 
without interruption.  If the protein level is 2 to 3 g/24-hours, ramucirumab (or placebo) therapy 
will be held for 1 week and a 24-hour urine collection will be repeated.  Ramucirumab (or 
placebo) treatment will resume at a reduced dose level (6 mg/kg every 2 weeks) once the protein 
level returns to <2 g/24-hours.  A second dose reduction of ramucirumab (or placebo) to 5 mg/kg 
every 2 weeks is permitted if proteinuria ≥2 g/24-hours recurs.  The patient will be discontinued 
from ramucirumab (or placebo) treatment if the protein level is >3 g/24-hours, if there is a third 
occurrence of proteinuria ≥2 g/24-hours, or if the protein level does not return to <2 g/24-hours 
within 2 weeks.
9.4.2.1.6. Gastrointestinal Perforation
Patients with unresected (or recurrent) primary tumors, 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.  
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.


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Patients with a history of GI perforation within 6 months prior to study entry are excluded from 
participation (Section 7.2).  Ramucirumab DP should be permanently discontinued for patients 
who have experienced GI perforation.
9.4.2.1.7. Fistula Formation
Gastrointestinal and non-GI fistula formation has been associated with antiangiogenic agents 
including bevacizumab and sunitinib (Kamba and McDonald 2007).  Some fistulas can be 
resolved with surgery procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and Cleck 
2009).  A small number of fistula events have been reported in ramucirumab clinical trials.  
Ramucirumab treatment should be discontinued in patients who develop fistulas.
9.4.2.1.8. Congestive Heart Failure in Patients Who Received Ramucirumab in 
Combination with Mitoxantrone or Following Prior Anthracycline 
Therapy
An increased risk of CHF has been associated with some antiangiogenic therapeutic agents, 
particularly in patients with metastatic breast cancer previously treated with anthracyclines or 
with other risk factors for CHF, including prior radiotherapy to the left chest wall.  Findings have 
ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF 
requiring treatment or hospitalization.  Caution should be exercised when treating patients with 
clinically significant cardiovascular disease such as preexisting coronary artery disease or CHF.  
Patients with symptomatic CHF, unstable angina pectoris, or symptomatic or poorly controlled 
cardiac arrhythmia should not be enrolled in clinical trials with ramucirumab.
Ramucirumab should be discontinued in the event of any Grade 3 to 4 events consistent with 
CHF.
9.4.2.1.9. Surgery and Impaired Wound Healing
Surgery and impaired wound healing have been observed with some antiangiogenic agents.  
Ramucirumab will not be administered to patients who have undergone major surgery within 
28 days prior to randomization or have undergone central venous access device placement within 
7 days prior to randomization.  Patients with postoperative and other nonhealing wound 
complications are excluded, as are patients for whom major surgical procedures are planned.
9.4.2.1.10.Liver Injury/Liver Failure
An independent data monitoring committee (IDMC) for the ramucirumab study CP12-0919 
(I4T-IE-JVBF [JVBF]) (a randomized, blinded study evaluating ramucirumab versus placebo in 
hepatocellular carcinoma following prior sorafenib therapy) recommended modifications 
following a meeting on 02 August 2012.  This 02 August 2012 meeting was the fifth meeting of 
the IDMC for this study (the prior meetings had concluded with recommendations to continue 
this study without modifications), and occurred at the request of the Sponsor to investigate a 
potential association of liver failure and other events of severe liver injury with ramucirumab.  


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The IDMC reviewed unblinded safety data from 400 patients who had been treated with either 
ramucirumab or placebo.  The data cut-off date of this safety review was 18 July 2012.
In review of the safety data, the IDMC noted that death rates related to study medication were in 
the expected range for patients with hepatocellular carcinoma and cirrhosis.  However, the 
IDMC observed a numeric imbalance of liver-related AEs, specifically for hepatic 
encephalopathy, between the 2 treatment arms.  Based on this safety finding, the IDMC 
specifically addressed hepatic encephalopathy, hepatorenal syndrome, and ascites in the context 
of cirrhosis, exclusive of other etiologies of these diagnoses.
The IDMC recommended continuing the CP12-0919 study with modifications.  These 
modifications included:  (a) exclusion of patients with Child-Pugh B cirrhosis (or worse), 
(b) exclusion of patients with cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis, and (c) an additional criterion for 
discontinuation of study drug (ramucirumab or placebo) for patients with new occurrence of 
hepatic encephalopathy and/or hepatorenal syndrome resulting from liver cirrhosis.  Although 
the CP12-0919 IDMC’s recommendations are specific to the CP12-0919 study, ImClone 
Systems/Eli Lilly and Company (ImClone/Lilly) has chosen to implement these 
recommendations for ongoing ImClone/Lilly-sponsored studies in which patients are receiving 
investigational ramucirumab.
Ramucirumab should be discontinued following a new occurrence of hepatic encephalopathy 
and/or hepatorenal syndrome resulting from liver cirrhosis.
9.4.2.1.11.Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) 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).  
Magnetic resonance imaging represents the most reliable method for the 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).  has been associated with multiple 
clinical conditions including hypertensive encephalopathy, eclampsia, and renal failure with 
hypertension as well as the use of both immunosuppressive and cytotoxic drug (Hinchey et al.
1996; Marinella and Markert 2009).  More recently, RPLS has been associated with the use of 
the anti-VEGF agent bevacizumab, as described in the prescribing information for this agent 
(Marinella and Markert 2009; Avastin package insert, 2011). 
While the precise pathogenesis of RPLS has not been established, the pathophysiology may 
involve impaired cerebrovascular autoregulation leading to blood-brain barrier disruption and 
vasogenic edema (Schwartz 1996).  Although the pathogenesis of RPLS appears to be 


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multifactorial, drug-induced endothelial damage and acute hypertension are frequently proposed 
causes of cerebrovascular dysfunction in RPLS (Garg 2001).
RPLS should be identified and treated promptly in order to minimize potential for permanent 
neurological damage.  Treatment encompasses careful control of BP, withdrawal of potentially 
causative medication, and administration of anticonvulsant agents to those experiencing seizures
(Stott et al. 2005).
One SAE of RPLS has been reported in the double-blind, randomized, placebo-controlled,
Phase 3 colorectal cancer study CP12-0920 (I4T-MC-JVBB [JVBB]).  The event was 
determined to be related to administration of all study drugs, including blinded investigational 
DP (the treatment assignment for this patient remains blinded).  Because hypertension is an 
identified risk for ramucirumab, investigators should control BP in accordance with the 
guidelines in Section 9.4.2.1.2.  In addition, investigators should consider a diagnosis of RPLS in 
the setting of seizures, headache, nausea, delirium, visual changes, and/or other unexplained 
neurological symptoms, especially in combination with hypertension and MRI findings of 
hyperintensity on T2-weighted and fluid attenuated inversion recovery images.  Ramucirumab 
DP should be permanently discontinued in patients with a confirmed diagnosis of RPLS.  
9.4.3. General Dose Modifications:  Paclitaxel
No dose modification for paclitaxel is allowed within a given cycle.  The paclitaxel dose will be 
reduced by 10 mg/m2 for the following cycle when NCI-CTCAE, Version 4.03, Grade 4 
hematological toxicity or Grade 3 paclitaxel-related nonhematological toxicity (except for 
alopecia) is observed.  If the dose of paclitaxel is reduced because of potentially related AEs, 
subsequent dose increases are not permitted.  Paclitaxel will be permanently discontinued if dose 
reduction to less than 60 mg/m2 would be required, or in case of any paclitaxel-related event that 
is deemed life-threatening, regardless of grade.
9.4.3.1.
Treatment Guideline and Dose Modification for Specific Adverse Events
of Paclitaxel
9.4.3.1.1. Paclitaxel Hypersensitivity Reactions
In each case of hypersensitivity reaction associated with paclitaxel, the investigator should 
institute treatment measures according to the best available medical practice.  The following 
treatment guidelines may be applicable:
For mild symptoms: Complete paclitaxel infusion.  Supervise at bedside.  No treatment required.
For moderate symptoms: Stop paclitaxel infusion.  Administer diphenhydramine 25 to 50 mg IV
and dexamethasone 8 to 20 mg IV (or equivalent, per institutional guidelines).  Resume the 
paclitaxel infusion after recovery of symptoms at a reduced rate (20 mL/hour for 15 minutes).  
The infusion rate may then be increased to 40 mL/hour for 15 minutes, and subsequently at the 
full rate if symptoms do not recur.  If symptoms recur, stop the paclitaxel infusion and remove 
patient from paclitaxel treatment.


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For severe life-threatening symptoms: Stop paclitaxel infusion.  Give IV diphenhydramine and 
dexamethasone (per institutional guidelines).  Add epinephrine or bronchodilators if indicated.  
The patient should be removed from paclitaxel treatment.
9.5.
Blinding
This is a randomized, double-blind, Phase 3 study.  The randomization number will be assigned 
based on information obtained from the IWRS.  Patients will be randomized to receive 
ramucirumab or matching placebo in a double-blind fashion such that neither the investigator, 
nor the patient, nor medical and ancillary medical staff, nor the Sponsor or its designees, will 
know which drug is being administered in addition to paclitaxel.  
Ramucirumab and placebo for infusion will be identical in appearance in order to preserve 
blinding.  In order to maintain this blind, study drug (ramucirumab or placebo) will be uniquely 
labeled and will be assigned to a patient by using IWRS.
9.5.1. Emergency Unblinding
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP prior to unblinding 
a patient’s treatment assignment unless this could delay emergency treatment of the patient.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.
9.5.2. Inadvertent Unblinding
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur.  A double-blind study design is 
known to be imperfect in the oncolytic setting because the potential for individual unblinding 
exists due to treatment-related signs and symptoms.  If an investigator, site personnel performing 
assessments, or patient is unblinded, the unblinding will not be sufficient cause (in and of itself) 
for that patient to be discontinued from study therapy or excluded from any safety or efficacy 
analyses.
Additionally, there may be ethical reasons to have the patient remain on the study treatment.  For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the eCRF.  Concomitant medications and 
supportive care therapies must also be documented at the time of discontinuation and at the
30-day short-term follow-up visit.
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to all patients on this trial.  Supportive care measures may include but 


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are not limited to antidiarrheal agents, antiemetic agents, opiate and nonopiate analgesic agents, 
appetite stimulants, and granulocyte and erythroid growth factors.  Nondrug supportive care 
procedures may be performed as medically necessary and appropriate in the opinion of the 
investigator.  Appropriate management of hypersensitivity reactions is described in 
Section 9.4.2.1.2 (ramucirumab) and Section 9.4.3.1.1 (paclitaxel).  
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment.  
9.6.1.
Antidiarrheal Agents
In the event of diarrhea, the following supportive measures are allowed: hydration, octreotide, 
and antidiarrheals.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe (Grade 3 or 
4) neutropenia, broad-spectrum antibiotics must be prescribed.  Patients with severe diarrhea or 
any diarrhea associated with severe nausea or vomiting must be hospitalized for IV hydration 
and correction of electrolyte imbalances.
9.6.2.
Antiemetic Agents
The use of antiemetic agents is permitted at the discretion of the investigator.
9.6.3.
Analgesic Agents
The use of analgesic agents 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 unless at the discretion and responsibility of the 
investigator after careful assessment of the individual bleeding risk of the patient.  Chronic use of 
analgesic agents with no or low bleeding risk (for example, paracetamol/acetaminophen, 
metamizole, dipyrone, or propyphenazone) is acceptable.
9.6.4.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.
9.6.5.
Granulocyte-Colony Stimulating Factors
The protocol does not permit the routine use of colony-stimulating factors during treatment.  The 
protocol does not allow the use of products that stimulate thrombopoiesis.  
The use of granulocyte-colony stimulating factors is permitted during investigational therapy at 
the discretion of the investigator.  Granulocyte-colony stimulating factors or similar agents are 
strongly recommended following Grade 3 or 4 neutropenia of duration >5 days or following any 
incidence of febrile neutropenia (ANC <1.0 × 109/L with temperature ≥38.5°C).


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9.6.6.
Erythroid Growth Factors
The use of erythroid-stimulating factors (for example, erythropoietin) is permitted at the 
discretion of the investigator.  Erythropoietic therapy may be considered for treatment of 
chemotherapy-induced anemia for patients; refer to American Society of Clinical Oncology and 
FDA guidelines (FDA 2007; Rizzo et al. 2008), or according to local guidelines.
9.7.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit.  Treatment compliance 
is monitored by the review of drug accountability records (Section 9.1), and study medication 
administration data recorded in the patient’s medical record and eCRF.  The study medication 
will be administered only at the investigational sites by the authorized study personnel.  As a 
result, treatment compliance is ensured.
A patient will be considered significantly noncompliant if he or she is judged by the investigator 
to have intentionally missed more than 28 consecutive days of study medication (full doses) 
during the study.  Potential discontinuation of a patient due to study drug noncompliance will be 
discussed between the investigator and the Lilly CRP before the final determination is made to 
discontinue the patient.


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10. Efficacy, Patient-Reported Outcomes, Safety Evaluations, 
Sample Collection and Testing, and Appropriateness of 
Measurements
Study procedures related to efficacy, PROs, safety, sample collection, and testing assessments 
and their timing are described in the sections below and shown in the Study Schedule 
(Attachment 1).
10.1. Efficacy Measures
10.1.1. Efficacy Assessments at Baseline and During Study Treatment
Before the first dose of study drug, baseline tumor measurements will be performed on each 
patient.  Computed tomography, including spiral CT scans, and MRIs are the preferred methods 
of measurement.  
Investigators may collect PET scans for additional analyses, but PET scans will not be used as a 
method of response assessment.  Bone scans may be performed if clinically indicated.
The method of assessment used at baseline must be used consistently for tumor assessment and 
will be repeated every 6 weeks (±5 days) following the first dose of study therapy for the first 
6 months, and every 9 weeks (±5 days) thereafter, until radiographic documentation of PD.
The Sponsor or its designee will collect and store all tumor measurement images on all enrolled
patients throughout the study; if necessary, independent review of all scans may be considered 
following the completion of the study (Section 8.1.3).
10.1.2. Efficacy Assessments During the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1). 
For those patients who discontinue study treatment without radiographical PD, the investigative 
sites will continue to monitor patients and periodically evaluate tumor response every 6 weeks 
(±5 days) following the first dose of study therapy for the first 6 months, and every 9 weeks (±5
days) thereafter, until radiographic documentation of PD, by the same method used at baseline 
and throughout the study.  After the patient has radiographic disease progression, radiologic tests 
are no longer required and the patient will be followed up approximately every 8 weeks (+0 to 7
days) until the patient’s death or overall study completion.
After patients have discontinued study treatment, they may receive additional anticancer therapy 
at the discretion of the investigator.  The additional treatments should be documented on the CRF
during the study period.
10.1.3. Primary Efficacy Measure
The primary efficacy measures are the duration of PFS and OS.


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
Progression-free survival is measured from the date of randomization to the date of the 
first radiographically documented PD as defined by RECIST, Version1.1, or the date of 
death due to any cause, whichever is first.  The censoring is taken in the following order:
-
if a patient does not have a complete baseline or post-baseline radiographic disease 
assessment, then the PFS will be censored at the date of randomization, regardless of 
whether or not radiographically determined disease progression or death has been 
observed for the patient; otherwise, 
-
if a patient is alive and does not have radiographic progression as of the 
data-inclusion cut-off date, the PFS time will be censored at the date of the last 
adequate radiographic tumor assessment prior to cut-off date.

Overall survival is measured from the date of randomization to the date of death from 
any cause.  For each patient who is not known to have died as of the data-inclusion cut-
off date, OS duration will be censored at the date of last known alive date prior to the 
data-inclusion cut-off date.
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  The date of first documented radiographic disease progression must be 
recorded on the CRF even if it occurs after the patient has started a new therapy.
10.1.4. Secondary Efficacy Measures 
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1). A responder is defined as any patient who exhibits an unconfirmed 
complete response (CR) or PR. Best response is determined from the sequence of responses 
assessed.
The following definitions for secondary efficacy measures will apply:

Time to progression is defined as the time of randomization to the date of the first 
radiographically documented PD as defined by RECIST, Version 1.1.  For each patient 
who is not known to have had radiographic progression of disease as of the data-inclusion 
cut-off date, or who has died without radiographic progression of disease, TTP will be 
censored at the date of the patient’s last radiographic tumor assessment prior to that cut-
off date.

Objective response rate is defined as the proportion of patients with a best overall 
response (BOR) of PR or CR.  Patients who do not have a tumor response assessment for 
any reason are considered nonresponders and are included in the denominator when 
calculating the response rate.  For each treatment arm, the number of patients achieving a 
response will be divided by the total of patients randomized to yield the proportion 
responding:
ORR (%) = # of evaluable patients who have a best response of PR or CR  × 100
# of patients in analysis population 

Duration of objective response is measured from the time measurement criteria are first 
met for CR or PR (whichever is first recorded) to the date of the first radiographically 
documented PD as defined by RECIST, Version 1.1, or death due to any cause, 
whichever is first.


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10.2. Health Outcome/Quality of Life Measures
10.2.1. Patient-Reported Outcomes
Disease-free, OS, and toxicity endpoints are typically included in oncology clinical trials to 
evaluate the effect of study treatment.  Recently, however, inclusion of PROs has become routine 
as greater emphasis is placed on evaluating patient self-reports of the treatment benefit including 
the effect on symptoms and overall functioning or quality of life (QoL).  These PRO 
measurements are intended to result in data useful to inform treatment decisions.
The assessment of QoL and health status endpoints will be conducted through use of the EORTC 
QLQ-C30 and the EQ-5D-3L questionnaires, respectively.  The instruments should be 
administered together and in sequence order, with the EORTC QLQ-C30 presented first, 
followed by presentation of the EQ-5D-3L.  Please refer to Section 8.1 for the specific timing of 
these assessments.
10.2.1.1. EORTC QLQ-C30
The EORTC QLQ-C30 is a self-administered, cancer-specific questionnaire with 
multidimensional scales (Aaronson et al. 1993).  It consists of both multi-item scales and 
single-item measures, including 5 functional domains, a global QoL domain, 3 symptom 
domains, and 6 single items.  Only patients for whom there is a validated translation in language 
in which the patient is fluent will complete the QLQ-C30.
10.2.1.2. EQ-5D-3L
The EQ-5D is a nonspecific and standardized instrument for use as a measure of self-reported 
health status. The EQ-5D 3 level version (EQ-5D-3L) was introduced in 1990 (EuroQol Group 
1990). The EQ-5D-3L essentially consists of 2 pages - the EQ-5D descriptive system and the 
EQ visual analogue scale. The EQ-5D-3L descriptive system comprises 5 dimensions and each 
dimension has 3 levels. The respondent is asked to indicate his/her health state by ticking (or 
placing a cross) in the box against the most appropriate statement in each of the 5 dimensions.  
Additionally, patients will indicate their current health status by marking on a continuum ranging 
from 100 (best imaginable health state) to 0 (worst imaginable health state) (EuroQol Group 
1990; Brooks et al. 1996). In 2014, investigators had validated EQ-5D-3L and generated a
Chinese general population–based social value set using the time trade-off method (Liu et al.
2014).
10.3. Safety Evaluations
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, or that caused the patient to discontinue 
treatment before completing the study.  The patient should be followed until the event is resolved, 


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stabilized, returned to baseline, until deemed irreversible, or otherwise explained.  Frequency of 
follow-up evaluation is left to the discretion of the investigator.
10.3.1. 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 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 AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.  Any clinically significant findings from 
ECGs, laboratory assessments, vital sign measurements, or other procedures that result in a 
diagnosis should be reported to Lilly or its designee.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to study treatment and up to 
12 weeks following last study treatment dose should be reported immediately.  Data on fetal 
outcome and breastfeeding 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 condition(s).  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 
study treatment until 30 days after the decision is made to discontinue study treatment must be 
reported to the Sponsor or its designee via eCRF.
Any clinically significant findings from labs and vital sign measurements that result in a 
diagnosis should be reported to the Sponsor or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, study drug, or chemotherapy via eCRF.
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the study drug or 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


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
Does not know:  the investigator cannot determine

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/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.
The NCI-CTCAE, Version 4.03, will serve as a reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the NCI-CTCAE, Version 4.03, 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, the NCI-CTCAE term, and the NCI-CTCAE severity 
grade, AE verbatim text will also be mapped by the Sponsor or designee to corresponding
terminology within Medical Dictionary for Regulatory Activities.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
An SAE is any AE 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 informed consent and has 
received study drug.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving study drug, 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.


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Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
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 therapy 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 the study drug.
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 drug, the investigator should report the SAE 
to the sponsor, 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 the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
10.3.1.2. 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 the investigational product or study procedure.  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.
10.3.2. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within timeframes mandated by company procedures.
The Lilly CRP, will, as is appropriate, consult with the functionally independent GPS therapeutic 
area physician or clinical scientist, and review trends in safety data, laboratory analyses, and 
AEs:

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 


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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.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at
the group level, only the GPS therapeutic area physician or clinical scientist can conduct 
additional analyses of the safety data.
For the purpose of this study, in which survival is a primary endpoint, all deaths and SAE reports 
will be reviewed in a blinded manner by Lilly during the clinical trial.  These reports will be 
reviewed to assure completeness and accuracy but will not be unblinded to Lilly during the 
clinical trial.  If a death or other clinical AE is deemed serious, unexpected, and possibly related 
to study drug, only Lilly representatives external to the study team will be unblinded for 
regulatory reporting and safety monitoring purposes.  These measures will preserve the integrity 
of the data collected during this trial and minimize any potential for bias while providing for 
appropriate safety monitoring.
10.3.3. Complaint Handling
Lilly collects product complaints on study drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and to facilitate process and product improvements.
Complaints related to unblinded comparator drugs or concomitant drugs are reported directly to 
the manufacturers of those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or its designee will be reported.
The investigator or his or 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 or she will return a copy of 
the product complaint form with the product.
10.4. Sample Collection and Testing 
10.4.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria (Section 7) and to monitor patient health.


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Attachment 1 lists the schedule for sample collections during study period.  Attachment 2
summarizes all data required to be collected on the eCRF during the extension period (as defined 
in Section 8.1.4).
Attachment 3 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.  Standard laboratory tests, including hematology, 
coagulation, and urinalysis panels will be performed and analyzed by a local laboratory.  Patient 
randomization and treatment decisions are based on local laboratory results only, unless the 
investigator chooses to use the central laboratory for such a purpose. Central laboratory results 
are used for study report purposes and where appropriate for safety analyses.  Central laboratory 
samples should be collected even when local laboratory results are used to assess eligibility.  A 
pregnancy test will be performed locally. For chemistry test, both central and local laboratory
test should be performed at screening/baseline and prior to D1 of each treatment cycle. But only 
local laboratory test is required for chemistry test prior to D8 and D15 of each treatment cycle.
Investigators must document their review of each laboratory safety report.
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded.
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.
10.4.2. Samples for Translational Research
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 ERB allow, a whole blood sample will be collected for pharmacogenetic 
analysis.  This collection is a one-time whole blood collection that can be taken at any time 
during the study.  However, it is recommended that the sample be collected before the first dose 
of study treatment.
Collection of samples for other biomarker research is also part of this study.  Plasma and tumor 
tissue will be collected. 
Required samples for translational research to be collected from all patients in this study are the 
following:

Whole blood 

Plasma.


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Optional samples for translational research that should be collected from patients in the study 
where possible are the following:

Tumor tissues.
Attachment 5 lists the sampling schedule for translational research.  
Whole blood samples will be stored and analysis may be performed on biomarker variants
thought to play a role in endothelial cell proliferation, angiogenesis, ramucirumab mechanism of 
action, and/or cancer, which may include but not  limited to VEGFR-2 and VEGF-A, to evaluate 
their association with clinical outcomes to ramucirumab.  Polymorphisms in VEGF-A have been 
associated with OS and hypertension using other antiangiogenesis agents (Schneider et al. 2008).  
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.  Pharmacogenetic data 
will not be provided back to the investigator or the patient except where required by local law.
Plasma will be stored and may be used for the analyses of various circulating factors related to 
the VEGF pathway and/or cancer; these factors may include, but not be limited to, levels of 
circulating VEGF-A, VEGF-B, VEGF-C, VEGF-D, placental growth factor (PlGF), soluble 
VEGFR-1, and soluble VEGFR-2, basic fibroblast growth factor (bFGF), and stromal cell-
derived factor 1a (SDF1a).  
Slides with unstained tumor sections or archived tissue blocks are required for biomarker 
research.  Due diligence should be used to make sure that tumor specimen (not a normal adjacent 
or a tumor margin sample) is provided.  Pathology reports accompanying archival tissue may 
also be requested.
Previously archived tumor tissue will be identified at baseline and designated for submission to 
the central laboratory.  Pretreatment, formalin-fixed, paraffin-embedded tumor tissue obtained 
from the primary tumor or metastatic site should be provided as a whole block or unstained 
slides.  After sectioning has been completed, the paraffin-embedded whole blocks will be 
returned to the investigator within 2 months.  Slides will not be returned. 
The tissue may be used to assess biomarkers that predict clinical outcome to treatment with 
ramucirumab.  Mutations in VEGFR-2 have been identified in tumors and have been associated 
with VEGFR-2 expression and clinical outcome (Cerri et al. 2010; Yang et al. 2011).  Such 
mutations may have an impact on ramucirumab binding and efficacy.  This study may determine 
if these VEGFR-2 findings are relevant for gastric cancer and specifically for ramucirumab 
efficacy.  Mutation profiling, copy number variability, gene expression, and 


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immunohistochemistry may be performed on tissue samples to determine an association between 
these biomarkers and ramucirumab efficacy.
The samples will be coded with the patient number and stored for up to a maximum of 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
10.5. Appropriateness of Measurements
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials.


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11. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

Provide instructional material to the study sites, as appropriate.

Sponsor start-up training to instruct the investigators and study coordinators.  This 
session will give instruction on the protocol, the completion of the CRFs, and study 
procedures.

Make periodic visits to the study site.

Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

Review and evaluate CRF data and use standard computer edits to detect errors in data 
collection.

Conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
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.
11.1. Data Capture System
An electronic data capture system will be used in this trial. The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database. Data managed by a 
central vendor, such as laboratory test data or ECG data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly data warehouse.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file. Paper 
documentation provided by the patient may include, for example, a paper diary to collect PRO 
measures (for example, a rating scale), a daily dosing schedule, or an event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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12. Sample Size and Statistical Methods 
12.1. Determination of Sample Size 
The study plan is to enroll approximately 450 patients with advanced gastric or GEJ 
adenocarcinoma after failure of any platinum and fluoropyrimidine doublet with or without 
anthracycline. 
The approximately 450 patients will be randomized in a 2:1 ratio to Arm A (paclitaxel plus 
ramucirumab) and Arm B (paclitaxel plus placebo).  Patients will be randomized using 
stratification factors ECOG PS (0 versus 1) and peritoneal metastatis (yes versus no).   
Under the following assumptions: 
 The randomization ratio is 2:1; 
 OS in each arm follows exponential distribution; 
 The OS hazard ratio for Arm A vs Arm B is 0.81; 
 Control arm median OS = 10.5 months, 
336 deaths (that is, 25% censoring rate) will provide at least 80% probability to assure that the 
effect size observed in this study is consistent with the global study, where effect size is defined 
by 
1
1 
HR

.  The above assurance probability is defined by Probඋߜመ௃௏஼ோ൐ ߩߜመ௃௏஻ாඏ, where
JVBE
ˆ
=0.235 was estimated from the observed HR of 0.81 in the global study and
JVCR
ˆ
 will be 
estimated from the observed HR in this study.   is a constant set to 0.5, corresponding to 50% 
effect size retention from the global study. 
Assuming further a constant accrual rate of 12 patients/month, it is estimated that the study will 
take approximately 44 months to obtain the required 336 deaths, with 37 months for accrual and 
7 months for follow-up.   
12.2. Statistical and Analytical Plans 
12.2.1. General Considerations 
Statistical analysis of this study will be the responsibility of Eli Lilly and Company. 
Analyses of OS, PFS, and ORR 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.  Sensitivity analyses of the primary efficacy endpoints and 
other selected efficacy endpoints based on the per-protocol set (PPS) of patients may be 
performed if there are significant numbers of patients with major protocol violations.  The PPS is 
defined as those patients in the ITT set who are compliant with the study protocol without major 
protocol violations.  Safety will be analyzed for randomized patients receiving at least 1 dose of 
study treatment grouped by actual treatment received.  Analyses of PROs will include 


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randomized patients that provide (for the instrument being analyzed) a baseline assessment and 
at least 1 postbaseline assessment; however, compliance will be based on the ITT population. 
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.
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided.  It will include:

Summary of patients entered and randomized by country

Total number of patients entered

Total number of patients randomized, by treatment arm

Summary of reasons for patients entered, but not randomized

Total number of patients treated, by treatment arm

Summary of reasons for patients randomly assigned but not treated.
A detailed summary of reasons for patient discontinuation from study treatment will be provided.  
A summary of all identified important protocol violations will be provided.
12.2.3. Patient Characteristics
Patient demographics, including the following, will be reported using descriptive statistics:

Patient demographics

Baseline disease characteristics

Preexisting conditions

Prior therapies

Baseline factors.
12.2.4. Concomitant Therapy
Concomitant medications will be summarized for the safety population. 
12.2.5. Treatment Compliance
The number of dose omissions, reductions, delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients per treatment arm.  
12.2.6. Primary Outcome and Methodology
The co-primary efficacy objectives include evaluations of PFS and OS.
12.2.6.1. Progression-free Survival
The PFS is defined as the time from randomization to the date of the first radiographically
documented PD as defined by RECIST, Version 1.1, or death due to any cause, whichever is 
first. 


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Imaging will be performed every 6 weeks (±5 days) following the first dose of study therapy for 
the first 6 months, and every 9 weeks (±5 days) thereafter, until documentation of radiographic
PD. Patients alive and without disease progression at data cut-off date or patients lost to follow-
up will be censored at the day of their last adequate radiographic tumor assessment. If no 
baseline or post-baseline radiographic assessment is available, the patient will be censored at the 
date of randomization. If death or PD occurs after two or more consecutively missed 
radiographic visits, censoring will occur at the date of the last radiographic visit prior to the 
missed visits. The use of a new anticancer therapy prior to the occurrence of PD will result in 
censoring at the date of last adequate radiographic assessment prior to initiation of new therapy.
The primary analysis of PFS in this study will estimate the HR and its 2-sided 95% CI in a 
stratified Cox’s proportional hazards model using treatment arm as a single covariate. The 
stratification factors included in the Cox model are the same as randomization strata. A
sensitivity analysis with an unstratified Cox proportional hazards model will be employed. 
Stratified and unstratified log-rank tests will also be conducted.  
The survival curves for each randomization arm will be estimated using the Kaplan-Meier (KM) 
product-limit method. Two-sided, 95% CIs for median PFS will be computed by the 
Brookmeyer and Crowley method (Brookmeyer and Crowley 1982) using log-log-
transformation. Survival rates at 6, 12, 18 and 24 months will also be estimated using KM 
estimates on the survival curve for each arm. Associated two-sided 95% CIs will also be 
calculated.  
In addition, a multivariate Cox model will be used to adjust for baseline covariates because 
imbalances in potential prognostic factors could impact the analysis of survival. Covariates that 
are planned to be included are those prognostic factors identified in Study JVBE. Details of pre-
specified covariates will be listed in the statistical analysis plan (SAP).
Additional sensitivity analyses for PFS using alternative censoring rules described in the SAP 
will be performed.
12.2.6.2. Overall Survival
Overall survival is measured from the date of randomization to the date of death from any cause.  
For each patient who is not known to have died as of the data-inclusion cut-off date, OS will be 
censored at the date of last known alive date prior to the data-inclusion cut-off date.
The analysis of OS will be conducted via similar methods for PFS, that is, stratified and 
unstratified Cox model and log-rank tests, KM curve, median estimates and survival rates with 
CI.  
An interim OS analysis will be performed concurrently with the primary PFS analysis, and a 
final OS analysis will be performed if the primary objective is not achieved at interim.
12.2.7. Secondary Efficacy Analyses
Secondary efficacy endpoints include TTP, ORR and DOR. 


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Time to progression is defined as the time of randomization to the date of the first 
radiographically documented PD as defined by RECIST, Version 1.1.  For each patient who is 
not known to have had radiographic progression of disease as of the data-inclusion cut-off date, 
or who has died without radiographic progression, TTP will be censored at the date of the 
patient’s last adequate radiographic tumor assessment prior to that cut-off date.
Time to progression will be analyzed using similar methods as described for PFS in Section 
12.2.6.  Additional sensitivity analyses for TTP using alternative censoring rules will be 
specified in the SAP.
Best overall response (BOR) will be determined using RECIST, Version 1.1.  Objective response 
rate will be calculated as the number of patients who achieve a BOR of CR or PR, divided by the 
total number of patients randomized to the corresponding treatment arm (ITT analysis set).  
Patients who do not have a tumor response assessment for any reason are considered as 
nonresponders and are included in the denominator when calculating the response rate.
Objective response rate will be reported along with 2-sided 95% exact CIs using Clopper and 
Pearson’s method for each treatment arm.  The difference of ORR between 2 treatment arms will 
be evaluated using the Cochran-Mantel-Haenszel test adjusting for ECOG PS and peritoneal 
metastases.
Duration of objective response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first) to the date of the first radiographically documented PD as defined 
by RECIST, v 1.1, or death due to any cause, whichever is first.  Patients alive and without 
radiographic disease progression at data-inclusion cut-off date or patients lost to follow-up will 
be censored at the date of their last radiographic tumor assessment.  DOR will be analyzed using 
KM method.  Medians and their two-sided 95% CIs will be calculated.
12.2.8. Health Outcome/Quality of Life Analyses
Patient-reported outcome measures (that is, EORTC QLQ-C30 and EQ-5D-3L) data will be 
summarized by treatment arm using descriptive statistics including questionnaire compliance 
rates for the ITT population.  Exploratory analyses may be performed to investigate associations 
between the PRO and clinical efficacy endpoints.
Following the EORTC guidelines (Fayers et al. 2001), the 30 items of the QLQ-C30 will be 
transformed into the 15 scales (1 global health status/QoL scale, 5 functional scales, and 
9 symptoms scales/items).  A linear transformation will be used to obtain scales ranging from 0 
to 100, with a high score indicating a high level of functioning for the global and the functional 
scales and, conversely, a high level of symptomatology for the symptoms scales.  Missing items 
within a scale will be handled according to the EORTC recommendations (Fayers et al. 2001).  
Scales will be presented using descriptive statistics.
The 5-dimension single-item 3-level EQ-5D-3L responses will be summarized using frequency 
distributions.  The index score for the EQ-5D-3L will be calculated from a combination of 
responses using a weighting algorithm currently in development based on EQ-5D-3L Chinese 
validation study (EuroQol Group 1990; Brooks et al. 1996; Liu et al. 2014).  The visual analog 


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scale is scored from 0 (worst imaginable health state) through 100 (best imaginable health state) 
to represent the patient’s self-reported health during that day.  The index score and the visual 
analog scale will be presented using summary statistics.
QoL scores and change from baseline will be summarized descriptively at each assessment time 
point by subtracting baseline scores for each individual from his or her own scores at the specific 
time point.  The proportion of patients in each arm with deterioration in scores, improvement in 
scores, and stable scores at specific time points will be presented.  Scores will be considered 
improved or deteriorated if change is ≥10 points (Osoba et al. 1998).
12.2.9. Safety Analyses 
All safety summaries and analyses will be based upon the safety population as defined in 
Section 12.2.1.
Safety analyses will include summaries of the incidence of AEs by maximum NCI-CTCAE 
grade (Version 4.03) that occur during the study treatment period or within approximately 
30 days after the decision is made for discontinuation from study treatment.  Additionally, the 
following safety-related outcomes will be summarized:

Study treatment discontinuations due to AEs

Deaths during the study treatment period or within 30 days after the decision is made to 
discontinue study treatment

SAEs during the study treatment period or within 30 days after the decision is made to 
discontinue study treatment

All hospitalizations and transfusions during the study treatment period or within 30 days 
after the decision is made to discontinue study treatment

Selected concomitant medications, including growth factors (erythroid growth factors, 
granulocyte-colony stimulating factors, granulocyte-macrophage colony-stimulating 
factor), antiemetics, antihypertensive agents, and antibiotics, during the study treatment 
period or within 30 days after the decision is made to discontinue study treatment.
12.2.10.
Subgroup Analyses
The following prespecified subgroup analyses are planned according to baseline characteristics.  
More subgroups may be provided in the SAP.

Gender (males versus females)

Age (<65 years versus ≥65 years)

Ethnicity (Chinese versus non-Chinese)

Eastern Cooperative Oncology Group PS (0 versus 1)

Peritoneal metastases (yes versus no)

Post discontinuation therapy use (yes versus no)

Weight loss over the prior 3 months (≥10% versus <10%)

Primary tumor location (gastric versus GEJ tumor)

Time to progression on first-line therapy (<6 months versus ≥6 months)

Presence of ascites (yes versus no)


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
Pharmacodynamic biomarkers.
Cox models using treatment arm as a single covariate will be employed to estimate these HRs 
and CIs.  
12.2.11.
Statistical Analysis for Translational Research
Pharmacodynamic biomarker (that is, soluble VEGR-1 and VEGR-2; VEGF-A, VEGF-B, 
VEGF-C, and VEGF-D; PlGF, bFGF, and SDF1a) characteristics will be summarized by 
treatment arm.  To explore the predictive features of biomarkers, subgroup analyses by these 
biomarkers will be performed for selected primary and secondary endpoints.  For time-to-event 
variables such as OS and PFS, KM estimates will be generated by these biomarkers and Cox’s 
proportional hazard models will be fitted including treatment-by-biomarker interactions.  
Objective response rate will be summarized by treatment and biomarkers.
12.2.12.
Interim Analyses and Data Monitoring
The primary PFS analysis and an interim OS analysis will be reviewed by the Independent Data 
Monitoring Committee (IDMC) after at least 256 PFS events have been observed. The interim 
analysis will be conducted to provide early efficacy information and could potentially result in 
early communication with regulatory agencies.  The IDMC will be instructed to engage the 
Senior Management Designee (SMD), who may, if necessary, subsequently form an Internal 
Review Committee (IRC) to propose actions based upon the IDMC’s recommendation. If the 
study shows early efficacy at interim (that is, both of the conditions described below are met), 
enrollment will be terminated and subjects randomized to the control arm may be permitted to 
cross over to the treatment arm under investigator discretion.  
The primary objective will be claimed achieved if both of the following conditions are met:  
(1) The point estimate of stratified HR for investigator-assessed OS is less than 1. 
(2) The analysis of investigator-assessed PFS shows a one-sided, stratified p-value favoring 
Ramucirumab+paclitaxel arm less than 0.025.
If at least one of the conditions above are not met, the blinded study continues and a final OS 
analysis will apply.  The final analysis will be conducted when approximately 336 OS events 
have been observed.
The unblinded interim analysis, including the efficacy and safety data, will be reviewed by the
IDMC. Only the IDMC is authorized to evaluate unblinded interim efficacy and safety analyses.
Study sites will receive information about interim results ONLY if they need to know for the 
safety of their patients.  
Unblinding details are specified in the unblinding plan section of the SAP.  


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13. Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. 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 
where permitted by local law or regulation, by the patient's 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 drug.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are submitted to the ERB and are 
used at the 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. 
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERBs should be provided with the following:

The current IB or package labeling (for example, Patient Information Leaflet, Package 
Insert, or Summary of Product Characteristics) and updates during the course of the study

Informed consent form

Relevant curricula vitae.
13.3. Regulatory Considerations
This study will be conducted in accordance with:
1. Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 


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2. The ICH GCP Guideline (E6)
3. Applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of Lilly will be assigned to a third-party organization.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
The Lilly responsible medical officer and statistician will sign/approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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14. References
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filberti A, Flechtner H, 
Fleishman SB, de Haes JC, Kassa S, Klee M, Osoba D, Razavi D, Rofe PB, Schraub S, 
Sneeuw K, Sullivan M, Takeda F. The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst. 1993;85(5):365-376.
Avastin [package insert]. South San Francisco, CA: Genentech, Inc; 2011.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, 
Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial 
Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for 
treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): 
a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697.
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53-72.
Cerri E, Kashyap S, Chen PX, Das S, Cipriani N, Kanteti R, Husain A, Salgia R, Innocenti F. 
Vascular endothelial growth factor receptor-2 (VEGFR-2) gene variations in 
bronchioloalveolar cell carcinoma (BAC). Cancer Res. 2010;70(8 Suppl):Abstract 2176.
Chen W, Zheng R, Zeng H, Zhang S, He J. Annual report on status of cancer in China, 2011. 
Chin J Cancer Res. 2015;27(1):2-12.
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. 
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Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH. Salvage chemotherapy for pretreated 
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(CCOG0302 study). Anticancer Res. 2007;27(4C):2667-2671.


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formula for new drugs. J Clin Oncol. 2003;21(14):2633-2635.
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.
Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, 
Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as 
first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled 
phase III study. J Clin Oncol. 2011;29(30):3968-3976.
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-144.
Pozzo C, Barone C. Is there an optimal chemotherapy regimen for the treatment of advanced
gastric cancer that will provide a platform for the introduction of new biological agents? The
Oncologist. 2008;13(7):794-806.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
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darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American 
Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-149.
Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, Flockhart, Hancock B, 
Davidson N, Gralow J, Dickler M, Perez EA, Cobleigh M, Shenkier T, Edgerton S, Miller KD; 
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growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared 
with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 
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Schwartz RB. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 
1996;334(26):1743.
Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, Kelsen DP. Phase II 
study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with 
metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011;29(7):868-874. 


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randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 
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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, 
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(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.
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Pettaway CA, Dinney CP. Anti-vascular endothelial growth factor receptor 2 antibody reduces 
tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of 
endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 
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Tajima Y, Isonishi K, Kashiwaba T, Tashiro K. Two similar cases of encephalopathy, possibly a 
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and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant 
chemotherapy. Cancer Res. 2011;71(16):5512–5521.






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Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; D/d = day; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; 
EQ-5D-3L = EuroQol-5 Dimension-3 Level Questionnaire; F/U = follow-up; IRR = infusion-related reaction; IWRS = interactive web response system; 
MUGA = multi-gated acquisition scan; PD = progressive disease; PRO = patient-reported outcome; SAE = serious adverse event; Wk = week; WOCBP = 
women of child-bearing potential.
a
The short-term follow-up begins the day after the decision is made to discontinue study treatment and lasts approximately 30 days (no more than 37 days).  If 
it is deemed to be in the best interest of the patient to start a new anti-cancer treatment prior to the scheduled end of the short-term follow-up visit, the follow-
up visit duration may be shortened. In this case, the short-term follow-up assessments should be completed prior to the initiation of the new therapy. 
b
Written informed consent must be obtained prior to any study-related procedures or evaluations.  Informed consent form signature alone does not define start 
of screening period, but first study-related procedure or evaluation date is to be used for IWRS call/date of screening visit.
c
Any preexisting toxicity within 28 days prior to randomization should be documented and recorded as part of the medical history at baseline.
d
Electrocardiogram and imaging will be performed locally.
e
Additional ECGs will be collected within 3 days prior to the first infusion of Cycle 2, Cycle 3 and then every odd-numbered cycles. Thereafter, within 30
days after the discontinuation of chemotherapy, and within 30 days after the discontinuation of ramucirumab/placebo.
f
To be performed at screening/baseline (within 21 days prior to randomization), within 3 days prior to the first infusion of Cycle 3 only, thereafter, within 30 
days after the discontinuation of chemotherapy, and within 30 days after the discontinuation of ramucirumab/placebo.
g
Assessment at baseline includes all medications taken within 28 days prior to randomization. Medication assessment during long-term follow up only collects
information on any subsequent systemic anticancer therapy.
h
Height measurements to be performed at screening/baseline only.
i
To be obtained at every treatment visit, before and at the completion of each infusion of ramucirumab/placebo, and before and at the completion of 
chemotherapy administration. If paclitaxel is administrated within 30 minutes after the completion of ramuciumab/placebo infusion, the measurement of vital 
signs before paclitaxel administration is optional.
j
All SAEs and all AEs considered at least possibly related to any study therapy will be followed until resolution, stabilization, return to baseline, or until 
deemed irreversible.
k
To be completed within 3 days prior to the start of each cycle and at the short-term 30-day safety follow-up visit, before blood sampling or any extensive 
contact and consultation with the clinician/study investigator; such encounters may thereafter bias patient responses.  The instruments should be administered 
together and in sequence order, with the EORTC QLQ-C30 presented first, followed by presentation of the EQ-5D-3L. Does not need to be completed prior 
to Cycle 1 if completed at screening/baseline.
l
Hematology profile to be collected within 36 hours (blood may be collected the morning of study therapy or the day before, results to be available and 
evaluated prior to start of infusion) prior to treatment on Days 1, 8, and 15 of each cycle until discontinuation of paclitaxel and prior to the start (Day 1) of 
each 28-day cycle only thereafter (Arms A and B). Baseline lab assessments can be used for dosing for Cycle 1 Day 1 if performed within 7 days prior to 
Cycle 1 Day 1.
m ALT, AST, and total bilirubin to be collected within 36 hours (blood may be collected the morning of study therapy or the day before, results to be available 
and evaluated prior to start of infusion) prior to treatment on Days 1, 8, and 15 of each cycle until discontinuation of paclitaxel, prior to the start (Day 1) of 
each 28-day cycle thereafter (with full serum chemistry profile). Baseline lab assessments can be used for dosing for Cycle 1 Day 1 if performed within 7 
days prior to Cycle 1 Day 1.


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n
Routine dipstick measurements and, if clinically indicated, microscopic analysis.  If urine dipstick or routine analysis indicates proteinuria ≥2+, a 24-hour 
urine collection (to assess protein) must be obtained.
o
Performed within 3 days prior to Day1 of every odd-numbered cycles. Or according to institutional guidelines (serum pregnancy test for WOCBP mandatory 
at baseline).
p
Imaging studies and tumor assessments should be performed as scheduled every 6 weeks (±5 days) following the first dose of study therapy for the first 6 
months, and every 9 weeks (±5 days) thereafter, until documentation of radiographic PD, even if therapy is delayed.  
q
For patients removed from the study due to symptomatic deterioration characterized as PD in the absence of radiographic documentation of PD.
r
Paclitaxel must not be started earlier than 60 minutes after completion of the ramucirumab/placebo infusion. The 1-hour observation period between 
administration of ramucirumab/placebo and paclitaxel is mandatory for the first 2 cycles, but may be omitted in Cycle 3 and beyond, provided there has been 
no evidence of IRR
s
Baseline lab assessments can be used for dosing for Cycle 1 Day 1 if performed within 7 days prior to Cycle 1 Day 1. Thereafter, performed within 3 days 
prior to treatment at Day 1 of every odd-numbered cycle. The coagulation profile test could be more often if clinically indicated.


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Attachment 2.Protocol JVCR Study Schedule – Study 
Extension Period
Procedurea
Treatment Period in 
Extension Period
(every cycle)
30-Day 
Short-Term 
Follow-Upb (+ 0-
7d)
Visit
501-5XX
901
Toxicity 
Assessment/AEs
X
X
Administer Study 
Therapy
X
Abbreviations:  AE = adverse event; d = days. 
a
During the extension period, routine safety and efficacy monitoring, including radiographic evaluation of disease 
and laboratory testing, such as pregnancy testing, should be continued as necessary, and documentation retained 
within the source files, to confirm patient eligibility to continue on treatment or the 30-day short-term follow-up 
visit.  The Sponsor will collect only data shown in this table for the extension period.
b
The short-term follow-up begins the day after the decision is made to discontinue study treatment and lasts 
approximately 30 days (no more than 37 days).


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Attachment 3.Protocol JVCR Clinical Laboratory Tests
Hematologya:
Clinical Chemistryb,c:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean corpuscular volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils
Lymphocytes
Alanine aminotranferase/serum glutamic pyruvic 
transaminase (ALT/SGPT)
Monocytes
Eosinophils
Aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase (AST/SGOT)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatinine
Uric acid
Urinalysisa:
Calcium
Routine dipstick measurements, and if clinically
Glucose, random
indicated, microscopic analysis.  If urine dipstick or
Albumin
routine analysis indicates proteinuria ≥2+ at
evaluation, a 24-hour urine collection (to assess
protein) must be obtained. 
Coagulation Testsa:
Chloride
Total protein
Lactate dehydrogenase
Magnesium
Phosphorus
Prothrombin time (PT/INR)
Partial thromboplastin time/activated Partial 
thromboplastin time (PTT/aPTT)
Serum Pregnancy Test (females only)a
Abbreviations:  INR = international normalized ratio; IU = international units; L = liter; RBC = red blood cells;
WBC = white blood cells.
a
Assayed by investigator-designated (local) laboratory.
b
Assayed by sponsor-designated (central) laboratory and/or investigator-designated (local) laboratory.
c
Patient randomization and treatment decisions are based on local laboratory results only, unless the investigator 
chooses to use the central laboratory for such a purpose. Central laboratory results are used for study report 
purposes and where appropriate for safety analyses.  Central laboratory samples should be collected at 
screening/baseline and prior to D1 of each treatment cycle even when local laboratory results are used to assess 
eligibility and make treatment decisions.


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Attachment 4.Protocol JVCR Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented and bands
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 transpeptidase; IgG = immunoglobulin G; IgM = immunoglobulin M; 
INR = international normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated central laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 5.Protocol JVCR Sampling Schedule for 
Translational Research
Procedure
Cycle 1
Cycle 2 Day 15c
4th 
ramucirumab/pla
cebo infusion
Cycle 4 Day 1d
7th 
ramucirumab/pla
cebo infusion
30-Day 
Short-Term 
Follow-Upb
(+0-7 d)
Preinfusiona,b
Preinfusionb
Preinfusionb
Tumor tissue 
submissione
X
Whole blood sample 
collectionf
X
Plasma sample 
collection
X
X
X
Xg
Note:  It is essential that the draw dates and draw times are accurately recorded.
Abbreviations:  IRB = institutional review board.
a
Prior to the first infusion.  (It is recommended that this sample be taken after randomization and prior to 
administration of study treatment at Cycle 1.)
b
Samples for plasma pharmacodynamic biomarkers: 1 tube.  
c
Approximately 6 weeks following the first infusion (that is, fourth infusion) of ramucirumab/placebo. Sampling 
applies only to patients receiving ramucirumab /placebo, excluding patients that discontinued 
ramucirumab/placebo.
d
Approximately 12 weeks following the first infusion (that is, seventh infusion) of ramucirumab/placebo.
Sampling applies only to patients receiving ramucirumab/placebo, excluding patients that discontinued 
ramucirumab/placebo.
e
Collection of tumor tissue is optional in this study.  Previously archived tumor tissue will be identified prior to 
randomization and designated for submission to the central laboratory. 
f
Unless precluded by local regulations or IRB policy, whole blood samples will be collected for pharmacogenetic 
analysis.  
g
If ramucirumab/placebo has to be discontinued, blood samples for plasma pharmacodynamic analysis has to be 
taken after 30 days (+0 to 7 days) of last ramucirumab/placebo infusion regardless if the paclitaxel administration 
is continuing.


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




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Attachment 8.Protocol JVCR 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.
-OR-
GFR (mL/min/1.73m2) = 170 × [PCr]-0.999 × [age]-0.176
× [0.762 if patient is female] × [1.18 if patient is black]
× [SUN]-0.17 × [Alb]+0.318
Abbreviations:  Alb = serum albumin, g/dL; CrCl = creatinine clearance; GFR = glomerular filtration rate; 
PCr = plasma creatinine, mg/dL; SUN = serum urea nitrogen, mg/dL; wt = weight.
Source:  Murray and Ratain 2003.


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Attachment 9.Protocol JVCR Amendment(c) Summary
A Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, Phase 3 Study of Weekly Paclitaxel 
with or without Ramucirumab (IMC-1121B) in Patients with 
Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma, Refractory to or Progressive after 
First-Line Therapy with Platinum and Fluoropyrimidine
Overview
Protocol I4T-CR-JVCR (b) A Randomized, Multicenter, Double-Blind, Placebo-Controlled,
Phase 3 Study of Weekly Paclitaxel with or without Ramucirumab (IMC-1121B) in Patients with 
Advanced Gastric or Gastroesophageal Junction Adenocarcinoma, Refractory to or Progressive 
after First-Line Therapy with Platinum and Fluoropyrimidine has been amended.  The new 
protocol is indicated by amendment (c) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

An interim analysis was added. Evaluation of PFS was added as a co-primary objectives
along OS. Statistical assumptions and corresponding analysis plan were updated
accordingly. 

Deleted the “follow up” and “study completion” in Figure JVCR 8.1, since the detailed 
information has been clarified in Figure JVCR 8.2. 

For the benefit of the patient, clarified crossover to the control arm may be permitted if the 
study show early efficacy at interim.

Clarified the short-term follow-up procedure for subject initiating new anti-cancer therapy 
within this period.

“Different drug product lots must not be mixed in a single infusion” was deleted, as
Ramucirumab is commercial product and there is no such requirement. 

Clarified the treatment delay is at investigator discretion when AE/toxicities not listed in the 
protocol happened.  

To keep consistency with IB, “Fistula Formation” was added to “Treatment Guideline and 
Dose modification for Specific Adverse Events of Ramucirumab” and the following chapter
numbers were updated. 

The footnotes e and f in attachment 1 are not applied for ECG and ECHO of V801, therefore 
they were deleted. 


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Revised Protocol Sections
Note: Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2. Synopsis
Number of Planned Patients:
   Entered:  500
   Randomized:  450
   OS events:  336
Length of Study:  
Planned first patient visit:  November 2016
Planned last patient visit:  July 2020
Planned interim analysis: An interim analysis is planned with a total of 256 PFS events  
Objectives: The co-primary objective of this study is to evaluate PFS and OS in patients treated 
with paclitaxel plus ramucirumab (IMC 1121B) versus paclitaxel plus placebo as second-line 
treatment in patients with advanced gastric or GEJ adenocarcinoma after failure of any platinum 
and fluoropyrimidine doublet with or without anthracycline (epirubicin or doxorubicin).
The secondary objectives of the study are to evaluate:

PFS

Time to progression

Objective response rate

Duration of objective response

Safety profile

Patient-reported outcome measures
In addition, exploratory objectives include:

To explore biomarkers relevant to gastric or GEJ adenocarcinoma or safety, efficacy, and 
mechanism of action of ramucirumab.  
Planned Duration of Treatment:  
Long-term follow-up period (postdiscontinuation):  After the decision is made to discontinue 
study treatment, follow-up information regarding further anticancer treatment and survival status 
will be collected at least every 8 weeks (+0 to 7 days).  For patients who discontinue treatment 
for any reason other than radiographically documented PD (for example, symptomatic 
deterioration), information on disease progression (radiographic assessment) will also be 
collected until PD is documented by imaging.  Follow-up will continue as long as the patient is 
alive, or until study completion (336 deaths have occurred in the study), whichever is first.


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Criteria for Evaluation:
Efficacy: 
Progression-free survival is defined as the time from the date of randomization to the date of 
the first radiographically documented PD as defined by RECIST, Version 1.1, or death due to 
any cause, whichever is first.  
Overall survival is defined as the time from the date of randomization to the date of death 
from any cause. 
Progression free survival is defined as the time from the date of randomization to the date of 
the first radiographically documented PD as defined by RECIST, Version 1.1, or death due to 
any cause, whichever is first.  
Statistical Methods:  
Statistical:  
Approximately 450 patients will be randomized to the 2 treatment arms in a 2:1 ratio (300
patients in Arm A [paclitaxel plus ramucirumab] and 150 patients in Arm B [paclitaxel plus 
placebo]) in order to obtain at least 336 deaths.  Assuming an exponential distribution in each 
arm and a true underlying HR of 0.81 as observed in the global study, 336 deaths will provide at 
least 80% probability to assure that the effect size observed in this study is consistent with the 
global study. Also assuming a constant accrual rate of 12 patients/month, a median OS of 10.5 
months in Arm B and a median OS of 13 months in Arm A, the study will take approximately 44
months to obtain the required 336 deaths (37 months for accrual and 7 months for the follow-up). 
The primary PFS analysis and an interim OS analysis will be performed when at least 256 PFS 
events have occurred.
Efficacy:  
The primary analysis of OS PFS/OS in this study is to estimate the HR and its 2-sided 95% CIs 
in a stratified Cox’s proportional hazards model using treatment arm as a single covariate.  The 
stratification factors included in the Cox model are ECOG PS (0 versus 1) and peritoneal 
metastases (yes versus no). An additional A sensitivity analysis with an unstratified Cox 
proportional hazards model will be employed to explore the effect of the stratification factor.  
Stratified (using the same stratification factor) and unstratified log-rank tests will also be 
conducted. The OS survival curves for each randomized arm will be estimated using the Kaplan-
Meier (KM) product-limit method.  Two-sided, 95% CIs for median OS PFS/OS will be 
computed by the Brookmeyer and Crowley method.  Landmark survival rates will also be 
estimated using KM estimates on the OS survival curve for each randomized arm.  Associated 2-
sided 95% CIs will also be calculated.
6. Objectives
6.1 Primary Objective
The co-primary objective of this study is to evaluate PFS and OS in patients treated with 
paclitaxel plus ramucirumab (IMC-1121B, LY3009806) versus paclitaxel plus placebo as 
second-line treatment in patients with advanced gastric or GEJ adenocarcinoma after failure of 
any platinum and fluoropyrimidine doublet with or without anthracycline (epirubicin or 
doxorubicin).




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8.1.2.1. Short-Term Follow-Up
For patients who discontinue treatment for reasons other than radiographic PD, imaging studies 
with tumor measurements/disease response assessments will continue to be performed every 
6 weeks (±5 days) following the first dose of study therapy for the first 6 months, and every 
9 weeks (±5 days) thereafter, until documentation of radiographic PD.
If it is deemed to be in the best interest of the patient to start a new anti-cancer treatment prior to 
the scheduled end of the short-term follow-up visit, the follow-up visit duration may be 
shortened. In this case, the short-term follow-up assessments should be completed prior to the 
initiation of the new therapy. 
8.1.3. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the interim analysis (256 PFS events) if the study is stopped early, or 
following final analysies of OS (336 deaths; see Section 12) if the study is not stopped early, as 
determined by Lilly.  
Investigators will continue to follow the Study Schedule for all patients until notified otherwise 
by Lilly.  
Figure JVCR 8.2 provides an illustration of study completion, the extension period, and the end 
of trial.




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than 60 minutes (based on the patient’s body weight), the infusion time should be accurately 
recorded on the eCRF.  The first dose of ramucirumab (or placebo) is dependent upon the 
patient’s screening/baseline body weight in kilograms.  Subsequent doses of ramucirumab (or 
placebo) must be recalculated if there is a ≥10% change (increase or decrease) in body weight 
from the time of the most recent dose calculation; subsequent doses may be recalculated if there 
is a <10% change (increase or decrease) in body weight from the time of the most recent dose 
calculation.  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 within 30 days prior to dose.  If no recent dry weight is available, actual 
weight will be used.
Different drug product lots must not be mixed in a single infusion.
9.4.1.1.1. Requirements Prior to Day 1 of Each Treatment Cycle
Prior to Day 1 of each administration of study therapy, hematology, urine protein (dipstick), liver, 
and renal function must be adequate, and all toxicities (except for alopecia, venous 
thromboembolic events, hypertension, and proteinuria) must have resolved to Grade <2 or 
baseline.  Preinfusion laboratory data may not be older than 36 hours.  The following criteria in 
Table JVCR 9.1 and Table JVCR 9.2 must be fulfilled. as required in Table JVCR 9.1 and Table 
JVCR 9.2. Preinfusion laboratory data may not be older than 36 hours. For AE/toxicities not 
listed in Table JVCR 9.1 and Table JVCR 9.2, treatment delay is at investigator discretion. 
Table JVCR 14.1.
Criteria for Paclitaxel Treatment on Day 1 of Each Cycle
Parameter
Criterion
Neutrophils
>1.5 × 109/L
Platelets
>100 × 109/L
Hemoglobin
≥8 g/dL
Serum Creatinine
<1.5× ULN or calculated creatinine clearance >50 ml/min
Bilirubin
<1.5× ULN
AST/ALT
≤3× ULN if no liver metastases, <5× ULN if liver metastases
Paclitaxel related 
Toxicities/AEs
NCI CTCAE, Version 4.03, Grade <2 or baseline (except for alopecia) 
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; min = 
minute; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; ULN = 
upper limit of normal.
Table JVCR 14.2.
Criteria for Ramucirumab Treatment on Day 1 of Each Cycle
Parameter
Criterion
Urine Protein
Dipstick <2+ or protein level <2 g/24-hr
Ramucirumab related 
Toxicities/AEs Specific Adverse 
Event of Ramucirumab
NCI CTCAE, Version 4.03, Grade <2 or baseline (except for 
hypertension, venous thromboembolic events, and proteinuria)  
Refer to 9.4.2.1


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Abbreviations:  AE = adverse event; hr = hour; NCI-CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events.
9.4.1.1.2. Requirements Prior to Days 8 and 15 of Each Treatment Cycle
Prior to Days 8 and 15 of each administration of study therapy, hematology, urine protein (dipstick), 
and liver function must be adequate (see Table JVCR 9.3 and Table JVCR 9.4), and all toxicities 
(except for alopecia, venous thromboembolic events, hypertension, and proteinuria) must have 
resolved to Grade <2 or baseline.  Preinfusion laboratory data may not be older than 36 hours. For 
AE/toxicities not listed in Table JVCR 9.3 and Table JVCR 9.4, treatment delay is at investigator 
discretion.
Table JVCR 14.3.
Criteria for Paclitaxel Treatment on Days 8 and 15 of Each Cycle
Parameter
Criterion
Absolute neutrophil count
≥1.0 × 109/L
Platelet count
≥75 × 109/L
Hemoglobin
≥8 g/dL
Bilirubin
≤1.5× ULN
AST/ALT
≤3× ULN if no liver metastases, <5× ULN if liver metastases
Paclitaxel related toxicities/AEs
NCI CTCAE, Version 4.03, Grade <2 or baseline (except for alopecia) 
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; ULN = upper 
limit of normal.
Table JVCR 14.4.
Criteria for Ramucirumab Treatment on Day 15 of Each Cycle
Parameter
Criterion
Urine Protein
Dipstick <2+ or protein level <2 g/24-hr
Ramucirumab related 
Toxicities/AEs Specific Adverse 
Event of Ramucirumab
NCI CTCAE, Version 4.03, Grade <2 or baseline (except for 
hypertension, venous thromboembolic events, and proteinuria) 
Refer to 9.4.2.1
Abbreviations:  AE = adverse event; hr = hour; NCI-CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events.
9.4.2.1.7. Fistula Formation
Gastrointestinal and non-GI fistula formation has been associated with antiangiogenic agents 
including bevacizumab and sunitinib (Kamba and McDonald 2007).  Some fistulas can be 
resolved with surgery procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and Cleck 
2009).  A small number of fistula events have been reported in ramucirumab clinical trials.  
Ramucirumab treatment should be discontinued in patients who develop fistulas.


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9.4.2.1.7. 9.4.2.1.8. Congestive Heart Failure in Patients Who Received Ramucirumab in 
Combination with Mitoxantrone or Following Prior Anthracycline Therapy
An increased risk of CHF has been associated with some antiangiogenic therapeutic agents, 
particularly in patients with metastatic breast cancer previously treated with anthracyclines or 
with other risk factors for CHF, including prior radiotherapy to the left chest wall.  Findings have 
ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF 
requiring treatment or hospitalization.  Caution should be exercised when treating patients with 
clinically significant cardiovascular disease such as preexisting coronary artery disease or CHF.  
Patients with symptomatic CHF, unstable angina pectoris, or symptomatic or poorly controlled 
cardiac arrhythmia should not be enrolled in clinical trials with ramucirumab.
Ramucirumab should be discontinued in the event of any Grade 3 to 4 events consistent with 
CHF.
9.4.2.1.8. 9.4.2.1.9. Surgery and Impaired Wound Healing
Surgery and impaired wound healing have been observed with some antiangiogenic agents.  
Ramucirumab will not be administered to patients who have undergone major surgery within 
28 days prior to randomization or have undergone central venous access device placement within 
7 days prior to randomization.  Patients with postoperative and other nonhealing wound 
complications are excluded, as are patients for whom major surgical procedures are planned.
9.4.2.1.9. 9.4.2.1.10. Liver Injury/Liver Failure
An independent data monitoring committee (IDMC) for the ramucirumab study CP12-0919 
(I4T-IE-JVBF [JVBF]) (a randomized, blinded study evaluating ramucirumab versus placebo in 
hepatocellular carcinoma following prior sorafenib therapy) recommended modifications 
following a meeting on 02 August 2012.  This 02 August 2012 meeting was the fifth meeting of 
the IDMC for this study (the prior meetings had concluded with recommendations to continue 
this study without modifications), and occurred at the request of the Sponsor to investigate a 
potential association of liver failure and other events of severe liver injury with ramucirumab.  
The IDMC reviewed unblinded safety data from 400 patients who had been treated with either 
ramucirumab or placebo.  The data cut-off date of this safety review was 18 July 2012.
In review of the safety data, the IDMC noted that death rates related to study medication were in 
the expected range for patients with hepatocellular carcinoma and cirrhosis.  However, the 
IDMC observed a numeric imbalance of liver-related AEs, specifically for hepatic 
encephalopathy, between the 2 treatment arms.  Based on this safety finding, the IDMC 
specifically addressed hepatic encephalopathy, hepatorenal syndrome, and ascites in the context 
of cirrhosis, exclusive of other etiologies of these diagnoses.
The IDMC recommended continuing the CP12-0919 study with modifications.  These 
modifications included:  (a) exclusion of patients with Child-Pugh B cirrhosis (or worse), 
(b) exclusion of patients with cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis, and (c) an additional criterion for 
discontinuation of study drug (ramucirumab or placebo) for patients with new occurrence of 


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hepatic encephalopathy and/or hepatorenal syndrome resulting from liver cirrhosis.  Although 
the CP12-0919 IDMC’s recommendations are specific to the CP12-0919 study, ImClone 
Systems/Eli Lilly and Company (ImClone/Lilly) has chosen to implement these 
recommendations for ongoing ImClone/Lilly-sponsored studies in which patients are receiving 
investigational ramucirumab.
Ramucirumab should be discontinued following a new occurrence of hepatic encephalopathy 
and/or hepatorenal syndrome resulting from liver cirrhosis.
9.4.2.1.10. 9.4.2.1.11. Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) 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).  
Magnetic resonance imaging represents the most reliable method for the 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).   has been associated with multiple 
clinical conditions including hypertensive encephalopathy, eclampsia, and renal failure with 
hypertension as well as the use of both immunosuppressive and cytotoxic drug (Hinchey et al. 
1996; Marinella and Markert 2009).  More recently, RPLS has been associated with the use of 
the anti-VEGF agent bevacizumab, as described in the prescribing information for this agent 
(Marinella and Markert 2009; Avastin package insert, 2011). 
10 Efficacy, Patient-Reported Outcomes, Safety Evaluations, Sample Collection and 
Testing, and Appropriateness of Measurements
10.1.3. Primary Efficacy Measure
The primary efficacy measures is are the duration of PFS and OS.

Progression-free survival is measured from the date of randomization to the date of the 
first radiographically documented PD as defined by RECIST, Version1.1, or the date of 
death due to any cause, whichever is first.  The censoring is taken in the following order:
-
if a patient does not have a complete baseline or post-baseline radiographic disease 
assessment, then the PFS will be censored at the date of randomization, regardless of 
whether or not radiographically determined disease progression or death has been 
observed for the patient; otherwise, 
-
if a patient is alive and does not have radiographic progression as of the 
data-inclusion cut-off date, the PFS time will be censored at the date of the last 
adequate radiographic tumor assessment prior to cut-off date.


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
Overall survival is measured from the date of randomization to the date of death from 
any cause.  For each patient who is not known to have died as of the data-inclusion cut-
off date, OS duration will be censored at the date of last known alive date prior to the 
data-inclusion cut-off date. 
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  The date of first documented radiographic disease progression must be 
recorded on the CRF even if it occurs after the patient has started a new therapy.
10.1.4. Secondary Efficacy Measures 
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1). A responder is defined as any patient who exhibits an unconfirmed 
complete response (CR) or PR. Best response is determined from the sequence of responses 
assessed.
The following definitions for secondary efficacy measures will apply:

Progression free survival is measured from the date of randomization to the date of the 
first radiographically documented PD as defined by RECIST, Version1.1, or the date of 
death due to any cause, whichever is first.  The censoring is taken in the following order:
-
if a patient does not have a complete baseline or post-baseline radiographic disease 
assessment, then the PFS will be censored at the date of randomization, regardless of 
whether or not radiographically determined disease progression or death has been 
observed for the patient; otherwise, 
-
if a patient is alive and  does not have radiographic progression as of the 
data inclusion cut off date , the PFS time will be censored at the date of the last 
adequate radiographic tumor assessment.

Time to progression is defined as the time of randomization to the date of the first 
radiographically documented PD as defined by RECIST, Version 1.1.  For each patient 
who is not known to have had radiographic progression of disease as of the data-inclusion 
cut-off date, or who has died without radiographic progression of disease, TTP will be 
censored at the date of the patient’s last radiographic tumor assessment prior to that cut-
off date.

Objective response rate is defined as the proportion of patients with a best overall 
response (BOR) of PR or CR.  Patients who do not have a tumor response assessment for 
any reason are considered nonresponders and are included in the denominator when 
calculating the response rate.  For each treatment arm, the number of patients achieving a 
response will be divided by the total of patients randomized to yield the proportion 
responding:
ORR (%) = # of evaluable patients who have a best response of PR or CR  × 100
# of patients in analysis population 

Duration of objective response is measured from the time measurement criteria are first 
met for CR or PR (whichever is first recorded) to the date of the first radiographically 
documented PD as defined by RECIST, Version 1.1, or death due to any cause, 
whichever is first.


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12. Sample Size and Statistical Methods 
12.1. Determination of Sample Size 
The study plan is to enroll approximately 450 patients with advanced gastric or GEJ 
adenocarcinoma after failure of any platinum and fluoropyrimidine doublet with or without 
anthracycline. 
The approximately 450 patients will be randomized in a 2:1 ratio to Arm A (paclitaxel plus 
ramucirumab) and Arm B (paclitaxel plus placebo).  Patients will be randomized using 
stratification factors ECOG PS (0 versus 1) and peritoneal metastatis (yes versus no). 
Under the following assumptions: 
 The randomization ratio is 2:1; 
 OS in each arm follows exponential distribution; 
 The OS hazard ratio for Arm A vs Arm B is 0.81; 
 Control arm median OS = 10.5 months.   
The primary objective of this study is to evaluate the OS in patients treated with Arm A 
(paclitaxel plus ramucirumab) versus Arm B (paclitaxel plus placebo) as second line treatment in 
patients with advanced gastric or GEJ adenocarcinoma after failure of any platinum and 
fluoropyrimidine doublet with or without anthracycline (epirubicin or doxorubicin).  The study 
will randomize approximately 450 patients in a 2:1 ratio (300 patients in Arm A and 150 patients 
in Arm B).  The primary analysis will be performed after 336 deaths have occurred (that is, a 25% 
censoring rate).  Assuming an exponential distribution in each arm and a true underlying HR of 
0.81 as observed in the global Study JVBE, 336 deaths (that is, 25% censoring rate) will provide 
at least 80% probability to assure that the effect size observed in this study is consistent with the 
global study, where effect size is defined by 
1
1 
HR

.  The above assurance probability is 
defined by Probඋߜመ௃௏஼ோ൐ ߩߜመ௃௏஻ாඏ, where
JVBE
ˆ
=0.235 was estimated from the observed HR of 
0.81 in the global study and
JVCR
ˆ
 will be estimated from the observed HR in this study.   is a 
constant set to 0.5, corresponding to 50% effect size retention from the global study. 
Assuming further a constant accrual rate of 12 patients/month, it is estimated that a median OS 
of 10.5 months in Arm B and a median OS of 13 months in Arm A, the study will take 
approximately 44 months to obtain the required 336 deaths, with (37 months for accrual and 
7 months for the follow-up).  
12.2.6. Primary Outcome and Methodology 
Overall survival is measured from the date of randomization to the date of death from any cause.  
For each patient who is not known to have died as of the data inclusion cut off date, OS will be 
censored at the date of last known alive date prior to the data inclusion cut off date. 


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The primary analysis of OS in this study will estimate the HR and its 2 sided 95% CIs in a 
stratified Cox’s proportional hazards model using treatment arm as a single covariate.  The 
stratification factors included in the Cox model are ECOG PS (0 versus 1) and peritoneal
metastases (yes versus no).  An additional analysis with an unstratified Cox proportional hazards 
model will be employed to explore the impact of the stratification factor.  Stratified (using the 
same stratification factor) and unstratified log rank tests will also be conducted.
The OS curves for each randomized arm will be estimated using the Kaplan Meier (KM) 
product limit method.  Two sided, 95% CIs for median OS will be computed by the Brookmeyer 
and Crowley method.  Survival rates at 6, 12, 18 and 24 months will also be estimated using KM 
estimates on the OS curve for each randomized arm.  Associated two sided 95% CIs will also be 
calculated.
In addition, a multivariate Cox model will be used to adjust for baseline covariates as small 
imbalances in potential prognostic factors could impact the analysis of survival. Covariates that 
are planned to be included are those prognostic factors identified in Study JVBE.  Details of pre
specified covariates will be listed in the statistical analysis plan (SAP).
The final efficacy analysis will be performed when at least 336 deaths are observed.  No interim 
analysis is planned.
The co-primary efficacy objectives include evaluations of PFS and OS.
12.2.6.1. Progression-free Survival
The PFS is defined as the time from randomization to the date of the first radiographically 
documented PD as defined by RECIST, Version 1.1, or death due to any cause, whichever is 
first. 
Imaging will be performed every 6 weeks (±5 days) following the first dose of study therapy for 
the first 6 months, and every 9 weeks (±5 days) thereafter, until documentation of radiographic 
PD. Patients alive and without disease progression at data cut-off date or patients lost to follow-
up will be censored at the day of their last adequate radiographic tumor assessment. If no 
baseline or post-baseline radiographic assessment is available, the patient will be censored at the 
date of randomization. If death or PD occurs after two or more consecutively missed 
radiographic visits, censoring will occur at the date of the last radiographic visit prior to the 
missed visits. The use of a new anticancer therapy prior to the occurrence of PD will result in 
censoring at the date of last adequate radiographic assessment prior to initiation of new therapy. 
The primary analysis of PFS in this study will estimate the HR and its 2-sided 95% CI in a 
stratified Cox’s proportional hazards model using treatment arm as a single covariate. The 
stratification factors included in the Cox model are the same as randomization strata. A 
sensitivity analysis with an unstratified Cox proportional hazards model will be employed. 
Stratified and unstratified log-rank tests will also be conducted.
The survival curves for each randomization arm will be estimated using the Kaplan-Meier (KM) 
product-limit method. Two-sided, 95% CIs for median PFS will be computed by the 


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Brookmeyer and Crowley method (Brookmeyer and Crowley 1982) using log-log-
transformation. Survival rates at 6, 12, 18 and 24 months will also be estimated using KM 
estimates on the survival curve for each arm. Associated two-sided 95% CIs will also be 
calculated.
In addition, a multivariate Cox model will be used to adjust for baseline covariates because 
imbalances in potential prognostic factors could impact the analysis of survival. Covariates that 
are planned to be included are those prognostic factors identified in Study JVBE. Details of pre-
specified covariates will be listed in the statistical analysis plan (SAP).
Additional sensitivity analyses for PFS using alternative censoring rules described in the SAP 
will be performed.
12.2.6.2. Overall Survival
Overall survival is measured from the date of randomization to the date of death from any cause.  
For each patient who is not known to have died as of the data-inclusion cut-off date, OS will be 
censored at the date of last known alive date prior to the data-inclusion cut-off date.
The analysis of OS will be conducted via similar methods for PFS, that is, stratified and 
unstratified Cox model and log-rank tests, KM curve, median estimates and survival rates with 
CI.
An interim OS analysis will be performed concurrently with the primary PFS analysis, and a 
final OS analysis will be performed if the primary objective is not achieved at interim.
12.2.7. Secondary Efficacy Analyses
Secondary efficacy endpoints include PFS, TTP, ORR and DOR. 
The PFS is defined as the time from randomization to the date of the first radiographically 
documented PD as defined by RECIST, Version 1.1, or death due to any cause, whichever is 
first.  Imaging will be performed every 6 weeks (±5 days) following the first dose of study 
therapy for the first 6 months, and every 9 weeks (±5 days) thereafter, until documentation of 
radiographic PD.  The primary censoring rules are the following: 

if a patient does not have a complete baseline or post baseline radiographic disease 
assessment, then the PFS will be censored at the date of randomization, regardless of 
whether or not radiographically determined disease progression or death has been 
observed for the patient; otherwise, 

if a patient is alive and does not have radiographic progression as of the data inclusion 
cut off date, the PFS time will be censored at the date of the last adequate radiographic 
tumor assessment. 
The analysis of PFS distributions in the two treatment arms will be conducted via similar 
methods as described in Section 12.2.6.  Additional sensitivity analyses for PFS using alternative
censoring rules will be specified in the SAP.


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Progression free survival final analysis will be conducted concurrently with OS final analysis 
when at least 336 deaths have occurred.  It is projected that approximately 430 PFS events would 
have occurred at that time assuming an exponential distribution for each arm and median PFS
times of 4.35 months and 3 months for Arm A and Arm B, respectively (HR=0.69), for which it 
will provide at least 95% power assuming a two sided alpha of 0.05.
Time to progression is defined as the time of randomization to the date of the first 
radiographically documented PD as defined by RECIST, Version1.1.  For each patient who is 
not known to have had radiographic progression of disease as of the data-inclusion cut-off date, 
or who has died without radiographic progression, TTP will be censored at the date of the 
patient’s last adequate radiographic tumor assessment prior to that cut-off date.
Time to progression will be analyzed at the same time of the final analysis for OS using similar 
methods as described for OS PFS in Section 12.2.6.  Additional sensitivity analyses for TTP 
using alternative censoring rules will be specified in the SAP.
Best overall response (BOR) will be determined using RECIST, Version 1.1.  Objective response 
rate will be calculated as the number of patients who achieve a BOR of CR or PR, divided by the 
total number of patients randomized to the corresponding treatment arm (ITT analysis set).  
Patients who do not have a tumor response assessment for any reason are considered as 
nonresponders and are included in the denominator when calculating the response rate.
Objective response rate will be reported along with 2-sided 95% exact CIs using Clopper and 
Pearson’s method for each treatment arm.  The difference of ORR between 2 treatment arms will 
be evaluated using the Cochran-Mantel-Haenszel test adjusting for ECOG PS and peritoneal 
metastases.  Analyses will be conducted at the same time of the final analysis for OS.
Duration of objective response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first) to the date of the first radiographically documented PD as defined 
by RECIST, v 1.1, or death due to any cause, whichever is first.  Patients alive and without 
radiographic disease progression at data-inclusion cut-off date or patients lost to follow-up will 
be censored at the date of their last radiographic tumor assessment.  DOR will be analyzed using 
KM method.  Medians and their two-sided 95% CIs will be calculated.  Analyses will be 
conducted at the same time of the final analysis for OS.
12.2.12. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.
12.2.12. Interim Analyses and Data Monitoring
The primary PFS analysis and an interim OS analysis will be reviewed by the Independent Data 
Monitoring Committee (IDMC) after at least 256 PFS events have been observed. The interim 
analysis will be conducted to provide early efficacy information and could potentially result in 
early communication with regulatory agencies.  The IDMC will be instructed to engage the 
Senior Management Designee (SMD), who may, if necessary, subsequently form an Internal 


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Review Committee (IRC) to propose actions based upon the IDMC’s recommendation. If the 
study shows early efficacy at interim (that is, both of the conditions described below are met), 
enrollment will be terminated and subjects randomized to the control arm may be permitted to 
cross over to the treatment arm under investigator discretion.
The primary objective will be claimed achieved if both of the following conditions are met:
(1) The point estimate of stratified HR for investigator-assessed OS is less than 1. 
(2) The analysis of investigator-assessed PFS shows a one-sided, stratified p-value favoring 
Ramucirumab+paclitaxel arm less than 0.025. 
If at least one of the conditions above are not met, the blinded study continues and a final OS 
analysis will apply.  The final analysis will be conducted when approximately 336 OS events 
have been observed.
The unblinded interim analysis, including the efficacy and safety data, will be reviewed by the 
IDMC. Only the IDMC is authorized to evaluate unblinded interim efficacy and safety analyses. 
Study sites will receive information about interim results ONLY if they need to know for the 
safety of their patients.
Unblinding details are specified in the unblinding plan section of the SAP.






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a
The short-term follow-up begins the day after the decision is made to discontinue study treatment and lasts approximately 30 days (no more than 37 days).
If it is deemed to be in the best interest of the patient to start a new anti-cancer treatment prior to the scheduled end of the short-term follow-up visit, the 
follow-up visit duration may be shortened. In this case, the short-term follow-up assessments should be completed prior to the initiation of the new therapy.


Leo Document ID = 13684bac-c7c7-4162-b684-381c7c97e494
Approver: 
Approval Date & Time: 13-Mar-2019 15:12:16 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 14-Mar-2019 12:41:07 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
I4T-CR-JVCR Statistical Analysis Plan Version 5.0 
A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase 3 Study of Weekly 
Paclitaxel with or without Ramucirumab (IMC-1121B) in Patients with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma, Refractory to or Progressive after First-Line 
Therapy with Platinum and Fluoropyrimidine Study 
NCT02898077
Approval Date: 30-Jul-2020 


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1.
Statistical Analysis Plan:
I4T-CR-JVCR:  A Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, Phase 3 Study of Weekly Paclitaxel 
with or without Ramucirumab (IMC-1121B) in Patients 
with Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma, Refractory to or Progressive after First-
Line Therapy with Platinum and Fluoropyrimidine Study 
Confidential Information 
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.    
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Ramucirumab (LY3009806) Gastric or Gastroesophageal Junction Adenocarcinoma 
This is a randomized, placebo-controlled, double-blind, multicenter, Phase 3 study of 
patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, 
refractory to or progressive after first-line therapy with platinum and fluoropyrimidine.  
Patients will be randomized to receive either paclitaxel plus ramucirumab or paclitaxel plus 
placebo.  Treatment will continue until disease progression, unacceptable toxicity, or 
meeting other treatment discontinuation criteria. 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol I4T-CR-JVCR 
Phase 3 
SAP Version 1 electronically signed and approved by Lilly 31-Jul-2019 
SAP Version 2 electronically signed and approved by Lilly 02-Aug-2019 
SAP Version 3 electronically signed and approved by Lilly 05-Aug-2019 
SAP Version 4 electronically signed and approved by Lilly 29-Jul-2020 
SAP Version 5 electronically signed and approved by Lilly on the date provided below 
Approval Date: 30-Jul-2020 GMT


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2. Table of Contents 
Section                                                                                                                                   Page 
1. 
Statistical Analysis Plan:   I4T-CR-JVCR:  A Randomized, 
Multicenter, Double-Blind, Placebo-Controlled, Phase 3 Study of 
Weekly Paclitaxel with or without Ramucirumab (IMC-1121B) in 
Patients with Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma, Refractory to or Progressive after First-Line 
Therapy with Platinum and Fluoropyrimidine Study ........................................................... 1 
2. 
Table of Contents ................................................................................................................ 2 
3. 
Revision History ................................................................................................................. 6 
4. 
Study Objectives ................................................................................................................. 7 
4.1. 
Primary Objective .......................................................................................................... 7 
4.2. 
Secondary Objectives ..................................................................................................... 7 
4.3. 
Exploratory Objectives ................................................................................................... 7 
5. 
Study Design....................................................................................................................... 8 
5.1. 
Summary of Study Design .............................................................................................. 8 
5.2. 
Determination of Sample Size ...................................................................................... 10 
5.3. 
Method of Assignment to Treatment ............................................................................ 10 
6. 
A Priori Statistical Methods .............................................................................................. 12 
6.1. 
General Considerations ................................................................................................ 12 
6.1.1. 
Analysis Populations ............................................................................................ 12 
6.2. 
Adjustments for Covariates .......................................................................................... 12 
6.3. 
Handling of Dropouts or Missing Data ......................................................................... 13 
6.4. 
General Data Handling ................................................................................................. 15 
6.5. 
Multiple Comparisons/Multiplicity ............................................................................... 16 
6.6. 
Patient Disposition ....................................................................................................... 16 
6.7. 
Patient Characteristics .................................................................................................. 16 
6.7.1. 
Demographics and Performance Status................................................................. 16 
6.7.2. 
Baseline Disease Characteristics .......................................................................... 17 
6.7.3. 
Medical History/Pre-existing Conditions .............................................................. 18 
6.7.4. 
Prior Therapies ..................................................................................................... 18 
6.8. 
Concomitant Therapy ................................................................................................... 19 
6.8.1. 
Post-discontinuation Therapies (PDT) .................................................................. 20 
6.9. 
Efficacy Analyses ........................................................................................................ 20 
6.9.1. 
Primary Outcome and Methodology ..................................................................... 20 
6.9.2. 
Secondary Efficacy Analyses ............................................................................... 22 
6.9.3. 
Sensitivity Analyses ............................................................................................. 24 


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6.10. Health Outcomes/Quality-of-Life Analyses .................................................................. 25 
6.10.1. 
EORTC QLQ-C30 ............................................................................................... 25 
6.10.2. 
EQ-5D-3L Analysis ............................................................................................. 27 
6.11. Safety Analyses ............................................................................................................ 28 
6.11.1. 
Extent of Exposure ............................................................................................... 28 
6.11.2. 
Adverse Events .................................................................................................... 30 
6.11.3. 
Deaths .................................................................................................................. 32 
6.11.4. 
Clinical Laboratory Evaluation ............................................................................. 32 
6.11.5. 
Vital Signs and Other Physical Findings ............................................................... 32 
6.11.6. 
Electrocardiograms and Echocardiogram/MUGA ................................................. 33 
6.11.7. 
Hospitalizations ................................................................................................... 33 
6.12. Subgroup Analyses....................................................................................................... 33 
6.13. Protocol Deviation ....................................................................................................... 34 
6.13.1. 
Protocol Deviations due to COVID-19 ................................................................. 34 
6.14. Interim Analyses and Data Monitoring ......................................................................... 34 
6.15. Clinical Trial Registry Analyses ................................................................................... 35 
7. 
Unblinding Plan ................................................................................................................ 37 
8. 
References ........................................................................................................................ 38 
9. 
Appendices ....................................................................................................................... 39 
Appendix 1. 
Scoring for the EORTC QLQ-C30 Questionnaire 
Version 3.0 40 
Appendix 2. Model for Calculating China Population-Based Predicted 
Index Scores ..................................................................................................................... 42 
 
 
 
 
 
 
 
 
 
 
 


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Figure 
Figure 5.1. Illustration of study design for Study I4T-CR-JVCR ................................................. 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 
Table 6.1. Coding for Tumor Grades ......................................................................................... 18 
Table 6.2. Primary Censoring Rules for PFS ............................................................................. 21 
Table 6.3. Censoring rules for TTP............................................................................................ 22 
Table 6.4. Alternative Censoring Rules for PFS ........................................................................ 24 
Table 6.5. Dose Reduction for Ramucirumab DP and Paclitaxel ................................................ 30 
 


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3. Revision History 
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first unblinding, to allow 
execution of activities related to the interim analysis. 
SAP Version 2 was approved prior to the first unblinding. AE reporting process was revised in 
this version. 
SAP Version 3 was approved prior to the first unblinding. Revised definition of baseline disease 
characteristics “time to progression on first-line therapy” 
SAP Version 4 was approved prior to the final database lock. The changes made in this version 
include: 
1) Added additional sensitivity analyses for OS and PFS in Section 6.9.3. 
2) Adjusted language for major protocol deviations 
SAP Version 5 was approved prior to the final database lock. Definition for “time to progression 
during first-line therapy” was revised. 


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4. Study Objectives 
4.1. Primary Objective 
The co-primary objective of this study is to evaluate PFS and OS in patients treated with 
paclitaxel plus ramucirumab (IMC-1121B, LY3009806) versus paclitaxel plus placebo as 
second-line treatment in patients with advanced gastric or GEJ adenocarcinoma after failure of 
any platinum and fluoropyrimidine doublet with or without anthracycline (epirubicin or 
doxorubicin). 
4.2. Secondary Objectives 
Secondary objectives are to evaluate: 
• Objective response rate (ORR) 
• Time to progression (TTP) 
• Duration of objective response (DOR) 
• Safety profile 
• Patient-reported outcome (PRO) measures (EORTC QLQ-C30 and EQ-5D-3L) 
4.3. Exploratory Objectives 
The exploratory objectives of the study include: 
• To explore biomarkers relevant to gastric or GEJ adenocarcinoma or safety, efficacy, and 
mechanism of action of ramucirumab. 


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5. Study Design 
5.1. Summary of Study Design 
Study I4T-CR-JVCR (JVCR) is a multinational, randomized, multicenter, double-blind, 
placebo-controlled, Phase 3 study in patients with histologically or cytologically confirmed 
advanced gastric or GEJ adenocarcinoma, refractory to or progressive after first-line therapy 
with platinum and fluoropyrimidine.  
Approximately 450 patients will be randomized on a 2:1 ratio to Arm A (paclitaxel plus 
ramucirumab) and Arm B (paclitaxel plus placebo) to observe approximately 336 deaths.  
Randomization will be stratified by ECOG PS (0 versus 1) and peritoneal metastasis (yes versus 
no). 
Figure 5.1 illustrates the study design. 
 
Figure 5.1. Illustration of study design for Study I4T-CR-JVCR 
Terms used to describe the periods during the study are defined below: 
• Baseline:  begins when the ICF is signed and ends at the first study treatment (or 
discontinuation, if no treatment is given) 
• Study Period:  begins at the first study treatment and ends at study completion.  The 
study period does not include the extension period. 
o Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue study 
treatment. 


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o Post-discontinuation Follow-Up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment. 
Short-term follow-up begins 1 day after the patient and the investigator agree that 
the patient will no longer continue study treatment and lasts approximately 
30 days (no more than 37 days).   
Long-term follow-up begins 1 day after short-term follow-up is completed and 
continues until the patient’s death or overall study completion, whichever comes 
first. 
• Extension Period:  begins after study completion and ends at the end of trial.  During the 
extension period, patients on study therapy who continue to experience clinical benefit 
may continue to receive study therapy (except placebo) until one of the criteria for 
discontinuation is met.  The extension period includes extension period follow-up. 
o Extension Period Follow-Up:  begins 1 day after the patient and the investigator 
agree that the patient will no longer continue treatment in the extension period 
and lasts approximately 30 days (no more than 37 days). 
Baseline radiographic assessment of disease will be performed within 21 days prior to 
randomization; first treatment will be administered within 7 days following randomization.  
Patients in both arms will receive any necessary premedication prior to the first infusion of study 
therapy at each treatment session. 
A planned treatment cycle will be defined as 28 days (4 weeks) in each arm and includes the 
period of treatment with paclitaxel given on Days 1, 8, and 15, in combination with either 
ramucirumab or placebo given on Days 1 and 15. The period during which no treatment will be 
administered is required for patients to recover from toxicities to NCI-CTCAE, Version 4.03 
criteria Grade <2 or baseline (with the exception of alopecia), and is expected to last 14 days. 
Patients will undergo radiographic assessment of disease status every 6 weeks (±5 days) 
following the first dose of study therapy for the first 6 months, and every 9 weeks (±5 days) 
thereafter, until documentation of radiographic PD. Patients in both arms will continue to receive 
all treatments until there is radiographic or symptomatic progression of disease, toxicity 
requiring cessation, protocol noncompliance, or withdrawal of consent. In case of treatment 
discontinuation for any reason other than radiographically confirmed PD, radiographic tumor 
assessments will continue every 6 weeks (±5 days) following the first dose of study therapy for 
the first 6 months, and every 9 weeks (±5 days) thereafter, until documentation of radiographic 
PD.  
Follow-up information regarding further anticancer treatment and survival status will be 
collected at least every 8 weeks (+0 to 7 days). Long-term follow-up will continue as long as the 
patient is alive, or until study completion, whichever is first. 
Adverse event information will be collected up to approximately 30 days (no more than 37 days) 
after the decision is made to discontinue study treatment, or until all SAEs and all therapy-related 


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AEs have resolved, stabilized, returned to baseline, or been deemed irreversible, whichever date 
is later. 
Patients with evidence of sustained clinical benefit (that is, no disease progression) may continue 
to receive study drug(s) for long-term durations during the extension period. 
Upon study completion, investigators and patients may be unblinded to study treatment 
assignment. 
5.2. Determination of Sample Size 
The study plan is to enroll approximately 450 patients with advanced gastric or GEJ 
adenocarcinoma after failure of any platinum and fluoropyrimidine doublet with or without 
anthracycline. 
The approximately 450 patients will be randomized in a 2:1 ratio to Arm A (paclitaxel plus 
Ramucirumab) and Arm B (paclitaxel plus placebo). Patients will be randomized using 
stratification factors ECOG PS (0 vs 1) and peritoneal metastasis (yes vs no).  
Under the following assumptions: 
• The randomization ratio is 2:1; 
• OS in each arm follows an exponential distribution; 
• The OS hazard ratio for Arm A vs Arm B is 0.81; 
• Control arm median OS = 10.5 months, 
336 deaths (i.e. 25% censoring rate) will provide at least 80% probability to assure that the effect 
size observed in this study is consistent with the global study, where effect size is defined by 
1
1 −
= HR

. The above assurance probability is defined by Prob⌊𝛿̂𝐽𝑉𝐶𝑅>  𝜌𝛿̂𝐽𝑉𝐵𝐸⌋, where
JVBE
ˆ
 
= 0.235 was estimated from the observed HR of 0.81 in the global study JVBE and
JVCR
ˆ
 will be 
estimated from the observed HR in this study.  is a constant set to 0.5, corresponding to 50% 
effect size retention from the global study.  
Assuming further a constant accrual rate of 12 patients per month, it is estimated that the study 
will take approximately 44 months to obtain the required 336 deaths, with 37 months for full 
accrual and 7 months for follow-up. 
5.3. Method of Assignment to Treatment 
Upon completion of all screening evaluations to confirm a patient’s eligibility, the site will 
register the patient via the Interactive Web Response System (IWRS).  The IWRS registration 
consists of assigning the patient a unique study identification number and randomizing the 
patient to 1 of the 2 treatment arms.  Once the patient is registered through the IWRS, he/she is 
considered to be enrolled in the study.  


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Randomization will be stratified by ECOG PS (0 versus 1) and peritoneal metastasis (yes versus 
no). To balance the treatment allocation among the stratification factors, a stratified permuted 
block randomization will be utilized and incorporated into the IWRS. 
 


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6. A Priori Statistical Methods 
6.1. General Considerations 
Statistical analysis of this study will be the responsibility of Eli Lilly and Company. 
All tests of efficacy will be conducted at a 2-sided significance level of 0.05, unless otherwise 
stated. All confidence intervals will be given at a 2-sided 95% level, unless otherwise stated. 
The assumptions for each statistical method may be evaluated. If there is violation of 
assumptions, alternative statistical methods may be used. 
Additional exploratory analyses of the data may be conducted as deemed appropriate. 
6.1.1. Analysis Populations 
The entered population includes all patients who sign the informed consent document.  
The intention-to-treat (ITT) population will include all randomized patients. Patients will be 
grouped according to randomized treatment.  
The per-protocol (PP) population will include all patients in the ITT population who are 
compliant with the study protocol without major protocol violations.  
The safety population will include all randomized patients who received at least 1 dose of study 
treatment. 
Unless otherwise stated, all patient characteristic and efficacy analyses will be performed on the 
ITT population, and all safety and exposure analyses will be performed on the safety population. 
Analysis of duration of response (DOR) will be performed only for ITT patients who achieve a 
best overall response of CR or PR, which is denoted as mITT1 population. 
Analysis of PROs will include randomized patients that provide a baseline assessment and at 
least 1 post-baseline assessment, denoted as mITT2 population; however, compliance will be 
based on the ITT population. 
Unless otherwise stated, all analyses on the ITT population will be performed by randomized 
treatment arm, and all analyses on the safety population will be performed by actual treatment 
received on Cycle 1 Day 1. 
Rescreening: For rescreened patients, all analyses including summary of disposition and 
baseline characteristics, will only consider the data collected during the last screening. 
Treatment switching: For patients in the safety population who switched treatment due to any 
reason, they will still be analyzed based on the first actual treatment received. 
6.2. Adjustments for Covariates 
As a supportive analysis, PFS and OS will be analyzed after adjusting for selected prognostic 
factors. Potential prognostic factors include the stratification factors and other factors used for 
subgroup analysis discussed in Section 6.12. 


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The hazard ratio for treatment effect will be estimated using an unstratified multivariate Cox 
proportional hazard model to be constructed by selecting variables among all the potential 
variables using stepwise selection method with entry p-value 0.05 and exit p-value 0.1. The 
treatment factor will be kept out of the model throughout the covariate selection process and only 
added into the final model. HR for treatment effect and corresponding 95% CI will be estimated 
from the final model. 
6.3. Handling of Dropouts or Missing Data 
All analyses and descriptive summaries will be based on the observed data. With the exception 
of dates, missing data will not be imputed. For the patient data listings, no imputation of 
incomplete dates will be applied. The listings will present the incomplete dates without any 
change. 
General rules for imputing dates related to AE, concomitant therapy or post discontinuation 
therapy: 
• Onset date of an AE or start date of a concomitant therapy or post discontinuation 
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. 
▪ The date of informed consent, if the onset yyyy-mm is before the yyyy-
mm of the first treatment. 
o If both the day and month are missing, the complete date will be set to: 
▪ January 01 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. 
▪ The date of informed consent, if the onset year is before the year of the 
first 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 December 31 of the 
year of occurrence or to the date of death if the patient died in the same year. 


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If a date is completely missing, then no imputation will be done, and the event will be considered 
as treatment emergent (for AEs) or concomitant (for medications) unless the end date rules out 
the possibility. 
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 or month, but the day is missing, then assign 1 to day. 
▪ If the date has no missing year, but has missing month, then assign January to month. 
However, after imputation, check if the imputed date is logically consistent with other relevant 
date variables and make appropriate correction if necessary. For example, if a visit start date was 
May 10, 2008 and a tumor assessment date was May dd, 2008 (missing day) but it was known 
that the assessment occurred after that visit, then after imputation, the tumor assessment date 
would become May 01, 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, May 10, 2008. 
Patient-reported outcome analysis: For percentage compliance of the EORTC QLQ-C30 and 
EQ-5D, instruments with at least one item completed will be considered as having been 
completed. Multi-item QLQ-C30 scales with ≥50% of items completed will be scored using 
imputation rules per the scoring manual (Fayers et al. 2001). No other adjustment or imputation 
for missing data will be performed. 
The QLQ-C30 scoring manual imputes missing items as follows: 
▪ Have at least half of the items from the scale been answered? 
▪ If Yes, use all the items that were completed, and apply the standard equations for 
calculating the scale scores; ignore any items with missing values when making the 
calculations. 
▪ If No, set scale score to missing. 
▪ For single-item measures, set score to missing. 
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. 


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6.4. General Data Handling 
• Age will be computed from July 1 of the year of birth (since only year of birth is 
recorded in eCRF) to the date of Informed Consent, as  
(Date of Informed Consent - July 1 of the year of Birth +1) / 365.25. 
Age will be rounded to the integer part of the computed age using the above formula. 
• Baseline Measurements:   
- 
Efficacy: The last measurement on or prior to the date of randomization will serve as 
the baseline measurement.  In the event such a value is missing, the first assessment 
completed prior to the first study drug administration will be used as the baseline 
assessment so long as this assessment was taken within 7 days of randomization. 
- 
Safety: The last measurement prior to the first study drug administration will be used 
as the baseline assessment.  
- 
Other baseline characteristics (including vital sign assessments):  The last 
measurement on or prior to the date of randomization will serve as the baseline 
measurement.  In the event such a value is missing, the first assessment completed 
on or prior to the date of first study drug administration will be used as the baseline 
assessment. 
• Study Day:  
- 
For safety analysis: Study day is calculated as: 
o  Assessment date – first dose date + 1; if the assessment was performed on or 
after the first dose day.  
o Assessment date – first dose date; if the assessment was performed prior to the 
first dose date.  
- 
For efficacy (time to event) analysis: Study day is calculated as: 
o  Assessment date – randomization date + 1; if the assessment was performed 
on or after the randomization date.  
o Assessment date – randomization date; if the assessment was performed prior 
to the randomization date.  
• Time-to-event: The event or censoring time (days) is calculated as: 
- 
Date of event/censoring − Date of randomization + 1 
• Duration: Duration (except for duration of study treatment) is calculated as:  


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- 
Duration (days): 
(End Date – Start Date + 1) 
- 
Duration (weeks): 
(End Date – Start Date + 1) / 7 
- 
Duration (months):      (End Date – Start Date + 1) / 30.4375; (Days in months = 
30.4375, which is average number of days in a year /12) 
- 
Duration (years): 
(End Date – Start Date + 1) / 365.25; (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) 
6.5. Multiple Comparisons/Multiplicity 
No adjustment for multiplicity is planned for this study. All p-values are of descriptive nature. 
6.6. Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
• Summary of patients entered and randomized by country 
• Total number of patients entered 
• Total number of patients randomized, by treatment arm 
• Summary of reasons for patients entered, but not randomized 
• Total number of patients treated, by treatment arm 
• Summary of reasons for patients randomized but not treated 
A detailed summary of reasons for patient discontinuation from study treatment will be provided. 
A listing of AEs leading to treatment discontinuation will be provided. 
The number and percentage of patients included/excluded in ITT population, Safety population 
and PP population as well as exclusion reasons will be summarized for all subjects who signed 
the Informed Consent. 
Moreover, the number and percentage of patients still receiving treatment (i.e., have not 
completed the End of Treatment visit) and those still on study evaluation (i.e., have not 
completed the End of Study Evaluation visit) at data cut-off date will be summarized by 
treatment group. Patients having completed their End of Treatment and End of Study Evaluation 
visits will be presented by reason for discontinuation of study treatment and study, respectively. 
6.7. Patient Characteristics 
6.7.1. Demographics and Performance Status 
The following demographic and baseline characteristics will be summarized using the ITT 
population: 
• Sex 
• Race 
• Age (years) 


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• Age group (<65 vs ≥65 years) 
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI) (kg/m2) 
• Body surface area (BSA) (m2) 
• Baseline ECOG PS [per eCRF] 
Height and weight will be based on “Vital Signs: Baseline” eCRF. BMI is defined as weight 
divided by the square of height. 
6.7.2. Baseline Disease Characteristics 
The following baseline disease characteristics will be summarized using the ITT population: 
• Duration of disease 
• Peritoneal metastasis [per eCRF] 
• TNM classification at initial diagnosis 
• Extent of disease at study entry (locally advanced vs. metastatic) 
• Primary tumor location (gastric vs. gastroesophageal junction tumor) 
• Primary tumor present (yes vs. no) 
• Disease measurability (measurable vs. non measurable)  
• Time to progression on first-line therapy (<6 months vs. ≥6 months)  
• Histopathological diagnosis grade at initial diagnosis (well differentiated, moderately 
differentiated, poorly differentiated, undifferentiated, unknown) 
• Pathological diagnosis HER2 status at initial diagnosis (negative finding, positive finding, 
not done, unknown) 
• Sites of metastatic disease (Liver, Lung, Lymph nodes, etc.) 
• Number of organs involved (0, 1, 2, ≥ 3, derived from sites of metastatic disease) 
• Weight loss (≥ 10% over the 3 months prior to study entry vs. < 10%) 
• Presence of ascites (yes vs. no) 
Duration of disease is defined as time from date of diagnosis confirmation to date of 
randomization. Date of diagnosis confirmation will be derived from “Pathological Diagnosis” 
eCRF. If only the month and year of the date of diagnosis confirmation is known, the day will be 
imputed as 15. 
Tumor location will be reported directly from “Pathological Diagnosis (MH_IPD)” eCRF. 


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Time to progression on first-line therapy is defined as time from start of first-line therapy to 
disease progression. It will be calculated as (progressive disease date – start date of first-line 
therapy + 1).  
Pathological diagnosis HER2 status and histopathological diagnosis grade are directly available 
on “Pathological Diagnosis” eCRF, where the grades are coded according to Table 6.1. 
Table 6.1. Coding for Tumor Grades 
Tumor Grade 
eCRF Entry 
Well differentiated 
G1 Grade 1 
Moderately differentiated 
G2 Grade 2 
Poorly differentiated 
G3 Grade 3 
Undifferentiated 
G4 Grade 4 
Unknown 
GX – grade cannot be assessed 
 
Disease measurability will be derived from “Target Tumor: RECIST 1.1” and “Non Target 
Tumor: RECIST 1.1” eCRFs at baseline. All patients with at least one lesion on the target lesion 
form will be counted as having measurable disease.  
The number of organs involved and sites of metastatic disease will be summarized based on data 
in “Nature of Disease” eCRF. 
Weight loss and presence of ascites are documented in “Stratification and Subgroup Criteria” 
eCRF. Extent of disease at study entry can be derived from “Pathological Diagnosis” eCRF: If 
TNM metastasis is “M1” then the extent of disease is “metastatic”, otherwise, it’s “locally 
advanced”. 
6.7.3. Medical History/Pre-existing Conditions 
A summary of medical history will be presented by System Organ Class (SOC) and Preferred 
Term (PT) of the historical/pre-existing conditions using version 21.1 of the Medical Dictionary 
for Regulatory Activities (MedDRA). The number and percentage of subjects in the ITT 
population that experienced each condition will be summarized by treatment arm. 
6.7.4. Prior Therapies 
Prior radiotherapy, surgery, and systemic and locoregional therapy will be summarized. Prior 
radiotherapy will be categorized by reason for regimen (adjuvant, neoadjuvant, neoadjuvant plus 
adjuvant, advanced/metastatic). Surgery will be categorized by surgical intent (palliative, 
curative). Prior systemic and locoregional therapy will be categorized by setting of regimen 
(adjuvant, locally advanced, metastatic, neoadjuvant) and type of therapy (chemotherapy, 
monoclonal antibody, etc.). Patients will also be categorized based on the number of regimens 


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received during first-line therapy. Frequency of each specific therapy will be tabulated within 
each setting of regimen. 
Select prior therapies of interest will also be summarized, as listed below: 
• Medication classes of interest: Anthracyclines and related substances, detoxifying agents for 
antineoplastic treatment, folic acid analogues, monoclonal antibodies, platinum compounds, 
pyrimidine analogues, and taxanes 
• Previous treatment with a targeted agent containing regimen (EGFR only, HER2 only, EGFR 
and HER2, others) vs. previous treatment without a targeted agent 
• Previous treatment with platinum/fluoropyrimidine with anthracycline vs. without 
anthracycline 
• Previous gastrectomy (total, partial, other, no) 
Listings of prior systemic therapies, radiotherapies and surgeries will be provided. 
6.8. Concomitant Therapy 
A medication will be regarded as concomitant if: 
• It started on or after the date of first dose of study treatment and within 30 days after the 
date of last study treatment; or 
• It started prior to date of first dose of study treatment but was ongoing at the time of the 
first dose of study treatment. 
The following concomitant medications will be summarized: 
▪ All concomitant medications, by medication class and preferred term. 
▪ Selected concomitant medications, including growth factors (erythroid growth factors, 
granulocyte-colony stimulating factors, granulocyte-macrophage colony-stimulating 
factor), antiemetics, anti-hypertensive agents, and antibiotics. 
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.  
Premedication usage will be summarized overall and by cycle. 
The frequency and percentage of patients with any blood transfusions experienced in study 
treatment period or the 30-day post-discontinuation follow-up period will be summarized by 
treatment group. Transfusions will be further characterized by transfused blood product (e.g. 
packed red blood cells, whole blood, platelets, or fresh frozen plasma). Reasons for transfusion 
will be presented by listing the corresponding AE and MH PTs. 


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6.8.1. Post-discontinuation Therapies (PDT) 
Post-discontinuation anti-cancer therapies, including systemic therapies, radiotherapies and 
surgeries, will be summarized by treatment arm. Systemic therapies will also be summarized by 
type of therapy, medication class and specific medication terms. The number of subjects who 
received 1, 2, 3, … subsequent regimens will be summarized. Patient-level listings of PDT will 
be provided. 
 
6.9. Efficacy Analyses 
Efficacy endpoints will be analyzed using the ITT population and presented by treatment group. 
The stratification factors for the analyses of primary and secondary endpoints are:  
▪ Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1) 
▪ Peritoneal metastasis (yes versus no) 
The stratification factors are captured in the IWRS and on eCRFs. Unless otherwise specified, all 
primary efficacy analyses will be based on the stratification factors per IWRS. A cross-tabulation 
of the frequency of each level of each stratification factor per IWRS and per eCRF will be 
produced. 
6.9.1. Primary Outcome and Methodology 
6.9.1.1. Progression-free Survival 
The PFS is defined as the duration from the date of randomization to the date of the first 
radiographically documented PD as defined by RECIST 1.1, or to the date of death due to any 
cause, whichever is earlier. The primary censoring rules are described in Table 6.1. 
The analysis of PFS in this study will estimate the HR and its corresponding CI in a stratified 
Cox proportional hazards model using treatment arm as a single covariate. The stratification 
factors included in the Cox model are the same as randomization strata. An additional analysis 
with an unstratified Cox proportional hazards model will be employed to explore the impact of 
the stratification factor. Stratified (using the same stratification factor) and unstratified log-rank 
tests will also be conducted. 
The survival curves for each randomized arm will be estimated using the Kaplan-Meier (KM) 
product-limit method. CI for median PFS will be computed by the Brookmeyer and Crowley 
method (Brookmeyer and Crowley 1982) using log-log transformation. Survival rates at 6, 12, 18 
and 24 months will also be estimated using KM estimates on the PFS curve for each randomized 
arm. Associated CI for survival rates will also be calculated using normal approximation. 
In addition, a multivariate Cox model will be used to adjust for baseline covariates as imbalances 
in potential prognostic factors could impact the analysis of survival. Covariates that are planned 
to be included are described in section 6.12. 
A patient-level listing of PFS time will be provided. 


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The primary PFS analysis will be performed when at least 256 PFS events have occurred (see 
Section 6.13).  
Table 6.2. Primary Censoring Rules for PFS 
Index 
Situation 
Date of Event or Censor 
Event / Censor 
1 
No baseline radiological tumor 
assessment available 
Date of randomization 
Censored 
2 
No post baseline radiological tumor 
assessment available  
and no death reported within 2 scan 
intervals following randomization 
Date of randomization 
Censored 
3 
No post baseline radiological tumor 
assessment available  
but death reported within 2 scan intervals 
following randomization 
Date of death 
Event 
4 
No tumor progression (per RECIST 1.1) 
and no death reported within 2 scan 
intervals following adequate last 
radiological tumor assessment (or 
following randomization if no adequate 
assessment available) 
Date of last adequate radiological 
tumor assessment (or date of 
randomization if no adequate 
assessment available) 
Censored 
5 
No tumor progression (per RECIST 1.1) 
but death reported within 2 scan intervals 
following last adequate radiological 
tumor assessment 
Date of death 
Event 
6 
Tumor progression (per RECIST 1.1) 
documented within 2 scan intervals 
following adequate previous radiological 
tumor assessment or following 
randomization 
Earliest of the target, non-target and 
new tumor assessment dates 
Event 
7 
Tumor progression (per RECIST 1.1) 
documented after ≥2 consecutively 
missed tumor assessment visits following 
adequate previous radiological tumor 
assessment (or following randomization if 
no adequate assessment available) 
Date of last adequate radiological 
assessment before missed assessments 
(or date of randomization if no 
adequate assessment available) 
Censored 
8 
New anticancer treatment started 
Date of previous adequate radiological 
assessment prior to start of new therapy 
(or randomization date if no adequate 
assessment available) 
Censored 
9 
No tumor progression (per RECIST 1.1) 
and patient lost to follow-up or 
withdrawal of consent 
Date of last adequate radiological 
assessment (or randomization date if no 
adequate assessment available) 
Censored 


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Notes: (1) Symptomatic deteriorations (i.e. symptomatic progressions, which are not radiologically 
confirmed) will not be considered as progressions. 
(2) If target, non-target and new lesion assessments have different dates within a visit, then the earliest of 
those dates will be considered as the date of the tumor assessment if the assessment for that visit is 
progressive disease (PD); otherwise the latest date will be used. 
(3) Adequate radiological tumor assessment refers to an assessment with overall response of CR, PR, SD 
or PD. 
(4) New anticancer treatment includes systemic and locoregional therapies, radiotherapy and surgical 
procedures. 
6.9.1.2. Overall Survival 
Overall survival (OS) is measured from the date of randomization to the date of death from any 
cause. For each subject who is not known to have died as of the data cut-off date, if the subject is 
lost to follow-up, then OS for that subject will be censored to the last known alive date, as 
recorded in “Post Discontinuation Follow-up” CRF page; otherwise, OS will be censored at the 
date of last contact prior to the data cut-off date. Contacts considered in the determination of last 
contact date include: clinical evaluation dates (AE, vital sign, ECG), laboratory evaluation dates 
(local and central), tumor assessment dates, visit dates and withdrawal of consent date. 
The analysis of OS distributions in the two treatment arms will be conducted via similar methods 
as for PFS (i.e. HR and CI from stratified and unstratified Cox models, p-value from stratified 
and unstratified log-rank tests, KM curve, median estimates with CI and survival rate estimates 
with CI). A patient-level listing of overall survival time will be provided. 
An interim OS analysis is planned, and a final OS analysis will be performed if the primary 
objective is not achieved at interim. Details are discussed in Section 6.13. 
6.9.2. Secondary Efficacy Analyses 
 
Table 6.3. Censoring rules for TTP 
Index 
Situation 
Date of Event or Censor 
Event / Censor 
1 
No baseline radiological tumor assessment available 
Date of randomization 
Censored 
2 
No post-baseline radiological tumor assessment 
available  
and no death reported within 2 scan intervals following 
randomization 
Date of randomization 
Censored 
3 
No post baseline radiological tumor assessment 
available  
but death reported within 2 scan intervals following 
randomization 
Date of death 
Censored 
4 
No tumor progression (per RECIST 1.1) 
and no death reported within 2 scan intervals following 
last adequate radiological tumor assessment 
Date of last adequate 
radiological tumor assessment 
Censored 
5 
No tumor progression (per RECIST 1.1) 
Date of death 
Censored 


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6.9.2.1. Time to Progression  
Time to progression (TTP) is defined as the duration from the date of randomization to the date 
of the first radiographically documented PD as defined by RECIST 1.1. TTP will be analyzed 
using similar methods as described for PFS (i.e. the stratified and unstratified Cox model and 
log-rank test, KM curve and median estimates with CI). Censoring rules for this analysis are 
described in Table 6.3. 
6.9.2.2. Objective Response Rate and Disease Control Rate 
The Best Overall Response (BOR) will be determined using RECIST (Version 1.1). It is defined 
as the best response across all time points from randomization until radiologically confirmed 
tumor progression, if any. Tumor assessments performed after initiation of new anticancer 
treatment (including systemic therapy, surgical procedures and radiotherapy) will be excluded 
from evaluating the best overall response. 
Objective response rate (ORR) will be calculated as the number of patients who achieve a BOR 
of CR or PR divided by the total number of patients randomized to the corresponding treatment 
arm. Patients who do not have a tumor response assessment for any reason are considered as 
non-responders and are included in the denominator when calculating the response rate. 
Disease control rate (DCR) will be calculated as the proportion of patients with BOR of CR, PR 
or SD, using the same denominator as ORR. 
but death reported within 2 scan intervals following 
last adequate radiological tumor assessment 
6 
Tumor progression (per RECIST 1.1) 
documented within 2 scan intervals following previous 
adequate radiological tumor assessment 
Earliest of the target, non-target 
and new tumor assessment dates 
Event 
7 
Tumor progression (per RECIST 1.1) 
documented after ≥2 consecutively missed tumor 
assessment visits following previous adequate 
radiological tumor assessment 
Date of last adequate 
radiological assessment before 
missed assessments 
Censored 
8 
New anticancer treatment started 
Date of previous adequate 
radiological assessment prior to 
start of new therapy 
Censored 
9 
No tumor progression (per RECIST 1.1) and patient 
lost to follow-up or withdrawal of consent 
Date of last adequate 
radiological assessment  
Censored 
 
Notes: (1) Symptomatic deteriorations (i.e. symptomatic progressions, which are not radiologically confirmed) 
will not be considered as progressions. 
(2) If target, non-target and new lesion assessments have different dates within a visit, then the earliest of 
those dates will be considered as the date of the tumor assessment if the response for that visit is PD; 
otherwise the latest date will be used. 
(3) Adequate radiological tumor assessment refers to an assessment with overall response of CR, PR, SD 
or PD 


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Frequencies and proportions of BOR will be presented by treatment group, along with two-sided 
95% Clopper-Pearson CI. The ORR and DCR observed in each treatment group will be 
compared using the Cochran-Mantel-Haenszel test adjusting for ECOG PS and peritoneal 
metastasis as captured by IWRS. 
Waterfall plots of the best percent change in tumor size will be provided by treatment arm for 
subjects in the ITT population who have measurable disease (i.e. who have at least 1 target lesion 
at baseline tumor assessment). 
A patient-level listing of overall tumor response will be provided. 
6.9.2.3. Duration of Response 
Duration of objective response (DOR) is measured from the time measurement criteria are first 
met for CR or PR (whichever is first) to the date of the first radiographically documented PD as 
defined by RECIST 1.1, or to the date of death due to any cause, whichever is first. DOR will be 
analyzed only for patients who achieve a BOR of CR or PR. Patients alive and without 
radiographic disease progression at data cut-off date or patients lost to follow-up will be 
censored at the date of their last adequate radiographic tumor assessment. KM method will be 
used to analyze DOR to estimate the median and corresponding CI for each treatment arm.  
6.9.3. Sensitivity Analyses 
6.9.3.1. Sensitivity Analyses for OS 
The following sensitivity analyses will be performed for OS: 
• 
Analyses based on PP population 
• 
Censoring OS for users of post-discontinuation therapy (PDT) to the start date of PDT 
• 
Censoring OS for users of targeted PDT (including immunotherapy, anti-angiogenesis, anti-
HER2) 
• 
Censoring OS for users of anti-angiogenesis PDT 
6.9.3.2. Sensitivity Analyses for PFS 
PFS will be analyzed based on PP population. Additional sensitivity analyses will be performed 
for PFS using alternative censoring rules described in Table 6.4. 
Table 6.4. Alternative Censoring Rules for PFS 
Index 
Sensitivity Analysis  
Situation in Table 6.2 
Date of Progression or Censor 
Outcome 
1 
Count symptomatic 
deterioration as 
progression 
Documented progression or 
symptomatic deterioration 
Date of documented progression 
(New Lesion, Unequivocal 
Progression of Non-Target Lesion, 
or Progression of Target Lesion).  If 
a tumor assessment was performed 
on multiple days, use the earliest 
date for that visit. 
Progressed 


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Index 
Sensitivity Analysis  
Situation in Table 6.2 
Date of Progression or Censor 
Outcome 
Or date of symptomatic 
deterioration, whichever occurred 
first. 
2 
Ignore new anticancer 
treatment 
New anticancer treatment 
started prior to documented 
progression or death 
Date of progression or death based 
on subsequent tumor assessments 
 
Progressed 
3 
Ignore missing tumor 
assessments 
Death or documented 
progression after ≥ two 
consecutively missed tumor 
assessment visits 
Date of first missed tumor 
assessment 
Progressed 
4 
Treat lost to follow-
up as progression 
Patient lost to follow-up 
without documented 
progression or death 
Date of next scheduled visit after 
last tumor assessment 
Progressed  
5 
Treat lost to follow-
up as progression for 
experimental arm 
only (worst case 
scenario) 
Patient lost to follow-up 
without documented 
progression or death (worst 
case scenario) 
Patients in the active treatment 
group will be considered to have 
progressed at the date of the next 
scheduled visit after last tumor 
assessment. Patients in the control 
group will be censored at the date of 
last adequate tumor assessment 
Progressed 
(experiment
al) or 
Censored 
(control) 
 
6.10. Health Outcomes/Quality-of-Life Analyses 
Patient-reported outcome (PRO) measures (EORTC QLQ-C30 and EQ-5D) data will be 
summarized by treatment arm using the ITT population for patients who had a baseline 
assessment and at least one post-baseline assessment. 
Questionnaire compliance will be summarized for the ITT population. Compliance rates for each 
PRO instrument will be calculated at each assessment time point. Compliance at an assessment 
time point is defined as the number of patients who were assessed for that PRO instrument 
divided by the expected number of patients at that time point. The expected number of patients: 
• at baseline is equal to the number of patients randomized  
• at any post-baseline visit is equal to the number of patients who are alive and have not 
progressed 
A patient who answers at least one item at a time point is considered to have been assessed. 
Reasons for non-compliance will be tabulated by treatment arm and by assessment time point. 
6.10.1. EORTC QLQ-C30 
Following the EORTC guidelines (Fayers et al. 2001), the 30 items of the QLQ-C30 will be 
transformed into the 15 scales (1 global health status/QoL scale, 5 functional scales, and 9 
symptoms scales/items). For each scale, a linear transformation will be used to obtain scores 


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ranging from 0 to 100, with a high score indicating a high level of functioning for the global and 
the functional scales and, conversely, a high level of symptomatology/problems for the symptom 
scales/items. The scoring for EORTC QLQ-C30 is detailed in Appendix 1. 
The following variables will be derived for each scale: 
• Change from baseline is calculated by subtracting baseline assessment result from current 
assessment result. 
• Best score for each scale is the highest post-baseline score for the functional scales and 
global health status, and is the lowest score for the symptom scales. The change from 
baseline corresponding to the best score will be called the best change from baseline. 
• Worst score for each scale is the lowest post-baseline score for the functional scales and 
global health status, and is the highest score for the symptom scales. The change from 
baseline corresponding to the worst score will be called the worst change from baseline. 
Each scale at every assessment point will be compared to its baseline value and be categorized as 
follows (Osoba et al. 1998): 
• Deterioration: Defined as an increase of ≥10 points for the symptom scales or a decrease 
of ≥10 points for the functional scales and global health status/QoL scale. 
• Improvement: Defined as a decrease of ≥10 points for the symptom scales or an increase 
of ≥10 points for the functional scales and global health status/QoL scale. 
• Stable: Defined as no change or an increase/decrease of <10 points. 
Floor/Ceiling effect: The ceiling effect is defined as the percentage of patients who have a 
baseline score of <10 points on the symptom scales/items, and >90 points on the functional 
scales and global health status/QoL scale. The floor effect is defined as the percentage of patients 
who have a baseline score of >90 points on the symptom scales, and <10 points on the functional 
scales and global health status/QoL scale. 
The presence of a significant ceiling effect suggests that not much improvement is possible for 
that scale. Likewise, the presence of a floor effect suggests that deterioration is less likely. 
6.10.1.1. Descriptive Summaries 
The proportion of patients in each arm with deterioration in scores, improvement in scores, stable 
scores, and missing scores (due to progression, death, or failure to complete) at each assessment 
time point will be presented for each of the 15 scales both in a summary table and graphically 
using stacked bar charts.  
The denominator should include all patients from the group with a baseline assessment and at 
least one post-baseline assessment for the given scale. The proportion of patients who 
deteriorated at each assessment time point will be compared using Pearson’s χ2 test.  


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Data will be summarized descriptively for all 15 scales at each assessment time by treatment 
arm, provided at least 30% of the patients have assessments at that assessment time.  Shift tables 
will be presented for the 6 single-item symptom scales.  
Floor and ceiling effects will be summarized for each of the 15 scales.  
6.10.1.2. Analysis of Best and Worst Post-Baseline Change Score 
The best change score from baseline for each of the 15 scales will be compared statistically 
between treatment arms using analysis of covariance (with baseline score and randomization 
stratification factors per IWRS as covariates) and the Mann-Whitney-Wilcoxon test. The worst 
change score from baseline will be analyzed in a similar manner. 
6.10.1.3. Time to Deterioration (TTD) from Baseline 
For each of the 15 scales, the following analyses will be performed for time to first deterioration 
from baseline score: 
• Obtain p-value from stratified log-rank test 
• Survival estimates and curves using Kaplan-Meier product limit method 
• Hazard ratio estimate and CI using stratified Cox proportional hazard model (covariates 
include treatment arm and baseline score) 
• Forest plot to display HR and CI 
Censoring: If deterioration is observed immediately after a missing value, it will be assumed 
that the deterioration occurred at the time of the missing value. Patients who do not deteriorate 
will be censored at the date of last EORTC assessment. 
6.10.2. EQ-5D-3L Analysis 
By treatment arm and at each assessment time, the frequency and percentage of patient’s 
responses (no problem, some problem, and extreme problem) will be presented for each of the 5 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 
responses will be presented graphically using stacked bar charts by assessment time point. 
The index score for the EQ-5D-3L will be calculated from a combination of responses using a 
weighting algorithm currently in development based on EQ-5D-3L Chinese validation study 
(EuroQol Group 1990; Brooks et al. 1996; Liu et al. 2014). The model for calculating index 
scores corresponding to each of 243 health states is given in Appendix 2. The index score and the 
VAS will be presented using summary statistics, including change from baseline, for each 
assessment time by treatment arm. These will also be graphically represented using box plots by 
assessment time point. 
 


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6.11. Safety Analyses 
6.11.1. Extent of Exposure 
Exposure analyses will be based on the actual dose administered (in mg) and body weight (in kg) 
(for ramucirumab/placebo) or BSA (in m2) (for paclitaxel). The body weight to be used for 
calculating each dose of ramucirumab or placebo will be the last available measure of the patient 
recorded on CRF prior to each infusion. The BSA to be used for calculating each dose of 
paclitaxel will be calculated using the Dubois & Dubois formula (see below) based on the last 
available weight and height prior to each infusion. 
BSA [𝑚2] = (𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔]0.425 ∗𝐻𝑒𝑖𝑔ℎ𝑡 [𝑐𝑚]0.725) ∗0.007184 
For patients who did not receive any amount of study drug, the dose exposure parameters for that 
treatment (number of infusions, duration of treatment, cumulative dose, dose intensity, relative 
dose intensity) will be set to 0. Cumulative dose, dose intensity and relative dose intensity will 
remain missing if they cannot be derived due to missing weight or BSA. 
6.11.1.1. Summary of Exposure 
The following variables will be presented with summary statistics for each study drug 
(ramucirumab DP or placebo and paclitaxel) by treatment arm: 
• Number of infusions 
• Number of cycles received by patient 
• Duration on therapy 
• Cumulative dose 
• Weekly dose intensity 
• Relative dose intensity 
Additionally, the following information will be presented: 
• Number of patients treated by cycle 
• Number and percentage of patients with dose delay, dose reduction, dose omission and 
infusion interruption 
6.11.1.2. Calculation of Exposure Parameters 
The calculation of exposure parameters will be based on the following rules. 
Ramucirumab DP or Placebo Treatment: 
• Duration on therapy (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: 


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o Cumulative dose (mg/kg) = Sum of all (total dose administered [mg] ÷ Last 
available weight [kg]) 
o Weekly dose intensity (mg/kg/week) = (Cumulative dose) ÷ (Duration on therapy) 
o Planned weekly dose intensity (mg/kg/week) = 2 × 8 mg/kg ÷ 4 weeks = 4 
mg/kg/week 
o Relative dose intensity (%) = (Weekly dose intensity) ÷ (Planned weekly dose 
intensity) × 100 
• Number of dose level reductions: Sum of the number of dose level reductions as reported 
in CRF 
• Dose delays: As reported in CRF 
• Dose omissions: As reported in CRF 
Paclitaxel Treatment: 
• Duration on therapy (weeks) = [(Date of last dose – Date of first dose) + 14] ÷ 7 
• Cumulative dose, dose intensity, relative dose intensity: 
o Cumulative dose (mg/m2) = Sum of all (total dose administered [mg] ÷ BSA 
using last available weight and height [m2]) 
o Weekly dose intensity (mg/m2/week) = (Cumulative dose) ÷ (Duration on 
therapy) 
o Planned weekly dose intensity (mg/m2/week) = 3 × 80 mg/m2 ÷ 4 weeks = 60 
mg/m2/week 
o Relative dose intensity (%) = (Weekly dose intensity) ÷ (Planned weekly dose 
intensity) × 100 
• Number of dose level reductions: Sum of the number of dose level reductions as reported 
in CRF 
• Dose delays: As reported in CRF 
• Dose omissions: As reported in CRF 
In the case of dose reduction, the correct level of reduction is given in Table 6.5. 


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Table 6.5. Dose Reduction for Ramucirumab DP and Paclitaxel 
Dose Level 
Ramucirumab DP 
Paclitaxel 
Starting dose 
8 mg/kg 
80 mg/m² 
Reduction to first dose level 
6 mg/kg 
70 mg/m² 
Reduction to second dose level 
5 mg/kg 
60 mg/m² 
 
6.11.2. Adverse Events 
All AEs will be summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT). 
AE verbatim text will be mapped by the sponsor or designee to corresponding terminology 
within MedDRA, and the resulting SOC and PT will be used for AE reporting. AEs will be 
graded according to National Cancer Institute – Common Terminology Criteria for Adverse 
Events Verson 4.0 (NCI-CTCAE v4.0). 
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 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 CTCAE grade and the closest relationship to treatment. 
The investigator should classify all “probably related”, “possibly related”, or “does not know” 
AEs and SAEs as related to study treatment/procedure and report this relationship in “Adverse 
Events (AE)” eCRF. Missing classifications concerning study medication relationship will be 
considered as related to study medication by the investigator. 
Consolidated AE: Consolidated terms comprising clinically synonymous MedDRA preferred 
terms, have been defined in order to assist in identifying relevant safety differences between 
treatment arms. Summaries of the incidence of these consolidated terms will supplement the 
summaries by MedDRA PTs specified in this section. The MedDRA preferred terms that are 
grouped under each of the consolidated terms will be provided in compound-level safety 
document. 
6.11.2.1. Overview of Treatment-Emergent Adverse Events (TEAE) 
An AE will be regarded as treatment-emergent, if 
• Its onset date occurs any time on or after the date of administration of the first dose of 
study treatment (either ramucirumab DP or placebo or paclitaxel) up to 30 days after the 
last dose of study treatment (or up to any time if serious and considered related to study 
treatment); or 
• It occurs prior to first dose date and worsens while on therapy or up to 30 days after the 
last dose of study treatment (or up to any time if serious and considered related to study 
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An overview of TEAEs will be provided to summarize the following categories using frequency 
counts and percentages: 
▪ Patients with at least one TEAE, SAE, CTCAE Grade ≥3 TEAE 
▪ Patients with TEAEs that led to death 
▪ Patients with TEAEs that led to study treatment discontinuation 
▪ Patients with TE-SAEs that led to study treatment discontinuation 
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. 
6.11.2.2. Summary of TEAE 
The following set of summaries will be provided for any TEAE: 
• By SOC and PT (all grades, and grade >= 3) 
• By PT (all grades, and grade >= 3) 
• By consolidated terms (all grades, grades 3, 4 and 5) 
• By maximum CTCAE grade 
These summaries will be repeated for TEAEs considered related to study treatment by the 
investigator. TEAEs leading to hospitalization will be summarized by SOC and PT. 
All collected AEs (treatment emergent and non-treatment emergent) will be presented in a 
listing. 
6.11.2.3. Treatment-Emergent Serious Adverse Events 
Treatment-emergent serious adverse events will be summarized: 
• By SOC and PT (all grades, and grade >= 3) 
• By maximum CTCAE grade 
These summaries will be repeated for TE-SAEs considered related to study treatment by the 
investigator.  
A listing of SAEs (regardless of treatment-emergent or not) will be produced. 
6.11.2.4. Other Notable Adverse Events 
AEs leading to discontinuation of study drug, AEs leading to dose modification, and AEs leading 
to death will be summarized by SOC and PT, and by maximum CTCAE grade.  
Patient-level listings will be provided for the aforementioned AEs. 
6.11.2.5. Treatment Emergent Adverse Events of Special Interest (AESI) 
The list of AESIs consists of pre-specified selected adverse events that are given special 
consideration because they have been associated with other agents in a similar class of drugs or 


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that were observed in preclinical evaluation or earlier clinical studies of ramucirumab. For each 
AESI, a list of clinically relevant MedDRA preferred terms will be pre-specified based on review 
of blinded data as well as review of standard MedDRA queries (SMQs). 
In order to review AESIs in the most medically meaningful way, selected preferred terms that 
represent the same phenomenon will be grouped together. The MedDRA preferred terms that are 
grouped under each of the AESI terms will be provided in compound-level safety document. 
Treatment-emergent AESIs will be summarized by AESI category and PT. AESI categories for 
ramucirumab include the following: arterial and venous thromboembolic events, 
bleeding/hemorrhage events, GI hemorrhage events, congestive heart failure, GI fistula, GI 
perforation, hypertension, proteinuria, liver injury/failure, IRR, healing complication, RPLS, 
thrombotic microangiopathy, pulmonary hemorrhage events, and hepatic bleeding/hemorrhage 
events. 
Liver injury/liver failure AESI will also be summarized by clinical and laboratory terms, as 
defined in compound-level safety document. Immediate and non-immediate hypersensitivity 
reactions AESI will be separately summarized. 
6.11.3. Deaths 
All deaths that occur after the administration of the first dose of any study drug and within 
30 days after treatment discontinuation, as well as primary cause of death, will be presented in a 
listing for the Safety Population. The number and percentage of patients who died during the 
study and within 30 days after the treatment discontinuation will be summarized by primary 
cause of death and by treatment arm using the Safety Population. 
6.11.4. Clinical Laboratory Evaluation 
Laboratory values will be converted to standard (SI) units, and the numerical results will be 
graded using NCI-CTCAE Version 4.03. Laboratory results not corresponding to a NCI-CTCAE 
Version 4.03 term will not be graded. The list of lab parameters that can be graded as well as the 
programming specifications can be found in compound-level safety document. 
For the graded laboratory parameters, a summary of lab test severity by cycle and by treatment 
arm will be provided. Shift from baseline will be provided by cycle and for the worst value on 
the study. For test results of each lab parameter, side-by-side boxplot for the absolute values and 
change from baseline will be provided by cycle. 
Laboratory results will be presented in listings with a flag for values outside of the laboratory 
normal range. If the normal range is not available from the institution performing the laboratory 
test, Harrison’s (Braunwald et al. 2005) will be used as a general reference. Retest results will be 
reported in the listing as well. 
6.11.5. Vital Signs and Other Physical Findings 
Vital signs and shift from baseline will be summarized by cycle. 


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For systolic and diastolic blood pressure, shift from baseline will be provided by cycle and for 
the worst value on the study using the following categories: 
• Systolic Blood Pressure (<140, 140-<160, ≥160 mmHg) 
• Diastolic Blood Pressure (<90, 90-<100, ≥100 mmHg) 
A patient-level listing of vital signs will be provided. 
6.11.6. Electrocardiograms and Echocardiogram/MUGA 
Baseline ECG and left ventricular ejection fraction (LVEF) will be summarized. Shift of 
“ejection fraction decreased” from baseline to worst post-baseline will be summarized by 
treatment arm. 
6.11.7. Hospitalizations 
The number and percentage of patients who were hospitalized will be summarized by treatment 
arm. The reasons for hospitalization, number of hospitalizations due to AE and total duration of 
hospitalization due to AE will also be summarized by treatment arm. 
6.12. Subgroup Analyses 
Subgroup analyses will be performed for PFS and OS for subgroups identified below. Each 
analysis will include the following: 
• Estimate HR and 95% CI by fitting unstratified Cox proportional hazard regression 
model with treatment arm as single covariate on subgroup population. 
• Obtain p-value from unstratified log-rank test on subgroup population. 
• Obtain p-value for interaction term between treatment arm and subgroup factor by fitting 
unstratified Cox PH model with treatment arm, subgroup factor and their interaction as 
covariates on the whole ITT population. 
A forest plot containing above information will be provided. 
Subgroup factors: In addition to the two stratification factors, i.e. ECOG PS (0 versus 1) and 
peritoneal metastasis (yes versus no) per IWRS, the following subgroup factors are added: 
• Gender (males vs. females) 
• Age group (<65 years vs. ≥65 years) 
• Country (China vs. non-China) 
• Post-discontinuation therapy use (yes vs. no) 
• Weight loss over the 3 months prior to study entry (≥10% vs. <10%) 
• Primary tumor location (gastric vs. GEJ) 
• Prior first-line chemotherapy (doublets vs. triplets) 


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• Number of metastatic site (≤2 vs. ≥3) 
• Liver metastasis (yes vs. no) 
• Tumor differentiation at initial diagnosis (well, moderately, poorly, undifferentiated, 
unknown) 
• Time to progression on first-line therapy (<6 months vs. ≥6 months) 
• Number of previous treatment lines (1 vs >1 [including 1st line, adjuvant and 
neoadjuvant]) 
• Presence of ascites (yes vs. no) 
• Prior gastrectomy (yes [full or partial] vs. no) 
• Post-discontinuation therapy usage (yes vs. no) 
6.13. Protocol Deviation 
Important protocol deviations (IPDs) are defined as those deviations that could potentially 
impact data interpretation, data integrity and patient safety across the study. IPDs will be 
identified from the clinical database and from site monitoring. Categories of IPDs will be 
documented in the trial issue management plan (TIMP), which will contain detailed criteria used 
to identify IPDs. 
After further review, a comprehensive listing of patients with major protocol deviations (MPDs) 
among IPDs that might have significantly affected the interpretation and integrity of data or 
patient safety will be provided. Patients with MPDs will be excluded from PP population. 
A listing of patients with MPDs will be defined prior to database lock, and the PP population will 
be derived using this list. The PP population may be used for select sensitivity analyses of the 
efficacy data. 
IPDs and MPDs will be summarized by treatment arm and by the category and subcategory of 
deviation.  
6.13.1. Protocol Deviations due to COVID-19 
A listing of protocol deviations (both important and non-important) caused by COVID-19 will be 
provided. 
6.14. Interim Analyses and Data Monitoring 
An Independent Data Monitoring Committee (IDMC) will be established as an oversight 
mechanism to monitor overall study conduct. The membership, roles and responsibilities for the 
IDMC during the conduct of the study are defined in the IDMC Charter. All interim analyses 
will include complete assessments of safety-related data. The IDMC will evaluate unblinded data 
and make recommendations to the designated representative of the sponsor. Only the IDMC is 
authorized to evaluate unblinded interim efficacy analyses. All study team members will remain 


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blinded to all interim results, except in case that IDMC concludes that criteria for early efficacy 
have been demonstrated. 
Since this study is a bridging study in nature, no study-wise Type I error control or multiplicity 
adjustments will be done in the testing/estimation procedures. All analyses (including p-values) 
are descriptive. 
One interim OS analysis and the primary PFS analysis will be conducted to provide early 
efficacy information and could potentially result in early communication with regulatory 
agencies if the primary objective is claimed to have been achieved based on these results. 
These analyses will be performed after at least 256 PFS events have occurred. At this time, 
approximately 160 OS events would have occurred assuming the same median OS values in 
Section 5.2. 
Assuming a true underlying HR of 0.81, with 160 OS events, the probability of obtaining a point 
estimate of HR less than 1 is at least 90%. Also assuming an exponential PFS distribution for 
each treatment arm and median PFS durations of 4.35 months and 3 months (HR = 0.69) for Arm 
A and Arm B, respectively, 256 PFS events will provide at least 80% probability of obtaining a 
one-sided p-value less than 0.025 for testing the hypothesis HR = 1 versus HR < 1 using log-rank 
test (as calculated with EAST with up-to-date accrual status). 
The primary objective will be claimed achieved if both of the following conditions are satisfied 
at interim: 
(1) The point estimate of stratified HR for investigator-assessed OS is less than 1. 
(2) The analysis of investigator-assessed PFS shows a one-sided, stratified p-value favoring 
Ramucirumab+paclitaxel arm less than 0.025 (or a two-sided p-value less than 0.05).  
If either condition is not met at interim, the blinded study will continue until approximately 336 
OS events have occurred, at which time the final OS analysis will be performed. 
6.15. Clinical Trial Registry Analyses 
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.   
Analyses provided for the CTR requirements include the following: 
Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by treatment 
group, by MedDRA preferred term. 
• An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE). 
• An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided: 


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o the number of participants at risk of an event 
o the number of participants who experienced each event term 
o the number of events experienced. 
• Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold). 
• AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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7. Unblinding Plan 
Randomization will occur using an IWRS system. Assignment to treatment groups will be 
determined by a computer-generated random sequence. Security measures will be taken so that 
treatment group code and other variables that can link patients to study arm will be blinded in the 
database.  
In order to maintain the scientific integrity of this double-blind trial, access to study data will be 
strictly controlled prior to the interim and final analyses. Dummy treatment assignment will be 
used in the reporting database until the database lock for the final analysis. During this time, 
analyses using unblinded treatment codes will be performed only at the interim analysis points 
specified in the protocol/SAP. For those safety and efficacy analyses assigned to the IDMC, only 
the designated Statistical Analysis Center (SAC), who is independent of the sponsor, will 
perform analyses on unblinded data.  
Data sets will be created for the purpose of aggregate data review in which treatment assignment 
is scrambled so that personnel involved in the day-to-day conduct of the trial and development 
and validation of analysis programs will be blinded to patient treatment assignment.  
While every effort will be made to blind both the patient and the investigator to the identity of 
the treatment, the inadvertent unblinding of a patient may occur. This unblinding will not be 
sufficient cause (in and of itself) for that patient to be excluded from any safety or efficacy 
analyses. 


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8. References 
Braunwald E.; Fauci A.; Hauser S.; Jameson J.; Kasper D.; Longo D.; Harrison's Principles of 
Internal Medicine. 16th Edition.  McGraw-Hill Medical Publishing Division, New York, 2005.  
Appendix A, Reference Values For Laboratory Tests, pages A1-A9. 
Brookmeyer R.; Crowley J. (1982). “A Confidence Interval for the Median Survival Time”. 
Biometrics. 38(1): 29-41. 
Brooks R.; Group E. (1996-7-31). “EuroQol: the current state of play”. Health policy. 37(1): 53-
72. 
Clopper C.; Pearson E. (1934). “The use of confidence or fiducial limits illustrated in the case of 
the binomial”. Biometrika. 26: 404-413. 
EuroQol—a new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy. 1990 Dec;16(3): 199-208. 
Liu G. G.; Wu H.; Li M; Gao C.; Luo N. (2014). “Chinese Time Trade-Off Values for EQ-5D 
Health States”. Value in Health. 17: 597-604. 
Meier P.; Karrison T.; Chappell R.; Xie H. (2004). “The Price of Kaplan-Meier”, Journal of the 
American Statistical Association, 99(467): 890-896. 
Wilson E. B. (1927). “Probable inference, the law of succession, and statistical inference”, 
Journal of the American Statistical Association, 22: 209-212. 


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9. Appendices 
 


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Appendix 1. Scoring for the EORTC QLQ-C30 
Questionnaire Version 3.0 
EORTC QLQ-C30 will be scored according to the scoring manual including transforming the 
raw score to the final score and handling of missing item responses as follows:  
• Raw Scores (RS):   
a) Global Health Status: 
• Global Health Status (QL2) = (Q29+Q30)/2 
b) Functional Scales: 
• Physical Functioning (PF2) = (Q1+Q2+Q3+Q4+Q5)/5 
• Role Functioning (RF2) = (Q6+Q7)/2 
• Emotional Functioning (EF) = (Q21+Q22+Q23+Q24)/4 
• Cognitive Functioning (CF) = (Q20+Q25)/2 
• Social Functioning (SF) = (Q26+Q27)/2 
c) Symptoms/Items: 
• Fatigue (FA) = (Q10+Q12+Q18)/3 
• Nausea and Vomiting (NV) = (Q14+Q15)/2 
• Pain (PA) = (Q9 +Q19)/2 
• Dyspnea (DY) = Q8 
• Insomnia (SL) = Q11 
• Appetite Loss (AP) = Q13 
• Constipation (CO) = Q16 
• Diarrhea (DI) = Q17 
• Financial Difficulties (FI) = Q28 
  
• Transformed Scores (TS): 
a) For Global Health Status: TS = (RS-1) /6 *100  
b) For Symptom Scales / Items: TS = (RS-1) /3 *100 
c) For Functioning Scales: TS = [1-(RS-1) /3 ]*100  


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• Missing Data: 
If there are missing items, raw scores derived from more than one question can be prorated so 
long as the respondent completed >50% of the items on a given subscale: 
a) For status/scales/items derived from an odd total number of questions: 
    [(Number of questions answered+1)/2] questions must be answered 
b) For status/scales/items derived from an even total number of questions: 
    [Number of questions answered/2] questions must be answered 
Prorated raw score = [Sum of answered item scores] ÷[N of items answered] 
If any subscale has > 50% missing items then the subscale total score will be missing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2. Model for Calculating China Population-Based 
Predicted Index Scores 
An ordinary least squares multiple regression model was proposed and fitted by Liu et al (2014) 
to calculate the EQ-5D-3L index (utility) scores based on Chinese population. To recapitulate, 
the five dimensions are mobility (MO), self-care (SC), usual activities (UA), pain/discomfort 
(PD) and anxiety/depression (AD). The independent variables include indicator variables 
corresponding to levels 2 (some problem) and 3 (extreme problem) of each of the 5 dimensions, 
plus an indicator variable for the presence of any level 3 problems in the state. This model was 
referred to as the N3 model in the article. 
The fitted N3 model can be written as follows: 
Index score = 1 −(0.039 + 0.099MO2 + 0.246MO3 + 0.105SC2 + 0.208SC3 + 0.074UA2
+ 0.193UA3 + 0.092PD2 + 0.236PD3 + 0.086AD2 + 0.205AD3 + 0.022N3) 
In the above model, N3 = 1 if any of the 5 responses is 3 and N3 = 0 otherwise. Moreover, MO2 
= 1 if mobility = 2 and MO2 = 0 otherwise; other indicator variables are defined similarly. An 
important exception is that when all responses are 1, the index score is set to 1. 
If answers to one or more dimensions are missing, no imputation will be done, and the index 
score will be set to missing. 
 
 
 
 


Leo Document ID = a2e74790-6b39-4f71-9edf-4e77bdbe1912
Approver: 
Approval Date & Time: 30-Jul-2020 02:00:16 GMT
Signature meaning: Approved
PPD