A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ramucirumab Plus Docetaxel Versus Placebo Plus Docetaxel in Patients With Locally Advanced or Unresectable or Metastatic Urothelial Carcinoma Who Progressed on or After Platinum-Based Therapy
Phase: PHASE3
Conditions: Urothelial Carcinoma
Sponsor: Eli Lilly and Company

I4T-MC-JVDC Protocol 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ramucirumab Plus 
Docetaxel Versus Placebo Plus Docetaxel in Patients With Locally Advanced or Unresectable or 
Metastatic Urothelial Carcinoma Who Progressed on or After Platinum-Based Therapy   
 
 
NCT02426125 
 
Approval Date:   14-Jan-2015
 

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1. Protocol I4T-MC-JVDC
A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study of Ramucirumab plus 
DocetaxelVersus Placebo plus Docetaxel in Patients with 
Locally Advanced or Unresectable or Metastatic 
Urothelial Carcinoma WhoProgressed onor After
Platinum-Based Therapy
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
ramucirumab (LY3009806)unless such personsare bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments are subject to United States Freedom of Information Act Exemption 4.
Ramucirumab(LY3009806)
Phase 3, randomized, double-blind, pla
cebo-controlled study of ramucirumab plus 
docetaxelversus pla
cebo plus docetaxel in patients with locally advanced or unresectable 
or metastatic urothelial carcinomawho progressed onor after one prior first-line
platinum-based chemotherapy.  Patients will be randomized 1:1 to receive one of these 
study regimens on Day 1 of each 21-day cycle:  ramucirumab (10 mg/kg)I.V.plus 
docetaxel (75mg/m
2) I.V. OR placebo (10 mg/kg volume equivalent)I.V.plus docetaxel 
(75mg/m
2) I.V.  Provided no prespecified discontinuation criteria have been met (including 
radiographic documentation of disease progression, toxicity requiring cessation, protocol 
noncompliance, or withdrawal of consent), treatment with docetaxel may continue for up to 
six 21-day cycles;further cycles of docetaxel (up to 4 additional cycles [maximum of 
10cycles total]) may be administered with approval of the Lilly clinical research 
physician/clinical research scientistor designee.  Treatment with ramucirumab or placebo 
(monotherapy) may continue on21-day cycles until at least one discontinuation criterion is 
met.
Approval Date: 14-Jan-2015 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lillyon date provided below.

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2. Synopsis
Study Rationale
Efficacy data fromthe 75% interim analysisforthe Phase 2 Study I4Y-IE-JCDC(JCDC)showed 
a clinically significant improvement in progression-free survival (PFS), objective response rate 
(ORR), and disease control rate (DCR) when ramucirumab was given with docetaxel versus
docetaxel alone. Furthermore, early evaluation of overall survival (OS;43% censoring) 
demonstrated survival resultstrending in favor ofthe ramucirumab arm. The combination was 
well tolerated. As a result, the currentconfirmatory Phase 3 Study I4T-MC-JVDC(JVDC)is 
planned.

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Clinical Protocol Synopsis:  Study I4T-MC-JVDC
Name of Investigational Product:  Ramucirumab (LY3009806)
Title of Study:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ramucirumab plus 
DocetaxelVersus Placebo plus Docetaxel in Patients with Locally Advanced or Unresectable or Metastatic 
Urothelial Carcinoma WhoProgressed onor AfterPlatinum-Based Therapy
Number of Planned Patients:
Entered:  699
Enrolled/Randomized:  524
Completed (number of patients who will complete 
the OS endpoint):  382
Phase of Development:  3
Length of Study:  approximately 33months(duration from first patient visit to last patient visit;applies to all 
patients in trial; excludesthe Continued Access Period)
Planned first patient visit:  JUN 2015
Planned last patient visit, excluding the Continued Access Period:  MAR2018
Planned interim analysis:  One interim efficacy analysis for OS (based on all randomized patients) will be 
performed at the time of PFS final analysis.
Objectives:  The primary objective of this study is to compare the progression-free survival (PFS) of ramucirumab 
in combination with docetaxel with the PFS of placebo in combination with docetaxel, in patients with locally 
advanced or unresectable or metastatic urothelial carcinoma who have had disease progression onor after oneprior 
first-line platinum-basedchemotherapy.
The secondary objectives of this study are to compare each of the following variables between the treatment arms:
overall survival (OS) time
objective response rate (ORR; complete response[CR]+ partial response[PR]) and disease control rate 
(DCR)
duration of response (DOR)
safety profile
patient-reported outcome (PRO) measures (European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-C30 [EORTC QLQ-C30]and EQ-5D-5L)
Secondary objectives also include the evaluation of:
the pharmacokinetic profile of ramucirumab
the immunogenicity of ramucirumab (anti-ramucirumab antibodies)
The exploratory objectives of this study are to:
assess the change in tumor sizein patients with measurable disease
examine biomarkers relevant to ramucirumab, angiogenesis, and the disease state, and to correlate these 
markers to clinical outcome

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Study Design:  Phase 3, randomized, double-blind, placebo-controlled study of ramucirumab plus docetaxel
versus placebo plus docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma
who progressed onor after one prior first-lineplatinum-based chemotherapy. Patients will be randomized 1:1 to 
receive one of these study regimens on Day 1 of each 21-day cycle:  ramucirumab (10 mg/kg)intravenously (I.V.)
plus docetaxel (75 mg/m2) I.V. OR placebo (10 mg/kg volume equivalent)I.V.plus docetaxel (75 mg/m2) I.V.  
Provided no prespecified discontinuation criteria have been met (including radiographic documentation of disease
progression, toxicity requiring cessation, protocol noncompliance, or withdrawal of consent), treatment with 
docetaxel may continue for up to six 21-day cycles(up to 4 additional cycles of docetaxel [maximumof 10 cycles 
total] may be administeredwith approval of the Lilly clinical research physician [CRP]/clinical research scientist 
[CRS]or designee).  Treatment with ramucirumab or placebo (monotherapy) may continue on21-day cycles until 
at least one discontinuation criterion is met.  This is an outpatient study.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Key Inclusion Criteria
The patient has histologically or cytologically confirmed,locally advanced or unresectable or metastatic 
urothelial (transitional cell) carcinoma of the bladder, urethra, ureter, or renal pelvis.  Patients with mixed 
pathology are eligible only if they have predominantly transitional celltumorbased on local pathology 
review.
The patient has demonstrated disease progression while on a platinum-containing regimen in the first-line
setting or within 14 months of completing the first-lineplatinum regimen.  Patients who received 
treatment with oneimmune checkpointinhibitor (for example, PD-1, PDL1, or CTLA4)regimen 
following platinum therapy may have a longer interval since prior platinum-containing therapy
(≤24months); such patientsare eligible.
The patient has received no more than oneprior systemic chemotherapy regimen in the relapsedor 
metastatic setting.  Prior cytotoxic therapy in an adjuvant or neoadjuvant setting is not considered as a 
prior line ofsystemic chemotherapy in the relapsed or metastatic setting. Prior treatment with 
intravesicular chemotherapy, bacillus Calmette-Guérin (BCG), or platinum given as a radiation-
sensitizing agent will not be considered as a systemic line of treatment.  Prior treatment with no more than 
oneprior immunecheckpointinhibitor is permittedand will not be consideredas a line of systemic 
chemotherapy.  Patients enrolling after immunecheckpointinhibitor therapy must have demonstrated 
disease progression while on that therapy or within 24 months after the last dose of that therapy.
The patient has measurable disease or nonmeasurable but evaluable disease as defined by Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).
The patient has an Eastern Cooperative Oncology Group performance status of 0 or 1.
The patient is willing to provide blood, urine,and tissue samples for research purposes.  Submission of 
blood and urine specimens is mandatory for participation in this study, unless restricted per local 
regulations.  If prior archived tumor specimens are available, and unless restricted by local regulations, 
submission of archived tumor tissue is mandatory.  If an archived specimen is not available, submission of 
a newly acquired biopsy is requested when biopsy is safe and feasible.
The patient hasadequate organ function.
Key Exclusion Criteria
The patient has received more than one prior systemic chemotherapyregimen for metastatic disease 
(except as noted in Inclusion Criteria).  A treatment regimen must consist of minimum of 2 cycles to be 
considered as a prior regimen.

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Test Product, Dosage, and Mode of Administration:
Ramucirumab drug productis a sterile, preservative-free, solution for infusion of ramucirumab drug substance 
formulated in an aqueous solution at a concentration of 10mg/mL (500mg/50-mLvial).
Placebo drug productis a sterile, preservative-free solution for infusion containing histidine buffer in a 50-mL vial 
to mimic the ramucirumab drug product container and closure.
Patients will receive ramucirumabby I.V. infusion at a dose of 10 mg/kg(or placebo at a dose of 10 mg/kg volume 
equivalent) over approximately 60 minutes on Day 1 of each21-daycycle.
Reference Therapy, Dosage, and Mode of Administration:
Docetaxelwill be administered at a dose of 75mg/m2I.V. over 60 minutes on Day 1 of each 21-daytreatment 
cycle.  (A commercial preparation of docetaxelwill be used and should be prepared and administered according to 
the manufacturer’s instructions).
Planned Duration of Treatment:  The following describesthe intended duration of treatment for a single patient, 
excluding the Continued Access Period.
A treatmentcycle will be defined as 21 days, with radiographic evaluation of tumor response at these time points:
at Baseline
every 6 weeks (±7days) after randomization(regardless of treatment delays) during the Study Treatment 
Period, until disease progression OR overall study completion OR 1 year after randomization, whichever 
occurs first
In addition, any patient whose disease has not progressed by 1 year after randomization (note that the patient may 
or may not still be on study treatment) will be evaluated for response at these time points:
every 12weeks (±7days) from 1 year after randomization, until disease progression OR overall study 
completion OR 3 years after randomization, whichever occurs first; then as per standard clinical practice 
after that.
Provided no prespecified discontinuation criteria have been met (including radiographic documentation of disease
progression, toxicity requiring cessation, protocolnoncompliance, or withdrawal of consent), treatment with 
docetaxel may continue for up to six 21-day cycles(up to 4additional cyclesof docetaxel[maximum of10 cycles 
total] may be administeredwithapproval of the Lilly CRP/CRS or designee).  Treatment with ramucirumab or 
placebo (monotherapy) may continue on21-day cycles until at least one discontinuation criterion is met.
Short-termFollow-up (postdiscontinuation):  Approximately 30 daysafter the date of discontinuation.
Long-termFollow-up (postdiscontinuation):  Patients will be followed for survival every 3 months (±7 days) until
the patient’s death oroverall study completion, whichever occurs first.

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Criteria for Evaluation:
Efficacy:
PFS is defined as the time from the date of randomization tothe date of first observation of objectiveprogression 
as defined by RECIST 1.1 or the date of death due to any cause, whichever is earlier.
OS is defined as the time from the date of randomization to the date of death from any cause.
ORR is defined as the proportion of randomized patients achievinga best response of CR or PR, using the 
investigator response assessments.
DCR is defined as the proportion of randomized patients achievinga best response of CR, PR, or stable disease 
(SD).SD is defined per RECIST criteria and must last a minimum of 5 weeks from randomization.
DOR is defined only for responders (patients with CR or PR [confirmation not required]) and is measured from the 
date of first evidence of CR or PR to the date of objective progression or the date of death due to any cause, 
whichever is earlier.
Safety:  Drug exposure; adverse events (AEs); treatment-emergent adverse events(TEAEs); deaths; serious 
adverse events (SAEs); other significant AEs(includingTEAEs leading to study treatment discontinuationsand
dose modifications); vital signs; transfusions; other observations related to safety; and clinical laboratory 
evaluations.  AEswill be coded using the Medical Dictionary for Regulatory Activities (MedDRA
®).  AEsand 
clinical laboratory values will be graded using the National Cancer Institute Common Terminology Criteria for 
Adverse Events(CTCAE),Version 4.0(v4.0).
Health Outcomes:  Assessment of PROs will be conducted through the use of the EORTC QLQ-C30 and the 
EQ-5D-5L questionnaires, which measure quality of life and health status, respectively. A change of ≥10points on 
the 100-point EORTC QLQ-C30 scales is considered clinically meaningful.
Immunogenicity (anti-ramucirumab antibodies):  Blood samples for immunogenicity (anti-ramucirumab 
antibodies) testing will be collected from all study patients to determine antibody production against ramucirumab 
(placebo) at baseline (beforethe first infusion of ramucirumab/placebo on Cycle 1, Day 1 of treatment); at 
specified time points during the study; and in the event of an infusion-related reaction, as close to the onset of the 
reaction as possible, at the resolution of the event, and 30 days following the event.  Immunogenicity will be 
assessed by a validated assay designed to detect anti-drug antibodies in the presence of the ramucirumab.  
Antibodies may be further characterized and/or evaluated for their ability to neutralize the activity of ramucirumab.
Pharmacokinetics:  Blood samples will be collected from all study patients to assess ramucirumab concentrations 
in serum, including concentrations prior to ramucirumab infusion (C
min[troughconcentration]) and at 1-hour post 
end of ramucirumab infusion (approximately C
max[peakconcentration]).
Translational research/Tailoring biomarkers:  Deoxyribonucleic acid (DNA)from whole blood samples will be 
collected for pharmacogenetic analysis. Plasma samples for analysis of circulating markers will be collected prior 
to infusion on Day 1,Cycle 1andon Day 1,Cycle 3, and at the (30-day) Short-termFollow-up visit. Urine 
samples for analysis of biomarkerswill be collected at baseline (within 28 days prior to infusion on Day 1,
Cycle1), prior to infusion on Day 1,Cycle 3, and at the (30-day) Short-termFollow-up visit. Submission of prior 
archived tumor specimen, if available, is mandatory; if archived specimen is not available, submission of newly 
acquired biopsy obtained at baselineis requested when biopsy is safe and feasible.  Tumor tissue and plasma 
samples will be examined for markers that may include, but are not limited to, those related to locally advancedor
unresectable or metastatic urothelialcarcinoma, angiogenesis, docetaxel, and/or ramucirumab. Mutation profiling, 
copy number variability, gene expression, and/or immunohistochemistry may be performed on these tissue samples 
to assess potential associations with these biomarkers and clinical outcomes.  The pharmacogenetic biomarker 
samples will only beused for investigations related to disease, cancer-related conditions, 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.

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Statistical Methods:
Statistical:
A gatekeeping design will be used to assess PFS, OS,and ORR.  PFS, OS,and ORRare tested in a sequential 
manner.  The OS superiority is tested only if the PFS superiority test is significant.  Similarly,the ORRsuperiority 
is tested only if the OS superiority test is significant.  Although the primary endpoint is PFS, the sample size is 
powered to show a superiority test for comparing OS between the 2 arms.
The sample size to test PFS superiority at the PFS final analysis is determined based on the following assumptions:
The PFS hazard ratio(HR)for treatment group (ramucirumab plus docetaxel) versus control group 
(placebo plus docetaxel) is 0.70.
The randomization ratio is 1:1.
A 2-tailed significance level of 0.05.
Control arm median PFS = 2 months.
The type II error rate is 0.1, i.e., the power of the trial is set to 90%.
Enrollment rate is approximately 36.3patients per month.  This includes an estimated 25% chance of 
screen failure patients.
Under these assumptions, the estimated total number of PFS events at thePFS final analysis is 331, from an 
expected accrual of 371 patients.Assuming a15% patient dropout rate from PFS follow-up, it is estimated that 
approximately 437 patients are needed to reach 331 PFS events in approximately18.4months.
The sample size to test OS superiority is determined based on the following assumptions:
α = 0.049 (2-sided), statistical power = 80%.
The randomization ratio is 1:1.
Control arm median OS = 9 months.
HR=0.75
Interim efficacy analysis for OS (at the PFS final analysis) with testing at α = 0.001 (2-sided).
Under these assumptions, the estimated total number of OS events at the final OS analysis is 382, from an expected 
accrual of 497 patients.  Assuming a 5% dropout rate from survival follow-up, it is estimated that 524 patients will 
need to be randomized to reach target number of OS events in approximately32.6 months.
In order to ensure that the PFS final analysis at 331 PFS events reflects both early and later events by having an 
appropriate censoring rate, the cohort of the first 437 randomized patients will be used for the PFS final analysis, 
and this analysis will occur when a minimum of 331 PFS events have been observed in this cohortand enrollment 
is completed. All randomized patients up to that date will be used to compare (interim) OS between the 2 arms.
The final OS analysis is expected at 32.6 months from first patient enrollment.  At the final analysis, all 
randomized patients (planned to be about 524 patients) will be used to compare OS between the 2 arms.  The 
rejection boundary for HR is approximately0.82.
An independent data monitoring committee (IDMC) will be established to conduct safety reviews (unblinded 
safety analyses)after at least 100 and 250 evaluable patients total have either started treatment in Cycle 3 or 
discontinued all study treatment prior to Cycle 3 due to any reasons.  Additional safety reviews may be done at the 
discretion of the IDMC.

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Efficacy:
The primary analysis will be performed on the intent-to-treat (ITT) population, which will include all randomized 
patients.  Additional sensitivity analysis for PFS and OS will be repeated on the per-protocol population and other 
criteria.  The primary analysis of PFS will be based on stratified log-rank test, stratified by randomization strata 
(interactive Web response system [IWRS]).  PFS survival curves and the median with 95% confidence interval 
(CI) will be given using the Kaplan-Meier method.  The HR will be estimated using a stratified Cox regression 
model, stratified by randomization strata (IWRS).  The time-to-event efficacy endpoints, including PFS, OS, and 
DOR, will be analyzed with the Kaplan-Meier method by treatment groups, along with a summary of associated 
statistics (for example, median survival time and survival rates,including the corresponding 2-sided 95% CIs).  
ORR and DCR will be compared between the treatment groups using theCochran-Mantel-Haenszel test on the 
entire ITT population.
Safety:
Safety analyses will be performed on the safety population (that is, all randomized patients who received any 
quantity of any study treatment, including a partial dose [ramucirumab/placebo, docetaxel]), and will include 
summaries of incidences of TEAEs by maximum CTCAE grade.  Additionally, the following (but not limited to) 
safety-related outcomes will be summarized:  study treatment discontinuationsdue to TEAEs, deaths, SAEs, 
hospitalizations, and transfusions.
Health Outcomes:
Time to deterioration in EORTC QLQ-C30 scales will be estimated with the Kaplan-Meier method.  At each 
postbaseline assessment, patients’ scores for each scale will be classified as improved, worsened, or stable; rates of 
improved/stable will be compared between arms using the ITT population.  The EQ-5D-5L will be analyzed using 
descriptive statistics.
Immunogenicity:
Immunogenicity incidence will be tabulated, and correlation of immunogenicity to ramucirumab drug level, 
activity, and safety will be assessed as appropriate.
Pharmacokinetics:
Ramucirumab Cmin(trough concentration) and concentration at 1-hour postend of ramucirumab infusion 
(approximately C
max[peakconcentration]) in serum will be summarized usingdescriptive statistics. Additional 
analysis usingthe population pharmacokinetic approach may be conducted if deemed appropriate.  Relationships 
between ramucirumab exposure and measures of efficacy and safety will be explored.
Translational research/Tailoring biomarkers:  The profiles of biomarkers assessed over time will be summarizedby 
treatment.  The associationsbetween biomarker measures with clinicaloutcomes will be analyzed.

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3. Table of Contents
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study of Ramucirumab plus DocetaxelVersus Placebo plus 
Docetaxel in Patients with Locally Advanced or Unresectable 
or Metastatic Urothelial Carcinoma Who Progressed onor 
AfterPlatinum-Based Therapy
Section
Page
1.
Protocol I4T-MC-JVDC  A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study of Ramucirumab plus Docetaxel Versus 
Placebo plus Docetaxel in Patients with Locally Advanced or 
Unresectable or Metastatic Urothelial Carcinoma WhoProgressed on 
or After Platinum-Based Therapy........................................................................................1
2.
Synopsis.............................................................................................................................2
3.
Table of Contents................................................................................................................9
4.
Abbreviations and Definitions...........................................................................................17
5.
Introduction......................................................................................................................24
5.1. Bladder Cancer.............................................................................................................24
5.1.1.
Background and Epidemiology............................................................................24
5.1.2.
Therapy................................................................................................................24
5.1.2.1.
First-Line Therapy..........................................................................................24
5.1.2.2.
Second-Line Therapy......................................................................................25
5.2. The Role of VEGF and VEGF Receptor 2 in Angiogenesis and 
Tumor Growth.............................................................................................................25
5.3. VEGF and Bladder Cancer...........................................................................................26
5.4. Ramucirumab (IMC-1121B)........................................................................................27
5.4.1.
Background..........................................................................................................27
5.4.2.
Study JCDC:  Phase 2 Study of Ramucirumab in Bladder 
Cancer..................................................................................................................27
5.4.3.
Dose Rationale.....................................................................................................29
5.4.4.
Study JVDC:  Clinical Trial Rationale..................................................................29
6.
Objectives.........................................................................................................................31
6.1. Primary Objective........................................................................................................31
6.2. Secondary Objectives...................................................................................................31
6.3. Exploratory Objectives.................................................................................................31
7.
Study Population...............................................................................................................32
7.1. Inclusion Criteria..........................................................................................................32

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7.2. Exclusion Criteria........................................................................................................35
7.3. Discontinuation............................................................................................................37
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................37
7.3.2.
Discontinuation of Study Treatment.....................................................................37
7.3.3.
Discontinuation from the Study............................................................................39
7.3.4.
Patients Who Are Lost to Follow-up....................................................................39
7.3.5.
Discontinuation of Study Sites.............................................................................40
7.3.6.
Discontinuation of the Study................................................................................40
8.
Investigational Plan...........................................................................................................41
8.1. Summary of Study Design............................................................................................41
8.1.1.
Study Completion and End of Trial......................................................................44
8.1.2.
Continued Access Period......................................................................................46
8.2. Discussion of Design and Control................................................................................47
9.
Treatment..........................................................................................................................48
9.1. Treatments Administered.............................................................................................48
9.1.1.
Premedication......................................................................................................50
9.1.1.1.
Premedication for Ramucirumab or Placebo...................................................50
9.1.1.2.
Premedication for Docetaxel...........................................................................50
9.1.2.
Study Drugs.........................................................................................................50
9.1.2.1.
Ramucirumab or Placebo................................................................................50
9.1.2.2.
Docetaxel.......................................................................................................52
9.2. Materials and Supplies.................................................................................................52
9.2.1.
Ramucirumab Drug Product or Placebo................................................................52
9.2.2.
Docetaxel.............................................................................................................52
9.3. Method of Assignment to Treatment............................................................................52
9.4. Selection and Timing of Doses.....................................................................................53
9.4.1.
Dose Adjustments and Delays..............................................................................54
9.4.1.1.
Dose Modifications for Ramucirumab/Placebo...............................................54
9.4.1.1.1.
Infusion-Related Reactions.......................................................................57
9.4.1.1.2.
Hypertension............................................................................................58
9.4.1.1.3.
Thromboembolic Events...........................................................................58
9.4.1.1.3.1.
Arterial Thromboembolic Events........................................................58
9.4.1.1.3.2.
Venous Thromboembolic Events.........................................................58
9.4.1.1.4.
Bleeding (Hemorrhagic) Events................................................................59
9.4.1.1.5. 
Gastrointestinal Perforation.......................................................................59
9.4.1.1.6.
Fistula.......................................................................................................59
9.4.1.1.7.
Proteinuria................................................................................................59
9.4.1.1.8.
Congestive Heart Failure..........................................................................60

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9.4.1.1.9.
Surgery and Impaired Wound Healing......................................................60
9.4.1.1.10. Liver Injury/Liver Failure.........................................................................61
9.4.1.1.10.1. Reversible Posterior Leukoencephalopathy 
Syndrome............................................................................................61
9.4.1.2.
Dose Modifications for Docetaxel..................................................................62
9.4.1.2.1.
Hypersensitivity Reactions........................................................................64
9.4.1.2.2.
Hematologic Toxicity...............................................................................65
9.4.1.2.3.
Fluid Retention.........................................................................................66
9.4.1.2.4.
Cutaneous.................................................................................................66
9.5. Blinding.......................................................................................................................66
9.5.1.
Emergency Unblinding........................................................................................67
9.5.2.
Inadvertent Unblinding........................................................................................67
9.6. Concomitant Therapy...................................................................................................67
9.6.1.
Supportive Care...................................................................................................68
9.6.1.1.
Colony-Stimulating Factors............................................................................68
9.6.1.2.
Erythropoiesis-Stimulating Agents.................................................................68
9.6.1.3.
Antidiarrheal Agents.......................................................................................68
9.6.1.4.
Antiemetic Therapy........................................................................................69
9.6.1.5.
Analgesic Agents............................................................................................69
9.6.2.
Prohibited Medication..........................................................................................69
9.6.3.
Restricted Therapies.............................................................................................69
9.6.4.
Other Study Conditions:  Surgery (or Procedure) during 
Study Treatment Period........................................................................................70
9.7. Treatment Compliance.................................................................................................70
10. Efficacy, Health Outcomes Measures, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of Measurements.........................................71
10.1. Efficacy Measures........................................................................................................71
10.1.1. Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................71
10.1.1.1. Centralized Radiologic Collection..................................................................72
10.1.2. Efficacy Assessments during Postdiscontinuation Follow-up................................72
10.1.3. Primary Efficacy Measure....................................................................................72
10.1.4. Secondary Efficacy Measures...............................................................................73
10.2. Health Outcomes Measures..........................................................................................74
10.2.1. EORTC QLQ-C30...............................................................................................74
10.2.2. EQ-5D-5L............................................................................................................74
10.3. Safety Evaluations........................................................................................................74
10.3.1. Adverse Events....................................................................................................75
10.3.1.1. Serious Adverse Events..................................................................................77

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10.3.1.2. Suspected Unexpected Serious Adverse Reactions..........................................78
10.3.2. Other Safety Measures.........................................................................................78
10.3.2.1. Electrocardiograms.........................................................................................78
10.3.3. Safety Monitoring................................................................................................78
10.3.4. Complaint Handling.............................................................................................79
10.4.Sample Collection and Testing.....................................................................................79
10.4.1. Samples for Study Qualification and Health Monitoring.......................................79
10.4.2. Samples for Translational Research......................................................................80
10.4.2.1. Tumor Tissue.................................................................................................81
10.4.2.2. Plasma and Urine for Biomarkers...................................................................81
10.4.2.3. Whole Blood for DNA Collection...................................................................82
10.4.3. Samples for Immunogenicity Research.................................................................82
10.4.4. Samples for Drug Concentration Measurements 
(Pharmacokinetics)...............................................................................................83
11. Data Quality Assurance.....................................................................................................84
11.1. Data Capture System....................................................................................................84
12. Sample Size and Statistical Methods.................................................................................85
12.1. Determination of Sample Size......................................................................................85
12.2. Statistical and Analytical Plans.....................................................................................87
12.2.1. General Considerations........................................................................................87
12.2.1.1. Analysis Populations......................................................................................87
12.2.2. Patient Disposition...............................................................................................87
12.2.3. Patient Characteristics..........................................................................................88
12.2.4. Concomitant Therapy...........................................................................................88
12.2.4.1. Postdiscontinuation Anticancer Therapy.........................................................88
12.2.5. Treatment Compliance.........................................................................................88
12.2.6. Primary Outcome and Methodology.....................................................................88
12.2.7. Other Analyses of Efficacy..................................................................................88
12.2.7.1. Sensitivity Analysis for Progression-Free Survival.........................................88
12.2.7.2. Overall Survival.............................................................................................89
12.2.7.3. Objective Response Rate and Disease Control Rate........................................89
12.2.7.4. Duration of Response.....................................................................................89
12.2.7.5. Other..............................................................................................................90
12.2.8. Pharmacokinetic and Immunogenicity Analyses...................................................90
12.2.9. Translational Research Analyses..........................................................................90
12.2.10. Health Outcomes Analyses...................................................................................90
12.2.10.1. EORTC QLQ-C30..........................................................................................90
12.2.10.2. EQ-5D-5L......................................................................................................91

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12.2.11. Safety Analyses....................................................................................................91
12.2.12. Subgroup Analyses..............................................................................................91
12.2.13. Interim Analyses..................................................................................................92
12.2.13.1.Predefined TimePoints for IDMC Safety Reviews.........................................92
12.2.13.2. Predefined TimePoints for Lilly Efficacy Reviews.........................................92
13. Informed Consent, Ethical Review, and Regulatory Considerations..................................94
13.1. Informed Consent.........................................................................................................94
13.2. Ethical Review.............................................................................................................94
13.3. Regulatory Considerations...........................................................................................94
13.3.1. Investigator Information.......................................................................................95
13.3.2. Protocol Signatures..............................................................................................95
13.3.3. Final Report Signature.........................................................................................95
14. References........................................................................................................................96

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List of Tables
Table
Page
Table JVDC.1.
Treatment Regimens and Dosing Schedule.............................................49
Table JVDC.2.
Ramucirumab/Placebo Dose Reduction Schedule...................................54
Table JVDC.3.
Ramucirumab/Placebo Dosing Guidelines for Managing Infusion 
Reactions, Hypertension, and Proteinuria................................................56
Table JVDC.4.
Docetaxel Dose Reduction Schedule.......................................................62
Table JVDC.5.
Docetaxel Dose Modifications for Nonhematologic Toxicity..................63
Table JVDC.6.
Docetaxel Dose Modifications for Hematologic Toxicity........................66
Table JVDC.7.
Secondary Efficacy Endpoints................................................................73
TableJVDC.8.
Adverse Event and Serious Adverse Event Reporting Guidelines...........75
TableJVDC.9.
Study Design and Operating Characteristics...........................................86

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List of Figures
Figure
Page
FigureJVDC.1.
Illustration of study design......................................................................42
Figure JVDC.2.
Study period and continued access diagram............................................45

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List ofAttachments
Attachment
Page
Attachment 1.
Protocol JVDC Study Schedule............................................................101
Attachment 2.
Protocol JVDC Clinical Laboratory Tests.............................................112
Attachment 3.
Protocol JVDC Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality.........................................................................................113
Attachment 4.
Protocol JVDC ECOG Performance Status...........................................114
Attachment 5.
Protocol JVDC Creatinine Clearance Formula......................................115
Attachment 6.
Protocol JVDC RECIST Criteria 1.1.....................................................116
Attachment 7.
Protocol JVDC Pharmacokinetic, Immunogenicity, and 
Translational Research Sampling Schedule Sampling Schedule............123
Attachment 8.
Protocol JVDC NCI-CTCAE v 4.0 Infusion-Related Reactions............126

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4. Abbreviations and Definitions
Term
Definition
β-hCG
beta human chorionic gonadotropin
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
AP
alkaline phosphatase
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
Att
Attachment (at the end ofthe protocol)
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).
BCG
bacillus Calmette-Guérin
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.
BP
blood pressure
BSA
body surface area

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BSC
best supportive care
CHF
congestive heart failure
CI
confidence interval
Cmax
peak concentration
Cmin
trough concentration
CIOMS
Council for International Organizations of Medical Sciences
collection database
A computer database where clinical trial data are entered and validated.
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
Continued Access 
Period
The period between study completion and end of trial during which patients on study 
treatment who continue to experience clinical benefit and no undue risks may continue 
to receive study treatment until one of the criteria for discontinuation is met.
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRP
(Lilly) clinical research physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician,clinical research scientist, global safety 
physician, or other medical officer.
CRS
(Lilly) clinical research scientist
CSFs
colony-stimulating factors
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DC
discontinuation
DC101
a murine-specific anti-VEGF Receptor surrogate antibody for ramucirumab
DCR
disease control rate

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DCSI
Development Core Safety Information (part of the Investigator’s Brochure)
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
ethylenediaminetetraacetic acid
end of trial
End of trial is the date of the last visit or last scheduled procedure for thelast patient.
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.
EORTCQLQ-C30
European Organisation for Research and Treatment of CancerQuality of Life 
Questionnaire-C30
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.
evaluable patients
Must have received at least one dose of study therapy and have either started treatment 
in Cycle 3 or discontinued all study treatment prior to Cycle 3 due to any reasons.  This 
population applies only to the safety interim analyses.
Flt-1
VEGF Receptor 1
FOLFIRI
folinic acid + fluorouracil + irinotecan chemotherapy regimen
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
HCT
hematocrit
HGB
hemoglobin
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form

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ICH
International Conference on Harmonisation
icrucumab(generic 
name)
icrucumab drug product; LY3012212 or IMC-18F1 (code names)
recombinant human mAb that binds VEGFReceptor 1
IDMC
independent data monitoring committee
Ig
immunoglobulin
IgG1
immunoglobulin G, subclass 1
IMC-1121B(code 
name)
a code name for ramucirumab (proprietary name is Cyramza
®)
IMC-18F1(code name) a code name for icrucumab
immunogenicity
anti-drug antibodies (that is, anti-ramucirumab antibodies)
inf
infusion (used only in Attachment 7)
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, afterhaving been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product(IP)
A pharmaceutical form of an active ingredient substance or placebo being tested,or 
used as a reference,in a clinical trial.  Investigational product(IP)includes a product 
with a marketing authorization when:
1. used or assembled (formulated or packaged) in a way different from the 
authorized form,
2. used for an unauthorized indication, or
3. 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(population)
intention-to-treat(or intent-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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I.V.
intravenous(ly)
IWRS
interactive Web response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LY3009806
A code name for ramucirumab
LY3012212
A code name for icrucumab
mAb
monoclonal antibody
MedDRA®
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MVAC
methotrexate, vinblastine, and adriamycin
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
overall response rate(also known as 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
per protocol 
population
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.
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PlGF
placental growth factor
PLT
platelets
PR
partial response

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primary analysis
The primary analysis will be performed when a minimum of 331 PFS events have been 
observed from the first 437 randomized patients.  If full enrollment is not reached at the
pointwhen 331 PFS events have been observed, the primary analysis will be performed
when full enrollment is reached, on the number of PFS events observed upon full 
enrollment from the first 437 randomized patients.
PRO
patient-reported outcome
PS
(ECOG) performance status
PT
prothrombin time
PTT
partial thromboplastintime
QoL
quality of life
ramucirumab (generic 
name)
ramucirumab drug product; LY3009806 or IMC-1121B (code names); proprietary name 
isCyramza
®
recombinant human mAb that binds VEGFReceptor 2
randomize
the process of assigning patients to an experimental group on a random basis
RBC
red blood cells
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analysesand output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
ROW
rest of the world (geographic regionstratification variable)
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, 
diagnostic psychological tests, x-rays, blood draws).  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
study completion
This study will be considered complete after the final analysis for overall survival is 
performed.

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SUSARs
suspected unexpected serious adverse reactions
TCC
transitional cell carcinoma
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
TR
translational research
ULN
upper limit of normal
v 4.0
Version 4.0 (of NCI-CTCAE)
VAS
visual analogue scale
VEGF
vascular endothelial growth factor
vs
versus
VTE
venous thromboembolic event
WBC
white blood cells
WNL
within normal limits
WOCBP
women of childbearing potential

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A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study of Ramucirumab plus DocetaxelVersus Placebo plus 
Docetaxel in Patients with Locally Advanced or Unresectable 
or Metastatic Urothelial Carcinoma Who Progressed onor 
AfterPlatinum-Based Therapy
5. Introduction
5.1. Bladder Cancer
5.1.1.
Backgroundand Epidemiology
Urothelial carcinoma, a cancer involving the transitional epithelial lining of the urinary system,
is a type of cancer that typically occurs in the urinary bladder (90% of cases), renal pelvis(8%), 
orureters or urethra(remaining 2%, combined).  For simplicity,the disease is often referred to as 
bladder cancer.  Transitional cell carcinoma (TCC)is the predominant histologic typeof 
urothelial carcinomain North Americaand Europe, where it accounts for ≥90%of all bladder 
cancers(Billis et al. 2001; Chalasani et al. 2009). Other histologic subtypes are squamous cell, 
adenocarcinoma, and small-cell tumors.  Urothelial tumors with a mixture of histologic subtypes 
and a transitional cell predominance are generally treated similarly as urothelial (transitional cell) 
carcinomas (NCCN 2014).
Worldwide, bladdercancer was the ninth most common cancer, with 430,000 new cases 
diagnosed in 2012 with highest incidence in North America and Europe and lowest incidence in 
Asia and Latin America and Caribbean. The highest incidence rate ofbladder cancer by country 
is in Belgium, followed by Lebanon, Malta, Turkey, Denmark,and Hungary(IARC 2014).It is 
expected that more than 74,000 cases (56,000 men and 18,000women) of bladdercancer will be 
diagnosed in the United States in 2014, withapproximately 16,000 deaths (11,000 men and 5000 
women) attributable to this form of malignancy.In the United States, 5-year relative survival 
rates are 70% for local stage disease at diagnosis but decline to 33% and 5%, respectively, for 
regional or distant disease (American Cancer Society 2014).  In Europe, it is the fourth most 
frequent malignancy, accounting for 136,000 new cases leading to 49,000 deaths.  The incidence 
of bladder cancer rises with age, peaking between age 50 years and 70 years, and is 3times more 
common in men than in women. At initial presentation, 30% of bladder cancer has muscle-
invasive disease associated with a high risk of death from distant metastases.
5.1.2.
Therapy
5.1.2.1. First-Line Therapy
Cisplatin-containing combination chemotherapy, eitherwith gemcitabine or with methotrexate, 
vinblastine, and adriamycin (MVAC),is standard first-line treatment in advanced metastatic 
patients.  Although bladder cancer is a chemosensitive malignancy, the responses with first-line 
MVAC or gemcitabinetherapy are generally transient and the median survival ranges from 12 to 
14 months(Loehrer et al. 1992; Saxman et al. 1997; von der Maase et al. 2000; Galsky 2005). 

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To date, no improvement in survival has been achieved with newer triplets, novel 4-drug 
regimens,or dose-dense chemotherapy(Galsky et al.2007; Milowsky et al.2009; Bellmunt et al. 
2012).Gemcitabinehas a safety and tolerability advantage overMVACparticularly around 
neutropenia, febrile neutropenia,and mucositis(vonder Maaseet al. 2000).
About 50% of patients are unfit for cisplatin-containing chemotherapy due to a poor performance 
status, impaired renal function,or comorbidity. Patients unfit for cisplatin-based chemotherapy 
may be administered a carboplatin-based regimen such as carboplatinplus gemcitabine or 
single-agent taxane or gemcitabine.
5.1.2.2. Second-Line Therapy
In the second-line setting, gemcitabine, docetaxel, paclitaxel, and pemetrexed have been tested as 
single agents with response rates in the 10% to 20% range and median overall survival (OS)of 
5to10 months. Singleagents are typically preferred due to lower toxicityand the absence of a 
proven survival benefit with combination therapy.  Taxanes are accepted by the medical 
community for treatment of advanced disease based on evidence from Phase 2 studies
(McCaffrey et al. 1997; de Wit et al.1998;Sweeney et al.1999;Vaughn et al.2002).
The second-line treatment with docetaxel in patients with advanced or metastatic urothelial 
carcinomademonstrated an objective response rate (ORR) of 13.3% and a median OS of 
9months(McCaffrey et al. 1997). Taxanes such as docetaxel arerecommended by the National 
Comprehensive Cancer Network (NCCN) as a palliative option in the metastatic setting and are
widely accepted by the medical community in the United States and Canada for treatment of 
advanced disease(NCCN 2014).
Arandomized Phase 3trial tested vinflunine, athird-generation vinca alkaloid, plus best 
supportive care (BSC) versus (vs) BSC alonein patients progressing after first-line treatment 
with platinum-containing combination chemotherapy for metastatic disease (Bellmunt et al. 
2009). Compared withBSC, treatment with vinflunine resulted in an 8.6% ORRand a non-
statistically significant increase in survival (6.9 vs 4.6 months, hazard ratio [HR] 0.88,95% 
confidence interval [CI]: 0.69, 1.12; p=0.287).A statisticallysignificant difference in OS was 
observed only in post hoc analyses,whichexcluded subgroups ofpatients from the intent-to-treat 
(ITT) population (HR 0.77 [95% CI: 0.61, 0.98], p=0.0360).  Vinflunine ORR and OS results 
from the Phase 3study show no advantage over other singleagents,including taxanes. 
Nevertheless, vinflunine is the only approved drug in this settingand is approved only in Europe.
A review of the currently available therapies for second-line treatment of metastatic urothelial 
carcinomaof the bladder suggests that it represents an unmet clinical need,given there is no 
established and widely availabletreatment for patients with advanced bladder cancer who 
experience disease progression onor after first-lineplatinum-based regimens.
5.2. The Role of VEGF and VEGFReceptor 2 in Angiogenesis and 
Tumor Growth
Extensive scientific literature suggests that angiogenesis contributes substantially to cancer
growth and metastasis. As a result, the pathways that mediate angiogenesis are considered

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important targets in cancer drug development. Vascular endothelial growth factors (VEGFs;
including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor [PlGF]) have
emerged as key regulators of angiogenesis, and the expression of VEGFs has been correlated
with poor prognosis in several solid tumor types (Royet al. 2006a; Roy et al. 2006b;Aminiet al. 
2012; Oh et al. 2013; Xie et al. 2013). Vascular endothelial growth factor-A isdistinct within 
the VEGF ligandfamily in that it acts as a dominant endothelial cell-specific mitogen during 
angiogenesis (Leung et al. 1989; Ferrara 1993; Brown et al. 1997).VEGFReceptor 2 isthe 
primary mediator of proangiogenic effects of VEGF-A, and experimental evidence suggeststhat 
the VEGF-A/VEGF Receptor 2 interaction plays an important role in tumor angiogenesis, a
process essential for tumor growth and metastasis (Sullivan and Brekken 2010; Tugues et al. 
2011; Amini et al. 2012). Therefore, disruption of the interaction between VEGF-A and VEGF 
Receptor 2 may have therapeutic application in the treatment of cancer.
5.3. VEGF and Bladder Cancer
Tumor angiogenesis is considered an essential step for continued tumor growth and progression.
High levels of urinary VEGF have been reportedin patients with bladder cancer and were 
correlated with tumor recurrence rates(Crew et al. 1999).In a study of 72 patients with TCC of 
the bladder, increased VEGF Receptor 2 expression correlated with disease stage and invasive 
phenotype, demonstrating it as a factorfor progression ofurothelial cancer.  In a small study, 
86% of the tissues from 36 invasive bladder cancers were VEGF Receptor 2-positive while 14% 
of the tissues from 36 superficial cases were VEGF Receptor 2-negative (Xia et al.2006).  These 
findings support earlier work by Sato and colleagues who noted that the VEGF gene is 
frequently overexpressed in TCC of the bladder, particularly in muscle-invasive tumors (Sato et 
al. 1998).  Their findings also suggest a paracrine system including VEGF and Flt-1(VEGF 
Receptor 1)existsbetween the TCC cells andthe adjacent endothelial cells for regulation of 
angiogenesis.  Studies with a large tissue micro array have also demonstrated that the expression 
levels of VEGF and VEGF Receptor 1messenger ribonucleic acid levels were significantly 
higher in bladder cancer specimens than that of benign urothelial mucosa (Kopparapu et al. 
2013).  This study further confirmed that expression of VEGF Receptor 2 was significantly 
higher in muscle-invasive bladder cancer as compared with non-muscle-invasive bladder cancer.
In a human TCC-(253J-BV cells) derived mouse xenograft tumor model, in vivo treatment with 
the combination of a murine-specific anti-VEGF Receptor surrogate antibody for ramucirumab 
(DC101) and paclitaxel induced a significantly greater reduction in tumor growth compared with 
that seen with either agent alone (Inoue et al. 2000).  In addition, treatment with the combination 
was associated with a statistically significant reduction in the development of spontaneous lymph 
node metastasis.  Data from animal models suggest that DC101 may be capable of acting as a 
chemosensitizing agent when given in combination with a cytotoxic chemotherapy.  
Mobilization of circulating endothelial progenitors from the bone marrow can contribute to 
recovery of drug-treated tumors after administration of chemotherapeutic agents such as 
paclitaxel, docetaxel, and fluorouracil.  This effect may be blunted by treatment with a VEGF 
pathway-targeted antiangiogenic drug such as DC101.  Such data suggest that the administration 

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of an anti-VEGF Receptor 2 antibody may improve the antitumor effectiveness of certain 
cytotoxic agents such as paclitaxel, docetaxel, and fluorouracil (Shaked et al. 2008).
5.4. Ramucirumab (IMC-1121B)
5.4.1.
Background
Ramucirumabis a recombinant human monoclonal antibody (mAb) of the immunoglobulin G, 
subclass 1 (IgG1) that specifically binds to the extracellular domain of VEGFReceptor 2 with 
high affinity.  This antibody potently blocks the binding of the VEGF ligand to VEGF
Receptor2, inhibits VEGF-stimulated activation of both VEGFReceptor 2 and p44/p42 MAP 
kinases, and neutralizes VEGF-induced mitogenesis of human endothelial cells.
Ramucirumabhas been shown to block the interaction of VEGF and VEGFReceptor 2 (with a 
concentration that inhibits binding by 50% of approximately 1nM), and to inhibit 
VEGF-stimulated proliferation of endothelial cells and VEGF-induced migration of human 
leukemia cells.  The results of these preclinical pharmacodynamic studies supportedtheinitial
investigation of ramucirumabin the treatment of solid tumors.
Clinical investigations with ramucirumab in solid tumors have resulted in fourpositive Phase 3
trials, with twoingastric cancer(REGARD and RAINBOW), onein non-small cell lung cancer 
(NSCLC; REVEL), and onein metastatic colorectal cancer (CRC;RAISE). Ramucirumab 
(Cyramza
®)is approved in the United Statesas a single agent or in combination with paclitaxel 
as a treatment for people with advanced or metastatic gastric or gastroesophageal junction 
adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine-or platinum-
containing chemotherapy, and in combination with docetaxel as a treatment for people with 
metastatic NSCLC whose cancer has progressed on or after platinum-based chemotherapy.  In 
addition, the European Commission approved ramucirumab (Cyramza)in combination with 
paclitaxel and as a single agent when combination therapy is not appropriate, for people with 
advanced gastric cancer after prior chemotherapy.
5.4.2.
StudyJCDC: Phase 2 Study of Ramucirumab in Bladder 
Cancer
Study I4Y-IE-JCDC(JCDC),an open-label, multicenter, randomized Phase 2 study,evaluated
the safety and efficacy of docetaxel in combination with ramucirumab or icrucumabversus
docetaxel alone as second-line therapy in patients with locally advanced or metastatic urothelial 
(transitional cell) carcinoma of the bladder, urethra, ureter, or renal pelvis withdisease 
progression onor afterprior platinum-based treatment.Icrucumabis a recombinant human IgG1 
mAb, which specifically targets human VEGFReceptor 1, also known as Flt-1. Icrucumabbinds 
to VEGFReceptor 1 with high affinity and blocks the binding of VEGF, VEGF-B, and PlGF to 
the receptor, thereby inhibiting subsequent signaling.
A total of 138 patients were planned to be randomized in a 1:1:1 ratio to the treatment arms. 
Following randomization, 44 patients received docetaxel alone and 46 received ramucirumab 
plusdocetaxel. The primary objective of the study was progression-free survival (PFS);

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secondary objectives includedOS, ORR, duration of response (DOR), and safety. An interim 
analysis was performed when the study reached approximately 75% of the expected number of 
PFS events. For the purposes of this document,data only on the ramucirumab-plus-docetaxel 
and docetaxel-alone arms arepresented.
Ramucirumab in combination with docetaxel reduced the risk of disease progression by 61% 
(stratified HR = 0.388; 95% CI: 0.222, 0.677), resulting in a 112% longer median time to
disease progression in the ramucirumab-plus-docetaxel arm than in the docetaxel arm 
(22.0weeks [95% CI: 9.3, 30.0] vs10.4 weeks [95% CI:6.7, 16.9]).  Ramucirumab in 
combination with docetaxel increased the median OScompared withthat for docetaxel alone 
(48.9weeks [95% CI: 30.1, 65.9] vs 33.4 weeks [95% CI: 24.6, 44.4]).This analysis is based 
on interim data with approximately 43% OS censoring in the 2 arms combined. The 
ramucirumab-plus-docetaxel arm had a higher ORR than thedocetaxel arm at Analysis 2
(19.6%[95%CI: 9.4, 33.9] vs 4.5% [95% CI:0.6, 15.5]).
In regards tosafety, reported adverse events (AEs)were known effects for ramucirumab or 
docetaxel and most were Grade 1 or 2. The most common treatment-emergent adverse events 
(TEAEs)reported in patients receiving ramucirumab in combination with docetaxel werefatigue, 
occurring in 80% of patients (vs 75% in the docetaxel arm), neuropathy (50.0% vs 38.6%), and 
abdominal pain (32.6% vs 20.5%).
Grade 5 AEswere experienced by 3 patients in the ramucirumab-plus-docetaxel arm (cardiac 
arrest, decreased appetite, and sepsis) and 3 patients in the docetaxel arm (cardio-respiratory 
arrest, hypoxia, and multi-organ failure).
The observed rate of all-grade and Grade ≥3 neutropenia was numerically lower with the 
ramucirumab-plus-docetaxel combination.  Despite this difference,there were higher rates of 
all-grade pyrexia in the combination arm (26.1% vs 11.4%) and febrile neutropenia (21.7%vs 
11.4%).Other noted AEsinclude epistaxis (41.3% vs 6.8%), hematuria (28.3%vs2.3%), and 
hypertension (21.7% vs 4.5%). Higher rates of Grade 3 AEs in the combination arm include 
fatigue (32.6% vs11.4%), febrile neutropenia(21.7% vs 6.8%), and stomatitis (6.5% vs 0%).
Thisstudy allowed the use of growth factors at the discretion of the investigators.  However, the 
observed incidence of febrile neutropenia in the first cycle and an apparent limited use of 
prophylactic growth factor use suggest that practice patterns did not fully appreciate the 
frequency of febrile neutropenia with docetaxel use in this setting.  Per current American Society 
of Clinical Oncology (ASCO) guidelines(Smith et al. 2006), use of granulocyte
colony-stimulating factor (G-CSF)is recommended prophylactically when the anticipated 
frequency of febrile neutropeniaapproximates 20%.  These observations support prophylactic 
use of G-CSF in subsequent studies of this regimen for urothelial carcinoma, and it is anticipated 
that this intervention could mitigate the risk of febrile neutropenia and related 
infection-associated AEs such as, pneumonia, cough,or sepsis.

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5.4.3.
Dose Rationale
Single-agent dose regimens of every-2-week (6-10 mg/kg) and every-3-week (15-20 mg/kg) 
were evaluated in a dose-ranging study (Study I4T-IE-JVBN [IMCL CP12-0402]). No 
maximum tolerated dose was identified for either regimen; all dose regimens were well tolerated, 
and preliminary evidence of clinical efficacy was observed across a range of dose/schedule 
cohorts.
Two dose regimens, 8 mg/kg every 2 weeks and 10 mg/kg every 3 weeks, were selected for
subsequent Phase 2 and Phase 3 studies. These dose regimens were selected because they were
associated with pharmacokinetic (PK)profiles, suggesting target receptor saturation and 
associated with minimumdrug concentrations (serum trough levels) that exceeded those of 
DC101 associated withantitumor activity in preclinical models; preliminary activity was 
observed at and below thesedosesand schedules in Phase 1 studies.
The 10-mg/kg every-3-weekregimen was used in combination with docetaxel in StudyJCDC 
and proved to be a safe and effective regimen in patients with urothelial cancerand offers a 
favorable benefit-risk profile in patients with this disease. Thus, this dose regimen will be used 
in the current Phase 3 study.
5.4.4.
Study JVDC: Clinical Trial Rationale
Currently, there are no globallyapproved agents for thetreatment of second-line patients with 
metastatic urothelial cancer. Several agents have shown modest activitywhen tested as single-
agenttherapy, with median survival of 5 to 10 months (Yafi et al. 2011).  Combination regimens 
have shown similar median survival numbers as single agents, howeverwith more toxicities. 
Second-line treatment for advanced or metastatic urothelial (transitional cell) carcinomaremains 
a major unmet medical need.  Angiogenesis appears to be integral tothedevelopment and 
pathobiology of urothelial carcinoma, and in addition, muscle-invasive bladder cancer has been 
shown to express VEGFReceptor 2. Clinical investigations with ramucirumab,a recombinant 
human mAb that binds VEGFReceptor 2and prevents interaction of this receptor with its 
activating ligands, have resulted in fourpositive Phase 3 trials, with twoin gastric cancer, onein 
NSCLC, and onein metastatic CRC.  In a Phase 2 study in patients with urothelial carcinoma
who had disease relapse following first-linetreatment, ramucirumab plus docetaxel showed
clinically significant improvement in efficacy with an acceptable safety profile. The 
combination ofdocetaxel plusramucirumab has been administered to approximately 
1400patientsacross tumor typesin onePhase 2(JCDC) andtwoPhase 3 trials (REVEL and 
ROSE)and has been shown to be a tolerableregimen.  Therefore, this Phase 3 randomized study 
is being conducted to confirm results of the Phase 2 StudyJCDCin patients with urothelial 
carcinomawho have progressed onor after treatment withplatinum-based therapy.
More information about the known and expected benefits, risks,and reasonably anticipated AEs 
of ramucirumabmay be found in the Investigator’s Brochure (IB).  Information on AEs expected 
to be related to ramucirumabmay be found in Section 7 (Development Core Safety Information
[DCSI]) 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, 

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periodically during the course of the study, may be found in Section 6 (Effects in Humans) of the 
IB.
More detailed information about the known and expected benefits and risks of docetaxelmay be 
found in the following:  Package Insert(Taxoterepackage insert, 2013) andSection9.4.1.2.

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6. Objectives
6.1. Primary Objective
The primary objective of thisstudy is to compare the progression-free survival (PFS)of 
ramucirumab in combination withdocetaxel withthe PFS of placebo in combination with
docetaxel,in patients with locally advancedorunresectable or metastatic urothelial carcinoma
who have had disease progression onor afterone prior first-line platinum-basedchemotherapy.
6.2. Secondary Objectives
The secondary objectives of thisstudy are to compare each of the following variables between 
the treatment arms:
overall survival (OS) time
objective response rate (ORR; complete response[CR]+ partial response[PR]) and 
disease control rate (DCR)
duration of response (DOR)
safety profile
patient-reported outcome (PRO) measures (European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire-C30 [EORTC QLQ-C30] and 
EQ-5D-5Lquestionnaires)
Secondary objectives also includethe evaluation of:
the pharmacokinetic profile of ramucirumab
the immunogenicity of ramucirumab(anti-ramucirumab antibodies)
6.3. Exploratory Objectives
The exploratory objectives of thisstudy are to:
assess the change intumor sizein patients with measurable disease
examine biomarkers relevant to ramucirumab, angiogenesis, and the disease state, and to 
correlate these markers to clinical outcome

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7. Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened, only after discussion with and permission from the Lilly clinical research physician 
(CRP)/clinical research scientist (CRS)or designee.  Each time re-screening is performed, the 
individual must sign a new informed consent form (ICF)and will be assigned a new 
identification number.
Note that repeating laboratory tests during the screening period does not constitute re-screening.  
Screening laboratorytests may not be repeated more than twice in order to meet eligibility
during the screening period.  If a repeat screening laboratory value meets eligibility, it is 
recommended that the test is rechecked to confirm stability.
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 allof the following criteria:
[1] The patient has histologically or cytologically confirmed, locally advancedor 
unresectable or metastatic urothelial (transitional cell) carcinomaof the bladder, 
urethra, ureter, or renal pelvis.Patients with mixed pathology are eligible only if they 
have predominantly transitional cell tumor based on local pathology review.
[2] The patient has demonstrated disease progression while on a platinum-
containing regimen in thefirst-linesetting or within 14 months (≤14 months) 
aftercompleting the first-lineplatinum regimen.  Patients who received 
treatment with one immunecheckpointinhibitor (for example PD-1, PDL1, or 
CTLA4)regimen may have a longer interval since prior platinum-containing 
therapy(≤24 months),as noted in Inclusion Criterion [4]; such patientsare 
eligible.
[3] The patient has a life expectancy of ≥3 months, in the judgment of the 
investigator.
[4] The patient has received no more than oneprior systemic chemotherapy 
regimen in the relapsedor metastaticsetting.  Prior cytotoxic therapy in an 
adjuvant or neoadjuvant setting is not considered as a prior line of systemic 
chemotherapy in the relapsed or metastatic setting. Prior treatment with 
intravesicular chemotherapy, bacillus Calmette-Guérin (BCG), or platinum 
given as a radiation-sensitizing agent will not be considered as a systemic line 
of treatment.  Prior treatment with no more than oneprior immunecheckpoint
inhibitor is permitted and will not be considered as a line of systemic 
chemotherapy.  Patients enrolling after immunecheckpointinhibitor therapy 
must have demonstrated disease progression while on that therapy or within 
24months (≤24 months) after the last dose of that therapy.

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[5] The patient has measurable disease or nonmeasurable but evaluable disease as 
defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST 1.1) (Eisenhauer et al.2009).
[6] The patient has resolution, except where otherwise stated in the inclusion 
criteria, of all clinically significant toxic effects of prior chemotherapy, 
surgery, orradiotherapy to Grade ≤1 by National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events(CTCAE), Version 4.0 
(v4.0).
[7] The patient has an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1(Attachment 4).
[8] The patient has adequate hematologic function as defined by an absolute 
neutrophil count (ANC) ≥1.5 × 103/µL(1.5 × 109/L), hemoglobin ≥9 g/dL
(90g/L), and platelets ≥100 × 103/µL(100 × 109/L) and has not received 
blood or blood components transfusion within 2 weeks (≤2 weeks)prior to the 
laboratory test.
[9] The patient has adequate coagulation function as defined by international 
normalized ratio (INR) ≤1.5 and a partial thromboplastintime (PTT) ≤1.5 × 
upper limit of normal (ULN) if not receiving anticoagulation therapy.  Patients 
on full-dose anticoagulation must be on a stable dose of oral anticoagulant or 
low molecular weight heparin.  If on warfarin,the patient must have an INR 
≤3and have no active bleeding (defined as within 14 days [≤14 days]prior to 
randomization, excluding trace hematuria) or pathological condition that 
carries a high risk of bleeding (for example, tumor involving major vessels or 
known varices).
[10]The patient has adequate hepatic function as defined by bilirubin within 
normal limits (WNL), aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤3.0× ULN, and alkaline phosphatase (AP) ≤2.5 × 
ULN.
[11]The patient does not have:
cirrhosis at a level of Child-Pugh B (or worse)(Child and Turcotte 
1964; Pugh et al. 1973), or
cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis.  Clinically 
meaningful ascites is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.
[12]The patient has adequate renal function as defined by creatinine clearance 
>30mL/min either as measured by 24-hour urine collection or as calculated 
(for example,by Cockcroft-Gault [Cockcroft and Gault 1976] or another 
standard equation; Attachment 5).

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[13]The patient’s urinary protein is ≤1+ on dipstick or routine urinalysis; if urine 
protein ≥2+, a 24-hour urine collection must demonstrate <2g of protein in 
24hours to allow participation in the study.
[14]The patient, if female, is surgically sterile, postmenopausal*, or agrees to usea 
highly effective
†method of contraceptionduring and for 12 weeks after the 
treatment period (oral hormonal contraception alone is not considered highly 
reliable and must be used in combination with a barrier method).  The patient, 
if male, is surgically sterile or agrees to use areliable method of contraception
and to not donate sperm during and for 12 weeks after the treatment periodor 
country requirements, whichever is longer.
*A “postmenopausal woman” is a woman meeting either of the following criteria:
1. spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications during the 
amenorrhea that induced the amenorrhea (for example, oral contraceptives, 
hormones, gonadotropin-releasing hormone, antiestrogens, selective estrogen 
receptor modulators, or chemotherapy)
2. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone 
level >40 mIU/mL
†A highly effective method of contraceptionis defined as one that results in a low 
failure rate (that is, <1% per year) when used consistently and correctly, such as 
implants, injectables, combined oral contraceptives, some intrauterine contraceptive 
devices, sexual abstinence, or a vasectomized partner.  For patients using a hormonal 
contraceptive method, information regarding the product under evaluation and its 
potential effect on the contraceptive should be addressed.
[15]The patient is able to provide signed informed consent and is amenable to 
compliance with protocol schedules and testing.
[16]The patient is ≥18 years of ageor of an acceptable age to provide informed 
consent according to local regulations, whichever is older.
[17]The patientis willing to provide blood, urine,and tissue samples for research 
purposes.  Submission of blood and urinespecimens is mandatory for 
participation in this study, unless restricted per local regulations.  If prior 
archived tumor specimens are available, and unless restricted by local 
regulations,submission of archived tumor tissue is mandatory.  If an archived 
specimen is not available, submission of a newly acquired biopsy is requested 
when biopsy is safe and feasible.

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7.2. Exclusion Criteria
Patients will be excluded from the study if they meet anyof the following criteria:
[18]The patient has received more than one prior systemic chemotherapyregimen 
for metastatic disease (except as noted in Inclusion Criterion [4]).A treatment 
regimen must consist of a minimum of 2 cyclesto be considered as a prior 
regimen.
[19]The patient has received prior systemic taxane therapy for TCC of the bladder, 
urethra, ureter, or renal pelvis in any setting (neoadjuvant, adjuvant, 
metastatic).  Prior intravesicaltaxane therapy is allowedand will not be 
consideredas a prior line of systemic therapy.
[20]The patient has received more than one prior antiangiogenic agent (that is, 
bevacizumab, sorafenib, sunitinib) for TCC of the urothelium.
[21]The patient has received radiation therapy (including full-dose pelvic 
radiotherapy) within 4 weeks (≤4 weeks) prior to randomization or has not
recovered from toxic effects of the treatmentthat was given >4 weeks priorto 
randomization. Singlefraction radiotherapy for palliative bone stabilization 
within 4 weeks (≤4 weeks) prior to randomization is allowed.If any tumor 
lesion is administered radiotherapy, then it cannot be considered for response 
assessment.
[22]The patient has a history ofuncontrolled hereditary or acquired bleeding or 
thrombotic disorders.
[23]The patient has experienced a Grade ≥3 bleeding event (for example, via 
gastric ulcers, gastric varices, rectal bleeding, or gross hematuria) within 
3months (≤3 months) prior to randomization.Patients must have complete 
resolution of any prior bleeding event prior to randomization.
[24]The patient has uncontrolled intercurrent illness, including, but not limited to 
symptomatic anemia, uncontrolled hypertension(>160 mm Hg systolic and/or 
>100 mm Hg diastolic, despite antihypertensive medication), symptomatic 
congestive heart failure, unstable angina pectoris, symptomatic or poorly 
controlled cardiac arrhythmia, psychiatric illness, or any other serious 
uncontrolled medical disorders in the opinion of the investigator.
[25]The patient has experienced any arterial or venothrombotic or 
thromboembolic events, including, but not limited to myocardial infarction, 
transient ischemic attack, or cerebrovascular accident, within 6 months 
(≤6months) prior to randomization.
[26]The patient has known untreated brain metastases, uncontrolled spinal cord 
compression, or leptomeningeal disease.  (Note:  A brain scan via computed 
tomography [CT] with contrast or magnetic resonance imaging [MRI]is to be 
performed only after study eligibility is confirmed, to detect the presence of 
intracranial metastasis.)

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[27]The patient has an ongoing or active infection requiring antibiotic, antifungal, 
or antiviral therapy.
[28]The patient has known human immunodeficiency virus (HIV) infection or 
acquired immunodeficiency syndrome-related illness.
[29]The patient has received a prior autologous or allogeneic organ or tissue 
transplantation.
[30]The patient:
received chemotherapy within 21 days (≤21 days) prior to 
randomization; and/or
is currently enrolled in, or discontinued within 21 days (≤21 days) 
prior to randomization from, a clinical trial involving an 
investigational product(IP)or non-approved use of a drug or device, 
or is concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study;
and/or
was treated with antiangiogenic therapy within 28 days (≤28 days) 
prior to randomization.
[31]The patient has undergone major surgery within28 days (≤28 days) prior to 
randomizationor subcutaneous venous access device placement within 7 days 
(≤7 days) prior to randomization.
[32]The patient has had a serious nonhealing wound, ulcer, or bone fracture within 
28 days (≤28 days) prior to randomization.
[33]The patient has an elective or planned major surgery to be performed during 
the course of the trial.
[34]The patient is pregnant (confirmed within 7 days [≤7 days] prior to 
randomization by serum beta human chorionic gonadotropin [β-hCG] 
pregnancy test) or lactating.
[35]The patient has a concurrent malignancy or had another malignancy within 
5years (≤5 years) of study enrollment (with the exception of adequately 
treated non-melanomatous skin cancer, in-situ cervical cancer, other 
noninvasive carcinoma or in situ neoplasm, or localized prostate cancer with 
no evidence of biochemical or clinicalrecurrence over a minimum of 
6months[≥6 months]).
[36]The patient has an acute/subacute bowel obstruction or history of chronic 
diarrhea requiring ongoing medical intervention.
[37]The patient has a history of gastrointestinal perforation and/or fistula within 
6months (≤6 months) prior to randomization.
[38]The patient has active diverticulitis.

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[39]The patient has a known hypersensitivityto docetaxel or other drugs 
formulated with polysorbate 80.
[40]The patient has a known hypersensitivity to agents of similar biologic 
composition as ramucirumab, or other agents that specifically target VEGF.
7.3. Discontinuation
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
All randomizedpatients who discontinue, regardless of whether or not they received study drug, 
will have procedures performed as shown in the Study Schedule (Attachment 1).
Patients who are discontinued from all study drugwill have follow-up procedures performed as 
shown in the Study Schedule (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.3.1.
Discontinuation ofInadvertently EnrolledPatients
The criteria for enrollment must be followed explicitly. If the investigatoridentifies 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 CRP/CRSor designee and the investigator to determine whether it is medically 
appropriate for the patient to continue in the study, with or without study treatment.  The 
investigator must obtain documented approval from the sponsor CRP/CRSor designee to allow
an inadvertently enrolled patient to continue in the study, with or without study treatment.
7.3.2.
Discontinuation of Study Treatment
This section lists the reasons for permanent discontinuation of allstudy treatment, except as 
indicated otherwise.  For details regarding study treatment delays and dose modifications, refer 
to Section 9.4.1.
Patients will be replaced only if inadvertently enrolled and found to be ineligible.
All patients who are discontinued from all study treatment (except those patients who request 
withdrawal of consent from the study) shouldbe followed (for diseaseprogressionand/or 
survival, as applicable) until study completionor as instructed by Lilly.
After termination of allstudy therapy, the patient will be treated as clinically indicated by the 
investigator orreferring physician. All patients will be followed until resolution or stabilization 
of any study-related toxicity.

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Patients will be permanently discontinued from allstudy therapy(except as indicated otherwise)
in the following circumstances:
Enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study.
Screen failure or failure to meet enrollment criteria(refer also to Section7.3.1).
The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication;discontinuation 
from study treatmentoccurs prior to introduction of the new agent.
The investigator decides that the patient should be discontinuedfrom study treatment.
The patient or the patient’s designee (for example, parent, legal guardian, or caregiver) 
requests tobe discontinued from study treatment(this reason should not be used if there 
isclinical deterioration or an AE).
o In the event that apatient withdraws consent for studytreatment, he or she may
still enter Short-termand/or Long-termFollow-up if consent for follow-up is not 
also withdrawn.  It should be clarified with the patient and documented in the 
patient’s file whether follow-up information on tumor assessment and survival 
can be still obtained, and if so, to what extent.
The patient is significantlynoncompliant with study procedures and/or treatment.
Radiographic documentation of disease progression.
Symptomatic deterioration/clinical disease progression.
o Symptomatic deterioration sufficient to warrant discontinuation of therapy will 
not be considered a descriptor of response, but rather only a reason for stopping 
therapy.  Whenever possible, patients removed from therapy solely for 
symptomatic progression should be followed for subsequent radiographic 
progression. Response evaluation in a patient who discontinues treatment due to 
symptomatic deterioration in the absence of radiological confirmation of disease 
progressionshould be based on evaluation of target,nontarget lesions, and new 
lesions.
An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient), including any of the following:
o A Grade 3or 4 infusion-related reaction(IRR).
o A Grade 3or 4 arterial thrombotic event.
o A Grade 3or 4 venous thrombotic event that is considered to be life-threatening 
in the opinion of the investigator, or that cannot be adequately treated with 
anticoagulant therapy.  Patients with evidence of portal hypertension 
(splenomegaly, platelets <100 × 103/µL [100 × 10
9/L], or any prior history of 
variceal bleeding) who develop Grade 3or 4 venous thromboembolism will have 
study therapy discontinued.
o A Grade 4 hypertension (uncontrolled hypertension, hypertensive crisis, 
hypertensive encephalopathy).
o A Grade 3or 4 bleeding or hemorrhagic event.

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o Any event that wouldrequire study therapy to be modified by >2dose reductions 
or that necessitates 2or more consecutive missed doses of studytherapy.  In this 
case, all study therapy does not necessarily need tobe discontinued; the particular 
study drug that was responsible for such a dose modification or missed dose 
should be discontinued, and the other study drug may be continued.  In situations 
where 2(or more) consecutive doses have been missed, events related to the 
missed doses have resolved, and there is evidence of ongoing disease control, 
continuation of study therapymay be considered and must be discussed with the 
Lilly CRP/CRSor designee.
o Any study therapy-related event that is deemed life-threatening, regardless of 
grade, warrants discontinuation of that therapy and/or discontinuation from all 
therapy,if appropriate,in the opinion of the investigator.  If other identifiable risk 
factors are felt to be associated with the observed event and could be modified to 
substantially mitigate the risk of recurrence, continued therapy may be permitted 
following discussion between investigator and Lilly CRP/CRSor designee.
o Event of a gastrointestinal (GI)perforation.
o A confirmed occurrence of a GIor non-GI fistula.
o Proteinuria level is >3 g/24 hoursin the settingof nephrotic syndromeor there is 
a third occurrence of proteinuria ≥2g/24hours.
A concurrentillness or change in the patient’s condition that renders the patient 
unsuitable for further treatment, in the opinion of the investigator.
The patient becomespregnant or fails to use adequate birth control during treatment.
7.3.3. Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:
The investigator decides that the patient should be discontinued from the study.
Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).
The patient or the patient’s designee (for example, parent, legal guardian, or caregiver) 
requests that the patient be withdrawn from the study.
7.3.4. Patients Who Are Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and attempts to contact the patient are unsuccessful.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow.
Site personnel, or an independent third party, will attempt to collect the vital status (that is, alive 
or dead) for all randomized patients who are lost to follow-up, including randomized patients 
who do not receive study drug, within legal and ethical boundaries.  Site personnel, or an 
independent third party, may search public sources for vital status information.  If the patient’s 
vital status is determined, the vital status will be documented and the patient will not be 
considered lost to follow-up.

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Lilly personnel will not be involved in any attempts to collect vital status information.
7.3.5.
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 discontinuation of study site participation necessary for medical, 
safety, regulatory,ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.6.
Discontinuation of the Study
The study will be discontinued at any time if Lilly judges discontinuation of the study necessary 
for medical, safety, regulatory, ethical, or other reasons consistent with applicable laws, 
regulations, and GCP.

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8. Investigational Plan
8.1. Summary of Study Design
Study I4T-MC-JVDC is aPhase 3, global, multicenter, randomized, double-blind, placebo-
controlled trial in patients with locally advanced, or unresectable, or metastatic urothelial 
carcinoma who had disease progression onor afterone prior first-line platinum-based 
chemotherapy regimen.  Urothelial carcinomaincludes thosearising in thebladder, urethra, 
ureter, and/orrenal pelvis.
FigureJVDC.1illustrates the study design.

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a  ROW region includes countries outside the continents of Europe and North America.
b  Where visceral metastases involve the liver, lung, and/or bone.
c  Up to 4 additional cycles of docetaxel (maximum of 10 cycles total) may be 
administered with approval of the Lilly CRP/CRS or designee.  Refer to Section 9.1for 
further details regarding the number of cycles allowed for each study drug.
d  To be evaluablefor safety interimanalyses,patients must have received at least one 
dose of study therapy and have eitherstarted treatment in Cycle 3 or discontinued all 
study treatment prior to Cycle 3 due to any reasons.
Abbreviations:  CRP = (Lilly) clinical research physician; CRS = (Lilly) clinical 
research scientist; DC = discontinuation; ECOGPS= Eastern Cooperative Oncology 
Group performance status; I.V.= intravenous(ly); N = number of randomized patients; 
n=number of patients in arm; OS = overall survival; PFS = progression-free survival; 
ROW = rest of the world(geographic region stratification variable).
FigureJVDC.1.
Illustration of study design.
RANDOMIZATION (1:1)
N=524
Arm A: n=262
Ramucirumab 10 mg/kg I.V. on Day 1 of each 21-day  cycle
+
Docetaxel 75 mg/m2I.V. on Day 1 of each  21-day cycle
Patients may receive:  ≤ 6 cycles of docetaxelcand ramucirumab/placebo 
until disease progression (or until other DC criteria are met). 
Patients will be followed until the patient
's death or overall study completion, 
whichever occurs first.
Safety Interim #1: ≥100 evaluable patientsd
Stratification:
Region (North America, Europe, ROWa)
ECOG PS (0, 1) 
Visceral metastasisb(yes, no)
Arm B: n=262
Placebo 10 mg/kg I.V. on Day 1 of each 21-day cycle
+
Docetaxel 75 mg/m2I.V. on Day 1 of each 21-day cycle
Safety Interim #2: ≥250 evaluable patientsd
Primary Analysis of  Progression-Free Survival: 
331 PFS Events
Final Analysis of Overall Survival: 
382 OS Events

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Approximately 524 patientsare planned to be randomized in a 1:1 ratio to the following
treatment arms:
Arm A-ramucirumab (10 mg/kg) plus docetaxel (75 mg/m
2) on Day1 (± 3 days) of 
each 21-day cycle; n=262
Arm B-placebo (10 mg/kg volume equivalent) plus docetaxel (75mg/m2) on Day 1 
(± 3 days) of each 21-day cycle; n=262
Refer to Section 12.2.13for details on the safety interim analyses, Section 12.2.6for details on 
the primary endpoint (PFS) analysis, and Section 12.2.7for detailson the final OS analysis.
Terms used to describe the periods during the study are defined as follows:
Baseline:  begins when the ICF is signed and ends at the first study treatment (or at 
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 Continued Access 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 (any) 
study treatment.  The date of this agreement is to be reported on the case report 
form (CRF) as the Date of Discontinuation from study treatment.  Refer to 
Section 9.1for details regarding treatments administered.
o Postdiscontinuation Follow-up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue (any)studytreatment.
Short-termFollow-upbegins the day after the patient and the investigator agree 
that the patient will no longer continue (any)study treatment and lasts 
approximately 30 days(until the [30-day]Short-termFollow-up visit is 
completed).
Long-termFollow-upbegins the day after Short-termFollow-up is completed 
and continues until the patient’s death or overall study completion.  Patients who 
discontinue(all)study treatment for reasons other than disease progressionwill 
continue to undergo radiographic tumor assessments (as described in 
Section10.1)until radiographic documentation of disease progressionas defined 
by RECIST 1.1 or until overall study completion, whichever occurs first.  Patients 
will be followed for survival every 3 months (±7days) until the patient’s death or 
overall study completion, whichever occurs first.
Continued Access Period:  begins after study completion and ends at the end of trial.  
During the Continued Access Period, patients on study treatment who continue to 
experience clinical benefit and no undue risks may continue to receive study treatment 
until one of the criteria for discontinuation is met.  TheContinued Access Period includes 
Continued Access Follow-up.

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o Continued AccessFollow-up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue (any) treatment in the 
Continued Access Period and lasts approximately 30 days.
8.1.1.
StudyCompletion and End of Trial
The primary analysis will be performedwhen a minimumof 331 PFS events have been observed 
fromthe first 437randomized patients.  Iffull enrollment is not reachedat thepointwhen 
331PFS events have been observed, the primary analysis will be performedwhen full 
enrollment is reached, on the number of PFS events observed upon full enrollment from the first 
437 randomized patients.
This study will be considered complete (that is, the scientific evaluation will be complete [study
completion]) following the final analysis forOS, asdetermined by Lilly.  Note that patients will 
be followed for disease progression and/orsurvival, as applicable,until 382OS events (deaths)
have been confirmedor until study completion,as determined by Lilly.
Investigators will continue to follow the study schedule for all patients until notified by Lilly that 
study completion has occurred.  “End of trial” refers to the date of the last visit or last scheduled 
procedure for the last patient.
Upon study completion, investigators and patients may be unblinded to study treatment 
assignment.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable Continued Access Follow-up.

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Abbreviations:  OS = overall survival; PFS = progression-free survival.
Figure JVDC.2.
Study period and continued access diagram.
End of 
Trial
Study 
Completion
Patients 
on 
Treatment
Patient on Study Treatment
Study Period
Continued 
Access Perioda
Patient on 
Study 
Treatment
aLilly will notify sites when this begins and ends.  
Short-Term 
Follow-Up 
Long-Term 
Follow-Up
Patient 
Discontinues 
Study 
Treatment
Continued 
Accesss 
Follow-Up
Primary Analysis 
of PFS
Final Analysis 
of OS
Long-Term 
Follow-Up
Patient on 
Study 
Treatment
Short-Term 
Follow-Up 
Patient 
Discontinues 
Study 
Treatment
Last visit/
scheduled 
procedure for 
last 
patient
Patient 
Discontinues 
Study 
Treatment

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8.1.2.
Continued Access Period
The Continued Access Period will apply to this study only if at least onepatient is still on study 
treatment when study completion occurs.
After study completion, all patients who are on study treatmentand who are eligible for 
continued access will be unblinded.  Patients receiving study treatment and experiencing ongoing 
clinical benefit and no undue risks may continue to receive study treatment in the Continued 
Access Period until one of the criteria for discontinuation is met(Section7.3).  During the 
Continued Access Period, placebo will no longer be administered;the decision to permit
crossover or not will be made by Lilly after the final analysis of OS is completed.  First, written 
notification will be sent to the sites specifying the outcome of this decision.  Then, each patient 
will be evaluated individually (case-by-case basis) for eligibility of adding ramucirumab
treatment to docetaxel, following discussion with Lilly.  Lillywill notify investigators when the 
Continued AccessPeriod begins.
Patients who are in Short-termFollow-up when the Continued Access Period begins will 
continue in Short-termFollow-up until the (30-day)Short-termFollow-up visitis completed.  
Long-termFollow-up does not apply.
Patients who are in Long-termFollow-up when the Continued Access Period begins will be 
discontinued from Long-termFollow-up.
During the Continued Access Period, all AEs, SAEs, and exposure to study drugwill be reported 
on the CRF.  Serious adverse events will also be reported to Lilly Global Patient Safety (see 
Section10.3.1.1).  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.  Blood samples for PK and immunogenicity analysis will be collected 
in theevent of an IRRthat occursduring the Continued Access Period.
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly 
will not routinely collect the results of these assessments.

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8.2. Discussion of Design and Control
A randomized, controlled design is being used in this study.  Randomization minimizes 
systematic bias in the selection and assignment of patients to studytreatmentand provides 
justification for inferential statistical methods to be used on data from this study.  Using an 
appropriate concurrent control arm enables direct statistical estimation of benefits and harms due 
to study treatmentand minimizes biasin the assessment and interpretation of observed treatment
effects.Patients will be stratified for differences in factors thought to be associated with clinical 
outcomes to further reduce the potential for bias and improve the power of the analyses. 
Assessment of bias is further minimized by the use of a double blind and placebo control.
Investigational treatment administration in this study is doubleblind; that is, patients, 
investigational sites, and the sponsor study team do not have immediate access to treatment 
assignments for any patients.  This design feature minimizes potential bias due to knowledge of 
patient’s treatment during evaluation of study endpoints, at the patient level or aggregated across 
patients.

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9. Treatment
9.1. Treatments Administered
Patients in this study will be randomly assigned 1:1 to receive one of the following treatments:
Arm A(experimental arm)-ramucirumab (10 mg/kg)intravenously (I.V.)plus 
docetaxel (75 mg/m
2) I.V.on Day 1 (± 3 days) of each 21-day cycle
Arm B(comparator arm)-placebo (10 mg/kg volume equivalent)I.V.plus docetaxel 
(75 mg/m
2) I.V.on Day 1 (± 3 days) of each 21-day cycle
Following necessary premedication (Section 9.1.1), patientswill receive the treatment regimen 
shown in Table JVDC.1, in the order shown in the table, according to the study arm to which 
they wereassigned.
Treatment (that is, the Study Treatment Period) will continue until there is radiographic 
documentation of disease progression, toxicity or intolerance requiring cessation, protocol 
noncompliance, or withdrawal of consent.  Provided no prespecified discontinuation criteria have 
been met for a given patient(see Section7.3), the following duration of treatment for each study 
drug appliesfor that patient:
Treatment withdocetaxel may continue for up tosix 21-day cycles; further cycles of 
docetaxel (up to 4 additional cycles [maximum of 10 cycles total]) may be administered 
if adequate disease response(thatis, stabledisease [SD] or better [PR, CR],based on the 
investigator’s assessment)is observed and with approval of the Lilly CRP/CRS or 
designee.
Treatment with ramucirumabor placebo (monotherapy)may continue until at least one 
discontinuation criterion is met.
No other anticancer therapy, including chemotherapy,is permitteduntil radiographic 
documentation of disease progression, except as allowed in the protocol.Once a patient has 
demonstrated disease progressionand isin postdiscontinuationfollow-up,he/shemay receive 
other anticancer treatmentper investigator discretion.

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Table JVDC.1.
Treatment Regimensand Dosing Schedule
All treatments to be administered in the order shown in this table.
Combination Therapy-Up to six21-daycycles
aof the following:
Drug
Starting Doseb
Time for Administration
Arm A(experimental arm)
Ramucirumab
10 mg/kgI.V. infusion
Administered over approximately 60minutes on 
Day1 of each 21-daycycle.
Docetaxelc
75mg/m2I.V. infusion
Administered over 60minutes on Day1of each 
21-daycycle.
d
Arm B(comparator arm)
Placebo
10 mg/kg volume equivalent I.V. 
infusion
Administered over approximately 60 minutes on 
Day1 of each 21-day cycle.
Docetaxelc
75mg/m2I.V. infusion
Administered over 60minuteson Day 1 ofeach 
21-day cycle.
e
Monotherapy as follows, after patient has DCed treatment with docetaxele:
Drug
Starting Doseb
Time for Administration
Arm A
Ramucirumab
10 mg/kgI.V. infusion
Administered over approximately 60 minutes on 
Day1 of each 21-day cycle.
Arm B
Placebo
10 mg/kg volume equivalent I.V. 
infusion
Administered over approximately 60 minutes on 
Day1 of each 21-day cycle.
Monotherapy as follows, after patient has DCed treatment with ramucirumab/placebo
a:
Drug
Starting Doseb
Time for Administration
Arm A
Docetaxelc
75mg/m2I.V. infusion
Administered over 60 minuteson Day1 of each 
21-day cycle.
Arm B
Docetaxelc
75mg/m2I.V. infusion
Administered over 60 minutes on Day1 of each
21-day cycle.
Abbreviations:  CR = complete response; CRP = clinical research physician; CRS = clinical research scientist; 
DCed= discontinued; IRR = infusion-related reaction; I.V.=intravenous(ly); PR = partial response; SD = stable 
disease.
a Provided no prespecified discontinuation criteria have been met for a given patient, treatment with docetaxel may 
continue for up to six 21-day cycles; further cycles of docetaxel (up to 4 additional cycles [maximum of 
10cycles total]) may be administered if adequate disease response(thatis, SDor better [PR, CR],based on the 
investigator’s assessment)is observed and with approval of the Lilly CRP/CRS or designee.
b Refer toSection9.4.1for details regarding dose modifications.
c Taxoterepackage insert,2013.
d IRRsmay occur during or following administration of ramucirumab (placebo).  See Attachment 8for a definition 
of IRRs.  For the first and second treatment cycles:  Docetaxel administration should start only afterat least a
1-hour observation period(after ramucirumab/placebo administration).  If there is no evidence of an IRRduring 
the initial 2 infusions of ramucirumab/placebo (that is, first and second treatment cycles), then no observation 
period is required for subsequent (third and later) treatment cycles, and docetaxel can be administered 
immediately after the infusion of ramucirumab/placebo.
e Treatment with ramucirumab/placebo may continue until at least one discontinuation criterion is met.

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Refer to Section 9.4for the selection and timing of doses.
The investigator or his/her designee is responsible for the following:
explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the site personnel,
verifying that instructions are followed properly, 
maintaining accurate records of study drug dispensing and collection, and returning all 
unused medication to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinicaltrial materials.
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
Per ASCO guidelines(Smith et al.2006) and based on the observed rates of febrile neutropenia 
in both arms of the Phase 2studyand in prior studies with single-agent docetaxel in urothelial 
cancer(McCaffreyet al.1997), the use of colony-stimulating factors (CSFs)as primary 
prophylaxis (first and subsequent-cycle use)is recommended in patients randomized to either 
arm of StudyJVDC.
9.1.1.1. Premedication for Ramucirumabor Placebo
Premedication is required for all patients prior to each infusion of ramucirumabor placebo.  
Recommended premedication agents include histamine H1 antagonists such as diphenhydramine 
hydrochloride (or equivalent).  Additional premedication may be provided at the investigator’s
discretion.  All premedication administered must be adequately documented in the CRF.
9.1.1.2. Premedication for Docetaxel
Sites should consult the manufacturer’s instructions for docetaxel (Taxoterepackage insert, 
2013) for complete prescribing information (including warnings, precautions, contraindications, 
and adverse reactions) and follow institutional procedures for the administration of docetaxel.  
Patients should be premedicated with corticosteroids such as dexamethasone 16 mg/day (for 
example, 8 mg twice a day) for 3 days starting 1 day prior to each docetaxel infusion to reduce 
the severity of fluid retention and hypersensitivity reactions.  Additional antiemetic 
premedication may be employed at the discretion of the investigator.  All premedication 
administered must be adequately documented in the CRF.
9.1.2. Study Drugs
9.1.2.1. Ramucirumab or Placebo
Patients will receive ramucirumabby I.V. infusion at a dose of 10 mg/kg(or placebo at a dose of 
10 mg/kg volume equivalent) on Day 1 of each21-daycycle, in the absence of disease 
progression or other discontinuation criteria.

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Ramucirumab is compatible with common infusion containers. The use of a low protein binding 
0.22-micron in–line filter is required.  Based on the calculated volume of ramucirumab, add (or 
remove from pre-filled [with 0.9% normal saline] I.V infusion container) a sufficient quantity of 
sterile normal saline (0.9% weight/volume) to the container to make the total volume 
250mL. For dose volumes greater than 250 mL, the addition of sterilenormal 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 via infusion pump in approximately 
60 minutes.The infusion rate should not exceed 25 mg/minute.Infusions of durationslonger 
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 a prior 
ramucirumab IRR; refer to Attachment 8for definitions of IRRs); 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.
Aseptic technique is to be used when preparing and handlingramucirumab (or placebo)for 
infusion.  Different drug product lots must not be mixed in a single infusion.  Refer to the 
pharmacy dispensing manual and the ramucirumab IB for detailed information on reconstitution, 
infusion compatibility, infusion, storage, and accountability of ramucirumab (or placebo).
Ramucirumab (or placebo) drug product: The drug product must be stored under refrigeration at 
2°C to 8°C (36°F-46°F) with protection from light.  DO NOT FREEZE OR SHAKE 
RAMUCIRUMAB OR PLACEBO.  Stability studies have demonstrated that the drug product 
can withstand transient excursion to room temperature without adverse effect; however, storage 
at this temperature is not recommended.
Prepared ramucirumab (or placebo) for infusion:  Chemical and physical in-use stability for the 
prepared ramucirumab (or placebo) drug product has been demonstrated for up to 24hours 
below 25°C (77°F).  However, it is recommended that the prepared drug product be used 
immediately in order to minimize the risk of microbial contamination.  If not used immediately, 
the prepared ramucirumab (or placebo) solution must be stored for no more than 24 hoursat 2°C 
to 8°C (36°F-46°F)(refrigeration) or no more than 4 hours if held at room temperature (below 
25°C [77°F]).  DO NOT FREEZE OR SHAKE PREPARED RAMUCIRUMAB (OR 
PLACEBO)FOR INFUSION.
CAUTION: IRRsmay occur during or following ramucirumab(or placebo)administration.  
Refer toAttachment 8for definitions of Grade 3 and 4 IRRs.  During theadministration of 
ramucirumab(or placebo), patients should be in anarea with resuscitation equipmentand 
treatments necessary for advanced life-support and cardiopulmonary resuscitation,such as 
bronchodilators, vasopressor agents (for example, epinephrine), oxygen, glucocorticoids,
antihistamines, I.V. fluids, etc. A 1-hour observation period is required after the administration
of the first and second doses of ramucirumab(or placebo).Docetaxel administration should start 
only after this observation period.  If there is no evidence of an IRRduring the initial 2 infusions 
of ramucirumab(or placebo)(that is, first and second treatment cycles), then no observation 
period is requiredfor subsequent (third and later) treatment cycles, and docetaxel can be 

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administered immediately after the infusion oframucirumab (or placebo). In the event an IRR
occurs thereafter, the 1-hour observation should be reinstituted.
9.1.2.2. Docetaxel
Docetaxelwill be administered at a dose of75mg/m2I.V. over 60 minuteson Day 1 of each 
21-daytreatment cycle, in the absence of disease progression or other discontinuation criteria.  
Refer to Section 9.1for details regarding the maximum number of cycles of docetaxel permitted.
Aseptic technique is to be used when preparing and handlingdocetaxel.
A commercial preparation of docetaxelwill be used and should be prepared and administered
according to the manufacturer’sinstructions. Investigators should consult the approved 
docetaxelpackage insert (Taxoterepackage insert,2013) for complete prescribing information, 
and follow institutional procedures for the administration of docetaxel.
9.2. Materials and Supplies
Ramucirumabwill be provided by Lilly.  Commercialdocetaxel will be used.Clinical trial 
materials will be labeled according to the country’s regulatory requirements.
9.2.1.
Ramucirumab Drug Product or Placebo
Ramucirumab drug product is a sterile, preservative-free solution for infusion of ramucirumab 
drug substance formulated in an aqueous solution at aconcentration of 10mg/mL (500mg/50-
mLvial).  The buffer contains 10mM histidine, 75mM sodium chloride, 133mM glycine, and 
0.01%polysorbate 80.  The pH is 6.0.
Placebo drug product is a sterile, preservative-free solution for infusion containing histidine 
buffer in a 50-mL vial to mimic the ramucirumab drug product container and closure.  The buffer 
contains10mM histidine, 75mM sodium chloride, 133mM glycine, and 0.01% polysorbate 80.  
ThepH is 6.0.
All excipients used for the manufactureof ramucirumabdrug product(and placebo) are of 
pharmacopeial grade. No animal-derivedcomponents are used inthe manufacture of 
ramucirumab drug productexcipients.
9.2.2.
Docetaxel
A commercial preparation of docetaxelwill be used in this study, and will bepackaged, labeled,
and stored according to manufacturer standardsand according to the country’s regulatory 
requirements, if supplied by the sponsor.
9.3. Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomly assigned to receive either 
ramucirumab plus docetaxel (ArmA[experimental arm])or placeboplus docetaxel (Arm B
[comparator arm])within 24 to 72 hours prior toVisit 1(Day 1, Cycle 1).Every attempt should 
be made to randomize the patient as close as possible to Day 1 of Cycle 1 and not morethan 
72hours prior to Day 1.

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Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive Web response system (IWRS).
Randomization will be stratified by: geographic region(North America,Europe, orrest of the 
world);ECOG performance statusat baseline(0 or 1);and visceral metastasis (yesor no),where 
visceral metastases involve the liver, lung, and/or bone. Thechosen stratificationfactors have 
been identified as importantadverse prognostic factorsor regional considerations that could 
affectefficacy in this disease. Randomizationwill be performed separately within each of the 12
strata (or cells) defined by all combinations ofthese 3variables.
9.4. Selection and Timing of Doses
Local laboratory values will be used to determine the patient dose and/or dose adjustments.
A cycle is defined as an interval of 21 days (a delay of the start of a cycle due to holidays, 
weekends, bad weather, or other unforeseen circumstances will be permitted up to 3days and not 
counted as a protocol deviation).
The actual doses of ramucirumab/placebo administered will be determined by measuring the 
patient
's weight in kilograms at the beginning of each cycle.  If the patient’s weight does not 
fluctuate by more than 10% from the weight used to calculate the prior dose, the dose will not 
need to be recalculated.
The actual doses of docetaxeladministered will be determined by calculating the patient
's body 
surface area (BSA)at the beginning of each cycle.  If the patient’s weight does not fluctuate by 
more than 10% from the weight used to calculate the prior dose, the BSA will not need to be 
recalculated.
For the first and second treatment cycles, docetaxel administration should start only after at least 
a 1-hour observation period after ramucirumab or placebo administration.  If there is no evidence 
of an IRRafter theramucirumabor placeboinfusion during the first and second treatment cycles, 
then no observation period is required for subsequent (third and later) treatment cycles, and 
docetaxel can be administered immediately after the infusion of ramucirumab or placebo.
A patient may continue to receive docetaxeluntil he or she has received a maximum of 6cycles 
or until he or she meets at least oneof the specifiedreasons for discontinuation (as described in 
Section7.3); further cycles of docetaxel (up to 4 additional cycles [maximum of 10 cycles total]) 
may be administered if adequate disease response(that is, SDor better [PR, CR],basedon the 
investigator’s assessment)is observed and with approval of the Lilly CRP/CRS or designee.  A 
patient may continue to receive ramucirumab or placebo (monotherapy)until he or she meets at 
least oneof the specified reasons for discontinuation (as described in Section7.3).
Study treatmentwill be administered as described in Section9.1.

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9.4.1. Dose Adjustments and Delays
Treatment for thefirst cycle should commence only if all the inclusion and exclusion criteria are 
met. For subsequent cycles, dose delay/modification is permitted as described in sections 
specific for ramucirumab/placebo(Section 9.4.1.1) or docetaxel (Section 9.4.1.2).
Ramucirumab/placebo dose modifications are permanent; no dose escalations are allowed after 
dose reduction.
Ramucirumab/placebo therapy should continue as scheduled if there is a delay or discontinuation 
of docetaxel. Likewise, if there is a delay or modification of ramucirumab/placebo due to 
toxicity, treatment with docetaxel can continue as scheduled.
9.4.1.1. Dose Modifications for Ramucirumab/Placebo
Table JVDC.2presents the dose reduction schedule for ramucirumab/placebo.
Table JVDC.2. 
Ramucirumab/Placebo Dose Reduction Schedule
Starting Dose
Dose Level -1
Dose Level -2
10 mg/kg
8 mg/kg
6 mg/kg
No dose reduction is required for the first instance of reversible, Grade 3 or 4 non-life-
threatening toxicitythat is considered at least possibly related to treatment,provided that the AE
recovered to Grade≤1or pretreatment levelwithin the same treatment cycle without treatment 
interruption. However, if the eventrequired treatment interruption or delay or in the event of a 
second instance of the event, upon recovery (Grade ≤1or pretreatmentlevel),the dose should be 
reduced by one level(Table JVDC.2). Dose reductions may be warranted if worsening of 
symptoms or laboratory values is clinically significant in the opinion of the investigatorand after 
discussion and approval of the Lilly CRP/CRSor designee.  Dose adjustments or delays are not 
required for Grade ≤2 alopecia, fatigue, or peripheral neuropathy.
If a toxicity related to ramucirumab/placebo does not resolve in the same treatment cycle, the 
administration of ramucirumab/placebo can be delayed for up to 42 days (2 cycles). If the 
toxicity does not resolve within 42 days, ramucirumab/placebo will be discontinued.When 
restarting ramucirumab/placebo, an attempt should be made to resynchronize administration with 
docetaxel (that is, at Day 1 of the next normally scheduled cycle).If clinically appropriate, the 
investigator can delay all treatment components up to a maximum of 7 days to allow 
synchronized administration of bothagents.
A total of up to 2 dose-level decreases are allowed during the study;the patient needs to be 
discontinued from treatment if any further dose reduction beyond 2dose-level decreasesis 
needed.
The preceding information inthis section pertains only to general dose modificationsfor 
ramucirumab/placebo.The following information (in this section and the following subsections) 
pertainstodose modificationsand delays for and management of AEs of concern, which may or 
may not be associated with ramucirumab therapy,including the following:

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IRR
Hypertension
Arterial and venous thromboembolic events
Bleeding(hemorrhagic) events
Gastrointestinalperforation
Fistula
Proteinuria
Congestive heart failure
Surgery and impaired wound healing
Liver injury/failure
Reversible posteriorleukoencephalopathy syndrome (RPLS)
Table JVDC.3presentsramucirumab/placebo dosing guidelines for managinginfusion reactions, 
hypertension, and proteinuria, which are common ramucirumab toxicities.

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Table JVDC.3.
Ramucirumab/Placebo Dosing Guidelines for ManagingInfusion 
Reactions, Hypertension, and Proteinuria
Event and Gradea
Specifics
Ramucirumab/Placebo Dosing Guidelines, including Dose 
Reductions and Delays
IRR Events
Grade 1 or 2
Reduce the infusion rate by 50%for the duration of the 
infusion and for all future infusions.
If the patient has a second Grade 1 or 2 IRR, premedicate 
(also) with dexamethasone (or equivalent) and 
acetaminophen.
Grade 3 or 4
Discontinue ramucirumab/placebo
Hypertension
Grade1 
(hypertension 
controlled with 
medications)
10mg/kg (full dose) without interruption
Grade2 or 3 
(hypertension [non-
life-threatening])
Resolution to Grade <2 
within 3weeks
Delay ramucirumab/placeboadministration.  Administer 
10mg/kg (full dose) once hypertension is controlled with 
medications and is Grade <2 within 3 weeks.
Resolution to Grade <2 
within 3to 6 weeks
Delay ramucirumab/placebo administration.  Administer 
ramucirumab/placebo at 8 mg/kg if hypertension is Grade <2 
by the fourth week.  Administer ramucirumab/placebo at 
6mg/kg if hypertension is Grade <2 by the sixth week.  
Discontinue ramucirumab/placebo if blood pressure does not 
improve to Grade <2 by the sixth week (42 days), despite 
>2oral agents.
Grade4 (uncontrolled 
hypertension, 
hypertensive crisis, 
hypertensive 
encephalopathy)
Discontinue ramucirumab/placebo.

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Event and Gradea
Specifics
Ramucirumab/Placebo Dosing Guidelines, including Dose 
Reductions and Delays
Proteinuria
Dipstick(or routine 
urinalysis)<2+b
Administer baseline or full previous dose of 
ramucirumab/placebo without interruption.
Dipstick(or routine 
urinalysis)=2+b
Administer full previous dose of ramucirumab/placebo 
without interruption.
Perform a 24-h urine collection within 3d prior to next dose 
of ramucirumab/placebo.
If <2 g/24 h, administer unchanged dose of 
ramucirumab/placebo.
If ≥2 g/24 h, then follow dose adjustment based on 
24-h collection (belowin this table).
Dipstick(or routine 
urinalysis)>2+b
Delay ramucirumab/placebo dose up to 21 days.
Perform a 24-h urine collection within 3d prior to the next 
planned dose of ramucirumab/placebo.
If <2g/24 h, administer unchanged dose of 
ramucirumab/placebo.
If ≥2 g/24 h, then follow dose adjustment based on 
24-h collection (below in this table).
24-h Urine collection:  
≥2 g/24 hb
First instance
8 mg/kg once urinary protein returns to <2 g/24 h
Second instance
6 mg/kg once urinary protein returns to <2 g/24 h
Third instance
Discontinue ramucirumab/placebo(if a third dose reduction 
is required)
24-h Urine collection:  
>3g/24 hin the 
setting of nephrotic 
syndromeb
Discontinue ramucirumab/placebo
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction; 
NCI= National Cancer Institute.
a NCI-CTCAEv4.0 (CTEP2009).
b A dipstick test (or routine urinalysis) for proteinuria should be performed prior to each infusion of 
ramucirumab/placebo.  If both dipstick (or routine urinalysis) and 24-hour tests are performed, the results of 
24-hour collection should be used for clinical decision-making.
9.4.1.1.1. Infusion-Related Reactions
Any treatment-related, infusion-related reactions are defined according to the NCI-CTCAE v4.0 
definition (section “General disorders and administration site conditions”).  Symptoms occurring 
during or following infusion of ramucirumab/placebomay also be defined according to AE 
categories such as allergic reaction, anaphylaxis, or cytokine release syndrome (NCI-CTCAE, 
v4.0 section “Immune system disorders”).  In the setting of symptoms occurring during or 
following infusion of ramucirumab/placebo, investigators are encouraged to use the AE term 
“infusionrelated reaction” and any additional terms (including those not listed here) that best 
describe the event.  These reactions should be graded as shown inAttachment 8.

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As with other mAbs, IRRs were reported in clinical trials with ramucirumab, with the majority of 
events occurring during or following a first or second ramucirumab infusion.  It is thus required 
that patients are premedicated prior to each administration of ramucirumab/placebo.  
Recommended agentsinclude histamine H1 antagonists such as diphenhydramine hydrochloride.  
Monitor patients during the infusion for signs of hypersensitivity reactions with resuscitation 
equipment readily available.  Symptoms included rigors/tremors, back pain/spasms, chest pain 
and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.  In severe cases, 
symptoms included bronchospasm, supraventricular tachycardia, and hypotension.
Reduce the infusion rate of ramucirumab/placeboby 50% for Grade 1 or 2 IRRs.  For patients 
who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone 
(or equivalent) and acetaminophen prior to each ramucirumab/placeboinfusion.
Immediately and permanently discontinue ramucirumab/placebofor Grade 3 or 4 IRRs.
9.4.1.1.2. Hypertension
An increased incidence of severe hypertension was reported in patients receiving ramucirumab 
as compared with those receivingplacebo.  In most cases, hypertension was controlled using 
standard antihypertensive treatment.
Preexisting hypertension should be controlled before starting ramucirumab/placebotreatment.  
Monitoring of blood pressure (BP)is recommended during therapy.
Temporarily suspend ramucirumab/placebofor severe hypertension until controlledwith medical 
management.  Permanently discontinue ramucirumab/placeboif medically significant 
hypertension such as hypertensive crisis, malignant hypertension, or hypertensive 
encephalopathy occurs or cannot be controlled with antihypertensive therapy.
Patients whose hypertension is poorly controlled for >4 weeks (>160mmHg systolic or 
>100mm Hg diastolic) despite appropriate oral medication (>2oral agents at maximum tolerated 
dose) is considered refractory.  The patient will be discontinued from ramucirumab/placebo.  
Treatment with docetaxel may be continued, if appropriate in the opinion of the investigator.
9.4.1.1.3. ThromboembolicEvents
9.4.1.1.3.1. Arterial Thromboembolic Events
Serious, sometimes fatal,arterial thromboembolic events(ATEs), including myocardial 
infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, have been reported in 
clinical trials.  Permanently discontinue ramucirumab/placeboin patients who experience a 
severeATE.
9.4.1.1.3.2. Venous Thromboembolic Events
Venous thromboembolic events(VTEs) are associated with cancer; however, the incidence of 
VTEslikely varies depending on the type of cancer, stage, and intensity of imaging.  
Additionally, VTEshave been associated with some antiangiogenic therapy, although the 
incidence varies depending on the type of therapy, use of concomitant chemotherapy agents, and 

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specific disease state.  VTEshave been reported from clinical studies investigating ramucirumab, 
particularly in the context of metastatic disease or in regions adjacent to implanted venous access 
devices.
Most VTEslack early warning signs; therefore, awareness and prompt treatment is important, 
especially in those patients with risk factors and/or previous history of VTEs(Chen and Cleck 
2009; Suter and Ewer 2013).
Ramucirumab/placebotherapy should be discontinued in the event of any Grade 3or 4 VTEthat 
is considered by the investigator to be life-threatening or symptomatic and not adequately treated 
by anticoagulation therapy.  At the investigator’s discretion, ramucirumab/placebotherapy 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/placeboshould also be discontinued in the setting of a deep vein thrombosis or 
pulmonary embolism that occurs or intensifies while the patient is receiving therapeutic 
anticoagulation therapy.
9.4.1.1.4. Bleeding (Hemorrhagic) Events
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding.  Severe GI hemorrhages, including fatal events, have been reported in patients with 
gastric cancer treated with ramucirumab in combination with paclitaxel.
Permanently discontinue ramucirumab/placeboin patients who experience Grade 3 or 4 
bleeding.
9.4.1.1.5. Gastrointestinal Perforation
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of GI 
perforations.  Permanently discontinue ramucirumab/placeboin patients who experience GI 
perforations.
9.4.1.1.6. Fistula
Gastrointestinal and non-GI fistula formation have been associated with other antiangiogenic 
agents, including bevacizumab and sunitinib (Kamba and McDonald2007).  Some fistulas can 
be resolved with surgical procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and Cleck 
2009).
Patients may be at increased risk for the development of fistula when treated with ramuci
rumab. 
Ramucirumab/placebotreatment should be discontinued in patients who develop fistula.
9.4.1.1.7. Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGF Receptor 2 pathway.  
Proteinuria has been associated with ramucirumab in clinical studies.  The majority of events 
were Grade 1or 2.

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If, while on ramucirumab/placebo therapy, a patient has proteinuria >2+ per a dipstick or routine 
urinalysis test, delay ramucirumab/placebo administrationup to 21 daysand perform a 24-hour 
urine collectionwithin 3 days prior to the next planned dose of ramucirumab/placebo.  If the 
protein level is <2g/24 hours, the patient will continue on ramucirumab/placebo therapy at the 
same dose.
If the dipstick is 2+, administer full previous dose of ramucirumab/placebo without interruption.  
Perform a 24-hour urine collection within 3 days prior to the next dose of ramucirumab/placebo. 
If the proteinlevel is<2g/24 hours,administer unchanged dose of ramucirumab/placebo. If the 
protein level is≥2g/24 hours,perform a 24-hour urine collection prior to the next planned dose 
of ramucirumab/placebo.  Ramucirumab/placebo treatment will resume at a reduced dose level 
(8mg/kg) once the protein level returns to <2g/24hours.  A second dose reduction of 
ramucirumab/placebo to 6mg/kg is permittedin case of a second instance ofproteinuria ≥2 g/24 
hours.  The patient will be discontinued from ramucirumab/placebo treatment if the protein level 
is >3 g/24 hoursin the setting of nephrotic syndromeorif there is a third occurrence of 
proteinuria ≥2 g/24 hours.
9.4.1.1.8. Congestive Heart Failure
An increased risk of congestive heart failure (CHF)has been associated with some 
antiangiogenic therapeutic agents, particularly in patients with metastatic breast cancer 
previously treated with anthracyclines or with other risk factors for CHF, including prior 
radiotherapy to the left chest wall.  A small number of CHF events (including fatal) were also 
reported in patients who had received ramucirumab after prior treatment with anthracyclines in 
the Phase 2 and Phase 3 studies.
While the mechanism of action is currently unknown, based on the safety data received to date,it 
is likely that treatment with ramucirumab enhances the cardiotoxicity associated with 
mitoxantrone and has the potential to enhance cardiotoxicity of other agents within the 
anthracycline/anthracendione class of chemotherapy medications.
Patients with risk factors should be closely monitored for signs and symptoms of CHF.
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease,such as preexisting coronary artery disease or CHF.  Patients with symptomatic CHF, 
unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia should not be 
enrolled in clinical trials with ramucirumab.  Ramucirumab/placeboshould be discontinued in 
the event of any Grade3or 4 events consistent with CHF.
9.4.1.1.9. Surgery and Impaired Wound Healing
The impact of ramucirumab has not been evaluated in patients with serious or non-healing 
wounds.  In a study conducted in animals, ramucirumab did not impair wound healing.  
However, since ramucirumab is an antiangiogenic therapy and may have the potential to 
adversely affect wound healing, ramucirumab treatment should be withheld for at least 4 weeks 
prior to scheduled surgery.  Note: Central venousline replacement, such as a Hickman line, 

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should not be considereda significant surgery and would not require discontinuation of 
ramucirumab.
If a patient develops wound healing complications during therapy, temporarily discontinue 
ramucirumab/placebountil the wound is fully healed.  Should the wound persist beyond 2 cycles 
(42days*), permanently discontinue ramucirumab/placebo.
* This 42-day period is approximate and begins on the day that the next cycle of 
ramucirumab/placeboshould have been administeredbut was withheld specifically for toxicity.
9.4.1.1.10.Liver Injury/Liver Failure
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  Patients withthe following conditions should not 
be enrolled in clinical trials with ramucirumab: 1)cirrhosis at a level of Child-Pugh Class B (or 
worse),or2)cirrhosis (any degree) and a history of hepatic encephalopathy or clinically 
meaningful ascites resulting from cirrhosisor hepatorenal syndrome.  “Clinically meaningful 
ascites” is defined as ascites resulting from cirrhosis and requiring ongoing treatment with 
diuretics and/or paracentesis.
Ramucirumab/placeboshould be discontinued in the event of any new occurrence of hepatic 
encephalopathy and/or hepatorenal syndrome resulting from liver cirrhosis.
9.4.1.1.10.1.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 includegeneralized 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 (MRI) 
represents the most reliable method for the diagnosis (Lee et al. 2008).  Clinicalsymptoms and 
MRI abnormalities usually recover within days to weeks with proper management, although 
permanent neurologic dysfunction has been reported (Hinchey et al. 1996; Tajima et al. 1999; 
Garg 2001; Lee et al. 2008).
Across the ramucirumab clinical program, 2 cases of RPLS have been reported.  Both cases 
occurred in the double-blind, randomized, placebo-controlled Phase 3 Study I4T-MC-JVBB 
(IMCL CP12-0920; RAISE) evaluating folinic acid/fluorouracil/irinotecan chemotherapy 
(FOLFIRI)in combination with ramucirumab versusFOLFIRI in combination with placebo for 
patients with metastatic CRC.One RPLS case was reported in each arm of the study (1 patient 
in the ramucirumab-plus-FOLFIRIarm and 1 patient in the placebo-plus-FOLFIRI arm).
RPLSshould be identified and treated promptly to minimize potential for permanent 
neurological damage.  Treatment encompasses careful control of blood pressure, withdrawal of 
potentially causative medication, and administration of anticonvulsant agents to those 
experiencing seizures (Stott et al. 2005).

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If the diagnosis of RPLS is confirmed, ramucirumab/placeboshould be permanently 
discontinued.
9.4.1.2. Dose Modificationsfor Docetaxel
Investigators should consult the manufacturer’s instructions for docetaxel (Taxoterepackage 
insert,2013) for completeprescribing information (including warnings, precautions, 
contraindications, and adversereactions) and follow institutional procedures for the 
administration of docetaxel.Allimplemented dose modifications are permanent. The doses 
must be modified according to thelowest hematology values and the highest degree of 
nonhematologic toxicities observed at anytime during the previous cycle. If a patient develops 
several different toxic effects and there areconflicting recommendations, the dose reduction 
required for the clinically most severe toxiceffect must be chosen.
The docetaxel dose reduction schedule ispresented in Table JVDC.4.
Table JVDC.4.
DocetaxelDose Reduction Schedule
Dose
Dose Reduction Level
Starting dose
75 mg/m2
First dose reduction
60mg/m2
Second dose reduction
50 mg/m2
Dose modifications for hypersensitivity reactions and for hematologic toxicity(Table JVDC.6)
are discussed in Sections 9.4.1.2.1and 9.4.1.2.2, respectively.

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General guidelines for docetaxel dose modifications for nonhematologictoxicity are presented in 
Table JVDC.5.
Table JVDC.5.
Docetaxel Dose Modifications for Nonhematologic Toxicity
Toxicity (NCI-CTCAE Gradea)
Docetaxel Dose
Hepatic
AST/ALT and AP WNL and
bilirubin >1×ULN
Delay treatment until recovery
bup to 3 weeks.
AST/ALT ≤2 ×ULNand
AP ≤2 ×ULN and
bilirubin WNL
No change.
AST/ALT >2 -≤5 ×ULNand
AP ≤2.5 ×ULNand
bilirubin WNL
No change.
AST/ALT >2 -≤5 ×ULNand
AP >2.5 -≤5 ×ULNand
bilirubin WNL
Delay treatment until recovery
cup to 3 weeks.
AST/ALT >5 ×ULNand
AP >5 ×ULNand
bilirubin WNL
Delay treatment until recovery
cup to 3 weeks.
AST/ALT >5 ×ULNand
AP >5 ×ULNand
bilirubin >1 × ULN
Delay treatment until recovery
b,cup to 3 weeks.
Gastrointestinal
Grade 1-4 nausea and/or vomiting
No change.  Control with adequate antiemetics.
Mucositis
Grade 1-2
Delay treatment until recovery toGrade ≤1 up to 3 weeks.
Grade 3-4
Delay treatment until recovery toGrade ≤1 up to 3 weeks, then dose 
reduce.
Fluid Retention
Grade 1
No change.
Grade 2
No change.  Treat with oral diuretics.
Grade 3-4
Treat with oral diuretics.  Delay treatment untilGrade ≤1 up to 3weeks.  
Discontinue treatment if fluid retention is not responsive to diuretic therapy.
Neurologic
Grade 1
No change.
Grade 2
With the exception of peripheral neuropathy, delay treatment until toxicity 
recovers to Grade 1, then reduce docetaxel dose.  If Grade 2 toxicity 
persists >3weeks, discontinue docetaxel.
Grade 3-4
Discontinue treatment.

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Toxicity (NCI-CTCAE Gradea)
Docetaxel Dose
Other toxicities
Grade ≤ 2
Manage symptomatically, if possible and retreat without dose reduction or 
dose delay.
Grade 3
Delay treatment until toxicity resolves to Grade ≤1 (no longer than 3 
weeks) unless baseline value was Grade>1.  If medically appropriate, 
reduce docetaxel dose.
Grade 4
Discontinue treatment.
Abbreviations:  ALT= alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; ULN = upper 
limit of normal; WNL = within normal limits.
a Toxicity grades per NCI-CTCAE v4.0.
b Bilirubin ≤1 × ULN.
c AST/ALT/AP returns to level at trial entry or better.
Patients who are discontinued fromdocetaxel will continue in the study and may continue to 
receivefurther treatmentwith ramucirumab/placebo, if the toxicity that caused discontinuation of 
docetaxel is not considered by the investigator to be related to ramucirumab/placebo.
9.4.1.2.1. Hypersensitivity Reactions
Hypersensitivity reactions may occur within a few minutes following initiation of a docetaxel
infusion. All patients should be premedicated with acorticosteroid prior to theinitiation of the 
infusion of docetaxel (see Section 9.1.1.2).
Patients should be observed closely for hypersensitivity reactions, especially during thefirst and
second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema,
hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in
patients premedicated with 3 days of corticosteroids. Hypersensitivity reactions require
immediate discontinuation of the docetaxel infusion and administration of appropriatetherapy.
Patients with ahistory of severe hypersensitivity reactions to docetaxel or to other drugs 
formulated with polysorbate 80 mustnot be given (re-challenged with)docetaxel.
Descriptions and suggested management of docetaxel hypersensitivity reactions are as follows:
Mildsymptoms:flushing or localized cutaneous reaction such as mild pruritusorrash
Consider decreasing the rate of infusion until recovery of symptoms;stay at bedside.
Then, complete docetaxel infusion at the initial planned rate.
Interruption of docetaxel is not required.

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Moderate symptoms:  any symptom not listed as mild or severe, such as generalized pruritus, 
flushing, rash, dyspnea, or hypotension with systolic BP >80 mm Hg.
Stop docetaxel infusion.
Give I.V. dexamethasone 10 mg and/or diphenhydramine 50 mg I.V.
Resume docetaxelinfusion after recovery of symptoms.
Docetaxel should be administered over 2 hours for subsequent treatments.
Ifsymptoms recur, stop the docetaxel infusion and remove patient from docetaxel 
treatment.
Severe or life-threatening symptoms(CTCAE Grade 3 or4):such as bronchospasm, generalized 
urticaria, systolic BP ≤80 mm Hg, angioedema, oranaphylaxis
Stop docetaxel infusion.
Give I.V.diphenhydramine anddexamethasone as for moderate symptoms.Add 
epinephrine or bronchodilators if indicated.
The patient shouldbe permanently discontinuedfrom docetaxel treatment.
Management of subsequent treatment cycles: The recommended pretreatment for subsequent
infusions is 50 mg diphenhydramine I.V.and 10 mg dexamethasone I.V.30 minutes prior tothe 
docetaxel infusion. This is in addition to the prescribed dexamethasone(corticosteroid 
premedication).
Patients with hypersensitivity reactions to docetaxel are at risk for recurrent reactions. For
patients who experience moderate hypersensitivity reactions, the docetaxel should be
administered over 2 hours for subsequent treatment courses in addition to premedication as noted
in Section 9.1.1.2.These patients must be informed of the potential risk of recurrent allergic 
reactions andmust be carefully monitored.
In cases of late-occurring (for example, appearance within 1 week after treatment)
hypersensitivity symptoms of a localized or generalized pruritus, symptomatic treatment may be
given (for example, oral antihistamine). Additional oral or I.V.premedication with antihistamine
may also be given for the next cycle of treatment,depending on the intensity of the reaction
observed. No dose reductions will be made in any case.
9.4.1.2.2. Hematologic Toxicity
Neutropenia (<2.0× 103/µL [<2.0× 109/L]) occurs in almost all patients treated with docetaxel 
60 to100 mg/m2,and Grade 4 neutropenia (<0.5× 103/µL [<0.5× 109/L]) occurs in 85% of 
patients given100mg/m2and 75% of patients given 60 mg/m
2. Frequent monitoring of blood 
counts istherefore essential so that the dose can be adjusted. Docetaxel should not be 
administered topatients with neutrophils <1.5× 103/µL (<1.5× 109/L).  Primary prophylaxis 
with growth factor support is recommended.

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Table JVDC.6.
Docetaxel Dose Modifications for Hematologic Toxicity
Docetaxel DoseModification
ANC on Day 1 of cycle
<1.5× 103/µL (<1.5 × 109/L)
≥1.5× 103/µL (≥1.5 × 109/L)
Nadir of ANC during last course:
CTCAE Grade 1
LLN-1.5× 103/µL (1.5 × 109/L)
No change
No change
CTCAE Grade 2
<1.5-1.0× 103/µL (<1.5-1.0 × 109/L)
Delay up to 3weeks
No change
CTCAE Grade 3
<1.0-0.5× 103/µL (<1.0-0.5 × 109/L)
Delay up to 3weeks
No change if asymptomatic, 
otherwise dose reduce
CTCAE Grade 4
<0.5× 103/µL (<0.5 × 109/L)
Delay up to 3weeks
No change if asymptomatic, 
otherwise dose reduce
Febrile neutropenia
Delay up to 3weeks
Dose reduce
Platelet count on Day 1 of cycle
<100× 103/µL (<100 × 109/L)
≥100× 103/µL (≥100 × 109/L)
Nadir of platelet count during last course:
≥25× 103/µL (≥25× 109/L)
Delay up to 3weeks
No change
<25× 103/µL (<25× 109/L)
Delay up to 3weeks
Dose reduce
Abbreviations:  ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events; 
LLN = lower limit of normal.
9.4.1.2.3. Fluid Retention
Severe fluid retention has been reported following docetaxel therapy.It is characterized by
poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage,
dyspnea at rest, cardiac tamponade, and pronounced abdominal distention (due to ascites).
Patients shouldbe premedicated with corticosteroids prior to each docetaxel administration to
reduce the incidence and severity of fluid retention (see Section9.1.1.2). When fluid retention
occurs, peripheral edema usually starts in the lower extremities and may become generalized
with a median weight gain of 2 kg.Patients with preexisting pleural effusions should be closely
monitored from the first dose of docetaxel for the possible exacerbation of the effusion.
9.4.1.2.4. Cutaneous
Localized erythema of the extremities with edema followed by desquamation has been observed.  
In case of severe skin toxicity, an adjustment in dosage is recommended.
9.5. Blinding
This is a double-blind, placebo-controlledstudy.
To preserve the blinding of the study, ramucirumab will bevisibly indistinguishable from 
placebo, unblinding will notoccur at disease progression.  Additionally, there areno anticipated 
or identified toxicitiesof ramucirumab that would potentially unblind investigators to treatment 

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assignment.  Unblinding of the study team will not occur until after the reporting database is
validated and locked for final statistical analysis(that is, final analysis of OS).
For this study, theindependent data monitoring committee (IDMC)will be permitted to access 
unblindedsafety data from the initial approximately 100and 250 evaluable patients(refer to 
Section4, Abbreviations and Definitions,for a definition of evaluablepatients).  Access to 
unblinded data/documents will be controlled by restricting access to the data/documentsto the 
IDMC.  Details of theunblinding plan willbe described in the IDMC Charter.
Interim analyses for safetywill be conductedby an IDMC,using unblinded data.  See 
Section12.2.13for further details.  Only the IDMC is authorized to evaluate unblinded interim 
safety analyses.  Appropriateteam memberswill be identified and documented (to be unblinded) 
prior to the database lock for the primary PFS analysis.  At that point, these team members will 
no longer be involved in trial management activities.  No by-patient level treatment data will be 
accessible to anyone else (for example, the rest of the study team and investigators) until the 
database lock for the final analysis of OS.  Study sites will receive information about interim 
results ONLY if they need to know for the safety of their patients.
Upon study completion (following final analysis of the OS endpoint), investigators and patients 
may be unblinded to study treatment assignment.
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 for medical management of the event.  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 
LillyCRP/CRSor designeeprior 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.  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 treatment 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/CRSor designee 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 CRF.  Concomitant medications and supportive 

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care therapies must also be documented at the time of discontinuation and at the (30-day)Short-
termFollow-up visit.
With the exceptions listedin 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.
Supportive Care
Palliative and supportive care for other disease-related symptoms and for toxicity associated with
treatment will be offered to all patients on this trial, with the intent to maximize quality of life.  
Patients will receive supportive care as judged by their treating physician.  If it is unclear 
whether a therapy should be regarded as supportive care, the investigator should consult the Lilly 
CRP/CRS or designee.
Details of interventions (for example,medications such as sedatives, antibiotics, analgesics, 
antihistamines, steroids, or erythropoietin), procedures (for example, paracentesisor
thoracentesis), or blood products (for example, blood cells, platelets, or fresh frozen serum 
transfusions) mustbe recorded on the CRFs.
Guidelines regarding the use of permittedsupportive care agents(which include, but are not 
limited to, CSFs, erythropoiesis-stimulating agents, antidiarrheal agents, antiemetic agents, and 
analgesic agents)are presented in the following sections.
Premedication and treatment of hypersensitivity(infusion-related)reactions is described in 
Section 9.4.1.1.1.
9.6.1.1. Colony-Stimulating Factors
The use of G-CSF is permitted at the discretion of the investigator based on ASCO(Smith et al. 
2006)andEuropean Society for Medical Oncology (Crawford et al. 2009)guidelines. G-CSF or 
similar agents are recommended as primary prophylaxis and are strongly recommended 
following Grade 3 or 4 neutropenia of duration >5days or following any incidence of febrile 
neutropenia (ANC<1.0×109/L with a single temperature ≥38.5°C)or a sustained temperature 
(≥38.0°Cfor >1 hour).
In addition, the use of prophylactic antibiotics such as ciprofloxacin may be considered for 
patients who may be susceptible to neutropenia or infections. Ciprofloxacin 250 to500mg 
orally daily starting on Day 2 of a cycle for 7 to 10 days may be considered.
9.6.1.2. Erythropoiesis-Stimulating Agents
The use of erythropoiesis-stimulating factors (for example, erythropoietin) is permitted at the 
discretion of the investigator based on ASCOguidelines(Rizzo et al. 2008).
9.6.1.3. Antidiarrheal Agents
In the event of Grade 3 or 4 diarrhea, supportive measures mayinclude hydration, loperamide, 
octreotide, and other antidiarrheals.If diarrhea is severe (that is, requires I.V.hydration) and 

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associated with fever or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics may be 
prescribed. Patients with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting should be considered for hospitalization for I.V.hydration and correction of electrolyte 
imbalance.
9.6.1.4. AntiemeticTherapy
The routine use of standard antiemetics,including dexamethasone plus 5-HT3antagonists (such 
as granisetron or ondansetron) as premedication and/or symptomatic management, should be 
administered as per the Multinational Association of Supportive Care in cancer and ASCO, or 
institutional guidelines.
9.6.1.5. Analgesic Agents
Theuse of analgesic agents is permitted at the discretion of the investigator.The chronic use of 
nonsteroidal anti-inflammatory drugs (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 
recommended.
9.6.2.
Prohibited Medication
No other chemotherapy, other anticancer therapy, immunotherapy, hormonal cancer therapy, 
radiation, surgery for cancer, or experimental medications will be permitted while patients are on 
study treatment.
Patients may not receive chronic antiplatelet therapy (for example, clopidogrel, ticlopidine, 
dipyridamole, and anagrelide).  Aspirin is permitted as per Section 9.6.3.
Concomitant interferon-alpha is not permitted while on study.
Palliative radiation therapy is permitted, after discussion with and agreement of the Lilly 
CRP/CRS or designee,for irradiatingsmall areas of painful metastases that cannot be managed 
adequately using systemic or local analgesics; such areasmust not constitute progressive disease 
or meet RECIST criteria for progressive disease.  Any symptomatic deterioration or clinical 
disease progression requiring, in the opinion of the investigator, other forms of specific 
antitumor therapywill be cause for discontinuation of study therapy.
9.6.3.
Restricted Therapies
Aspirin is permitted at doses ≤325 mg once daily.  Ongoing aspirin therapy at doses exceeding 
325 mg/day is not permitted.
Patients stabilized on chronic oral anticoagulation therapyare eligible,provided that the 
coagulation parameters defined in the inclusion criteria are met.

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Patients who develop venous thromboembolism during study therapy may continue study 
therapy and receive anticoagulation.  Patients who begin anticoagulation therapy during 
treatment on study must receive low-molecular-weight heparin (not oral anticoagulation).
9.6.4.
Other Study Conditions: Surgery (or Procedure) during Study 
Treatment Period
If any surgery should be required during the study (palliative surgery or medically indicated by
the investigator), the patient should undergo radiologic evaluation before surgery for
documentation of disease status. Elective,nonemergent surgery is strongly discouraged during
study participation. The time of study treatment interruption before surgery should be at least
28days following the last dose of study treatment. Patients may resume all study treatment no
less than 28 days following surgery, provided there has been adequate recovery in the opinion of
the investigator. Following surgery, radiological evaluation of disease is required prior to
resumption of study treatment.
The additional radiologic evaluation before surgery should not reset the schedule of periodic 
radiographic evaluation for disease.  Patients undergoing surgery before disease progression
should continue to be followed by imaging on their prior schedule (see Section 10.1).
9.7. Treatment Compliance
The study medication will be administered only at the investigational sites by the authorized 
study personnel.  As a result, treatment compliance is ensured.

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10.Efficacy, Health OutcomesMeasures, Safety Evaluations, 
Sample Collection and Testing, and Appropriateness of 
Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.
Study procedures related to efficacy, safety, health outcomesmeasures, sample collection and 
testingassessmentsand their timing are described in the sections below and shown in the Study 
Schedule (Attachment 1).
10.1.Efficacy Measures
Patients will be evaluated for tumor response according to RECIST 1.1, which are provided in 
Attachment 6(Eisenhauer et al. 2009).  All patients will be evaluated for response at these time 
points:
at baseline
every 6 weeks (±7 days) after randomization (regardless of treatment delays) during the 
Study Treatment Period, until disease progression ORoverall study completion OR1 
year after randomization, whichever occurs first
In addition, any patient whose disease has not progressed by 1 year after randomization (note 
that the patient may or may not still be on study treatment) will be evaluated for response at these 
time points:
every 12weeks (±7 days) from 1 year after randomization,until disease progression OR
overall study completionOR 3 years after randomization, whichever occurs first; then as 
per standard clinical practiceafter that.
Response assessments during the ongoing trial (and related treatment decisions) will be
performed by the treating investigator at the site in cooperation with the local radiologist(s).
The preferred methods of tumor measurement are computed tomography(CT; including spiral 
CT scans)and MRI.  Imaging studies include a CT scan of the chest and a contrast-enhanced CT 
scan of the abdomen and pelvis or an equivalent MRI scan.  Forany patient with bone metastasis 
at baseline, bone lesions (that is, nontarget) need to be followed by bone scan or another 
modality based on local clinical practice.
10.1.1. Efficacy Assessments at Baseline and during Study 
Treatment
Within 28days prior to randomization,baseline tumor measurement(s) will beperformed on 
each patient.  Computed tomography, including spiral CT, scans and MRI are the preferred 
methods of measurement.
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with I.V.and oral contrast).Low-dose or attenuation-corrected CTportions of a 

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combined PET-CT are not a substitutefor dedicated diagnostic contrast-enhanced CT scans for 
RECIST measurements.  A PET scan alone or as part of a PET-CT may be performed for 
additional analyses but cannot be used to assess response according to RECIST.
The method of assessment used at baselinemust be used consistently for tumor assessment and 
will be repeated as per Section 10.1.
During the Continued Access Period, efficacy assessments (frequency and type of assessments) 
will be at the discretion of the investigator, based on the standard of care.
10.1.1.1.Centralized Radiologic Collection
This study will be analyzedbased on results of local (investigative site) radiologic assessments, 
including dates of progression and death.Since radiographic imaging scans may be needed for 
future regulatory purposes,or an independent review of all or a representative sample of scans 
may be considered following the completion of PFS analysis, copies of all scans will be collected 
throughout the study and stored centrally by a coordinating vendor designated by Lilly.
Investigative sites will send radiologic images routinely to Lilly (or designee) based on the 
frequency described inSection 10.1.Lillywill collect and store tumor measurement images on 
all randomized patients.
Further details are provided in the manualof central radiology.
10.1.2. Efficacy Assessments during Postdiscontinuation Follow-up
For patients who discontinue study treatment without objectively measured disease progression, 
the investigative sites will continue to monitor patients and periodically evaluate tumor response 
(for timing, refer to Section 10.1), by the same method used at baselineand throughout the study, 
until the patient has radiographic documentation of disease progressionas defined by 
RECIST1.1 or until overall study completion (that is, the final analysisof OS),whichever 
occurs first.  After the patient has objective disease progression, radiographic tests are no longer 
required and the patient will be followed up approximately every 3 months (±7 days) until the 
patient’s death or overall study completion, whichever occurs first (see Section8.1.1).
After radiographic documentation of disease progression, patients may receive additional 
anticancer therapy at the discretion of the investigator.  The additional treatments should be 
documented in the CRF.
10.1.3. Primary Efficacy Measure
The primary efficacy measureisprogression-free survival (PFS).
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study(refer to Section 10.1.1.1).
The PFS timeismeasured from the date of randomization to the date of first observation of 
objective progression as defined by RECIST 1.1 or the date of death due to any cause, whichever 
is earlier.  The censoring is taken in the following order:

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If a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the randomization date, regardless of whether or not objectively 
determined progression or death has been observed for the patient; otherwise,
o if a patient is not known to have died or have objective progression as of the data 
inclusion cutoff date for the analysis, the PFS time will be censored at the last 
adequate objective progression-free disease assessment date.
If death or disease progressionoccurs after 2 ormore consecutive missing radiographic 
visits, censoring will occur at the date of the last adequate radiographic visit prior to the 
missed visits.
If death or disease progressionoccurs after postdiscontinuation systemic anticancer 
therapy, censoring will occur at the date of last adequate radiographic visit prior to the 
start of postdiscontinuation systemic anticancer therapy.
Refer to the statistical analysis plan (SAP) for further details.
10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures (Table JVDC.7) will be collected at the times shown 
in the Study Schedule (Attachment 1).
Table JVDC.7.
Secondary Efficacy Endpoints
Endpoint
Definition
Overall survival
(OS)
The time from the date of randomizationto the date of death from any cause.
For each patient who is not known to have died as of the datainclusion cutoff date for a 
particular analysis, OS will be censored for that analysis at the last knownalive dateprior to 
the datainclusion cutoff date.
Objective 
response rate 
(ORR)
The number of randomized patients who achieve a best response of CR or PR,using the 
investigator response assessments, divided by the total number of patients randomized to 
that study arm, based on the achievement of measurement criteria. RECIST 1.1will be 
used to make the determinationin this trial.
Disease control 
rate (DCR)
The proportion of randomized patients achieving a best response of CR, PR, or SD.Stable 
disease definition per RECIST (Attachment 6) and must achieve a minimum duration of 
5weeks from randomization.
Duration of 
response (DOR)
DOR is defined only for responders (patients with CR or PR[confirmation not required]).  
It is measured from the date of first evidence of CR or PR to the date of objective 
progression or the date of death due to any cause, whichever is earlier.  If a responder is not 
known to have died or have objective progression as of the data inclusion cutoff date, DOR 
will be censored at the date of the last complete objective progression-free disease 
assessment.
Abbreviations:  CR = complete response; DCR = disease control rate; DOR = duration of response; 
ORR=objective response rate; OS = overall survival; PR = partial response; RECIST = Response Evaluation 
Criteria in Solid Tumors; SD = stable disease.

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10.2.Health OutcomesMeasures
Assessment of PROswill be conducted through the use of the EORTC QLQ-C30 and the 
EQ-5D-5L questionnaires, which measure quality of life (QoL) and health status, respectively.  
The questionnaires will be completed at baseline, prior to each cycle of therapy (starting at 
Cycle2), and at the (30-day) Short-termFollow-up visitas detailed in Attachment 1.It is 
recommended that the instruments be administered together and in sequence order, at the 
beginning of the visit prior to other study procedures, with the EORTC QLQ-C30 presented first, 
followed by presentation of the EQ-5D-5L.  At each applicable time point, the instruments 
should be completed before any extensive contact and consultation,which may bias patient 
responses.
The questionnaires will be completed only by those patients who are fluentin an available 
translation.
10.2.1. EORTC QLQ-C30
Patients will complete the EORTC QLQ-C30 questionnaire (Version 3).  The EORTC QLQ-C30 
is a self-administered, cancer-specific questionnaire with multidimensional scales (Aaronson et 
al. 1993).  It consists of both multi-item and single-item scales, including 5 functional domains, a 
global QoL domain, 3 multi-item symptom domains, and 6 single-item domains.  A change of 
≥10 points on the 100-point scales is considered clinically meaningful (Osoba et al. 1998).
10.2.2. EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status 
(Herdman et al. 2011).  Patients will complete the 5-level (no problem, slight problem, moderate 
problem, severe problem, and inability or extreme problem),5-dimension (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current 
health state.  A unique EQ-5D health state is defined by combining 1 level from each of the 
5dimensions.  Additionally, patients will indicate their current health status by marking on a 
visual analogue scale (VAS) ranging from 100 (best imaginable health state) to 0 (worst 
imaginable health state).
10.3.Safety Evaluations
Investigators are responsible for monitoring the safety ofpatients who have entered this study 
and for alerting Lillyor its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment regimen or study procedure, or 
that caused the patient to discontinue before completing the study.  The patient should be 
followed until the event is resolved or explained.  Frequency of follow-up evaluation is left to the 
discretion of the investigator.

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The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
TableJVDC.8presents a summary of AE and SAE reporting guidelines.  TableJVDC.8also 
shows which database or system is used to store AE and SAE data.
TableJVDC.8.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to Be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEsa
x
SAEs related to protocol procedures
x
x
Study Treatment Period
All AEs
x
All SAEs
x
x
Short-termPostdiscontinuation 
Follow-up
All AEs
x
All SAEs
x
x
Long-termPostdiscontinuation 
Follow-up
All SAEsrelated to protocol procedures 
or study drug(s)
x
x
Continued Access (treatment) Period All AEs
x
All SAEs
x
x
Continued AccessFollow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment and 
no longer in follow-up)
All SAEs related to protocol procedures 
orstudy drug(s) that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
Note:  The investigator remains responsible for following, through an appropriate health care option, AEs that are 
serious, considered related to the study treatment or procedures, or that caused the patient to discontinue before 
completing the study.  The patient should be followed until the event is resolved or explained.
a For patients who fail screening,only AEs related to protocol procedures are collected in the collection database.
10.3.1. Adverse Events
Lillyhas standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from electrocardiograms(ECGs), laboratory results, and vital 
signsmeasurements that result in a diagnosis should be reported to Lillyor its designee.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breastfeeding are collected for regulatoryreporting 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.

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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 
Lillyor its designee.
In addition, all AEs occurring after the patient receives the first dose of study drug must be 
reported to Lillyor its designee via CRF.
Investigators will be instructed to report to Lillyor its designee their assessment of the potential 
relatedness of each AE to protocol procedureand/or study drug via CRF.
The investigator decides 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 study medication or study procedure, the following terminologies 
are defined:
Probably related:  a direct cause-and-effect relationship between the study treatment and 
the AE is likely.
Possibly related:  a cause-and-effect relationship between the study treatment and the 
AE has not been demonstrated at this time and is not probable, but is also not impossible.
Does not know:  the investigator cannot determine.
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 IP/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 v 4.0will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the NCI-CTCAE v 4.0 criteria, 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 CTCAE term,and the CTCAE severity grade, AE 
verbatim text will also be mapped by Lilly or its designee to corresponding terminology within 
the Medical Dictionary for Regulatory Activities (MedDRA
®).
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lillyor its designee via CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.

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10.3.1.1.Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:
death
a life-threatening experience (that is, immediate risk of dying)
persistent or significant disability/incapacity
initial or prolonged inpatient hospitalization
congenital anomaly/birth defect
considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed 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.
Study site personnel must alert Lillyor its designee of any seriousadverse event (SAE) within 
24 hours of investigator awareness of theevent via a sponsor-approved method.  Ifstudy site 
personnel contact Lilly or its designee by telephone regarding an SAE, study site personnel must 
alsoimmediately provide 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 treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events caused bydisease progression, including death,should not be reported 
unless the investigator deems them to be possiblyrelatedto the study drug.
The investigator does not need to actively monitor patients for AEsonce 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.

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Information on SAEsexpected 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 DCSI in the IB and that the investigator identifies as related to the study drugor study 
procedure.  United States 21 CFR 312.32 and European Union Clinical Trial Directive 
2001/20/EC and the associated detailed guidancesor national regulatory requirements in 
participating countries require the reporting of SUSARs.  Lillyhas 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. Other Safety Measures
10.3.2.1.Electrocardiograms
For each patient, 12-lead digital ECGs will be collected according to the Study Schedule 
(Attachment 1)as single ECGs (nooverread).  Patients must be supine for approximately 5 to 10 
minutes before ECG collection and remain supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high quality records.
Electrocardiograms will be interpreted by aqualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
The investigator or qualified designee is responsible for determining if any change in patient 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation.
10.3.3. Safety Monitoring
The LillyCRP/CRSor designee will monitor safety data throughout the course of the study
.
Lillywill review SAEs within time frames mandated by company procedures.  The Lilly
CRP/CRSor designee will, as is appropriate, consult with the functionally independent Lilly 
Global Patient Safety therapeutic area physician or clinical scientist, and review:
trends in safety data
laboratory analytes
adverse events
If a patient experiences elevated ALT >5× ULN and elevated total bilirubin >2× ULN, 
clinical and laboratory monitoring should be initiated by the investigator.

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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/CRSor designee regarding 
collection of specific recommended clinical information and follow-up laboratory tests.  
See Attachment 3.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring committee (an advisory group for this 
study formed to protect the integrity of data; refer to Section 12.2.13) can conduct additional 
unblinded analyses of the safety data.
Refer to Section 12.2.13for details regarding interim safety analyses.
10.3.4. Complaint Handling
Lillycollects product complaints onstudy drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and 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 Lillyor its designee will be reported.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:
recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose
faxing the completed product complaint form within 24 hours to Lillyor its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4.Sample Collection and Testing
Samples collected for this study will be coded with the patient number.  The samples and any 
data generated from them can be linked back to the patient only by investigator site personnel.
Attachment 1lists the schedule for sample collections in this study.
Attachment 2liststhe specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.
Attachment 7lists the schedules for sample collections for PK,immunogenicity, and 
translational research (tumor tissue, plasma, urine, and whole blood).
10.4.1. Samples for Study Qualification and Health Monitoring
Bloodandurine sampleswill be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.  Samples will be collected at the times 
specified in the Study Schedule(Attachment 1).

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Standard laboratory tests, including chemistry, hematology, coagulation, pregnancy testing (as
applicable,in women of childbearing potential), and urinalysis panels will be performed.  
Chemistry will be analyzed locally and centrally;hematology, coagulation, pregnancy testing, 
and urinalysis panelswill be analyzed locally. Attachment 2lists the laboratory tests that will be 
performed for this study.Locallaboratory results will be used to determine patient eligibility at
baseline, except for central analysis of chemistryresults. Local laboratory results may be used 
for on-study dosing decisions;if so, testing mustalso still be performed by the central laboratory
for chemistry results (only). These central chemistry laboratory results will be used for
subsequent safety analyses. In the event of minor discrepancies between local and central
laboratory results, the investigator may use the local results for treatment decisions, and the
central laboratory results will remain part of the safety database.
Based on laboratory safety values, unscheduled hepatic monitoring tests (seeAttachment 3) may
be performed as part of patient follow-up, in consultation with the LillyCRP/CRS or designee.
Investigators must document their review of each laboratory safety report.
Laboratory/analyte 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 daysafter receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, itis 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
As part of the sponsor’s ongoing efforts to understand the relationship between cancer, genetics,
and response to therapy, this study mayanalyze biomarkers relevant to ramucirumab, docetaxel,
and/orurothelial carcinoma. The study will analyze the clinical correlation between biomarkers 
and clinical outcome and may be used for related research methods or validation of diagnostic 
tools or assay(s).
Samplesfor translational research (TR) will be collected at the times specified inAttachment 7.
The following samples are mandatory(required) for biomarker research, except asindicated
otherwise:

Tumor tissue (newly biopsied or archived)(see Section10.4.2.1)

Plasma for biomarkers(see Section10.4.2.2)

Urine for biomarkers (see Section 10.4.2.2)

Whole blood for DNA sample (pharmacogenetic analysis) (see Section10.4.2.3)
For these mandatory samples:  All sites are required to participate in the TR portion of the study, 
and patient participation in the TR portion of the study is mandatory, unless restricted by local 
regulations.

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Patients will not receive results of these investigations except where required by local law.
10.4.2.1.Tumor Tissue
Collection of tumor tissue samples (either newly biopsied or archived) is mandatory(required)
for participation in this study, as follows, except as indicated otherwise:
If a prior archived tumor specimenisavailable, and unless restricted by local regulations, 
submission of archived tumor tissue is mandatory.
If an archived specimen is not available, submission of a newly acquired biopsy (obtained 
at baseline) is requested when biopsy is safe and feasible.
The availability of tumor tissues is important to better characterize the relationship of tumor 
biology and response evaluation in this study.  As such, this study is requesting submission of 
tumor tissue (newly biopsied or archived) to support correlative studies.
Pretreatment formalin-fixed paraffin-embedded tumor tissue obtained from the primary tumor or 
metastatic site should be provided as a block or (20) unstained slides.  Due diligence should be 
used to make sure that tumor specimen (not a normal adjacent or a tumor margin sample) is 
provided.  Pathology notes accompanying archival tissue may also be requested.
Tumor tissue will beexamined for biomarkers that may include, but are not limited to, those 
related to locally advancedorunresectable or metastatic urothelialcarcinoma, angiogenesis, 
docetaxel, and/orramucirumab.  Mutation profiling, copy number variability, gene expression, 
and/or immunohistochemistry may be performed on these tissue samples to assess potential 
associations with these biomarkers and clinical outcomes.
Tumor samples that become available secondary to a surgical procedure or a biopsy during the 
study should be collected. Similar analysis as described for the baselinesample may be 
conducted.
The samples will be stored for a maximum of 15 years after the last patient visit for the study at a 
facility selected by the sponsor. Any block of original tumor tissue will besectioned and
returned to the site. Any slides submitted or cut from the block at a central laboratory will be 
discardedwithin 15 years after the last patient visitfor the study.
10.4.2.2.Plasma and Urine for Biomarkers
CCI
 
 
 
 
 
 
 
CCI

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10.4.2.3.Whole Blood for DNA Collection
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the availability of 
receptors, the disease etiology, and/or the molecular subtype of the disease being treated.  
Therefore, where local regulations and ERBs allow, a blood sample will be collected for 
pharmacogenetic analysis.
Sampling for thisanalysis will be a one-time collection(refer to Attachment 7for timing of the 
collection).  Samples will be stored and analysis may be performed on genetic variants/copy 
number variations that are thought to play a role in locally advancedorunresectable or 
metastatic urothelialcarcinoma, angiogenesis, docetaxel, and/or ramucirumab.
In the event of an unexpected AE or the observation of an unusual response, the 
pharmacogenetic biomarker samples may be genotyped and analysis may be performed to 
evaluate a genetic association with response to ramucirumaband/or docetaxel.  These 
investigations maybe limited toa 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 biomarkersampleswill only be used for 
investigations related to disease, cancer-related conditions, and drug or class of drugs under 
study in the context of this clinical program.  They will not be used for broad exploratory 
unspecified disease or population genetic analysis.
The samples will be stored for up to a maximum 15 yearsafter the last patient visit for the study 
at a facility selected by the sponsor.  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.  
Pharmacogenetic data will not be provided to the investigator or the patient except where 
required by local law.
10.4.3. Samples for Immunogenicity Research
Blood samples for immunogenicity (anti-ramucirumabantibody) testing will be collected from 
all study patients to determine antibody production against ramucirumab(placebo)at baseline 
(beforethe first infusion of ramucirumab/placeboon Cycle 1,Day 1 of treatment);at specified 
timepoints during the study;and in the event of an IRR, as close to the onset of the reaction as 
possible, at the resolution of the event, and 30 days following the event (seeAttachment 7
CCI
).  
Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies in 
the presence of the ramucirumab.  Antibodies may be further characterized and/or evaluated for 
their ability to neutralize the activity of ramucirumab.

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When any immunogenicity sample is drawn, a sample for drug concentration measurement (PK) 
should also be drawn and analyzedto allow interpretation of immune response (see 
Section10.4.4).
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses toramucirumab.  
The duration allows the sponsor to respond to regulatory requests related to ramucirumab.
10.4.4. Samples for Drug Concentration Measurements 
(Pharmacokinetics)
Bloodsamples will be collected from all study patients to assess ramucirumab concentrations in 
serum,as specified inAttachment 7.
In the event of an IRR, every attempt should be made to collect a bloodsample for 
anti-ramucirumab antibody andserum ramucirumabconcentration determination at time points
noted in Attachment 7.
Serum concentrations of ramucirumabwill be analyzed at a laboratory designated by the sponsor 
using a validated method.
Bioanalytical samples collected to measure ramucirumabconcentration will be retained for a 
maximum of 1 year following last patient visit for the study.

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11.Data Quality Assurance
To ensure accurate, complete, and reliable data, Lillyor 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, Lillyor 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 Lillyor 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, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic laboratorysystem.
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).
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 primary objective of this study is to compare ramucirumab plus docetaxelwith placebo plus
docetaxelin terms of PFSin patients with locally advanced or unresectable or metastatic 
urothelialcarcinoma whoprogressed onor afterplatinum-based therapy.  The study will enroll 
approximately 524patients in a 1:1 randomization(262patients in the ramucirumab-plus-
docetaxelarmand 262patients intheplacebo-plus-docetaxel arm).  The primaryanalysis ofPFS 
will be performed when a minimum of 331PFS eventshave been observed fromthe first 
437randomized patients(that is, 24% censoring rate).  If full enrollment is not reachedat the
pointwhen 331 PFS events have been observed, the primary analysis will be performedwhen 
full enrollment is reached, on the number of PFS events observed upon full enrollment from the 
first 437 randomized patients. Although PFS is the primary endpoint, this studyis powered on 
OS.  Assuming an OShazard ratio of 0.75,this sample size yields at least 80%statistical power 
to detect superiority of the ramucirumab-plus-docetaxelarm over the placebo-plus-docetaxelarm 
with the use of a 2-sided log-rank test and a 2-sided type I error of 0.05.
A gatekeeping design will beused to assess PFS,OS,and ORR.  The PFS, OS,and ORRare 
tested in a sequential manner.  The OS superiority is tested onlyif the PFS superiority test is 
significant.Likewise, the ORRsuperiority is tested only if the OS superiority test is significant.  
For OS, an interim analysis for efficacy is planned at time of PFS final analysis;the Bonferroni 
method will be used foralpha splitting, with α=0.001 (2-sided) spent at the interim analysis and 
α=0.049 (2-sided) spent at the final analysis for OS.  Although the primary endpoint is PFS, the 
sample size is powered to show a superiority test for comparing OSbetween the 2 arms.
The sample size to test PFS superiority at the PFS finalanalysis is determined based on the 
following assumptions:
The PFS hazard ratio for treatment group (ramucirumab plus docetaxel) versus control 
group (placebo plus docetaxel) is 0.70.
The randomization ratio is 1:1.
A 2-tailed significance level of 0.05.
Control arm median PFS =2 months.
The type II error rate is 0.1, that is, the power of the trial is set to 90%.
Enrollment rateis approximately36.3patients per month. Thisincludes an estimated 
25% chance of screen failure patients.
Under these assumptions, the estimated total number of PFS events at the PFS final analysis is 
331,from an expected accrual of 371patients. Assuming a 15% patient dropout rate from PFS 
follow-up, it is estimated that approximately 437patients are needed to reach 331 PFS events in 
approximately18.4months.

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The sample size to test OS superiority was determined based on the following assumptions:
α = 0.049(2-sided), statistical power = 80%.
The randomization ratio is 1:1.
Control arm median OS = 9 months.
HR=0.75
Interimefficacy analysisfor OS (at the PFS final analysis)with testing atα = 0.001
(2-sided).
Under these assumptions, the estimated total number of OS events at the final OS analysisis 382, 
from an expected accrual of 497patients. Assuming a 5% dropout rate from survival follow-up, 
it is estimated that 524patients will need to be randomizedto reach 382 OS events in 
approximately 32.6 months.
At the PFS final analysis, the first 437randomized patients will be used for theanalysis.  An 
interim OS analysis will be performed;all patients who have been randomized at that pointwill 
be used to compare OS between the 2arms,based on Bonferroni alpha splitting of 0.001
(2-sided).
The final OS analysis is expected at 32.6months from first patient enrollment.  At the final 
analysis, all randomized patients will be used to compare OS between the 2arms. The type I 
error spend for OS is 0.049(2-sided),which approximately corresponds to observed HR <0.82.
The estimated number of events and efficacy boundaries and probabilities of first crossing the 
boundaries at each analysis are summarized inTableJVDC.9.  EAST®6.2is used to calculate 
the sample size and boundaries.
TableJVDC.9.
Study Design and Operating Characteristics
Statistical Analysis
Primary PFS
FinalOS
Duration of study(months)*
18.4
32.6
Estimated
# events
331
382
# patients
437
524
P value boundary
p ≤0.05
p ≤0.049
Rejectionboundaryfor HR
0.806
0.82
Abbreviations:  HR = hazard ratio; OS = overall survival; PFS = progression-free survival.
* Estimated numbers.

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12.2.Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Lillyor its designee.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All CIs will be given at a 2-sided 95% level, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Before unblinding of the aggregate 
database, minor modifications or clarifications to the data analysis methods may be described 
and justified in the SAP.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.
If study data violate key statistical assumptionsof an analysismethod, alternative statistical 
methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.1.1.Analysis Populations
The following populations will be defined for this study:
Intention-to-Treat population:will include all randomized patients. The ITT analysis of 
efficacy data will consider allocation of patients to treatment groups as randomized, and 
not by actual treatment received. This population will be used for all baseline, efficacy, 
and health outcome analyses.
Per-Protocol population:will include all patients who are randomized and received at 
least 1 cycle of study treatment, and do not have any major protocol violations that could 
potentially affect the efficacy conclusions of the study. This population will be defined 
in detail inthe SAP prior to database lock, and will be used for sensitivity analyses of OS 
and PFS; other efficacy endpoints may also be analyzed.
Safety population:will include all randomized patients who received any quantity of 
study treatment, regardless of their eligibility for the study. The safety evaluation will be 
performed based on the actual study treatment a patient has received, regardless of the 
arm to which he or she was randomized. The safety population will be used for all 
dosing/exposure, AEs, and resource utilization analyses.
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the
number and percentage of patients entered into the study, enrolled in the study, and treated,as 
well asthe number and percentage of patients completing the study or discontinuing (overall and 
by reason for discontinuation).  A summary of all important protocol deviations will be provided.

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12.2.3. Patient Characteristics
Description of patient characteristics at baseline, such as patient demographics, baseline disease 
characteristics, preexisting conditions, and prior therapies,will be reported using descriptive 
statistics.
12.2.4. Concomitant Therapy
Concomitant medications will be summarized for the safety population.
12.2.4.1.Postdiscontinuation Anticancer Therapy
The numbers and percentages of patients reporting postdiscontinuation anticancer therapieswill 
be provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name, for the ITT population.
12.2.5. Treatment Compliance
The numbersof dose omissions, dose reductions, dose delays, and cycles received, and the dose 
intensity will be summarized for all treated patients per treatment arm.
12.2.6. Primary Outcome and Methodology
PFS time is defined as the time from randomizationuntil the first radiographic documentation of 
progression as defined by RECIST 1.1,or death due to any cause, whichever is earlier.
The analysis of PFS will be based on stratified log-rank test,stratified by randomization strata
(IWRS).  The testing boundaries are summarized in TableJVDC.9.The actual test boundary 
will be adjusted according to actual number of events.  PFS survival curves, the median with 
95% CI,and survival rates at various time points for each treatment group will be estimated 
using Kaplan-Meier method(Kaplan and Meier 1958).  The HR will be estimated usinga 
stratified Cox regression model(Cox 1972),stratified by randomization strata(IWRS).
The first 437randomized patientsat finalPFS analysis as primary analysis and all randomized 
patientsat final PFS analysis as sensitivityanalysis, according to the ITT principle, will be 
included in the analysis of this endpoint.
12.2.7. Other Analyses of Efficacy
Other analyses of efficacy, including sensitivity analysis of the primary endpoint PFS, are 
described in the following subsections.
12.2.7.1.Sensitivity Analysis for Progression-Free Survival
The following sensitivity analyseswill be performed for PFS:
unstratified log-rank test and Cox regression models
stratified log-rank test and Cox regression models, stratified by strata collected in the 
CRF
analysis including both radiographic and symptomatic progressions as PFS events
analysis for the per-protocol population
sensitivity analysis for various PFS censoring rules (details will be providedin the SAP)

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at the primary analysis, sensitivity analysis using all PFS events from ITT population, 
that is,all PFS events from all patients randomized at the time of the primary analysis
univariate and multivariate Cox regressionmodel will be used to explore potential 
prognostic and/or predictive factors
12.2.7.2.Overall Survival
Theanalysis of OS will be based on stratified log-rank test,stratified by randomization strata
(IWRS).  The Bonferronialpha splitting method will be used for type I error allocation tointerim 
and final analyses.  The expected events number and testing boundaries are summarized in
TableJVDC.9.
OS survival curves, the median with 95% CI,and survival rates at various time points for each 
treatment group will be estimated using Kaplan-Meier method(Kaplan and Meier 1958).  The
HR will be estimated usinga stratified Coxregressionmodel,stratified by randomization strata
(IWRS).
OS will be analyzed for all randomized patients (ITT population)at both the primary PFS and 
final analyses.
The following sensitivity analyses will be performed for OS:
unstratified log-rank test and Cox regression models
stratified log-rank test and Cox regression models, stratified by strata collected in the 
CRF
analysis for the per-protocol population
univariate and multivariate Cox regressionmodel will be used to explore potential 
prognostic and/or predictive factors
Additional sensitivity analyses maybe specified in the SAP.
12.2.7.3.Objective Response Rate and Disease Control Rate
The best overall responsewill be determined using the RECIST 1.1 guidelines.
The ORR will be calculated as the number of patients who achieve a best overall response of CR 
or PR, divided by the total number of patients randomized to the corresponding treatment group 
(ITT population).  Additionally, a subgroup analysis will be performed for patients with 
measureable disease and for patients with nonmeasureable disease.  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.  The ORR with 95% CI observed in each 
treatment group will be summarized and compared using the Cochran-Mantel-Haenszel test 
adjusting for the randomization strataat time of OS final analysis.
12.2.7.4.Duration of Response
The survival curves and medianswith 95% CIswill be estimatedusing the Kaplan-Meier method
and will be compared using Cox regressionmodel and log-rank test.  The analysis is for 
responders only.

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12.2.7.5.Other
Additional exploratory analyses may be performed as deemed appropriate.
12.2.8. Pharmacokinetic and Immunogenicity Analyses
Serum concentrations of ramucirumab prior to infusion (Cmin[trough]) and at1-hour postend of 
(ramucirumab)infusion (approximately Cmax[peak]) will be summarized using descriptive 
statistics.  Additional analysis usingthe population pharmacokinetic approach may be conducted 
if deemed appropriate.Relationships between ramucirumab exposure and measures of efficacy 
and safety will be explored.  Details will be providedin the SAP.
Immunogenicity incidence will be tabulated, and correlation of immunogenicity to ramucirumab 
drug level, activity, and safety will be assessed as appropriate.
12.2.9. Translational ResearchAnalyses
The profiles of biomarkers assessed over time will be summarizedby treatment.  The 
associationsbetween biomarkermeasures with clinicaloutcomes will be analyzed.
12.2.10.Health OutcomesAnalyses
The compliance of completing the questionnaires will be summarized at each scheduled 
assessment.  Percentage compliance will be calculated based on the number of patients who 
completed the assessment divided by the number of patients expected (that is, still on study and 
alive). If there is a response to at least one item, the questionnaire will considered completed. 
Reasons for noncompliance will be summarized.
12.2.10.1.
EORTC QLQ-C30
Quality-of-life assessments will be scored according to the algorithm described in the EORTC 
QLQ-C30 Scoring Manual (Fayers et al. 2001).  All scales and single items are scored on 
categorical scales and linearly transformed to 0-to-100 scales where:
a high score for a functional scale represents a high or healthy level of functioning
a high score for the global health status/QoL represents a high level of QoL
a high score for a symptom scale or an item represents a high level of 
symptoms/problems
For each scale, time to deterioration will be estimated with the Kaplan-Meier method and 
analyzed with Cox regression models.  Time to deterioration is defined as date of randomization 
to first worsening of ≥10 points.  Patients without deterioration will be censored at their last 
non-deteriorated assessment.
For each scale, proportions of patients with improved or stable scores will be compared using 
Cochran-Mantel-Haenszel test adjusting for the randomization strata will be used, unless number 
of strata make Cochran-Mantel-Haenszelunstable, then a Fisher’s Exact test will be used, with 
the ITT population as the denominator.  Scores will be classified as improved or worsened if 
change from baseline is ≥10 points; change <10 points will be classified as stable.
Data will also be analyzed using descriptive statistics, including change from baseline.

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12.2.10.2.
EQ-5D-5L
The index score will be calculated from a set of item weights to derive a score based on a scale 
of 0 to 1, with 0 representing death and 1 representing the best health status; negative scores are 
possible.Item weights for the 5-level version of the EQ-5D are still being developed, but will be 
described in the SAP prior to final analysis.  Responses to the 5 dimensions will be summarized.  
Descriptive statistics for the index and VAS will be calculated.
12.2.11.Safety Analyses
All safety summaries and analyses will be based upon the safety population as defined in 
Section12.2.1, unless otherwise indicated, and include:
Treatment-emergent AEswill be summarized by MedDRA System Organ 
Class/Preferred Term, classifiedfrom verbatim terms.  The incidence and percentage of 
patients with at least one occurrence of a Preferred Term will be included, according to 
the most severe NCI-CTCAE v4.0grade.  Causality (relationship to study drug), action 
taken, severityor CTCAE grade,and outcome will be summarized separately.  Duration 
of TEAE will be determined and included in the listings.
Study drug exposure will be summarized for each arm with following variables: number 
of infusions(except docetaxel), number of cycles, duration of therapy, cumulative dose, 
dose intensity,and relative dose intensity.
Laboratory results will be classified according to the NCI-CTCAE, v4.0. Incidence of 
laboratory abnormalities will be summarized.
Hospitalizations andtransfusionswill be summarized.
Vital signs will be summarized.
Additionally, the following (but not limited to) safety-related outcomes will be summarized:  
study treatment discontinuationsdue to TEAEs, deaths, and SAEs.
12.2.12.Subgroup Analyses
Subgroup analyses of PFS and OS maybe performed for thefollowing subgroup variables:
Sex(males vs females)
Age (<65 year vs ≥65 years)
Race (white vs Asian vs all others)
Geographical region (North America, Europe, rest of world)
ECOG performance status(0 vs 1)
Time from diagnosis to randomization
Prior immune checkpoint inhibitor (Y/N)
Primary tumorlocation (bladder vs kidney/ureter/urethra)
Visceral metastasis (Y/N),where metastasesinvolve the liver, lung, and/or bone
Specific sites of metastases (Y/N)
Hemoglobin level (<10g/dL, ≥10g/dL)

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If number of patients in a subgroup is too small for an informative analysis, that particular
subgroup may be omittedor combined with other subgroups.  Other subgroup analyses may be 
performed as deemed appropriate.
12.2.13.Interim Analyses
In this study, the following interim analyses will be performed:
An unblinded safety analysis after at least 100 and 250 evaluable patientstotal have 
either started treatment in Cycle 3 or discontinued all study treatment prior to Cycle 3 due 
to any reasons. Additional safety reviewsmay be done at the discretion of the IDMC.
Analysis for OS interim (based on all randomized patients) will be performed at the time 
of PFS final analysis.
12.2.13.1.
Predefined TimePoints for IDMC Safety Reviews
An independent data monitoring committee (IDMC)will be established to conduct safety 
reviews.  The membership, roles,and responsibilities ofthe IDMC are defined in the IDMC 
Charter.
There will be no prespecified rules for stopping or modifying the trial due to safety concerns. 
The IDMC members will review unblinded safety data at prespecified time points to determine 
whether there are sufficient safety concernsto justify modifying the study or the termination of 
study treatment and/or enrollment.
Only the IDMC is authorized to evaluate unblinded safety analyses.  Study sites will receive 
information about interim results ONLY if they need to know for the safetyof their patients.
Unblinding details are providedin the blinding section of the protocol (Section 9.5).
IDMC safety reviewswill be performedforall randomizedpatients at the following 
timepoints:
After at least 100 and 250 patients total have either started treatment in Cycle 3 or 
discontinued all study treatment prior to Cycle 3due to any reasons. Additional safety 
reviews may be done annually, adjusted at the discretion of the IDMC.
The IDMC will evaluate unblinded safety data tomake recommendations for study 
modification, if required.  Details on the process flow/communication plan areprovided 
in the IDMC Charter.
Patient enrollment will continue during data assessment by the IDMC.
12.2.13.2.
Predefined TimePoints for LillyEfficacy Reviews
Lillywill conduct one OS interim efficacy analysis during study conduct.  The interim efficacy 
analysis for OS will occur at time of PFSfinal analysis.
The multiple testing and gatekeeping approach to be used in this study, including testing (alpha) 
levels at the primary and final analyses, is summarized inTableJVDC.9.  All the testing 
boundaries will be adjusted based on actual number of events at each analysis.

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All interim analyses will include complete assessments of safety-related data.Pharmacokinetic 
data will be available for PFS final analysis only and not for the safety interim analyses at 
100and 250 patients.

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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
'slegal 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 drugs.
As used inthis protocol, the term “informed consent” includes all consent given by patients or 
their legal representatives.
13.2.Ethical Review
Lillyor its representatives must approve all ICFs before they 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 Lillybefore the 
study may begin at the investigative sites.
The study site’s ERBs should be providedwith the following, at a minimum:
the current IB or package labeling and updates during the course of the study
the ICF
relevant curricula vitae
13.3.Regulatory Considerations
This study will be conducted in accordance with:
consensus ethics principles derivedfrom international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
ICHGCP Guideline (E6)
applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).

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Some of the obligations of Lillywill be assigned to a third-party organization.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial
-related data.
13.3.1. Investigator Information
Physicians with a specialty or experience intreating patients with urological malignancieswill
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 Lillyrepresentative.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicatingagreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator chosen by Lilly or a designeewill serve as the clinical study report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lillyto serve as the clinical study report coordinating investigator.
The Lillyresponsible 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, et al. 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.
American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 
2014. Available at: http://www.cancer.org/acs/groups/content/@research/
documents/webcontent/acspc-042151.pdf. Accessed November 10, 2014.
Amini A, Masoumi Moghaddam S, Morris DL, Pourgholami MH. Utility of vascular endothelial 
growth factor inhibitors in the treatment of ovarian cancer: from concept to application. 
JOncol. 2012;2012:540791.
Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, 
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Kopparapu PK, Boorjian SA, Robinson BD, Downes M, Gudas LJ, Mongan NP, Persson JL. 
Expression of VEGF and its receptors VEGFR1/VEGFR2 is associated with invasiveness of 
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Attachment 1.Protocol JVDCStudy Schedule

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Study Schedule, Protocol I4T-MC-JVDC
Perform procedure as indicatedin the following schedules.

I4T-MC-JVDC Clinical Protocol 
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LY3009806 
Baseline Schedule, I4T-MC-JVDC 
 
 
 
Baseline 
 
 
 
Cycle 
BL 
 
 
 
Visit 
0 
 
 
 
Relative day to Cycle 1, Day 1 (unless 
indicated otherwise) 
≤28 
≤7 
 
Procedure 
Category 
Protocol Section 
or Attachment 
Procedure 
 
 
Comments 
Study Entry/ 
Enrollment 
7.1, 13.1 
Informed consent form signed 
X 
 
ICF must be signed prior to performance of any protocol-specific 
tests/procedures. 
7.1, 7.2, 9.3, 
12.2.12 
Inclusion/exclusion evaluation and IWRS randomization 
X 
 
Randomization by IWRS to be done once all the screening 
(baseline) assessments are completed.  Patients will be randomized 
to treatment within 24 to 72 hours prior to Visit 1 (Day 1, Cycle 1).  
Every attempt should be made to randomize the patient as close as 
possible to Day 1 of Cycle 1 and not more than 72 hours prior to 
Day 1. 
Medical 
History 
7.1, 7.2, 10.3, 
10.3.1, 10.3.1.1, 
12.2.3 
Initial history/preexisting conditions 
X 
 
 
12.2.3, 12.2.12 
Demography 
X 
 
 
7.1, 7.2 
Historical illnesses 
X 
 
 
Physical 
Examination 
 
Height 
X 
 
Height measurement to be performed at baseline only. 
9.4 
Weight 
X 
 
 
7.2, 9.4.1.1.2, 
10.3.1, 12.2.11 
Blood pressure/pulse 
X 
 
 
7.1, 9.3, 12.2.12, 
Att 4 
ECOG performance status 
X 
  
 
Brain Scan 
7.2 
CT with contrast or MRI 
X 
 
To be performed only after study eligibility is confirmed, to detect 
the presence of intracranial metastasis. 
Patient-
Reported 
Outcomes 
10.2.1, 12.2.10.1 
EORTC QLQ-C30 questionnaire 
X 
 
The instruments should be completed before any extensive contact 
and consultation, which may bias patient responses.  It is 
recommended that the instruments be administered together, with 
the EORTC QLQ-C30 completed first, followed by the EQ-5D-5L. 
10.2.2, 12.2.10.2 
EQ-5D-5L questionnaire 
X 
 
Efficacy 
Assessment 
10.1, 10.1.1, 
Att 6 
Radiologic imaging (according to RECIST 1.1) and tumor 
measurement 
X* 
 
Imaging studies include a CT scan of the chest and a contrast-
enhanced CT scan of the abdomen and pelvis or an equivalent MRI 
scan.  Routine bone scans should be performed only in the setting of 
bone disease, or as deemed appropriate if there is clinical suspicion 
of new or worsening bone metastases. 
* To be performed within 28 days prior to randomization. 
Adverse 
Events 
10.3, 10.3.1, 
10.3.1.1, 10.3.3, 
12.2.11 
AE collection and CTCAE grading 
X 
 
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System. 
Concomitant 
Medications 
9.6, 12.2.4 
Concomitant medication notation 
X 
 
 

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Baseline
Cycle
BL
Visit
0
Relative day to Cycle 1, Day 1(unless 
indicated otherwise)
≤28
≤7
Procedure 
Category
Protocol Section 
or Attachment
Procedure
Comments
Laboratory/
Diagnostic 
Tests
10.3.1, 10.3.3, 
10.4.1, 12.2.11, 
12.2.12, Att2
Hematology
X
10.3.1, 10.3.3, 
10.4.1, 12.2.11, 
Att2
Chemistry
X
Central laboratoryresults to be used to determine eligibility.
10.3.1, 10.3.3, 
10.4.1, 12.2.11, 
Att2
Coagulation
X
7.2, 10.3.1, 
10.4.1, Att2
Pregnancy test
X*
Serum β-hCG (minimum sensitivity 25 IU/L or equivalent units of 
β-hCG).
Pregnancy test results will not be collected on the CRF.
* To be performed within 7 days prior to randomization.
7.1, 10.3.1, 
10.3.3, 10.4.1, 
12.2.11, Att2
Urinalysis
X
Routine dipstick measurements, and if clinically indicated, 
microscopic analysis.  If urine dipstick or routine analysis indicates 
proteinuria ≥2+ at evaluations, a 24-hour urine collection (to assess 
protein) must be obtained.
7.1, 10.4.2.1, 
12.2.9, Att7
Tumor tissue(requested; mandatory where applicable)
Refer toAttachment 7.
If prior archived tumor specimens are available, and unless 
restricted by local regulations, submission of archived tumor tissue 
is mandatory.
If an archived specimen is not available, submission of a newly 
acquired biopsy is requested when biopsy is safe and feasible.
7.1, 10.4.2.2, 
12.2.9, Att7
Urine samples (biomarkers)
Refer toAttachment 7.
7.1, 10.4.2.3, 
12.2.9, Att7
Whole blood for DNA sample (pharmacogenetic analysis)
Refer toAttachment 7.
10.3.1, 10.3.2.1
ECG
X
Abbreviations:  β-hCG = beta human chorionic gonadotropin;AE = adverse event; Att = Attachment; BL = baseline; CRF = case report form; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group;EORTC QLQ-C30 = European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire-C30; ICF = informed consent form; IWRS = interactive web response system; MRI = magnetic resonance imaging; RECIST 1.1 = 
Response Evaluation Criteria in Solid Tumors, version 1.1; SAE = serious adverse event.

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Treatment Period Schedule, I4T-MC-JVDC
Treatment Period
Comments
Cycle
(21-daycycle)
1-6
7-N
Visit
1-6
7-N
Relative day within a cycle
1
1
Except for the Cycle 1, Day 1 visit, allowable visit windows are ±3 days, unless 
indicated otherwise.
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Physical 
Examination
9.4
Weight
X
X
BSAto be calculated, as needed,at each cycle until docetaxel is discontinued.  (If 
the patient’s weight does not fluctuate by more than 10% from the weight used to 
calculate theprior dose, the BSA will not need to be recalculated.)
9.4.1.1.2, 
10.3.1, 
12.2.11
Blood pressure/pulse
X
X
9.3, 12.2.12, 
Att4
ECOG performance status
X
X
Patient-
Reported 
Outcomes
10.2.1, 
12.2.10.1
EORTC QLQ-C30 questionnaire
X
X
May be completed up to 3 days prior to start of each cycle, prior to any infusion.  
The instruments should be completed before any extensive contact and consultation,
which may bias patient responses.  It is recommended that the instruments be 
administered together, with the EORTC QLQ-C30 completed first, followed by the 
EQ-5D-5L. Patients do not need to complete prior to Cycle 1, if completed at 
baseline.
10.2.2, 
12.2.10.2
EQ-5D-5L questionnaire
X
X
Efficacy 
Assessment
10.1, 10.1.1, 
Att 6
Radiologic imaging (according to 
RECIST 1.1) and tumor measurement
X*
X*
*To be performed according to the following timing (also stated in Section 10.1):
Every 6 weeks (±7 days) after randomization(regardless of treatment delays) during 
the Study Treatment Period, until disease progression OR overall study completion 
OR 1 year after randomization, whichever occurs first.  In addition, any patient 
whose disease has not progressed by 1 yearafter randomization (note that the patient 
may or may not still be on study treatment) will be evaluated for response every 
12weeks (±7 days) from 1 year after randomization, until disease progression OR 
overall study completion OR 3 years after randomization, whichever occurs first; 
then as per standard clinical practice after that.
Imaging studies include a CT scan of the chest and a contrast-enhanced CT scan of 
the abdomenand pelvis or an equivalent MRI scan. Throughout the study,use the 
same imaging modality used at baseline. Routine bone scans should be performed 
only in the setting of bone disease,or as deemed appropriate if there is clinical 
suspicion of new or worsening bone metastases.
Adverse 
Events
10.3, 10.3.1, 
10.3.1.1, 
10.3.3, 
12.2.11
AE collection and CTCAE grading
X
X
Data on SAEs that occur before the end of trial will be stored in the collection 
database and the Lilly Safety System.
Concomitant 
Medications
9.6, 12.2.4
Concomitant medication notation
X
X

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Treatment Period
Comments
Cycle
(21-daycycle)
1-6
7-N
Visit
1-6
7-N
Relative day within a cycle
1
1
Except for the Cycle 1, Day 1 visit, allowable visit windows are ±3 days, unless 
indicated otherwise.
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Premedication
9.1.1, 
9.1.1.1, 
9.1.1.2
Premedication notation
X
X
Ramucirumab/Placebo:  Premedication is required for all patients prior to each 
infusion of ramucirumab or placebo.
Docetaxel:  Premedication is required for 3 days starting 1 day prior to infusion of 
docetaxel.
Study Drug
9.1, 9.1.2.1, 
9.2.1, 9.3, 
9.4, 9.4.1.1, 
9.7, 12.2.11
Ramucirumab/Placebo
X*
X
*Patients will be randomized to treatment within24 to 72 hours prior toVisit 1 
(Day1, Cycle 1).Every attempt should be made to randomize the patient as closeas 
possibleto Day 1 and not morethan 72 hours prior to Day 1.
Treatment with ramucirumab or placebo (monotherapy) may continue oncycles until 
at least one discontinuation criterion is met.
9.1, 9.1.2.2, 
9.3, 9.4, 
9.4.1.2, 9.7, 
12.2.11
Docetaxel
X*
(X)†
*Patients will be randomized to treatment within 24 to 72 hours prior toVisit 1 
(Day1, Cycle 1).Every attempt should be made to randomize the patient as close as 
possible to Day 1 and not morethan 72 hours prior to Day 1.
†Treatment with docetaxel may continue for up to six 21-day cycles; further cycles 
of docetaxel (up to 4 additional cycles [maximum of 10 cycles total]) may be 
administered if adequate disease response (that is, SDor better [PR, CR], based on 
the investigator’s assessment) is observed and with approval of the Lilly CRP/CRS 
or designee.

I4T-MC-JVDC Clinical Protocol
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LY3009806
Treatment Period
Comments
Cycle
(21-daycycle)
1-6
7-N
Visit
1-6
7-N
Relative day within a cycle
1
1
Except for the Cycle 1, Day 1 visit, allowable visit windows are ±3 days, unless 
indicated otherwise.
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Laboratory/
Diagnostic 
Tests
10.3.1, 
10.3.3, 
10.4.1, 
12.2.11, 
12.2.12, 
Att2
Hematology
X
X
10.3.1, 
10.3.3, 
10.4.1, 
12.2.11, 
Att2
Chemistry
X
X
Local chemistry laboratory results will beused for dosing decisions; the tests 
scheduled on thestudy protocol must also be performed by the central laboratory.  
Pretreatment laboratory data may not be older than 72 hours (Day 1 of each cycle).
10.3.1, 
10.3.3, 
10.4.1, 
12.2.11, 
Att2
Coagulation
X
10.3.1, 
10.4.1, Att 2
Pregnancy test
X*
X*
* Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
β-hCG)to be performed in WOCBP every second cycle or per institutional 
guidelines, whichever is shorter.
Pregnancy test results will not be collected on the CRF.
10.3.3, Att 3
Hepatic monitoring
(X)*
(X)*
* Hepatic monitoring tests (perAttachment 3; performed by Lilly-designated 
[central]laboratory)may be obtained in the event of a treatment-emergent hepatic 
abnormalityand may be required in follow-up with patients in consultation with the 
Lilly CRP/CRS or designee.
10.4.4, 
12.2.8, Att7
PK
Refer toAttachment 7.
If a patient experiences an IRR to ramucirumab/placebo, blood samples for both 
immunogenicity and PK analysis should be drawn, with no more than 15 minutes’ 
time difference.  Samples will be taken at the following time points:  (1) as soon as 
possible after the onset of the IRR, (2) at the resolution of the IRR, and (3) 30 days 
after the IRR.
10.4.3, 
12.2.8, Att7
Immunogenicity:  Anti-ramucirumab
antibodies
10.4.2.1, 
12.2.9, Att7
Tumor tissue(requested)
Refer toAttachment 7.
At any time during the study, if tumor tissue becomes available, a sample should be 
provided.
10.4.2.2, 
12.2.9, Att7
Plasma and urine samples
(biomarkers)
Refer toAttachment 7.
Abbreviations:  β-hCG = beta human chorionic gonadotropin;AE = adverse event; Att = Attachment; BSA = body surface area; CR = complete response; CRF = case report form; CRP = (Lilly) clinical 
research physician; CRS= (Lilly) clinical research scientist; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology Group; 
EORTCQLQ-C30= European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30; IRR = infusion-related reaction; MRI = magnetic resonance imaging; 
PK=pharmacokinetic(s);PR = partial response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; SAE = serious adverse event; SD = stable disease; WOCBP = women of 
childbearing potential.

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Postdiscontinuation Follow-up Schedule, I4T-MC-JVDC
Postdiscontinuation Follow-up
Cycle
Short-term
Follow-up
Long-termFollow-up
Visit
801
802-8XX
Duration
Refer to 
footnote for 
duration
Refer to footnote for duration
Procedure 
Category
Protocol Section 
or Attachment
Procedure
Comments
Physical 
Examination
Weight
X
9.4.1.1.2, 10.3.1, 
12.2.11
Blood pressure/pulse
X
9.3, 12.2.12, Att4
ECOG performance status
X
Patient-
Reported 
Outcomes
10.2.1, 12.2.10.1
EORTC QLQ-C30 
questionnaire
X
The instruments should be completed before any extensive contact and 
consultation,which may bias patient responses.  It is recommended 
that the instruments be administered together, with the EORTC QLQ-
C30 completed first, followed by the EQ-5D-5L.
10.2.2, 12.2.10.2
EQ-5D-5L questionnaire
X
Efficacy 
Assessment
10.1, 10.1.1, 
10.1.2, Att 6
Radiologic imaging (according 
to RECIST 1.1) and tumor 
measurement
X
X
Patients who discontinue study treatment for any reason other than 
disease progressionwill continue to undergo radiographic tumor 
assessments according to the following timing (also stated in 
Section10.1),by the same method used at baselineand throughout the 
study:
Every 6 weeks (±7 days)until disease progression OR overall study 
completion OR 1 year after randomization,whichever occurs first.  In 
addition, any patient whose disease has not progressed by 1 year after 
randomization will be evaluated for response every 12 weeks (±7days) 
from 1 year after randomization, until disease progression OR overall 
study completion OR 3 years after randomization, whichever occurs 
first; then as per standard clinical practice after that.
After the patient has objective disease progression, radiologic tests are 
no longer required and the patient will be followed for survivalevery
3months(±7days)until the patient’s death or overall study 
completion, whichever occurs first.
Imaging studies include a CT scan of the chest and a contrast-
enhanced CT scan of the abdomenand pelvis or an equivalent MRI 
scan. Throughout the study,use the same imaging modality used at 
baseline. Routine bone scans should be performed only in the setting 
of bone disease,or as deemed appropriate if there is clinical suspicion 
of new or worsening bone metastases.

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Postdiscontinuation Follow-up
Cycle
Short-term
Follow-up
Long-termFollow-up
Visit
801
802-8XX
Duration
Refer to 
footnote for 
duration
Refer to footnote for duration
Procedure 
Category
Protocol Section 
or Attachment
Procedure
Comments
Survival 
information
7.3.4, 8.1, 10.1.2
Collection of survival 
information
X
X
Collection of survival data every 3 months (±7 days)until the patient’s 
death or overall study completion, whichever occurs first.Whenever 
possible, survival follow-up is conducted in person.If an in-person 
visit is not possible, the site may confirm survival by contacting the 
patient directly via telephone.
Adverse 
Events
10.3, 10.3.1, 
10.3.1.1, 10.3.3, 
12.2.11
AE collection and CTCAE 
grading
X
X
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System.  During 
Postdiscontinuation Long-termFollow-up, only SAEs that are related 
to protocol procedures or study treatment will be collected.
Concomitant 
Medications
9.6, 12.2.4
Concomitant medication 
notation
X
Laboratory/
Diagnostic 
Tests
10.3.1, 10.3.3, 
10.4.1, 12.2.11, 
12.2.12, Att2
Hematology
X
10.3.1, 10.3.3, 
10.4.1, 12.2.11, 
Att2
Chemistry
X
10.3.1, 10.3.3, 
10.4.1, 12.2.11, 
Att2
Coagulation
X
10.3.1, 10.3.3, 
10.4.1, 12.2.11, 
Att2
Urinalysis
X
Routine dipstick measurements, and if clinically indicated, 
microscopic analysis.  If urine dipstick or routine analysis indicates 
proteinuria ≥2+ at evaluations, a 24-hour urine collection (to assess 
protein) must be obtained.
10.3.3, Att 3
Hepatic monitoring
(X)*
* Hepatic monitoring tests (perAttachment 3; performed by Lilly-
designated [central]laboratory)may be obtained in the event of a 
treatment-emergent hepatic abnormalityand may be required in 
follow-up with patients in consultation with the Lilly CRP/CRS or 
designee.
10.4.4, 12.2.8, 
Att7
PK
Refer to
Attachment 7.
10.4.3, 12.2.8, 
Att7
Immunogenicity:  Anti-
ramucirumabantibodies
10.4.2.2, 12.2.9, 
Att 7
Plasma and urine samples 
(biomarkers)

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Postdiscontinuation Follow-up
Cycle
Short-term
Follow-up
Long-termFollow-up
Visit
801
802-8XX
Duration
Refer to 
footnote for 
duration
Refer to footnote for duration
Procedure 
Category
Protocol Section 
or Attachment
Procedure
Comments
Other
12.2.4.1
Collection of 
postdiscontinuation anticancer 
therapy
X
X
Abbreviations:  AE = adverse event; Att = Attachment; CRP = (Lilly) clinical research physician; CRS = (Lilly) clinical research scientist; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-C30; MRI = magnetic resonance imaging; OS = overall survival; PK=pharmacokinetic(s); RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; SAEs = serious 
adverse events.
Note: No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.
Short-termFollow-upbegins the day after the patient and the investigator agree that the patient will nolonger continue study treatment and lasts approximately 30days.
Long-termFollow-upbegins the day after Short-termFollow-up is completed and continues until the patient’s death or overall study completion.  Patients who discontinue study treatment for reasons 
other than disease progressionwill continue to undergo radiographic tumor assessments according to the timing stated in Section 10.1, by the same method used at baselineand throughout the study, 
until the patient has radiographic documentation of disease progressionas defined by RECIST 1.1 or until overall study completion (that is, the final analysis of OS), whichever occurs first.  Patients will 
be followed for survival every 3 months (±7 days) until the patient’s death or overall study completion, whichever occurs first.

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Continued Access Schedule, I4T-MC-JVDC
Continued Access Period
Treatment Period
Continued Access 
Follow-up
Cycle
X-Y
Follow-up
Visit
501-5XX
901
Relative day within 
a cycle
1
Procedure 
Category
Protocol 
Section or
Attachment
Procedure
Comments
Physical 
Examination
9.4
Weight
X
BSAto be calculated at each cycle until docetaxel is discontinued.
Adverse Events
10.3, 10.3.1, 
10.3.1.1, 
10.3.3, 
12.2.11
AE collection and CTCAE grading
X
X
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System.
Laboratory/
Diagnostic 
Tests
10.4.4, 
12.2.8, Att 7
PK
Refer toAttachment 7.
If a patient experiences an IRR to ramucirumab, blood samples for 
both immunogenicity and PK analysis should be drawn, with no more 
than 15 minutes’ time difference.  Samples will be taken at the 
following time points:  (1) as soon as possible after the onset of the 
IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
10.4.3, 
12.2.8, Att 7
Immunogenicity:  Anti-ramucirumab
antibodies
Premedication
9.1.1, 
9.1.1.1, 
9.1.1.2
Premedication notation
X
Ramucirumab:  Premedication is required for all patients prior to each 
infusion of ramucirumab or placebo.
Docetaxel:  Premedicationis required for 3 days starting 1 day prior to 
infusion of docetaxel.
Study Drug
8.1.2, 9.1, 
9.1.2.1, 
9.2.1, 9.3, 
9.4, 9.4.1.1, 
9.7, 12.2.11
Ramucirumab
X
After study completion, all patients who are on study treatmentand 
who are eligible for continued access will be unblinded.  Patients 
receiving study treatment and experiencing ongoing clinical benefit and 
no undue risks may continue to receive study treatment in the 
Continued Access Period until one of the criteria for discontinuation is 
met (Section 7.3).  During the Continued Access Period, placebo will 
no longer be administered, the decision to permitcrossover or not will 
be made by Lilly after the final analysis of OS is completed.
8.1.2, 9.1, 
9.1.2.2, 9.3, 
9.4,9.4.1.2, 
9.7, 12.2.11
Docetaxel
X
Abbreviations:  AE = adverse event; Att = Attachment; BSA = body surface area; CTCAE = Common Terminology Criteria for Adverse Events; IRR=infusion-related reaction; 
PK=pharmacokinetics; OS = overall survival; SAE = serious adverse event.
Note:  No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.
Continued Access Periodbegins after study completion and ends at the end of trial.  During the Continued Access Period, patients on study treatment who continue to experience clinical benefit and no 
undue risks may continue to receive study treatment until one of the criteria for discontinuation is met.  The Continued Access Period includes Continued Access Follow-up.  During the Continued 
Access Period, required evaluations are shown in the table.  Investigators will perform any other standard procedures and tests needed to treat and evaluate patients and to confirm patient eligibility to 
continue on treatment; 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.
Continued Access Follow-upbegins the day after the patient and the investigator agree that the patient will no longer continue treatment in the Continued Access Period and lasts approximately
30days.
Note:  Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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Attachment 2.Protocol JVDCClinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistrya,b
Hemoglobin(HGB)
Serum Concentrations of:
Hematocrit(HCT)
Sodium
Erythrocytes(RBC)
Magnesium
Mean corpuscularvolume (MCV)
Potassium
Mean corpuscularhemoglobin concentration (MCHC)
Bilirubin, total
Leukocytes (WBC)
Bilirubin, direct
Neutrophilsc
Uric acid
Lymphocytes
Alkaline phosphatase
Monocytes
Alanine aminotransferase (ALT)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Blood urea nitrogen (BUN)
Platelets(PLT)
Creatinine
Calcium
Coagulationa,d:
Glucose, random
Prothrombin time (PT or INR)
Albumin
Partial thromboplastin time (PTT or aPTT)
Total protein
Lactate dehydrogenase
Chloride
Urinalysisa:
Phosphorus
Routine dipstick measurements, and if clinically 
indicated, microscopic analysis.  If urine dipstick or 
routine analysis indicates proteinuria ≥2+ at evaluations, a 
24-hour urine collection (to assess protein) must be 
obtained.
Otherb(seeAttachment 7):
Pregnancy Test(WOCBP only)
a,e
Anti-ramucirumab antibody (immunogenicity)
Ramucirumab concentrations in serum (PK)
Translationalresearch/biomarkers
Abbreviations:  β-hCG= beta human chorionic gonadotropin; aPTT = activated partial thromboplastin time; 
CRF=case report form; INR = international normalized ratio; PK = pharmacokinetic(s); PT = prothrombin time; 
RBC = red blood cells; WBC = white blood cells; WOCBP = women of childbearing potential.
a Assayed by local or investigator-designated laboratory.
b Assayed by Lilly-designated (central) laboratory.
c Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms.Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF,unless the CRF specifically provides an entry field for bands.
d For coagulation parametersPT and PTT/aPTT, thelaboratoryselectedfor eachat baselineshould be followed 
throughout the study.
e Serum pregnancy test in WOCBP will be done at baseline;thereafter,serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of β-hCG)to be performed in WOCBP every second cycle or per 
institutional guidelines, whichever is shorter.  Pregnancy test results will not be collected on the CRF.

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Attachment 3.Protocol JVDCHepatic 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 LillyCRP/CRSor designee.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin(HGB)
Hematocrit(HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets(PLT)
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Anti-nuclear antibodya
Aspartate aminotransferase (AST)
Gamma glutamyl transferase (GGT)
Anti-smooth muscle antibodya
Creatine phosphokinase (CPK)
Abbreviations:  CRP = (Lilly) clinical research physician; CRS = (Lilly) clinical research scientist; 
Ig=immunoglobulin; INR = international normalized ratio; RBC = red blood cells; WBC = white blood cells.
a Assayed by Lilly-designated (central) laboratory.
b Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms.Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together.
c Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 4.Protocol JVDCECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary
 nature, eg, 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 5.Protocol JVDCCreatinine Clearance Formula
Note:  This formula (or another standard formula)may beused forcalculating 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)
aage in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.

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Attachment 6.Protocol JVDCRECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm)
10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)
20 mm by chest X-ray
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitisinvolvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:
Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.
Blastic bone lesions are non-measurable.

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Cystic lesions:
Simple cysts should not be considered as malignant lesions (neither 
measurable nor nonmeasurable)
Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability.  If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions.
Lesions withPrior Local Treatment:
Tumor lesions situated at a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are non-measurable unless there has been demonstrated 
progression in the lesion.
Baseline Documentation of Target and Non-Target Lesion
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline.Non-nodal Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements.  
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of 15 mm by 
CT scan.  All measurements are to be recorded in the case record form (CRF) in millimeters (or 
decimal fractions of centimeters [cm]).
Nontarget Lesions
All other lesions (or sites of disease) are identified as nontarget lesions(chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline.  Measurement of these lesions are not required but should be 
followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal progression.’  In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as1 liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 

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should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient.  If prior to enrollment itis known a patient is not able to undergo CT scans with 
I.V.contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without I.V.contrast) should be used to evaluate the patient at baseline and follow-
up should be guided by the tumor type under investigation and the anatomic location of the 
disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion is recommended.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may be reviewed at the 
end of the study.
Chest X-ray:  Chest CT is preferred over chest X-ray when progression is an important endpoint.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
CT and MRI:  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm. When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (for example, for body scans).  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.
Ultrasound:  Ultrasound should not be used to measure lesion size.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or todetermine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  Specific guidelines for both prostate-specific antigen (PSA) response 
(in recurrent prostate cancer)and CA-125 response (in recurrent ovarian cancer) have been 
published.

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

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Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).
Non-CR/ non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable: When a change in method of measurement from baseline occursand impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy,taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.
Time Point Response
It is assumed that at each protocol-specified time point, a response assessmentoccurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable diseaseat baseline.
Table 1.
Time Point Response: Patients with Target (Nontarget) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; 
NE=inevaluable.

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Table 2 is to be used when patients have nonmeasurabledisease only.
Table 2.
Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations:  CR = complete response; PD = progressive disease; NE = inevaluable.
a non-CR/non-PD is preferred over SD for nontarget disease.
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6-8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective responsein clinical trials is to avoid overestimating 
the response rate observed.
Inrandomized trials(Phase 2 or 3) or studies where SD or progression is the primary endpoints, 
confirmation of response is not required.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from randomization.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for PD the smallest measurements recorded on 
study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met(minimum interval not less 
than 5weeksfrom Day 1must be achieved), taking as reference the smallest sum on study (if the 
baseline sum is the smallest, that is the reference for calculation of PD).

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Independent Review of Response and Progression
When objective response (CR + PR) is the primary endpoint, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.

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Attachment 7.Protocol JVDCPharmacokinetic, 
Immunogenicity, and Translational ResearchSampling
ScheduleSampling Schedule
It is essential that the exact infusion start and stop times (actual clock readings) are recorded.  
The exact time of collection of each venous blood sample will be based on the clock used to 
record infusion times.  It is essential that the pharmacokinetic blood samples not be withdrawn
from the same site as the drug infusion.

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Pharmacokinetic, Immunogenicity, and Translational Research Sampling Schedule
Baseline
Study Treatment Period (21-daycycles)
Post-DC
Follow-up
Cycle 1,
Day 1
Cycle 2,
Day 1
Cycle 3,
Day 1
Cycle 5,
Day 1
Cycle 9,
Day 1
1st infusion
2nd infusion
3rd infusion
5th infusion
9th infusion
Sample for:
Protocol 
Section
≤28 days
Pre-inf
Post-inf
Pre-inf
Pre-inf
Pre-inf
Pre-inf
Post-inf
Short-term
Follow-upa
PKb
10.4.4
Xc
Xd
Xc
Xc
Xc
Xc
Xd
X
Immunogenicity
b
10.4.3
Xc
Xc
X
Tumor tissue
10.4.2.1
Xe
Plasma for 
biomarkers
10.4.2.2
X
X
Xf
Urinefor 
biomarkers
10.4.2.2
X
X
X
Whole blood 
sample for DNA 
analysis
10.4.2.3
Xg
Abbreviations:  DC = discontinuation; DNA = deoxyribonucleic acid; EDTA = ethylenediaminetetraacetic acid; inf= infusion; IRR = infusion-related reaction; 
PK = pharmacokinetic(s).
Note:  It is essential that the draw dates and draw times are accurately recorded.
Note:  For all samples collected prior to an infusion, it is recommended that samples be collected after it is confirmed that the patient is qualified to receive the 
infusion at that time point.
a Short-termFollow-up begins the day after the patient and the investigator agree that the patient will no longer continue (any) study treatment (during the 
Study Treatment Period) and lasts approximately30 days(until the [30-day] Short-termFollow-up visit is completed).
b If a patient experiences an IRRat any time while on study treatment (including during the Continued Access Period), separate blood samples for 
immunogenicity (anti-ramucirumabantibody) and PK analysis should be drawn, within no more than 15 minutes’ time difference.  Samples will be taken at 
the following time points:  (1) as soon as possible after the onset of the IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
c At Cycle 1, Day 1:  A preinfusion sample is to be drawn at any time prior to the first (ramucirumab/placebo)infusion.  For all other time points:  A 
preinfusion sample is to be drawn within 4 hoursprior to the beginning of the infusion.  The exact time of collection of each blood sample needs tobe 
recorded.
d A postinfusion sample is to be drawn within 0.5 hours after the completion of the ramucirumab/placeboinfusion.  The exact time of collection of each blood 
sample needs to be recorded.

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Pharmacokinetic, Immunogenicity, and Translational Research Sampling Schedule (concluded)
e If prior archived tumor specimens are available, and unless restricted by local regulations, submission of archived tumor tissue is mandatory.  If an archived 
specimen is not available, submission of a newly acquired biopsy is requested when biopsy is safe and feasible.  In addition, at any time during the study, if 
tumor tissue becomes available, a sample should be provided.
f When applicable, EDTA plasma should be collected as near as possible to the time of disease progression, during the Study Treatment Period.  If, for any 
reason, the post-progression sample cannot be collected at the time of progression, it should be collected at (or by) the (30-day) Short-termFollow-up visit.  
The post-progression sample should be collected before the initiation of any new anticancer therapy.
g Collected at baseline(preferred) or at later visits.

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Attachment 8.Protocol JVDC NCI-CTCAE v4.0 
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, 
nonsteroidal 
anti-inflammatory drugs 
[NSAIDs], narcotics, 
I.V. fluids); prophylactic 
medications indicated for 
≤ 24h
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 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 h
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.
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, I.V. 
fluids); prophylactic 
medications indicated for 
≤ 24 h
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; 
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:  I.V. = intravenous(ly); NSAIDs = nonsteroidal anti-inflammatory drugs.