An Open-Label, Multicenter, Phase 1 Study of Ramucirumab Plus Pembrolizumab in Patients With Locally Advanced and Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma, Non-Small Cell Lung Cancer, Transitional Cell Carcinoma of the Urothelium, or Biliary Tract Cancer
Phase: PHASE1
Conditions: Gastric Adenocarcinoma, Adenocarcinoma of the Gastroesophageal Junction, Non-small Cell Lung Cancer, Carcinoma, Transitional Cell, Biliary Tract Cancer
Sponsor: Eli Lilly and Company

I4T-MC-JVDF(b) Clinical Protocol 
 
An Open-Label, Multicenter, Phase 1 Study of Ramucirumab plus Pembrolizumab in Patients 
with Locally Advanced and Unresectable or Metastatic Gastric or Gastroesophageal Junction 
Adenocarcinoma, Non-Small Cell Lung Cancer, Transitional Cell Carcinoma of the Urothelium, 
or Biliary Tract Cancer 
 
NCT02443324 
 
Approval Date: 11-Feb-2016 
 
 

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Protocol I4T-MC-JVDF(b)
An Open-Label, Multicenter, Phase 1 Study of Ramucirumab 
plus Pembrolizumab in Patients with Locally Advanced and 
Unresectable or Metastatic Gastric or Gastroesophageal 
Junction Adenocarcinoma, Non-Small Cell Lung Cancer,
Transitional Cell Carcinoma of the Urothelium, or Biliary 
Tract Cancer
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) or pembrolizumab (MK3475), unless such persons are bound 
by a confidentiality agreement with Eli Lilly and Company or its subsidiaries.  This 
document and its associated attachments are subject to United States Freedom of 
Information Act Exemption 4.
Ramucirumab (LY3009806) and Pembrolizumab (MK3475)
This is an open-label, multicenter, Phase 1 study of ramucirumab plus pembrolizumab:  
Phase 1a (dose-limiting toxicity) and Phase 1b (safety and preliminary efficacy) will include 
patients with locally advanced and unresectable or metastatic gastric or gastroesophageal 
junction adenocarcinoma, non-small cell lung cancer, or transitional cell carcinoma of the 
urothelium.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 30 April 2015.
Amendment (a) Electronically Signed and Approved by Lilly on 02 June 2015.
Amendment (b) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 11-Feb-2016 GMT

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Table of Contents
An Open-Label, Multicenter, Phase 1 Study of Ramucirumab 
plus Pembrolizumab in Patients with Locally Advanced and 
Unresectable or Metastatic Gastric or Gastroesophageal 
Junction Adenocarcinoma, Non-Small Cell Lung Cancer,
Transitional Cell Carcinoma of the Urothelium, or Biliary 
Tract Cancer
Section
Page
1.
Synopsis .............................................................................................................................9
2.
Introduction ......................................................................................................................11
3.
Objectives and Endpoints..................................................................................................20
4.
Study Design.....................................................................................................................21
4.1.
Overview of Study Design ...........................................................................................21
4.1.1.
Phase 1a: Dose-Limiting Toxicity Observation ....................................................22
4.1.2.
Phase 1b:  Expansion ...........................................................................................23
4.1.3.
Study Period and Continued Access Definitions...................................................23
4.2.
Rationale for Study Design...........................................................................................25
4.2.1.
Dose Selection for Ramucirumab.........................................................................25
4.2.1.1.
Rationale for Selection of Ramucirumab Dose Schedule 
1 (8mg/kg every 3 weeks on Day 1 and Day 8 in Patients 
with Gastric-GEJ Cancer and BTC)................................................................25
4.2.1.2.
Rationale for Selection of Dose Schedule 2 (10mg/kg 
every 3 weeks)................................................................................................26
4.2.2.
Dose Selection for Pembrolizumab.......................................................................27
4.3.
Benefit/Risk Assessment..............................................................................................28
4.4.
End of Study/Trial Definition.......................................................................................28
5.
Study Population...............................................................................................................29
5.1.
Inclusion Criteria..........................................................................................................29
5.2.
Exclusion Criteria ........................................................................................................33
5.3.
Rescreening..................................................................................................................37
6.
Treatment..........................................................................................................................38
6.1.
Treatments Administered .............................................................................................38
6.1.1.
Selection and Timing of Doses.............................................................................38
6.1.1.1.
Phase 1a: Dose-Limiting Toxicity Observation...............................................39
6.1.1.1.1.
Definition of Dose-Limiting Toxicities .....................................................39
6.1.2.
Investigator Responsibilities.................................................................................40

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6.2.
Treatment Assignment .................................................................................................41
6.3.
Blinding .......................................................................................................................41
6.4.
Packaging and Labeling ...............................................................................................41
6.5.
Preparation/Handling/Storage.......................................................................................41
6.6.
Dose Adjustments, Delays, and Discontinuation...........................................................41
6.6.1.
Ramucirumab Dose Adjustments, Delays, and 
Discontinuation....................................................................................................41
6.6.2.
Pembrolizumab Dose Delays and Discontinuation................................................47
6.6.3.
Dose Delays for Reasons Not Related to Study Treatment....................................52
6.7.
Treatment Compliance .................................................................................................52
6.8.
Lifestyle and/or Dietary Requirements .........................................................................52
6.8.1.
Diet......................................................................................................................52
6.8.2.
Contraception.......................................................................................................52
6.9.
Concomitant Therapy...................................................................................................53
6.9.1.
Supportive Care ...................................................................................................54
6.9.1.1.
Infusion-Related Reactions- Ramucirumab and 
Pembrolizumab...............................................................................................54
6.9.1.1.1.
Infusion-Related Reactions-Ramucirumab ................................................54
6.9.1.1.2.
Infusion-Related Reactions-Pembrolizumab..............................................55
6.9.1.2.
Supportive Care for Ramucirumab..................................................................55
6.9.1.2.1.
Supportive Care by Adverse Event of Special Interest...............................55
6.9.1.2.1.1.
Hypertension.......................................................................................55
6.9.1.2.1.2.
Proteinuria ..........................................................................................55
6.9.1.2.1.3.
Thromboembolic Events .....................................................................55
6.9.1.2.1.4.
Bleeding/Hemorrhage .........................................................................56
6.9.1.2.1.5.
Gastrointestinal Perforation.................................................................56
6.9.1.2.1.6.
Reversible Posterior Leukoencephalopathy 
Syndrome............................................................................................56
6.9.1.2.1.7.
Congestive Heart Failure.....................................................................57
6.9.1.2.1.8.
Fistula Formation................................................................................57
6.9.1.2.1.9.
Surgery and Impaired Wound Healing ................................................57
6.9.1.2.1.10.
Liver Failure and Other Significant Liver Injury .................................57
6.9.1.2.2.
Supportive Care Agents for Ramucirumab-
Guidelines ................................................................................................57
6.9.1.2.2.1.
Antiemetic Agents ..............................................................................58
6.9.1.2.2.2.
Analgesic Agents ................................................................................58
6.9.1.2.2.3.
Appetite Stimulants.............................................................................58
6.9.1.2.2.4.
Granulocyte-Colony Stimulating Factors.............................................58
6.9.1.2.2.5.
Erythroid Growth Factors....................................................................58

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6.9.1.2.2.6.
Other Supportive Care Agents.............................................................58
6.9.1.3.
Supportive Care for Pembrolizumab...............................................................58
6.9.1.3.1.
Pneumonitis - Pembrolizumab ..................................................................59
6.9.1.3.2.
Diarrhea/Colitis - Pembrolizumab.............................................................59
6.9.1.3.3.
Type 1 Diabetes Mellitus or Hyperglycemia -
Pembrolizumab.........................................................................................59
6.9.1.3.4.
Hypophysitis - Pembrolizumab.................................................................59
6.9.1.3.5.
Hyperthyroidism or Hypothyroidism -
Pembrolizumab.........................................................................................60
6.9.1.3.6.
Hepatic Events - Pembrolizumab ..............................................................60
6.9.1.3.7.
Renal Failure or Nephritis - Pembrolizumab .............................................60
6.10. Continued Access Period..............................................................................................60
7.
Discontinuation Criteria ....................................................................................................62
7.1.
Discontinuation from Study Treatment.........................................................................62
7.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................62
7.2.
Discontinuation from the Study....................................................................................62
7.2.1.
Patients Who are Lost to Follow-Up.....................................................................63
8.
Study Assessments and Procedures ...................................................................................64
8.1.
Efficacy........................................................................................................................64
8.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................64
8.1.1.1.
Baseline Tumor Imaging ................................................................................64
8.1.1.2.
Tumor Imaging During Study Treatment ........................................................64
8.1.1.3.
Immune-Related RECIST (irRECIST)............................................................65
8.1.2.
Efficacy Assessments during Postdiscontinuation Follow-Up...............................67
8.1.3.
Efficacy Measures................................................................................................67
8.1.4.
Appropriateness of Measurements........................................................................68
8.2.
Safety...........................................................................................................................68
8.2.1.
Adverse Events ....................................................................................................69
8.2.1.1.
Reporting Ramucirumab Adverse Events of Special 
Interest and Pembrolizumab Events of Clinical Interest ..................................70
8.2.1.1.1.
Infusion-Related Reactions-Ramucirumab and 
Pembrolizumab.........................................................................................70
8.2.1.1.2.
Adverse Events of Special Interest- Ramucirumab....................................70
8.2.1.1.3.
Events of Clinical Interest- Pembrolizumab ..............................................71
8.2.1.2.
Serious Adverse Events ..................................................................................71
8.2.1.3.
Pregnancy.......................................................................................................72
8.2.1.4.
Suspected Unexpected Serious Adverse Reactions..........................................72
8.2.2.
Other Safety Measures .........................................................................................73

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8.2.2.1.
Electrocardiograms.........................................................................................73
8.2.2.2.
Echocardiogram or Multiple-Gated Acquisition Scan .....................................73
8.2.3.
Safety Monitoring ................................................................................................73
8.3.
Pharmacokinetics .........................................................................................................74
8.4.
Biomarkers...................................................................................................................74
8.4.1.
Genetics...............................................................................................................75
8.4.2.
Tailoring and Pharmacodynamic Biomarkers .......................................................75
8.5.
Samples for Immunogenicity Research.........................................................................76
8.6.
Health Economic and Outcomes Research....................................................................76
9.
Statistical Considerations and Data Analysis.....................................................................77
9.1.
Determination of Sample Size ......................................................................................77
9.2.
General Statistical Considerations ................................................................................78
9.3.
Patient Characteristics ..................................................................................................79
9.3.1.
Concomitant Therapy...........................................................................................79
9.3.1.1.
Postdiscontinuation Therapy...........................................................................80
9.3.2.
Treatment Compliance .........................................................................................80
9.4.
Efficacy Analysis: Phase 1b .........................................................................................80
9.5.
Safety Analyses............................................................................................................80
9.6.
Pharmacokinetic/Pharmacodynamic Analyses..............................................................80
9.7.
Other Analysis .............................................................................................................81
9.7.1.
Immunogenicity...................................................................................................81
9.7.2.
Biomarker Analysis..............................................................................................81
9.8.
Interim Analyses ..........................................................................................................81
10.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process................................................................................................................82
10.1. Informed Consent.........................................................................................................82
10.2. Ethical Review.............................................................................................................82
10.3. Regulatory Considerations ...........................................................................................82
10.4. Investigator Information...............................................................................................83
10.5. Protocol Signatures ......................................................................................................83
10.6. Final Report Signature..................................................................................................83
10.7. Complaint Handling.....................................................................................................83
10.8. Data Quality Assurance................................................................................................83
10.8.1.
Data Capture System............................................................................................84
10.9. Study and Site Closure .................................................................................................84
10.9.1.
Discontinuation of Study Sites .............................................................................84
10.9.2.
Discontinuation of the Study................................................................................84
11.
References ........................................................................................................................85

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List of Tables
Table
Page
Table JVDF.1.
Ramucirumab and Pembrolizumab Data Summary: Gastric-GEJ, 
NSCLC, and Urothelial Indicationsa .......................................................15
Table JVDF.2.
Phase 1 Treatment Regimens/Dosing Schedule.......................................38
Table JVDF.3.
Ramucirumab Dose Reductionsa ............................................................42
Table JVDF.4.
Dose-Modification Guidelines for Ramucirumab for Adverse 
Events at Least Possibly Related to Ramucirumab, including 
Adverse Events of Special Interest..........................................................43
Table JVDF.5.
Pembrolizumab Treatment Discontinuation Guidelines for Specific 
Adverse Events at Least Possibly Related to Pembrolizumab..................48
Table JVDF.6.
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease................................................................................66
Table JVDF.7.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........69
Table JVDF.8.
Summary of Statistical Power for Overall Response Rates for 
NSCLC 2-4L, Bladder 2-4L, BTC 2-3L, and Gastric 2-3L......................78
Table JVDF.9.
Summary of Statistical Power for Overall Response Rates for 
NSCLC 1L and Gastric 1L .....................................................................78

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List of Figures
Figure
Page
Figure JVDF.1.
Illustration of study design......................................................................22
Figure JVDF.2.
Study period and continued access diagram. ...........................................24
Figure JVDF.3.
Predicted Cmin,ss following different dose regimens. ................................26

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JVDF Time and Events Tables .................................................91
Attachment 2.
Protocol JVDF Pharmacokinetic, Immunogenicity, and Biomarker 
Sampling Schedules................................................................................99
Attachment 3.
Protocol JVDF Clinical Laboratory Tests .............................................104
Attachment 4.
Protocol JVDF ECOG Performance Status ...........................................105
Attachment 5.
Protocol JVDF Creatinine Clearance Formula ......................................106
Attachment 6.
Protocol JVDF RECIST Criteria 1.1.....................................................107
Attachment 7.
Protocol JVDF Restricted and Prohibited Concomitant Therapy...........114
Attachment 8.
Protocol JVDF Abbreviations and Definitions ......................................116
Attachment 9.
Protocol JVDF Amendment(b)
Summary An Open-Label, Multicenter, Phase 1 Study of 
Ramucirumab plus Pembrolizumab in Patients with Locally 
Advanced and Unresectable or Metastatic Gastric or 
Gastroesophageal Junction Adenocarcinoma, Non-Small Cell Lung 
Cancer, Transitional Cell Carcinoma of the Urothelium, or Biliary 
Tract Cancer.........................................................................................122

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1.
Synopsis
Title of Study: An Open-Label, Multicenter, Phase 1 Study of Ramucirumab plus Pembrolizumab in Patients with 
Locally Advanced and Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma;
Non-Small Cell Lung Cancer; Transitional Cell Carcinoma of the Urothelium; or Biliary Tract Cancer
Summary of Study Design:
Study I4T-MC-JVDF is an open-label, multicenter Phase 1 study to evaluate the safety and efficacy of ramucirumab 
in combination with pembrolizumab.  Phase 1a (dose-limiting toxicity [DLT]) and Expansion Phase 1b (safety and 
preliminary efficacy) will include patients with locally advanced and unresectable or metastatic gastric or 
gastroesophageal junction adenocarcinoma; non-small cell lung cancer (NSCLC); transitional cell carcinoma of the 
urothelium (urothelial cancer); or biliary tract cancer (BTC).  If sufficient tolerability and preliminary efficacy are 
demonstrated in Phase 1, the protocol will be amended to further evaluate efficacy and safety, and re-submitted 
accordingly.
Objective(s)/Endpoints
Objectives
Endpoints
Phase 1a 
and 1b
Primary: To assess the safety and tolerability of 
2 dosing regimens of ramucirumab plus 
pembrolizumab
Dose-limiting toxicities, observed during a
21-day treatment cycle
Safety (include but are not limited to):
TEAEs, SAEs, deaths, laboratory 
abnormalities, vital signs, and physical exams
Secondary:
To characterize the PK of ramucirumab when co-
administered with pembrolizumab
PK: 
Cmin and approximate Cmax of ramucirumab 
in serum
Phase 1b
Secondary:
To assess the preliminary efficacy of ramucirumab 
plus pembrolizumab
Efficacy:
ORR (RECIST 1.1 and irRECIST)
DCR, DOR, TTR, PFS, and OS
Abbreviations: Cmax = maximum concentration; Cmin = minimum concentration; DCR = disease control rate; 
DOR= duration of response; irRECIST= immune-related RECIST; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response Evaluation Criteria In 
Solid Tumors; SAEs = serious adverse events; TEAEs = treatment-emergent adverse events; TTR = time to 
response.

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Treatment Arms and Duration:
DLT Phase 1a
Patients will be treated for up to 21 days (1 cycle); patients without a DLT may continue in Expansion 
Phase 1b.
Dosing Schedules

Schedule 1: ramucirumab 8 mg/kg on Day 1 and Day 8 and pembrolizumab 200 mg (fixed dose) on 
Day 1, in 3 patients with gastric-gastroesophageal (GEJ) cancer or biliary tract cancer (BTC)

Schedule 2: ramucirumab 10 mg/kg and pembrolizumab 200 mg (fixed dose) on Day 1, in 3 patients 
with either gastric-GEJ, NSCLC, or urothelial cancer
Number of patients: up to 12 DLT-evaluable patients (up to 6 enrolled in each dosing schedule)
Expansion Phase 1b
Duration: Continues until approximately 2 years after the first patient received study treatment.  
Individual patients may continue treatment for up to 35 cycles (approximately 2 years), until confirmed 
progressive disease or discontinuation for any other reason.
Treatment Cohorts

Schedule 1 Dose:  
o Gastric-GEJ (2nd - 3rd Line) Cohort A (15 patients),
o BTC (2nd - 3rd Line) Cohort A1 (25 patients), and 
o Gastric-GEJ (1st Line) Cohort A2 (25 patients).  

Schedule 2 Dose: 
o Gastric-GEJ (2nd - 3rd Line) Cohort B (15 patients), 
o NSCLC (2nd - 4th Line) Cohort C (25 patients), 
o Urothelial (2nd - 4th Line) Cohort D (25 patients), and
o NSCLC (1st Line) Cohort E (25 patients).
Number of patients: approximately 155 patients
Statistical Analysis:  
For the Phase 1a, a 3+3 design will be used to assess the safety of ramucirumab in combination with 
pembrolizumab.  Additional patients will be enrolled in a dosing schedule to achieve the minimum of 3 evaluable 
patients, if dropouts or dose interruptions or reductions occur that result in a patient being non-evaluable for DLTs.  
Data will be reviewed by dose schedule group (3 patients).
The final analysis of safety and preliminary efficacy will occur approximately 2 years after the first patient received 
first study treatment. Interim analyses will occur at a cohort level when the patients have completed approximately 
24 weeks of study treatment, or discontinued for any reason. Safety and preliminary efficacy will be analyzed 
separately for each cohort.  
Descriptive statistics will be derived where appropriate.  The rate of DLTs will be summarized by cohort; dose 
exposure and density for each study drug will be calculated for each cohort.

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2.
Introduction
Ramucirumab (Cyramza™), a human immunoglobulin, subclass 1 anti-vascular endothelial 
growth factor (VEGF) Receptor 2 monoclonal antibody, has obtained marketing authorization in 
the United States (US), European Union (EU), and Japan for the treatment of advanced gastric or 
gastroesophageal junction (gastric-GEJ) adenocarcinoma as monotherapy (Study I4T-IE-JVBD 
[REGARD]) or in combination with paclitaxel (Study I4T-IE-JVBE [RAINBOW]), with disease 
progression on or after prior fluoropyrimidine- and/or platinum-containing chemotherapy.  
Ramucirumab is also approved in the US and EU for the treatment of advanced non-small cell 
lung cancer (NSCLC) in combination with docetaxel (Study I4T-MC-JVBA [REVEL]), with 
disease progression on or after prior platinum-based chemotherapy. Patients with epidermal 
growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have 
disease progression on approved therapy for these aberrations prior to receiving ramucirumab.  
Ramucirumab is also approved in the US and EU for the treatment of metastatic colorectal 
cancer (CRC) in combination with FOLFIRI (irinotecan, 5-fluorouracil, and folinic acid; Study 
I4T-MC-JVBB [RAISE]) with disease progression on or after therapy with bevacizumab, 
oxaliplatin, and a fluoropyrimidine.
In a well-controlled, randomized urothelial Phase 2 Study I4Y-IE-JCDC (JCDC), the addition of 
ramucirumab to the standard docetaxel regimen provided a significant improvement in 
progression-free survival (PFS) compared with the control therapy.  The magnitude of 
improvement in PFS and investigator-assessed response versus the standard single-agent 
docetaxel regimen represents a meaningful therapeutic benefit.
In addition, the toxicity profile of ramucirumab has been manageable given as a monotherapy or 
in combination.  REGARD, a single-agent, placebo-controlled, Phase 3 gastric cancer study, 
25 patients (10.5%) receiving ramucirumab discontinued study treatment due to adverse events
(AEs).  The most common adverse drug reactions reported in ≥10% of ramucirumab-treated 
patients were abdominal pain, diarrhea, and hypertension.  Clinically relevant reactions 
(including Grade ≥3) associated with antiangiogenic therapy observed in ramucirumab-treated 
patients across clinical trials were proteinuria, infusion-related reactions, and gastrointestinal 
(GI) perforations.
Pembrolizumab [Keytruda (US)], a humanized monoclonal antibody against the programmed 
death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. 
Pembrolizumab is approved for treatment of melanoma in several countries; in the US and EU it 
is approved for the treatment of advanced (unresectable or metastatic) melanoma in adults. 
Pembrolizumab has also been approved for treatment of NSCLC in several countries; in the US 
it is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 
as determined by an FDA-approved test and who have disease progression on or after platinum-
containing chemotherapy. Patients with NSCLC and epidermal growth factor receptor (EGFR)
or anaplastic lymphoma (ALK) genomic tumor aberrations should also have disease progression 
on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.

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There are multiple Phase 3 programs ongoing, including but not limited to NSCLC (KEYNOTE 
024, 042), squamous cell head and neck squamous cell carcinoma (KEYNOTE 040), and 
urothelial cancer (KEYNOTE 045).  Results from studies of pembrolizumab used as a 
monotherapy in advanced NSCLC, gastric-GEJ cancer, and in urothelial cancer have shown 
preliminary antitumor activity with a manageable safety profile.  Single-agent efficacy in each of 
these tumor types ranged from 22% to 24% objective response rates in PD-L1-positive patients
(Table JVDF.1).  Additional efficacy and safety information is shown in the table below.
The toxicity profile of pembrolizumab has been manageable, with <10% of patients stopping 
drug because of side effects.  The most common adverse reactions (≥20%) seen with 
pembrolizumab were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, 
arthralgia, and diarrhea. Similar side effect profiles were seen in patients with tumor types other 
than melanoma. Although less common, immune-mediated adverse reactions, including 
pneumonitis, colitis, hepatitis, hypophysitis, renal failure, immune-mediated nephritis, 
hypothyroidism, and hyperthyroidism, need to be carefully monitored when treating with these 
types of agents (Keytruda US package insert [USPI]).
Table JVDF.1 presents a high level summary of the ramucirumab and pembrolizumab safety and 
efficacy data for the 3 patient populations that are being explored in this study, gastric-GEJ, 
NSCLC, and urothelial cancer.
More information about the clinical data, including known and expected benefits, risks, and 
reasonably anticipated AEs of monotherapy with either pembrolizumab or ramucirumab, may be 
found in the respective Investigator’s Brochures (IBs).
Immune Checkpoint Blockers Targeting PD-1/PD-L1
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.
Immune checkpoints, such as PD-1 and PD-L1, have been targeted with antagonist mAbs, such 
as PD-1 antibodies nivolumab and pembrolizumab and PD-L1 antibody MEDI4736.  In 
nivolumab and MEDI4736 trials, response rate ranged from 14% to 22% in NSCLC, head and 
neck cancer, and renal cell carcinoma in unselected patient populations (both PD-L1-positive and 
PD-L1-negative patients) (Brahmer et al. 2014a, 2014b; Fury et al 2014; Motzer et al. 2014).
Recent publications suggest multiple factors that predict outcomes of patients treated with 
immune checkpoint inhibitors.  Most notably is the evidence that higher expression levels of 
PD-L1 on the tumor-infiltrating immune cells is associated with better clinical outcomes 
(Herbst et al. 2014).  In pembrolizumab trials, response rate increased approximately 2-fold in 
PD-L1 “strong positive” patients, ranging from 39% to 50%, in NSCLC and head and neck 
cancer (Garon et al 2014, Chow et al 2014) In addition, tumor cells develop adaptive immune 
resistance through up-regulation of PD-L1 expression (Terme et al. 2012).  As the 
immuno-oncology field is gaining further knowledge on the biomarkers to predict antitumor 

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response, including biomarker assay consensus of expression level and validation, both 
PD-L1-positive and PD-L1-negative patients will be enrolled in this trial based on the 
ramucirumab and other PD-1 and PD-L1 blockers’ clinical activity in unselected patient 
population.  The Sponsor plans to utilize the current PD-L1 assay, under development with 
Merck, to explore whether PD-L1 expression further improves the outcome of patients when 
treating with a combination regimen of immune checkpoint inhibitor pembrolizumab and 
VEGF Receptor 2 inhibitor ramucirumab.
Further Rationale for the Study
The antitumor activity with manageable safety has been demonstrated by ramucirumab and 
pembrolizumab in the 3 tumor types (gastric-GEJ, NSCLC, and urothelial cancer) as described 
above, and the synergistic preclinical activity with the combination of ramucirumab and 
pembrolizumab described below, laid the foundation for investigating whether the combination 
therapy might further enhance the efficacy of these agents.
Preclinical Activity of the Combination
A synergistic antitumor effect when blocking VEGF Receptor 2 and PD-1 simultaneously was 
demonstrated in preclinical murine colon cancer model (Yasuda et al. 2013).  Dual blockade of 
both PD-1 and VEGF Receptor 2 inhibited tumor growth significantly compared to each mAb 
treatment, individually.  There were no overt toxicities in treated mice.  Treatment with 
anti-PD-1 mAb and anti-VEGF Receptor 2 mAb induced a significant increase in the expression 
of several potent pro-inflammatory cytokines and mediators.  There was also a constant tendency 
of increase in CD4+ and CD8+ T-cell infiltration in tumor tissues treated with the combination.
Preclinical data also demonstrated that vascular-normalizing doses of anti-VEGF Receptor 2 
antibody can reprogram the tumor microenvironment away from immunosuppression.  With 
T-cell activation induced by a whole cancer cell vaccine therapy, vascular-normalizing doses of 
anti-VEGF Receptor 2 antibody enhanced anticancer efficacy in a CD8+ T-cell–dependent 
manner in both immune-tolerant and immunogenic murine breast cancer models (Huang et al. 
2012).
Cellular and Molecular Rationale of the Combination 
Voron et al. recently demonstrated that VEGF-A enhances simultaneous expression of several 
inhibitory receptors, including PD-1, Tim-3, CTLA-4 and LAG3, on CD8+ T cells.  Anti-VEGF-
R2 antibody, not anti-VEGF-R1 antibody, can revert the expression of these inhibitory molecules 
that are involved in CD8+ T cell exhaustion (Voron et al. 2015).  Thus, combining anti-VEGF-
R2 antibody with anti-PD-1 antibody potentially alleviates effector CD8+ T cells from 
exhaustion in a synergistic way.  
This combination may also effectively target the two “parallel lives” as described by Motz and 
Coukos within the tumor microenvironment: immunosuppression and angiogenesis (Motz and 
Coukos 2011).  Multiple immunosuppressive cells recruited to the tumor microenvironment 
directly promote angiogenesis by secreting VEGF-A and other factors.  Tumor endothelium 
generated by angiogenesis not only supplies nutrients to the tumor, but also prevents T cell 

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infiltration through VEGF (derived from tumor)/VEGFR (expressed on endothelium) pathway
(Motz and Coukos 2013).  
In addition, as summarized by Terme et al, antiangiogenic molecules appear to have several 
advantages to combine with other immunotherapy agents: (1) they only restore regulatory T-cell 
proportion to a physiological level, avoiding autoimmune-mediated side effects; (2) they do not 
deplete activated T-cells; (3) they inhibit other immunosuppressive pathways such as myeloid-
derived suppressor cells (MDSC); and (4) they have potential antitumor effect on their own 
(Terme et al. 2012).
Clinical Safety of the Combination
A recent study combining MPDL3280A (anti-PD-L1) with bevacizumab (anti-VEGF-A) in 
patients with metastatic CRC demonstrated combining PD1/PD-L1 pathway blocker with 
antiangiogenic agent was well tolerated with no unexpected toxicities (Bendell et al. 2015).  
Most common AEs >20% in patients treated with MPDL3280A and bevacizumab were fatigue, 
diarrhea, nausea, pyrexia, vomiting, headache, and cough. Hodi et al. also demonstrated 
combining bevacizumab and ipilimumab (cytotoxic T-lymphocyte-associated antigen-4 
[CTLA-4] blocker) can be safely administered in melanoma patients.  The study findings 
provided a basis for further investigating future combinations of antiangiogenesis agents and 
immune checkpoint blockade (Hodi et al. 2014).
The manageable safety profile, clinical efficacy of these 2 agents individually, and the 
synergistic preclinical antitumor activity demonstrated, provide evidence supporting the rationale 
for clinically testing whether the simultaneous blockade of PD-1 and VEGF Receptor 2 enhances 
single-agent activity while maintaining an acceptable safety profile.

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Table JVDF.1.
Ramucirumab and Pembrolizumab Data Summary: Gastric-GEJ, NSCLC, and Urothelial Indicationsa
Indication
Study 
Treatment
N
Efficacy
Safety
Reference
Gastric-GEJ
Ram
238
ORR: 3%
Median PFS: 2.1 months
Median OS: 5.2 months
Adverse reactions occurring at a rate of ≥10% and in ≥2% more in 
ramucirumab than in placebo group: hypertension (16% [all grades]; 
8% [Grade 3-4]) and diarrhea (14% [all grades]; 1% [Grade 3-4])
Cyramza US Package 
Insert, April 2015
Ram + 
Paclitaxel
330
ORR:  28%
Median PFS:  4.4 months
Median OS: 9.6 months
Adverse reactions occurring at a rate of ≥30% and in ≥2% more in 
ramucirumab + paclitaxel than in the paclitaxel control group: 
fatigue/asthenia (57% [all grades]; 12% [Grade ≥3]), neutropenia 
(54% [all grades]; 41% [Grade ≥3]), diarrhea (32% [all grades]; 4% 
[Grade ≥3]), and epistaxis (31% [all grades]), 0% [Grade ≥3]).
Cyramza US Package 
Insert, April 2015
Pembro
39, 
PD-L1+ only
ORR: 22%
6-mo PFS rate:  24%
6-mo OS rate: 69%
Grade 3-5 drug-related AEs occurred in 4 patients, peripheral 
sensory neuropathy, fatigue, decreased appetite, hypoxia, and 
pneumonitis (n=1 each).
Muro et al. 2015
(ASCO GI 
Symposium)
NSCLC
Ram+ 
Docetaxel
628
ORR: 22.9%
Median PFS: 4.5 months
Median OS: 10.5 months
Adverse reactions occurred at a rate ≥30% and ≥2% more in the 
ramucirumab + docetaxel than in the docetaxel control group: 
fatigue/asthenia (55% [all grades]; 14% [Grade 3-4]), neutropenia 
(55% [all grades]; 49% [Grade 3-4]), and stomatitis/mucosal 
inflammation (37% [all grades]), 7% [Grade 3-4]).
Cyramza US Package 
Insert, April 2015
Pembro
495
ORR: 19.4% overall; 18% 
previously treated, 24.8% 
treatment naïve, 45.2% in 
PD-L1 strong + (≥50%), 
16.5% in PD-L1+ (1-49%), 
10.7% in PD-L1- (<1%)
Most common AEs were fatigue, pruritus, and decreased appetite.  
Grade 3-5 drug-related AE occurred in 47 patients (9.5%), most 
commonly dyspnea (n=19, 3.8%) and pneumonitis (n=9, 1.8%).
Garon et al. 2015

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Ramucirumab and Pembrolizumab Data Summary: Gastric-GEJ, NSCLC, and Urothelial Indications (concluded)
Indication
Study 
Treatment
N
Efficacy
Safety
Reference
Urothelial
Ram+
Docetaxel
46
ORR: 19.6%,
median PFS: 5.1 months
DCR: 67.4%
Most common AEs were fatigue (80.4%), decreased appetite 
(54.3%), nausea (54.3%), and neuropathy (50.0%). Grade ≥3 AEs, 
febrile neutropenia (19.6%), pneumonia (13%), and hypertension 
(4.3%) were higher with Doc + Ram.
Petrylak et al. 2015
(ASCO GU 
Symposium)
Pembro
33, PD-L1+ 
only
ORR: 24%
Median PFS:  8.6 weeks
Median OS: 9.3 months 
(6-month OS rate: 58%)
Most common AEs were fatigue (n=6), peripheral edema (n=4), and 
nausea (n=3); Grade 3-4 drug-related AEs were reported for 
4 patients (12%), with only rash seen in >1 patient (n=2).
O’Donnell et al. 2015
(ASCO GU
Symposium)
Abbreviations:  AE = adverse event; ASCO = American Society of Clinical Oncology; DCR = disease control rate; Doc = docetaxel; GEJ = gastroesophageal; 
GI = gastrointestinal; GU = genitourinary; N = number of patients; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall 
survival; PD-L1 = programmed death ligand 1; Pembro = pembrolizumab; PFS = progression-free survival; Ram = ramucirumab; US = United States.
a Preliminary efficacy and safety data for BTC (2nd -3rd Line), NSCLC (1st Line) and Gastric/GEJ (1st Line) are described below this table.

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Rationale for Expanding to Biliary Tract Cancer, First Line Gastric-GEJ, and First Line 
NSCLC
1). Biliary Tract Cancer:
Vascular endothelial growth factor (VEGF), one of the main proangiogenic factors, is 
overexpressed in approximately 50% to 60% of cholangiocarcinoma (CCC) (Yoshikawa, et al.
2008).  Benckert et al. also showed VEGF was secreted by tumor epithelial cells, and VEGFR1 
and VEGFR2 were exclusively expressed on tumor endothelial cells in CCC (Benckert et al. 
2003).  In gallbladder carcinomas, an increased VEGF secretion was significantly associated 
with increased angiogenesis (Giatromanolaki et al. 2003).  Increased microvascular density 
(MVD) was also observed in CCC (Benckert et al. 2003; Tang et al. 2006).  High MVD 
(increased angiogenesis) is associated with poor survival in BTC (Giatromanolaki et al. 2003; 
Möbius et al. 2007).  The above observations provided rationale for targeting angiogenesis 
pathway in developing therapies for BTC.
Anti-angiogenic agents have been investigated in BTC with comparable efficacy as standard 
chemotherapy, including bevacizumab in combination with gemcitabine and oxaliplatin, 
bevacizumab in combination with erlotinib, sorafenib, and sunitinib (Bengala et al. 2010; Lubner 
et al. 2010; Zhu et al. 2010; Yi et al. 2012; Lee et al. 2013).  In a more recent study, cediranib, a 
pan-VEGF receptor tyrosine kinase inhibitor, in combination with gemcitabine/cisplatin,
demonstrated an improved efficacy outcome in response rate (44% for 
cediranib/gemcitabine/cisplatin vs. 19% for placebo/gemcitabine/cisplatin) and 10% 
improvement in 6-month PFS survival and 1-year overall survival (71% vs. 61%; 58% vs. 48%, 
respectively) (Valle et al. 2015).  However, early discontinuation was observed due to the 
toxicity of the cediranib/chemotherapy combination. As a result, the early efficacy signal in this 
study did not translate into sustained anti-tumor activity. Thus, a well-tolerated anti-VEGFR 
therapy in combination with standard chemotherapy or other targeted therapy should be 
investigated further to enhance the efficacy outcome in BTC.  
Pembrolizumab has demonstrated preliminary efficacy in CRC and non-CRC patients with 
mismatch-repair (MMR)-deficiency in their tumors (Le et al. 2015). Patients with MMR-
deficient non-CRC had similar efficacy outcomes as MMR-deficient CRC.  MMR-deficiency is 
present in 2% to 20% of BTCs and other non-CRC GI cancers (Le et al. 2016). Recent data 
update confirmed the preliminary efficacy demonstrated previously in MMR–deficient non-CRC 
patients (n=10): objective response rate (ORR) is 50%, disease control rate (DCR) is 70%, and 
overall survival (OS) is 21 months (Le et al. 2016).  
This study will investigate the combination therapy in previously treated non-selected BTC 
patients with regard to MMR status based on several considerations: 1) ramucirumab targets
angiogenesis that is commonly observed in BTCs; 2) percentage of BTC patients whose tumors 
have MMR deficiency may be low (for example, occurrence of MMR deficiency in ampullary 
carcinoma appears less than in CRC [Agaram 2010]); 3) the hypothesis that the combination 
targets the two processes, angiogenesis and immunosuppression, simultaneously in the tumor 
microenvironment, may generate synergistic anti-tumor activity.  

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In summary, ramucirumab and pembrolizumab have demonstrated benefit across multiple tumor 
types, both as single agents or in combination with cytotoxic chemotherapy, and have been well 
tolerated.  Despite preliminary evidence of activity with both antiangiogenic agents in BTC or 
with checkpoint inhibitors, no targeted agent has been approved in this setting, and there remains 
a high unmet need for new treatment options.
2). First Line Gastric-GEJ:
Advanced gastric/GEJ cancer patients treated with current standard first-line chemotherapy have 
a median OS between 9 and 11 months (Cunningham et al. 2008; Pasini et al. 2011).  OS is 
further extended (13.8 months vs. 11.1 months) when adding trastuzumab to chemotherapy, 
capecitabine and cisplatin, for patients with HER2 overexpression/amplification, which accounts 
for only approximately 20% of gastric patients (Bang et al. 2010; Lordick 2011).  
Targeted therapies have been investigated to improve OS for the overall gastric patients in first 
line setting, but have yet to demonstrate significant improvement in OS.  AVAGAST trial 
indicated that adding bevacizumab to chemotherapy, fluoropyrimindine and cisplatin, increased 
OS as comparison with chemotherapy alone (12.1 months vs. 10.1 months), but failed to 
demonstrate statistical significance (p=.1002) (Ohtsu et al. 2011).  Regional differences in the 
efficacy outcome were observed between North America/Latin America versus Asia, in which a 
survival benefit was observed with addition of bevacizumab in North America and Latin 
America, but not in Asia.  Besides a preliminary efficacy signal with addition of bevacizumab, 
the combination therapy did not substantially alter the safety profile of the chemotherapy 
backbone.  Ramucirumab was also investigated in combination with mFOLFOX-6 in the first 
line setting for advanced adenocarcinoma of the esophagus, GEJ, or stomach (I4T-MC-JVBT 
CSR).  Although median PFS was similar between the ramucirumab + mFOLFOX-6 arm versus 
the mFOLFOX-6 alone arm, the PFS rate at 3 months and DCR were improved in the 
ramucirumab + mFOLFOX-6 arm.  In addition, median PFS was improved in patients with 
primary tumor location in gastric/GEJ/cardia (8.7 months vs. 7.1 months, HR=0.77).  Although 
the safety profile for ramucirumab in this study was consistent with the known safety profile of
ramucirumab, a higher discontinuation rate was observed in the ramucirumab + mFOLFOX-6 
arm than in the mFOLFOX-6 alone arm. A different chemotherapy backbone, capecitabine and 
cisplatin, is being utilized to combine with ramucirumab in a Phase 3 study for metastatic 
gastric/GEJ cancers in the first line setting (I4T-MC-JVCU, RAINFALL).
Pembrolizumab is also being investigated in first line setting for gastric/GEJ cancers as 
monotherapy and combination therapy with chemotherapy for advanced gastric/GEC cancers, 
KEYNOTE 059 (Phase 2 study) and KEYNOTE 062 (Phase 3 study).  Cisplatin and 5-FU or 
capecitabine was utilized as chemotherapy backbone for these two Keynote trials.  Preliminary 
results have not been released as of December 2015.
Based on the results of REGARD and RAINBOW, pembrolizumab preliminary data shown in 
gastric-GEJ cancer patients (KEYNOTE 012), and preliminary data combining anti-angiogenic 
agents with backbone chemotherapy, exploration of ramucirumab plus pembrolizumab
combination is warranted in the first line setting.  Simultaneously targeting angiogenesis and 

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immune checkpoint blocker, PD-1 may potentially further enhance the efficacy of either agent 
while maintaining tolerable safety profile.  This may be a viable first line therapy that does not 
contain a chemotherapy backbone for gastric/GEJ patients.
3). First Line NSCLC:
Inhibition of the angiogenesis pathway in combination with chemotherapy has been established
as a treatment option for NSCLC in the first line setting.  Bevacizumab in combination with 
paclitaxel and carboplatin obtained marketing authorization for non-squamous NSCLC as front 
line therapy (Sandler et al. 2006).  Preliminary efficacy was also demonstrated combining 
bevacizumab with erlotinib in Japanese patients with EGFR mutation-positive NSCLC as first 
line therapy in JO25567 study (Kato et al. 2014; Seto et al. 2014).  A Phase 3 study combining 
ramucirumab with erlotinib with safety run-in is currently ongoing in EGFR mutation-positive 
NSCLC patients in the first line setting (Study I4T-MC-JVCY, RELAY).
Immune checkpoint blockers have also been investigated in clinical studies with or without a 
chemotherapy backbone in the early line setting.  The KEYNOTE-021 evaluated the safety, 
tolerability, and clinical activity of pembrolizumab in combination with platinum doublet 
chemotherapy (PDC) for treatment-naive advanced NSCLC (Papadimitrakopoulou et al. 2015).  
Preliminary results in approximately 50 patients showed 28% and 58% objective response rates, 
depending on the backbone chemotherapies (pembrolizumab/carboplatin/paclitaxel and
pembrolizumab/carboplatin/pemetrexed, respectively).  Based on these KEYNOTE 021 results,
pembrolizumab is being investigated as a first-line therapy in multiple studies (KEYNOTE-024, 
042, and 189).  KEYNOTE 024 and 042 are to assess the efficacy of pembrolizumab 
monotherapy compared with standard of care (SOC) platinum-based chemotherapies in treatment 
naïve, advanced or metastatic NSCLC patients who are PD-L1 positive. Keynote 189 is to 
assess the safety and efficacy of pembrolizumab combined with platinum-pemetrexed 
chemotherapy versus platinum-pemetrexed chemotherapy alone in first line setting for advanced 
or metastatic non-squamous NSCLC.  Based on the established anti-tumor activities and 
tolerable safety profile of anti-angiogenic agents and anti-PD-1 antibodies in 
advanced/metastatic NSCLC (ramucirumab with chemotherapy in second line setting in REVEL, 
bevacizumab in combination with PDC in first line setting, pembrolizumab as monotherapy in 
later line setting in PD-L1+ patients in Keynote 001, pembrolizumab in combination with PDC 
in the first-line setting in Keynote 021, and nivolumab in NSCLC in Checkmate studies), 
investigation of ramucirumab plus pembrolizumab combination is warranted in the first-line 
NSCLC population as a potentially viable treatment option that does not contain a chemotherapy 
backbone.  Simultaneously targeting angiogenesis and immune checkpoint blocker, PD-1, may 
potentially further enhance the efficacy of either agent while maintaining tolerable safety profile.
As the PD-L1 assay in NSCLC patients has been validated and approved by regulatory 
authorities, PD-L1 positivity is required in the first line NSCLC patients to enhance the potential
for anti-tumor efficacy of the study treatment.  Pembrolizumab has demonstrated efficacy as 
monotherapy in PD-L1-positive NSCLC patients (KEYNOTE 001).  Current KEYNOTE 024 
and 042 studies also require PD-L1-positive NSCLC patients in the first line setting.

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3.
Objectives and Endpoints
Objective(s)/Endpoints
Objectives
Endpoints
Phase 1a 
and 1b
Primary:
To assess the safety and tolerability of 2 dosing 
regimens of ramucirumab plus pembrolizumab
Dose-limiting toxicities, observed during a 
21-day observation period
Safety 
(include but are not limited to):
TEAEs, SAEs, deaths, laboratory 
abnormalities, vital signs, and physical 
exams)
Secondary:
To characterize the PK of ramucirumab when co-
administered with pembrolizumab
PK:
Cmin and approximate Cmax  of 
ramucirumab in serum
Phase 1b
Secondary:

To assess the preliminary efficacy of 
ramucirumab plus pembrolizumab
Efficacy:
ORR (RECIST 1.1 and irRECIST)
DCR, DOR, TTR, PFS, and OS
Tertiary/Exploratory:

To explore the association between biomarkers 
and clinical outcomes

To characterize biomarker measures of 
immune functioning and angiogenesis

To assess  immunogenicity of ramucirumab 
when co-administered with pembrolizumab
Biomarkers: research on genetic and 
circulating factors
Immunogenicity: anti-ramucirumab 
antibody
NOTE: For a more complete description of terms and abbreviations, see Attachment 8.
Abbreviations: Cmax = maximum concentration; Cmin = minimum concentration; DCR = disease control rate; 
DOR= duration of response; irRECIST= immune-related RECIST; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response Evaluation Criteria In 
Solid Tumors; SAEs = serious adverse events; TEAEs = treatment-emergent adverse events; TTR = time to 
response.

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4.
Study Design
4.1.
Overview of Study Design
Study I4T-MC-JVDF is an open-label, multicenter Phase 1 study to evaluate the safety and 
preliminary efficacy of ramucirumab in combination with pembrolizumab.  Phase 1a 
(dose-limiting toxicity [DLT] observation) and Phase 1b (expansion; safety and preliminary 
efficacy) will include patients with locally advanced and unresectable or metastatic gastric or 
gastroesophageal junction (GEJ) adenocarcinoma (gastric-GEJ cancer), NSCLC, transitional cell 
carcinoma of the urothelium (urothelial cancer), or biliary tract cancer (BTC).
Based on the results of Phase 1, the Sponsor will consider various approaches toward developing 
the combination therapy, including but not limited to an adaptive Phase 2/3 trial design, enrolling 
additional patients, and/or testing alternative dosing levels and schedules.  If sufficient 
tolerability and activity are demonstrated in Phase 1, the protocol will be amended and 
resubmitted accordingly.
Figure JVDF.1 illustrates the study design.

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Abbreviations:  BTC = biliary tract cancer; GEJ = gastroesophageal; L = line; n = 
number of patients; NSCLC = non-small cell lung cancer; PK = pharmacokinetics; Ram 
= ramucirumab.
Note: The results of the Phase 1a interim analysis will confirm the dosing regimens to 
be used in Phase 1b.  Dose reductions (ramucirumab), delays, and discontinuations may 
occur per the guidelines in Section 6.6.
Figure JVDF.1.
Illustration of study design.
4.1.1. Phase 1a: Dose-Limiting Toxicity Observation
The DLT observation period of Phase 1a will employ a 3+3 design, enrolling up to 6 patients per 
dose schedule.  Patients will be allocated into one of 2 dose schedules, based on their diagnosis 
at baseline, as shown in Figure JVDF.1.
The DLT observation period will last for one 21-day treatment cycle (see Section 6.1.1 for 
selection and timing of doses).

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The definition for DLTs and the criteria used to determine progress of the study are provided in 
Section 6.1.1.1.
4.1.2. Phase 1b: Expansion
If results yield an acceptable number of DLTs (≤1) in the observation period of Phase 1a, then 
the Expansion Phase 1b (Expansion Portion) will start.
The results of the Phase 1a interim analysis will confirm the dosing regimens to be used in 
Phase 1b.  Dose reductions (ramucirumab), delays, and discontinuations may occur per the 
guidelines in Section 6.6.
Patients will be added to include 7 separate expansion cohorts, with dosing schedules
corresponding to those in DLT Phase 1a, as shown in Figure JVDF.1.  Gastric patients will be 
assigned to Cohort A, A2, or B (Section 6.2).
The final analysis of safety and preliminary efficacy will occur approximately 2 years after the 
first patient received first study treatment.  Interim analyses will occur at a cohort level when the 
patients have completed approximately 24 weeks of study treatment. The Phase 1b data will
provide additional safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and 
preliminary efficacy data for the combination.
4.1.3. Study Period and Continued Access Definitions
Terms used to describe the periods during the study are defined below and illustrated in
Figure JVDF.2.

Baseline/Screening:  begins when the informed consent form (ICF) is signed, and ends 
at the first study treatment (defined as receiving either ramucirumab or pembrolizumab);
if no study treatment is given, baseline/screening ends at discontinuation. Lasts up to 
28 days.

Study Period:  begins at the time of first study treatment and ends at study completion, 
which occurs approximately 2 years after the first patient received first study treatment
(Section 4.4).
o
Study Treatment Period:  begins with the day of the first patient’s first study 
treatment and ends the day that the decision is made to discontinue study 
treatment (discontinuation of both study drugs; Section 7.1).  Individual patients 
who enroll in Study JVDF may continue treatment for up to 35 cycles 
(approximately 2 years), until they have confirmed progressive disease or 
discontinued study treatment for any other reason.
o
Postdiscontinuation Follow-Up consists of the following 2 phases.

Short-Term (Safety) Follow-Up: begins the day after the patient and the 
investigator agree that the patient will discontinue study treatment and 
ends with the short-term follow up visit, to occur approximately 30 days 
thereafter.

Long-Term (Survival) Follow-Up: begins the day after short-term 
follow-up is completed and ends with the patient’s death, loss to 

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follow-up, or overall study completion, whichever is earlier. The 
long-term follow-up visit will occur approximately 90 days after the 
decision is made to discontinue from study treatment.  Subsequent 
follow-up (not a formal visit) will occur approximately every 90 days 
thereafter, for up to approximately 2 years from the first study treatment
(Attachment 1).

Continued Access Period: begins after study completion (final analysis and evaluation 
of the study endpoints) and ends at end of trial (defined in Section 4.4). In the continued 
access period, individual patients may continue the current study treatment after study 
completion, as long as they experience ongoing clinical benefit (details in Section 6.10).
Sites will be notified when the continued access period is to begin and end.
Patients who are in short-term follow-up when the continued access period begins will complete 
the 30-day short-term follow-up visit and then discontinue the study.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
Figure JVDF.2.
Study period and continued access diagram.
End of 
Trial
Study 
Completion
Study Period
Continued 
Access Period
Patient on 
Study 
Treatment
(Lilly will notify sites 
when the Continued 
Access Period  begins and ends.)  
Short-term 
(Safety)
Follow
-
Up 
Long-term
(Survival)
Follow -Up
Continued 
Access 
Period 
Follow -Up
Final analysis of 
study endpoints
Last visit/
scheduled procedure for 
last patient
Patient 
Discontinues 
Study 
Treatment
Interim analyses
Study Treatment
Individual patients continue on study treatment 
until a discontinuation criterion is met.
Patient 
Discontinues 
Study 
Treatment
If a discontinuation criterion occurs
Expansion Phase 1b 
Analysis of Primary 
Outcome

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4.2.
Rationale for Study Design
The general rationale for the study design is described in the Introduction (Section 2). The 
details regarding dose selections are described below.
4.2.1. Dose Selection for Ramucirumab
4.2.1.1. Rationale for Selection of Ramucirumab Dose Schedule 1 (8mg/kg every 
3 weeks on Day 1 and Day 8 in Patients with Gastric-GEJ Cancer and 
BTC)
Ramucirumab Dose Schedule 1 (8 mg/kg on Days 1 and 8; 21-day cycle) was based on 
exposure-response analyses in REGARD (8 mg/kg every 2 weeks [Q2W]) and RAINBOW
(8 mg/kg on Days 1 and 15; 28-day cycle).
Efficacy
Exposure-efficacy response analyses performed on data obtained from REGARD and 
RAINBOW demonstrated that an increase in exposure is associated with improved efficacy in 
terms of both overall survival (OS) and progression-free survival (PFS).  In both studies, patients 
with greater-than-median ramucirumab exposure demonstrated significantly longer OS and PFS 
(smaller hazard ratio [HR]) as compared to patients with less-than-median ramucirumab 
exposure.
These findings were consistent for all 4 exposure measures tested:  minimum concentration after 
first dose administration (Cmin,1), minimum concentration at steady state (Cmin,ss), maximum 
concentration at steady state (Cmax,ss), and average concentration at steady state (Cave,ss).
Safety
Weekly doses of ramucirumab ranging from 2 to 16 mg/kg were evaluated in the Phase 1 
Study JVBM.  A maximum tolerated dose (MTD) for weekly dosing was identified as 13 mg/kg.  
Every-2-week (6 to 10 mg/kg) and every-3-week (15 to 20 mg/kg) dose regimens were evaluated 
in another dose-ranging Study JVBN.  All dose regimens in Study JVBN were well tolerated and 
no MTD was identified in this study.
REGARD demonstrated a well-tolerated safety profile in the gastric-GEJ cancer monotherapy 
setting.  Due to the low incidence of hypertension and neutropenia, no safety-exposure 
relationship was identified for these treatment-emergent adverse events.
In RAINBOW, the overall safety profile was also considered manageable, although increasing 
ramucirumab exposure was correlated with increased incidence of Grade 3 or greater 
hypertension, neutropenia, and leukopenia. There were no Grade 4 or 5 hypertension events.  
Hypertension was managed primarily by the use of standard antihypertensive medication, and 
the association of neutropenia with ramucirumab exposure d id not appear to translate to an 
increased risk of febrile neutropenia with higher ramucirumab exposure.
These data indicate that there may be an opportunity to further improve ramucirumab activity in 
the gastric-GEJ indication.  Based on PK simulation, Dose Schedule 1 (8 mg/kg on Days 1 and 

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8; 21-day cycle) may produce Cmin,ss greater than the median Cmin,ss obtained from the standard 
8-mg/kg Q2W regimen in at least 70% of the patient population (Figure JVDF.3) and therefore
may produce better clinical efficacy outcomes relative to the 8-mg/kg Q2W regimen.  The 
ramucirumab-related safety risk in the gastric-GEJ cancer indication may not be significantly 
increased using Dose Schedule 1, as this dose is approximately 60% lower than the maximum 
tolerated weekly dose identified in the Phase 1 dose-escalation Study JVBM (13 mg/kg weekly).  
Thus, Dose Schedule 1 may further enhance the efficacy in Gastric-GEJ indication, and may be 
the appropriate dosing regimen for BTC as well.
Abbreviations:  Cmin,ss = minimum concentration at steady state; Q = every; W = week.
Box plots depict the 5th, 25th, 50th, 75th, and 95th percentiles calculated from 
1000 simulation iterations.
Figure JVDF.3.
Predicted Cmin,ss following different dose regimens.
4.2.1.2. Rationale for Selection of Dose Schedule 2 (10mg/kg every 3 weeks)
A ramucirumab dose of 10 mg/kg every 3 weeks (Q3W) in combination with docetaxel is the 
approved dose in second-line NSCLC, and has also been studied in second-line urothelial cancer
(JCDC).
In Study JCDC, ramucirumab 10 mg/kg Q3W in combination with docetaxel also demonstrated 
clinical safety and preliminary efficacy in previously treated urothelial cancer patients. No new 
unexpected safety findings were identified; the Grade ≥3 AEs occurring at a greater frequency in 
the docetaxel-plus-ramucirumab arm compared with the docetaxel-alone arm were fatigue 
(33% vs. 11%), febrile neutropenia (20% vs. 11%), diarrhea (7% vs. 2%), stomatitis (7% vs.
0%), and thrombocytopenia (7% vs. 0%).  Additionally, the preliminary efficacy results showed 
a median PFS of 10.4 weeks in the docetaxel monotherapy arm and 22.0 weeks in the 
docetaxel-plus-ramucirumab arm (stratified HR, 0.388; p<.001). This improvement in PFS 
represents a meaningful therapeutic benefit and warrants further exploration.

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Thus, Dose Schedule 2 (ramucirumab 10 mg/kg Q3W) was chosen for gastric-GEJ, NSCLC, and 
urothelial patients in Study JVDF.
4.2.2. Dose Selection for Pembrolizumab
An open-label Phase 1 trial (KEYNOTE 001) is being conducted to evaluate the safety and 
clinical activity of single-agent pembrolizumab (MK-3475).  The dose-escalation portion of this 
trial evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered Q2W in patients 
with advanced solid tumors.  All 3 dose levels were well tolerated and no DLTs were observed.  
This first-in-human study of pembrolizumab showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg, and 10 mg/kg 
Q2W).  No MTD has been identified.
In KEYNOTE 001, 2 randomized cohort evaluations of melanoma patients receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, and one 
randomized cohort evaluating of 10 mg/kg Q3W versus 10 mg/kg Q2W has also been 
completed.  The clinical efficacy and safety data demonstrate a lack of clinically important 
differences in efficacy response or safety profile at these doses.  For example, in Cohort B2, 
advanced melanoma patients who had received prior ipilimumab therapy were randomized to 
receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The objective response rate (ORR)
was 26% (21/81) in the 2-mg/kg group and 26% (20/76) in the 10-mg/kg group.  The proportion 
of patients with drug-related AE, Grade 3-5 drug-related AE, serious drug-related AE, death, or 
discontinuation due to an AE was comparable between groups or lower in the 10-mg/kg group.  
In Cohort B3, advanced melanoma patients (irrespective of prior ipilimumab therapy) were 
randomized to receive pembrolizumab at 10 mg/kg Q2W versus 10 mg/kg Q3W.  The ORR was 
30.9% (38/123) in the 10-mg/kg Q2W group and 24.8% (30/121) in the 10-mg/kg Q3W group 
(APaT).  The proportion of patients with drug-related AE, Grade 3-5 drug-related AE, serious 
drug-related AE, death, or discontinuation due to an AE was comparable between groups.
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (Pembrolizumab IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  These early PK and pharmacodynamic data provide scientific rationale for 
testing a Q3W dosing schedule.  Because Q3W dosing is more convenient for patients, Q3W 
dosing will be further studied.
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model), and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type.
The choice of 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 

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dose of 200 mg Q3W will provide exposures that 1) are optimally consistent with those obtained 
with the 2 mg/kg dose Q3W, 2) will maintain individual patient exposures in the exposure range 
established in melanoma as associated with maximal efficacy response, and 3) will maintain 
individual patients exposure in the exposure range established in melanoma that are well 
tolerated and safe.
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.
4.3.
Benefit/Risk Assessment
This study will provide benefit-risk data on the coadministration of pembrolizumab with 
ramucirumab.  An assessment of the hypothesized benefits and risks of co-administration is 
described in the Introduction (Section 2), and more details are included in the ramucirumab and 
pembrolizumab IBs.
4.4.
End of Study/Trial Definition
Study completion for Phase 1 of Study JVDF occurs after the clinical trial database is locked and 
the final analysis and evaluation of the study endpoints of dose-expansion Cohorts A through E
has occurred based on data available approximately 2 years after the first patient received first 
study treatment.  The end of trial occurs after study completion and when the last patient has 
discontinued study treatment and completed any applicable continued access follow -up (last 
patient last visit).  Section 6.1 describes the maximum duration of study treatment.

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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
5.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Have diagnosis with one of the following types of cancer:
a) Gastric-GEJ cancer (Cohort A [2nd-3rd Line] and Cohort B [2nd-3rd Line])

Histopathologically confirmed gastric or gastroesophageal junction (GEJ) 
adenocarcinoma (GEJ: Siewert Type I, II, and III)

Metastatic disease or locally advanced, unresectable disease

Documented disease progression to at least one prior line of systemic therapy 
and no more than two (2). Prior therapy for advanced disease must include a 
platinum and/or fluoropyrimidine.  Prior therapy in an adjuvant or 
neoadjuvant setting is not considered as a prior line of systemic 
chemotherapy, unless patient has rapidly progressed as defined by ≤ 6 months 
of last dose in this setting.  If it is ≤ 6 months, it will be regarded as a prior 
line of treatment.
b) Biliary Tract Cancer (Cohort A1 [2nd-3rd Line]) 

Have a histologically or cytologically confirmed diagnosis of non-resectable, 
recurrent, or metastatic biliary tract adenocarcinoma (intrahepatic or 
extrahepatic cholangiocarcinoma, gallbladder cancer, or Ampula of Vater).

Have adequate biliary drainage (per investigator’s discretion), with no 
evidence of ongoing infection.

Documented disease progression to at least 1 prior line of systemic therapy 
and no more than 2 prior lines of chemotherapy or biological therapy.  Prior 
therapy for advanced disease must include gemcitabine and cisplatin.  Prior 
therapy in an adjuvant or neoadjuvant setting is not considered as a prior line 
of systemic chemotherapy, unless patient has rapidly progressed, as defined 
by ≤ 6 months since the last dose of chemotherapy.
c) First-Line Gastric-GEJ Cancer (Cohort A2)

Histopathologically confirmed gastric or gastroesophageal junction (GEJ) 
adenocarcinoma (GEJ:  Siewert Type I, II, and III)

Metastatic disease or locally advanced, unresectable disease

No prior systemic chemotherapy for the treatment of the subject's advanced or 
metastatic (patients whose disease has progressed after>12 months following 
the last dose of systemic treatment in the adjuvant/neoadjuvant setting are 
eligible).

Patients are ineligible for or refuse standard chemotherapy approved for first 
line treatment
d) Second Line and later NSCLC (Cohort C [2nd-4th Line]) 

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
Histologically confirmed nonsquamous or squamous NSCLC

Metastatic disease or locally advanced, unresectable disease

Documented disease progression to at least one prior line of systemic therapy 
and no more than three (3).  Prior therapy for advanced disease must include a 
platinum.  Prior therapy in an adjuvant or neoadjuvant setting is not 
considered as a prior line of systemic chemotherapy, unless patient has rapidly 
progressed as defined by ≤ 6 months of last dose in this setting.  If it is 
≤6 months, it will be regarded as a prior line of treatment.

Patients with known EGFR or ALK mutations are eligible only if they have 
received at least one line of prior targeted therapy for these mutations.

A brain scan via computed tomography [CT] with contrast or magnetic 
resonance imaging [MRI] is to be performed to confirm absence of 
intracranial metastasis.
e) Urothelial Cancer (Cohort D [2nd-4th Line])

Histologically confirmed transitional cell carcinoma of the urothelium 
(bladder, urethra, or renal pelvis). Patients with mixed pathology are eligible 
only if they have predominantly transitional cell tumor based on local 
pathology review.

Metastatic disease or locally advanced, unresectable disease

Documented disease progression to at least one prior line of systemic therapy 
and no more than three (3). Prior therapy for advanced disease must include a 
platinum.  Prior therapy in an adjuvant or neoadjuvant setting is not 
considered as a prior line of systemic chemotherapy, unless patient has rapidly 
progressed as defined by ≤ 6months of last dose in this setting.  If it is 
≤6 months, it will be regarded as a prior line of treatment.

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.

A brain scan via CT with contrast or MRI is to be performed to confirm 
absence of intracranial metastasis.
f) First-Line NSCLC (Cohort E)

Histologically confirmed nonsquamous or squamous NSCLC

No prior systemic chemotherapy or radiotherapy for the treatment of the 
subject's advanced or metastatic (patients whose disease has progressed 
after>12 months following the last dose of systemic treatment in the 
adjuvant/neoadjuvant setting are eligible).

Patients are ineligible for or refuse standard chemotherapy approved for first 
line treatment

Metastatic disease or locally advanced, unresectable disease

Tumor specimen evaluable for PD-L1 expression by the central study 
laboratory and confirmation of PD-L1 expression level of at least 1% is 
required to be eligible

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
A brain scan via computed tomography (CT) with contrast or magnetic 
resonance imaging (MRI) is to be performed to confirm absence of 
intracranial metastasis.
[2]
Have the presence of measurable disease based on the Response Evaluation 
Criteria In Solid Tumors Version 1.1 (RECIST 1.1; Eisenhauer et al. 2009; 
Attachment 6) as determined by the site study team.  Tumor lesions situated in 
a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
[3]
Have provided signed informed consent and are amenable to compliance with 
protocol schedules and testing
[4]
Have submitted an evaluable tissue sample for biomarker analysis from a 
newly obtained core or excisional biopsy of a tumor lesion prior to 
enrollment.  Formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred.  Repeat samples may be required if adequate tissue is not provided.
Notes:  
Patients for whom newly obtained samples cannot be obtained (for example,
inaccessible or patient safety concern) may submit an archived specimen only 
upon agreement from the Sponsor. General guidance for archival samples is
in the biomarker section (Section 8.4.2).  See Criterion 1f for additional 
requirements for patients with 1st-Line NSCLC.
[5]
Have an Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) of 0 or 1 at the time of enrollment (Attachment 4)
[6]
Have urinary protein that is <2 on dipstick or routine urinalysis.  If urine 
dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine 
must be collected and must demonstrate <2 g of protein in 24 hours to allow 
participation in the study.

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[7]
Have adequate organ function, as defined in the table below, with all 
screening labs performed within 28 days of treatment initiation
Note: adequate organ function should be confirmed within 7 days prior to first dose 
on Cycle 1 Day 1.
System
Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
≥1.5 x 109/L
Platelets
≥100 x 109/L
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L (packed red blood cell transfusions are 
not allowed within one week prior to baseline hematology 
profile)
Renal
Creatinine OR
Measured or calculated creatinine 
clearance (see Attachment 5)
≤1.5 x ULN OR
≥60 mL/min
Hepatic
Total bilirubin
≤1.5 x ULN
AST (SGOT) and ALT (SGPT)
≤2.5 x ULN OR
≤5 x ULN for patients with liver metastases
Coagulationb
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
INR ≤1.5 x ULN or PT ≤ 5 seconds above ULN unless patient
is receiving anticoagulant therapy as long as INR or PT is 
within therapeutic range of intended use of anticoagulants
Partial Thromboplastin Time (PTT) or 
Activated Partial Thromboplastin Time 
(aPTT)
PTT or aPTT ≤ 5 seconds above ULN unless patient is 
receiving anticoagulant therapy as long as PTT or aPTT is 
within therapeutic range of intended use of anticoagulants
Thyroid
TSH, T3, and T4
TSH within the normal limits OR
Total T3 or free T3 and free T4 are within the normal limits.
Abbreviations:  ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin 
time; TSH = thyroid-stimulating hormone; ULN = upper limit of normal.
a
Creatinine clearance should be calculated per institutional standard.
b
Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant 
or low molecular weight heparin.  If receiving warfarin, the patient must have an INR ≤ 3.0 and no active 
bleeding (i.e., no bleeding within 14 days prior to first dose of study treatment) or pathological condition present 
that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices).  Patients on 
anticoagulation therapy with unresected primary tumors or local tumor recurrence following resection are not 
eligible.
[8]
Be males or females at least 18 years of age on day of signing informed 
consent
[9]
Have an anticipated life expectancy of ≥3 months

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[10] Have resolution, except where otherwise stated in the inclusion criteria, of all 
clinically significant toxic effects of prior systemic cancer therapy, surgery, or 
radiotherapy to Grade ≤1 by National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (v 4.0)
[11] For male patients, are sterile (including vasectomy confirmed by post-
vasectomy semen analysis) or agree to use a reliable method of birth control 
and to not donate sperm during the study and for at least 120 days following 
the last dose of study treatment
Note:  Abstinence is acceptable if this is the established and preferred contraception 
for the patient.
[12] For female patients, are surgically sterile, are postmenopausal, or agree to use 
a highly effective method of birth control (2 methods preferred) during the 
study and for 120 days following the last dose of study treatment
Note:  A "highly effective method of birth control" is defined in Section 6.8.2.
[13] If female and of childbearing potential, must have a negative serum or urine 
pregnancy test within 7 days prior to enrollment.
Note: Non-childbearing potential (by other than medical reasons) is defined in 
Section 6.8.2.
Note:  Abstinence is acceptable if this is the established and preferred contraception 
for the patient.
5.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] Have non-measurable disease
[15] Have known brain metastases, uncontrolled spinal cord compression, or 
leptomeningeal disease
[16] Have received equal to or greater than 3 lines of prior systemic anticancer 
therapy for advanced disease in GEJ patients, and equal to or greater than 4 in 
patients in NSCLC and urothelial cancer patients
[17] Have a serious illness or medical condition(s) including, but not limited to, the 
following:

Diagnosis of immunodeficiency or are receiving systemic steroid therapy 
or any other form of immunosuppressive therapy within 7 days prior to the 
first dose of trial treatment.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.

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
Active autoimmune disease that has required systemic treatment in past 2 
years (that is, with use of disease-modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (for example, thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.

Received a prior autologous or allogeneic organ or tissue transplantation

Evidence of active, non-infectious pneumonitis

History of interstitial lung disease

Known human immunodeficiency virus (HIV) infection or acquired 
immunodeficiency syndrome (AIDS)-related illness

Known active Hepatitis B or Hepatitis C infection

Liver cirrhosis at a level of Child-Pugh B (or worse)

Liver 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.

Have a serious cardiac condition, such as congestive heart failure; unstable 
angina pectoris; myocardial infarction within the last 6 months; 
valvulopathy that is severe, moderate, or deemed clinically significant; or 
arrhythmias that are symptomatic or require treatment (not including 
patients with rate-controlled atrial fibrillation)

Active or uncontrolled clinically serious infection

Known psychiatric or substance abuse disorders

Known allergy or hypersensitivity reaction to any of the treatment 
components

Have ongoing or recent (≤6 months) hepatorenal syndrome
[18] History of hematologic malignancy, malignant primary brain tumor, 
malignant sarcoma, or other malignant priory solid tumor not under study, 
except:

no evidence of that disease for 5 years

adequately treated non-melanomatous skin cancer

curatively treated cervical carcinoma in situ or other noninvasive 
carcinoma or in situ neoplasm

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[19] Have received any previous systemic therapy (including investigational 
agents) targeting VEGF/VEGF receptor, PD-1/PDL-1, or PD-1/PDL-2 
signaling pathways.  Prior therapy with other immune checkpoint inhibitor, 
including but not limited to, anti-CD137 antibody or anti-CTLA-4 antibody, is 
not permitted.  ONLY for NSCLC patients:  prior VEGF/VEGF receptor
treatment is allowed.
[20] Have received a live vaccine within 30 days prior to enrollment.  Seasonal flu 
vaccines that do not contain live virus are permitted.
[21] Have received transfusion of blood products (including platelets or red blood 
cells) or administration of colony-stimulating factors (including granulocyte 
colony-stimulating factor [G-CSF], granulocyte-macrophage 
colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 
4 weeks prior to Cycle 1 Day 1
[22] Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding 
episode within 12 weeks prior to enrollment
[23] Have experienced any arterial thrombotic event, including myocardial 
infarction, unstable angina, cerebrovascular accident, or transient ischemic 
attack, within 6 months prior to enrollment
[24] Have experienced any Grade 3 or 4 venous thromboembolic event (VTE) that 
is considered by the investigator to be life threatening or that is symptomatic 
and not adequately treated by anticoagulation therapy, within 6 months prior 
to enrollment
[25] Have a history of gastrointestinal perforation and/or fistula within 6 months 
prior to enrollment
[26] Have a bowel obstruction, history or presence of inflammatory enteropathy or 
extensive intestinal resection (hemicolectomy or extensive small intestine 
resection, either condition with chronic diarrhea), Crohn's disease, ulcerative 
colitis, or chronic diarrhea
[27] Have uncontrolled hypertension, as defined as Grade >2 CTCAE Version 4.0
(clinically, the patient continues to experience elevated blood pressure 
[systolic >160 mmHg and/or diastolic >100 mmHg] despite medications)
[28] Are receiving chronic therapy with any of the following within 7 days prior to 
enrollment: 

nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, 
ibuprofen, naproxen, or similar agents)

other anti-platelet agents (such as clopidogrel, ticlopidine, dipyridamole, 
or anagrelide)

Aspirin use at doses up to 325 mg/day is permitted.

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[29] Have had a serious or non-healing wound, ulcer, or bone fracture within 
28 days prior to enrollment
[30] Have an elective or a planned major surgery during the course of the trial or 
has undergone major surgery within 28 days prior to enrollment, or central 
venous access device placement within 7 days prior to enrollment.
Note:  If patient received major surgery, the patient must have recovered 
adequately from the toxicity and/or complications from the intervention prior 
to starting therapy.
[31] Have had chemotherapy, targeted small molecule therapy, or radiation therap y 
within 2 weeks and/or monoclonal antibody treatment within 4 weeks prior to 
enrollment or not recovered (that is, ≤ Grade 1 or at baseline) from previously 
administered agents
Note:  Neuropathy (≤ Grade 2) or nonserious and nonlife-threatening toxicities, such 
as alopecia, altered taste, or nail changes, are an exception to this criterion.  
Note: Palliative radiotherapy during the study, if clinically indicated, can be 
considered after consultation with the Lilly clinical research physician (CRP).
[32] Are currently enrolled in a clinical trial involving an investigational product or 
non-approved use of a drug, or concurrently enrolled in any other type of 
medical research judged not to be scientifically or medically compatible with 
this study or discontinued study drug within 28 days prior to enrollment.  
Patients participating in surveys or observational studies are eligible to 
participate in this study.
[33] Are or have an immediate family member (for example, spouse, parent/legal 
guardian, sibling, or child) who is investigational site or sponsor staff directly 
involved with this trial, unless prospective institutional review board (IRB)
approval (by chair or designee) is given allowing exception to this criterion 
for a specific patient
Additional Key Exclusion Criteria specific to all Gastric-GEJ patients:
[34] Have squamous cell or undifferentiated gastric-GEJ cancer
[35] Received previous systemic chemotherapy with a cumulative dose of 
>900 mg/m2 of epirubicin or >400 mg/m2 of doxorubicin
Additional Key Exclusion Criteria specific to all NSCLC patients:
[36] Have radiologically documented evidence of major blood vessel invasion or 
encasement by cancer
[37] Have radiographic evidence of intratumor cavitation, regardless of tumor 
histology
[38] Have a history of gross hemoptysis (defined as bright red blood or 
≥1/2 teaspoon) within 2 months prior to enrollment

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[39] Have pleural effusion, pericardial fluid, or ascites requiring drainage every 
other week or more frequently
[40] Have superior vena cava syndrome
[41] Have preexisting idiopathic pulmonary fibrosis as evidenced by 
CT scan/X-ray at baseline; have or had any disease of acute lung injury, 
idiopathic pulmonary fibrosis, or pneumoconiosis evident on an X-ray; have 
or had any disease of radiation pneumonia or drug-induced pneumonia
Additional Key Exclusion Criteria specific to First Line NSCLC patients
(Cohort E):
[42] Epidermal growth factor receptor (EGFR)-sensitizing mutation and/or is 
echinoderm microtubule-associated protein-like 4(EML4) gene/anaplastic 
lymphoma kinase (ALK) gene fusion positive, or these status never tested.
Additional Key Exclusion Criteria specific to BTC patients (Cohort A1):
[43] Has received more than 2 lines of therapy for advanced or metastatic disease.
[44] TACE or radiotherapy, including use of radioactive beads, is not allowed.  
[45] Received photodynamic treatment and does not have measurable or evaluable 
disease at the site.  Exception: there is clear evidence of disease progression at 
the local site or measurable and progressing disease is present at another site.
[46] Have mixed hepatocellular biliary tract cancer histology.
Additional Key Exclusion Criteria specific to First Line Gastric-GEJ patients 
(Cohort A2):
[47] HER2-positive status or HER2 status never tested
5.3.
Rescreening
Individuals who do not meet the criteria for participation in this study (screen failure) may be
re-screened, only after discussion with and permission from the Lilly CRP or designee.
Repeating laboratory tests during the screening period does not constitute 
re-screening. Screening laboratory tests may not be repeated more than twice in order to meet 
eligibility during the screening period.

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6.
Treatment
6.1.
Treatments Administered
Ramucirumab and pembrolizumab will be administered per Table JVDF.2.  For Gastric/GEJ, 
Urothelial, 2nd-4th line NSCLC and BTC, patients can receive study treatment after evaluable 
tumor tissue has been shipped to central study laboratory.  For first line NSCLC, patient can 
receive study treatment after PD-L1 expression has been confirmed to be at least 1% (Section 
5.1).
Across all study periods, including the continued access period, individual patients will be 
treated with ramucirumab and/or pembrolizumab, as follows:

until confirmed progressive disease (Section 8.1.1.3), unacceptable toxicity, or 
discontinuation for any other reason

for a maximum duration of study treatment of 35 cycles, approximately 2 years
Table JVDF.2.
Phase 1 Treatment Regimens/Dosing Schedule
Tumor Type
Drug
Dose 
(IV)
Dose 
Frequency
Dose Day
(21-day 
cycle)
Schedule 1 (Gastric-GEJ, BTC)
Ramucirumab
8 mg/kg
Q3W
Day 1, Day 8 
Pembrolizumab
200 mg
Q3W
Day 1
Schedule 2 (Gastric-GEJ, NSCLC or 
Urothelial)
Ramucirumab
10 mg/kg
Q3W
Day 1
Pembrolizumab
200 mg
Q3W
Day 1
Abbreviations: BTC = biliary tract cancer; GEJ = gastroesophageal junction; IV = intravenous; NSCLC = non-small 
cell lung cancer; Q3W = every 3 weeks.
NOTE: Ramucirumab will be administered prior to pembrolizumab for every cycle (Section 6.1.1).
6.1.1. Selection and Timing of Doses
The ramucirumab and the pembrolizumab Pharmacy Manuals contain specific instructions for 
premedication, the preparation of infusion, and administration of each infusion solutions, 
separately.
A cycle is defined as an interval of 21 days (a delay of a cycle due to holidays, weekends, bad 
weather, or other unforeseen circumstances will be permitted up to 7 days and not counted as a 
protocol deviation).
The actual doses of ramucirumab administered will be determined by measuring the patient's 
weight at the beginning of each cycle. If the patient’s weight fluctuates by more than 10% from 
the weight used to calculate the prior dose, the dose must be recalculated.  Recalculation of the 
ramucirumab dose for weight fluctuations of <10% is permitted but not require d.
Ramucirumab will be administered prior to pembrolizumab, over an approximately 60-minute 
intravenous (IV) infusion.  The maximum ramucirumab infusion rate is 25 mg/min.

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Pembrolizumab 200 mg (fixed dose) will be administered over a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (that is, infusion time is 30 minutes -5 min/+10 min).
The first 2 cycles will require a 1-hr observation period i) between ramucirumab and 
pembrolizumab administration, and ii) after pembrolizumab infusion.  For all cycles thereafter,
no observation period will be required unless clinically indicated.  
6.1.1.1. Phase 1a: Dose-Limiting Toxicity Observation
For the 21-day Phase 1a DLT observation period, the following criteria will be used to determine 
the progress of the study:

If none of the initial 3 patients within a dose schedule develops a DLT, 
Expansion Phase 1b will start.

If 1 of the initial 3 patients within a dose schedule develops a DLT, 3 additional patients 
will be added.

If ≤1 of 6 patients within a dose schedule develops a DLT, Expansion Phase 1b will start.

If 2 or more patients develop a DLT, enrollment will stop and an alternative dose level 
may be considered (in which case the protocol would be amended).
No intra-patient dose escalation or reduction is allowed during DLT observation.  For the 
purpose of patient management, DLTs will lead to dose interruption during the observation 
period.  Dose modifications will be allowed after the observation period.
For either group, if dropouts, dose interruptions, or reductions occur that result in a patient being 
nonevaluable for DLTs (“evaluable” is defined in Section 6.7), additional patients will be 
enrolled to achieve the minimum of 3 evaluable patients.  The need for patient replacement will 
be determined based on consultation with the investigator and Lilly CRP/clinical research 
scientist (CRS).  Patients who withdraw from the study during the DLT period for reasons other 
than a DLT may be replaced within the same dose level.
6.1.1.1.1. Definition of Dose-Limiting Toxicities
A DLT is defined as one of the following AEs reported during the DLT observation period, if 
considered to be definitely, probably, or possibly related to either study regimen by the 
investigator; and fulfills any one of the following criterion using NCI CTCAE Version 4.0:
1.
Nonhematologic toxicity as follows:
a) Grade 4 nonlaboratory toxicity
b) Grade 3 nonlaboratory toxicity (for example, nausea, vomiting, and diarrhea) lasting 
>3 days despite optimal supportive care
c) Any Grade 3 or Grade 4 laboratory value if:
i) Medical intervention is required to treat the patient, or
ii) The abnormality persists for >1 week.

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Note: Liver function abnormality: For patients with liver metastasis who begin 
treatment with Grade 2 asparatate aminotransferase (AST) or alanine amino 
transferase (ALT), if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 7 days
2.
Hematologic toxicity, as follows:
a)
Grade 4 toxicity lasting ≥ 7 days, or
b)
Grade 3 thrombocytopenia if associated with bleeding and requires platelet
transfusion, or
c)
Febrile neutropenia Grade 3 or Grade 4
3.
Grade 5 toxicity (that is, death)
4.
Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting, for example:
a)
Any toxicity that is possibly related to study treatment that requires the 
withdrawal of the patient from the study during Cycle 1, or
b)
A delay of > 14 days due to persistent Grade ≥ 2 toxicities in initiating Cycle 2, 
with the exception of Grade 2 fatigue
Any infusion or hypersensitivity reactions occurring during the infusion of the drug are not 
considered dose-related and therefore will NOT be considered to be a DLT.
After each of the 3 patients in a dose schedule completes the observation period, a safety analysis 
will occur; the data will be reviewed by study investigators and the Lilly CRP/CRS, and the 
findings documented, indicating whether each dose schedule is or is not well tolerated.  The 
results will inform the decision whether or not to move onto Expansion Phase 1b.
6.1.2. Investigator Responsibilities
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the site personnel,

verifying that instructions are followed properly, 

maintaining accurate and appropriate records, including those of investigational product 
(IP) dispensing and collection, 

ensure appropriate supply, storage, handling, distribution and usage of trial treatments in 
accordance with the protocol and any applicable laws and regulations,

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 clinical trial materials.

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Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the IP so that the situation can be assessed.
6.2.
Treatment Assignment
Patients meeting all inclusion/exclusion criteria will be assigned to a dose schedule based upon 
their diagnosis at baseline (Table JVDF.2). Study drug will be allocated to patients using an 
interactive web response system.
6.3.
Blinding
This is an open-label study.
6.4.
Packaging and Labeling
All IP materials will be provided by Lilly. Clinical trial materials will be labeled according to 
the country’s regulatory requirements.  Ramucirumab and pembrolizumab vials should be stored
under refrigeration at 2°C to 8°C (36°F to 46°F).
6.5.
Preparation/Handling/Storage
Refer to the respective IBs for detailed information about preparation, handling, and storage of 
ramucirumab and pembrolizumab.
6.6.
Dose Adjustments, Delays, and Discontinuation
Doses of either study drug may need to be delayed, reduced (ramucirumab only), or discontinued 
to manage specific AEs or other toxicities.
When a study drug is delayed, if possible and appropriate, patients should resume study 
treatment within 21 days, with every effort made to start on Day 1 of the next dosing schedule.
6.6.1. Ramucirumab Dose Adjustments, Delays, and Discontinuation
The ramucirumab dose may need to be delayed and/or reduced if the patient experiences an 
adverse event, including an adverse event of special interest (AESI) (Section 8.2.1.1.1). Doses 
may be delayed to allow time for the patient to recover from the event. Certain AEs require 
immediate and permanent discontinuation of study treatment. Any patient who requires a dose 
reduction will continue to receive a reduced dose until discontinuation from ramucirumab or 
discontinuation from the study.  Any patient who has had 2 dose reductions and who experiences 
a toxicity that would cause a third dose reduction must be discontinued from ra mucirumab.
Table JVDF.3 presents the ramucirumab dose reductions for each treatment cohort.
Table JVDF.4 presents the criteria for dose modifications and dose discontinuations applicable if 
the patient experiences a ramucirumab AESI or other AEs at least possibly related to 
ramucirumab.

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Table JVDF.3.
Ramucirumab Dose Reductionsa
Dose Schedule 1:
Gastric-GEJ/BTC
(21-day Cycle)
Dose Schedule 2
Gastric-GEJ/NSCLC/Urothelial
(21-day Cycle)
Starting dose
8 mg/kg
on D1, D8
10 mg/kg
on Day 1
First dose reduction
6 mg/kg
on Day 1, Day 8
8 mg/kg
on Day 1
Second dose reduction
5 mg/kg
on Day 1, Day 8
6 mg/kg
on Day 1
Abbreviations:  BTC = biliary tract cancer; D = Day; GEJ = gastroesophageal; NSCLC = non-small cell lung cancer.
a
Ramucirumab dose reductions are allowed between cycles and within a given cycle.

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Table JVDF.4. 
Dose-Modification Guidelines for Ramucirumab for Adverse Events at Least Possibly Related to 
Ramucirumab, including Adverse Events of Special Interest 
 
Adverse Event 
NOTE: All Specific Adverse Events Listed 
are defined as AESIs in Section 8.2.1.1.1). 
CTCAE 
Grade 
Dose-Modification Guidelines 
NOTES:  
Dose reductions to occur as defined in Table JVDF.3. 
Treating physicians can modify or discontinue ramucirumab more conservatively than 
in the guidance below.  
 
 
 
 
1. 
Infusion-related reaction 
 
 
1.a. 
Infusion-related reaction  
2 
Interrupt and reduce the infusion rate by 50% for the duration of the infusion and for all 
future infusions. 
 
 
 
Prior to all future infusions of ramucirumab, premedicate with: 
 
an intravenous histamine H1 antagonist, such as diphenhydramine hydrochloride 
 
dexamethasone or equivalent 
 
acetaminophen/paracetamol 
1.b. 
Infusion-related reaction 
3-4 
Immediately and permanently discontinue ramucirumab 
2. 
Hypertension 
 
 
2.a. 
Hypertension (non-life-threatening and 
associated with symptoms) 
NOTE:  Hypertension should be monitored 
prior to each ramucirumab infusion. 
3 
 
Delay ramucirumab until the hypertension is controlled with medication and is 
resolved to Grade 0-2. 
o 
If controlled with medication and resolved to Grade 0-2, then may resume 
ramucirumab at current dose. 
o 
If NOT controlled with medication and not resolved to Grade 0-2 within a 
reasonable timeframe, discontinue ramucirumab at investigator’s discretion. 
2.b. 
Uncontrolled hypertension, hypertensive crisis, 
or hypertensive encephalopathy  
4 
Immediately and permanently discontinue ramucirumab. 

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Dose-Modification Guidelines for Ramucirumab for Adverse Events at least Possibly Related to Ramucirumab, including Adverse Events of Special 
Interest (continued)
Adverse Event
NOTE: All Specific Adverse Events Listed are 
defined as AESIs in Section 8.2.1.1.1).
CTCAE 
Grade
Dose-Modification Guidelines
NOTE: Dose reductions to occur as defined in Table JVDF.3.
3.
Proteinuria
3.a.
Proteinuria = 2+ (dipstick or routine urinalysis)a

Administer ramucirumab at the current dose if clinically indicated.

Obtain 24-hour urine protein results within 3 days prior to the next ramucirumab 
dose.
o
If urine protein is <2 g/24 h, administer ramucirumab at the patient's current 
dose.
o
If urine protein is 2 g/24 h, modify the ramucirumab dose based on 24-hour 
collection.  See Proteinuria 2 g/24 h (24-hour urine collection), Line 3.c in 
this table.
3.b.
Proteinuria >2+ (dipstick or routine urinalysis)a

Delay ramucirumab until urine protein returns to <2 g/24 h.

Obtain 24-hour urine protein results within 3 days prior to the next ramucirumab 
dose.
o
If urine protein is <2 g/24 h, no further dose delay or dose reduction is 
required.
o
If urine protein remains 2 g/24 h and is not resolved within a reasonable 
timeframe, discontinue ramucirumab at investigator’s discretion.
3.c.
Proteinuria 2 g/24 h (24-hour urine collection)a

First or second occurrence:  delay ramucirumab until urine protein returns to 
<2 g/24 h.
o
If urine protein returns to <2 g/24 h, reduce ramucirumab dose.
o
If urine protein remains 2 g/24 h and is not resolved within a reasonable 
timeframe, discontinue ramucirumab at investigator’s discretion.

Third occurrence:  discontinue ramucirumab.
3.d.
Proteinuria >3 g/24 h or in the setting of nephrotic 
syndromea
Immediately and permanently discontinue ramucirumab.
4.
Arterial thromboembolic events, venous 
thromboembolic events
3 or 4
Immediately and permanently discontinue ramucirumab.
5.
Bleeding/hemorrhage
3 or 4
Immediately and permanently discontinue ramucirumab.
6.
Gastrointestinal perforation
Immediately and permanently discontinue ramucirumab.

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Adverse Event
NOTE: All Specific Adverse Events Listed are 
defined as AESIs in Section 8.2.1.1.1).
CTCAE 
Grade
Dose-Modification Guidelines
NOTE: Dose reductions to occur as defined in Table JVDF.3.
7.
Reversible posterior leukoencephalopathy 
syndrome
Immediately and permanently discontinue ramucirumab.
8.
Congestive heart failure
3-4
Immediately and permanently discontinue ramucirumab.
9.
Fistula formation
Immediately and permanently discontinue ramucirumab.
10.
Impaired wound healing
10.a.
Prior to planned surgery
Withhold ramucirumab.
10.b
After surgery
Resume ramucirumab based on clinical judgment.
10.c.
Wound-healing complications developed during 
study treatment
Delay ramucirumab dosing until the wound is fully healed.
11.
Liver injury/liver failure
11.a.
Hepatic encephalopathy and/or hepatorenal 
syndrome resulting from liver cirrhosis
Immediately and permanently discontinue ramucirumab.
12
Hypothyroidism
2-4
Therapy with ramucirumab can be continued while treatment for the thyroid disorder 
is instituted.
13
Other adverse events considered at least possibly 
related to ramucirumabb
13.a
Non-life threatening and reversible
3
May delay ramucirumab until resolved to Grade 0-1.

If resolved to Grade 0-1, may reduce ramucirumab dose.

If NOT resolved to Grade 0-1 within a reasonable timeframe, discontinue 
ramucirumab at investigator’s discretion
13.b
Adverse Event
4
Permanently discontinue treatment immediately, with the exception of Grade 4 fever 
or Grade 4 laboratory abnormality, in which case:

First occurrence: Delay ramucirumab until resolved to Grade 0-1.
o
If resolved to Grade 0-1, may resume ramucirumab original dose at the 
discretion of the investigator.
o
If NOT resolved to Grade 0-1 within a reasonable timeframe, discontinue 
ramucirumab at investigator’s discretion.

Second occurrence: Delay ramucirumab until resolved to Grade 0-1.
o
If resolved to Grade 0-1, reduce ramucirumab dose.
o
If NOT resolved to Grade 0-1 within a reasonable timeframe, discontinue 
ramucirumab at investigator’s discretion.

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Dose-Modification Guidelines for Ramucirumab for Adverse Events at least Possibly Related to Ramucirumab, including Adverse Events of Special 
Interest (concluded)
Abbreviations:  AESI = adverse event of special interest; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.
a
Perform urinalysis within 3 days prior to each infusion of ramucirumab.  If 24-hour urine collection is also performed, the results of 24-hour urine collection 
should be used for clinical decision-making.
b Patients who enter the study with symptoms or laboratory values equivalent to NCI-CTCAE Version 4.0 Grade 1-2 adverse events should not necessarily 
have dose delays or reductions related to the persistence or mild worsening of those symptoms or laboratory values.  Grade 2 toxicities which represent 
clinically significant worsening of symptoms from baseline, ramucirumab dose may be delayed at the discretion of the investigator.  If the toxicity is resolved 
to Grade 0-1, may reduce ramucirumab dose.  If the toxicity is not resolved to Grade 0-1, may discontinue ramucirumab.

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6.6.2. Pembrolizumab Dose Delays and Discontinuation
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or several 
months after the last dose of treatment.  Pembrolizumab must be withheld (dose reductions are 
not permitted) for drug-related toxicities and severe or life-threatening AEs.  See Section 6.9.1.3
for supportive care guidelines, including use of corticosteroids.  Table JVDF.5 presents the 
guidelines for treatment delays and discontinuation of pembrolizumab for specific AEs 
associated with pembrolizumab treatment.

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Table JVDF.5.
Pembrolizumab Treatment Discontinuation Guidelines for Specific Adverse Events at Least Possibly
Related to Pembrolizumab
Adverse Event
CTCAE 
Grade
Treatment Delay and Discontinuation
1
Diarrhea/Colitis
2-3
Delay pembrolizumab until resolved to Grade 0-1.

If resolved to Grade 0-1 within 12 weeks of last dose, then resume pembrolizumab.

Within 12 weeks of last dose, if toxicity does not resolve to Grade 0-1 *or* with inability to 
reduce corticosteroid to <10 mg/day of prednisone or equivalent per within 12 weeks, discontinue 
pembrolizumab.
4
Immediately and permanently discontinue pembrolizumab.
2
Increased AST, ALT, or Bilirubina
2
Delay pembrolizumab until resolved to Grade 0-1.

If resolved to Grade 0-1 within 12 weeks of last dose, then resume pembrolizumab.

If NOT resolved to Grade 0-1 within 12 weeks of last dose, then discontinue pembrolizumab.
3-4
Immediately and permanently discontinue pembrolizumab. See exceptions below.
3
Type 1 Diabetes Mellitus (if new 
onset) or Hyperglycemia associated 
with evidence of beta cell failure
T1DM or 
3-4
Delay pembrolizumab until patients are clinically and metabolically stable.

If clinically and metabolically within 12 weeks of last dose, then resume pembrolizumab.

If NOT clinically and metabolically stable within 12 weeks of last dose, then immediately and 
permanently discontinue pembrolizumab.
4
Hypophysitis
2-4
Delay pembrolizumab until resolved to Grade 0-1.

If resolved to Grade 0-1 within 12 weeks of last dose, then resume pembrolizumab.

Within 12 weeks of last dose, if toxicity does not resolve to Grade 0-1 *or* with inability to 
reduce corticosteroid to <10 mg/day of prednisone or equivalent per within 12 weeks, 
immediately and permanently discontinue pembrolizumab.

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Pembrolizumab Treatment Discontinuation Guidelines for Specific Adverse Events at Least Possibly Related to Pembrolizumab (continued)
Adverse Event
CTCAE 
Grade
Treatment Delay and Discontinuation
5
Hyperthyroidism
2
Therapy with pembrolizumab can be continued; non-selective beta-blockers (e.g.,
propranolol) are suggested as initial therapy for hyperthyroidism 
(Section 6.9.1.3.5).
3
Delay pembrolizumab until resolved to Grade 0-1.

If resolved to Grade 0-1 within 12 weeks of last dose, then resume 
pembrolizumab.

Within 12 weeks of last dose, if toxicity does not resolve to Grade 0-1 *or* 
with inability to reduce corticosteroid to ≤10 mg/day of prednisone or 
equivalent per within 12 weeks, immediately and permanently discontinue 
pembrolizumab.
4

Immediately and permanently discontinue pembrolizumab.
Hypothyroidism
2-4
Therapy with pembrolizumab can be continued while treatment for the thyroid 
disorder is instituted.
6
Infusion Reaction
2

First occurrence: Stop infusion of pembrolizumab until resolved to Grade 0-1.
o If resolved to Grade 0-1 within 1 hour of stopping infusion, then restart 
infusion at 50% of the original rate (e.g., from 100 mL/hr to 50 mL/hr).
o If NOT resolved to Grade 0-1 within 1 hour of stopping infusion, delay 
pembrolizumab until symptoms resolve, and premedicate for the next 
scheduled dose.
Second occurrence: If toxicity develops despite premedication, immediately and 
permanently discontinue pembrolizumab.
3-4
Immediately and permanently discontinue pembrolizumab.

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Pembrolizumab Treatment Discontinuation Guidelines for Specific Adverse Events at Least Possibly Related to Pembrolizumab (continued)
Adverse Event
CTCAE 
Grade
Treatment Delay and Discontinuation
7
Pneumonitis
2
Delay pembrolizumab until resolved to Grade 0-1.

If resolved to Grade 0-1 within 12 weeks of last dose, then resume 
pembrolizumab.
Within 12 weeks of last dose, if toxicity does not resolve to Grade 0-1 *or* with 
inability to reduce corticosteroid to ≤10 mg/day of prednisone or equivalent per 
within 12 weeks, immediately and permanently discontinue pembrolizumab.
3-4
Immediately and permanently discontinue pembrolizumab.
8
Renal Failure or Nephritis
2
Delay pembrolizumab until resolved to Grade 0-1.

If resolved to Grade 0-1 within 12 weeks of last dose, then resume 
pembrolizumab.

Within 12 weeks of last dose, if toxicity does not resolve to Grade 0-1 *or* with 
inability to reduce corticosteroid to≤10 mg/day of prednisone or equivalent per 
within 12 weeks, immediately and permanently discontinue pembrolizumab.
3-4
Immediately and permanently discontinue pembrolizumab.
9
Other Adverse Eventsb
3 or severe
Delay pembrolizumab until resolved to Grade 0-1.

If resolved to Grade 0-1 within 12 weeks of last dose, then resume 
pembrolizumab.

Within 12 weeks of last dose, if toxicity does not resolve to Grade 0-1 *or* with 
inability to reduce corticosteroid to ≤10 mg/day of prednisone or equivalent per 
within 12 weeks, immediately and permanently discontinue pembrolizumab.
4
Immediately and permanently discontinue pembrolizumab.

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Pembrolizumab Treatment Discontinuation Guidelines for Specific Adverse Events at Least Possibly Related to Pembrolizumab (concluded)
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; T1DM = type 1 diabetes mellitus.
Note:  Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.  Reoccurrence of Grade 2 
pneumonitis also warrants permanent discontinuation.
a
For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week, then patients should be discontinued.
b Patients with intolerable or persistent Grade 2 drug-related AE(s) may hold study medication at physician discretion.  Permanently discontinue 
pembrolizumab for persistent Grade 2 adverse reactions for which pembrolizumab has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose.

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6.6.3. Dose Delays for Reasons Not Related to Study Treatment
Dosing interruptions of either study drug are also permitted for reasons not related to study 
treatment (for example, elective surgery, unrelated medical events, patient vacation, and/or 
holidays).
Patients should resume the delayed study drug(s) within 21 days of the scheduled interruption,
with every effort made to start on Day 1 of the next dosing schedule, unless otherwise discussed 
with the Sponsor.  The reason for interruption should be documented on the case report form 
(CRF).
6.7.
Treatment Compliance
The study medication will be administered only at the investigational sites by the authorized 
study personnel.  As a result, treatment compliance is ensured.
During Phase 1a, DLT-evaluable population is defined as all enrolled patients in DLT Phase 1a
who either completed 21 days of observation or discontinued study treatment or study 
participation before completing 1 cycle due to a DLT.
Any patient who discontinued from the study before completing safety monitoring for the 21-day 
DLT observation period for any other reason than a DLT will be considered non-evaluable for
DLT assessment.
Patients who are not evaluable for pharmacokinetics, but who complete 1 cycle of therapy, may 
be replaced upon consultation with the investigator(s) and the Lilly CRP/CRS to ensure adequate 
PK data, unless accrual to that cohort has stopped due to a DLT.
6.8.
Lifestyle and/or Dietary Requirements
6.8.1. Diet
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting.
6.8.2. Contraception
Based on ramucirumab’s mechanism of action, it is likely that ramucirumab will inhibit 
angiogenesis and may potentially result in adverse effects during pregnancy and postnatal 
development.
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
Therefore, 1) non-pregnant, non-breast-feeding women may only be enrolled if they are willing 
to use a highly effective method of birth control or are considered to be of non-childbearing 
potential and 2) only men may be enrolled who use a reliable method of birth control, or who are 
sterile (including confirmed vasectomy) and do not donate sperm (Section 5.1).

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For female patients, non-childbearing potential (by other than medical reasons) is defined as any 
one of the following:

≥45 years of age and has not had menses for greater than 2 years

Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a
follicle-stimulating hormone (FSH) value in the postmenopausal range upon pretrial 
(screening) evaluation (FSH level >40 mIU/mL)

At least 6 weeks following surgical bilateral oophorectomy or tubal ligation with or 
without hysterectomy.  Documented hysterectomy or oophorectomy must be confirmed 
with medical records of the actual procedure or confirmed by an ultrasound. Tubal 
ligation must be confirmed with medical records of the actual procedure; otherwise, the 
patient must be willing to use an adequate barrier method throughout the study, starting 
with the screening visit through 120 days after the last dose of study treatment.

not heterosexually active for the duration of the study
A “highly effective method of birth control” is defined as one that results in a low failure rate 
(that is, <1% per year) when used consistently and correctly, such as implants, injectables, 
combined oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, or a 
vasectomized partner.
Two birth control methods are preferred, and can be either 2 barrier methods or a barrier method 
plus a hormonal method to prevent pregnancy. The following are considered adequate barrier 
methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, 
sponge, or spermicide as per local regulations or guidelines.
Appropriate hormonal contraceptives will include any registered and marketed contraceptive 
agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents).  For patients using a hormonal contraceptive method, 
information regarding pembrolizumab and its potential effect on the contraceptive should be 
addressed.
Patients should start using birth control from study Visit 1 throughout the study period up to 
120 days after the last dose of study treatment.
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  If there is any question that a 
patient will not reliably comply with the requirements for contraception, that patient should not 
be entered into the study.
6.9.
Concomitant Therapy
A list of restricted and excluded concomitant therapies and exceptions is provided in
Attachment 7.  All premedication, supportive care, and concomitant medication must be reported 
on the CRF at each visit.

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6.9.1. Supportive Care
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  For both study drugs, specific AEs have been identified based on past data for 
special monitoring and, when necessary, supportive care.  For ramucirumab, these are referred to 
as Adverse Events of Special Interest (AESI).  
See Table JVDF.4 and Table JVDF.5 for dose reductions (ramucirumab only), delays, or 
discontinuations for AEs considered to be at least possibly related to study treatment
(pembrolizumab or ramucirumab).
6.9.1.1. Infusion-Related Reactions- Ramucirumab and Pembrolizumab
Infusion-related reactions (IRRs) have been identified as events of interest for both ramucirumab 
and pembrolizumab. In the event of an IRR, blood samples will be collected for both PK and 
immunogenicity analysis for each drug at the following time points:  (i) as close as possible to 
the onset of the IRR, (ii) at the resolution of the IRR, and (iii) 30 days following the IRR.
IRRs may occur during or following ramucirumab or pembrolizumab administration.  Patients 
should be closely monitored for signs and symptoms indicative of an IRR from the initiation of 
the infusion in an area where resuscitation equipment and other agents (such as epinephrine and 
corticosteroids) are readily available.
Signs and symptoms usually develop during or shortly after infusion and generally resolve 
within 24 hours. Symptoms of IRRs include rigors/tremors, back pain/spasms, chest pain and/or 
tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.  In severe cases, 
symptoms include bronchospasm, supraventricular tachycardia, and hypotension.
The first 2 cycles will require a 1-hour observation period i) between ramucirumab and 
pembrolizumab administration, and ii) after pembrolizumab infusion.  For all cycles thereafter,
no observation period will be required unless clinically indicated.  If the patient shows no 
evidence of an IRR with the first 2 cycles of each study drug, no observation period is required 
for subsequent cycles, unless clinically indicated.  In the event an IRR occurs thereafter, the 1-
hour observation should be reinstituted.
6.9.1.1.1. Infusion-Related Reactions-Ramucirumab
Table JVDF.4 presents ramucirumab dose modification and supportive care guidelines for 
patients who experience an IRR associated with ramucirumab.
For the first 2 ramucirumab infusions, measure blood pressure and pulse at the following time 
points:  (i) within 15 minutes prior to the infusion, (ii) after completion of the infusion, and (iii) 
at the end of the 1-hour post-infusion observation period.  For all subsequent infusions of 
ramucirumab, measure blood pressure and pulse prior to the infusion. Measure other vital signs 
as clinically indicated.

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6.9.1.1.2. Infusion-Related Reactions-Pembrolizumab
Table JVDF.5 presents pembrolizumab dose modification and supportive care guidelines for 
patients who experience an IRR associated with pembrolizumab.  For Grade 3-4 IRRs, the 
patient is immediately and permanently discontinued from pembrolizumab.
6.9.1.2. Supportive Care for Ramucirumab
6.9.1.2.1. Supportive Care by Adverse Event of Special Interest
6.9.1.2.1.1.
Hypertension
An increased incidence of severe hypertension (CTCAE Grade 3) has been reported in patients 
receiving ramucirumab compared with placebo.  In most cases, hypertension was controlled 
using standard antihypertensive treatment.  Preexisting hypertension should be controlled before 
starting ramucirumab treatment.
Monitoring of blood pressure is required during, and should occur prior to, ramucirumab therapy.  
Every attempt should be made to control blood pressure to systolic <140 mm Hg and diastolic 
<90 mm Hg prior to starting treatment with ramucirumab.  Routine clinical and laboratory 
monitoring is required in patients who again develop hypertension or experience a deterioration 
in previous hypertension.
6.9.1.2.1.2.
Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGF Receptor 2 pathway, 
including ramucirumab.  In ramucirumab clinical trials, the majority of events were Grade 1 or 2.  
Monitoring for the development or worsening of proteinuria during ramucirumab therapy is 
required.  Discontinue ramucirumab if the patient experiences proteinuria >3 g/24 hours or 
nephrotic syndrome.
6.9.1.2.1.3.
Thromboembolic Events
6.9.1.2.1.3.1.
Arterial Thromboembolic Events
Serious, sometimes fatal arterial thromboembolic events, including myocardial infarction, 
cardiac arrest, cerebrovascular accident, and cerebral ischemia, have been reported in clinical 
trials.
6.9.1.2.1.3.2.
Venous Thromboembolic Events
Venous thromboembolic events are associated with cancer; however, the incidence of VTEs 
likely varies depending on the type of cancer, stage, and intensity of imaging.  Additionally, 
VTEs have been associated with some antiangiogenic therapy, although the incidence varies 
depending on the type of therapy, use of concomitant chemotherapy agents, and specific disease 
state.  VTEs have been reported from clinical studies investigating ramucirumab, particularly in 
the context of metastatic disease or in regions adjacent to implanted venous access devices.

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6.9.1.2.1.4.
Bleeding/Hemorrhage
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding.  Severe GI hemorrhages, including fatal events, have been reported in patients with 
gastric-GEJ cancer treated with ramucirumab in combination with paclitaxel.
Serious hemorrhagic AEs have been reported from clinical studies investigating ramucirumab.  
Hemorrhagic complications are associated with some malignancies (that is, variceal bleeding 
from portal hypertension in hepatocellular carcinoma, lower GI hemorrhage from bowel 
metastases in ovarian carcinoma), although the rate of these complications varies considerably.  
As detailed in the ramucirumab IB, the incidences of hemorrhagic events to date, significant 
background incidence of bleeding in some malignancies, and use of concomitant antiplatelet 
therapy in some of the reported cases preclude any definitive association between bleeding and 
ramucirumab, although ongoing surveillance and identification (and exclusion) of patients with 
high bleeding risk remain essential and are detailed in the inclusion/exclusion criteria.
6.9.1.2.1.5.
Gastrointestinal Perforation
Patients with unresected (or recurrent) primary tumors or mesenteric or peritoneal disease who 
participate in this clinical study may be at increased risk for GI perforation due to the nature of 
the disease (metastatic gastric-GEJ cancer).
An infrequent incidence of GI perforations has been associated with some antiangiogenic 
therapeutic agents, most specifically in the context of colorectal cancer (treated with combination 
regimens, including anti-VEGF antibodies and cytotoxic chemotherapy) and in advanced ovarian 
cancer. These events may be associated with extensive abdominal/peritoneal disease burden.  
Gastrointestinal perforation has been reported from clinical studies investigating ramucirumab.  
The incidences of these events to date and presence of significant comorbidities and risk factors 
preclude any definitive association with ramucirumab, although ongoing surveillance remains 
essential.  More information about GI perforation may be found in the IB.
6.9.1.2.1.6.
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical and radiologic 
syndrome typically consisting of reversible cortical neurological dysfunction and brain-imaging 
findings of subcortical edema involving the posterior circulation, particularly the occipital lobes 
(Hinchey et al. 1996).  The symptoms of RPLS most often include generalized seizures, 
headache, delirium, and cortical blindness, although these may vary significantly and 
occasionally include focal neurological deficits (Hinchey et al. 1996; Garg 2001; Lee et al. 
2008).  MRI represents the most reliable method for diagnosis (Lee et al. 2008).  Clinical 
symptoms and MRI abnormalities usually recover within days to weeks with proper 
management, although permanent neurologic dysfunction has been reported (Hinchey et al. 
1996; Tajima et al. 1999; Garg 2001; Lee et al. 2008).
Across the clinical program to date, 2 cases of RPLS have been reported: One case occurred in 
each arm of the recently completed double-blind, randomized, placebo-controlled Phase 3 
Study RAISE evaluating ramucirumab in combination with FOLFIRI versus FOLFIRI in 
combination with placebo for patients with metastatic colorectal cancer.

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RPLS should be identified and treated promptly in order to minimize potential for permanent 
neurological damage.  Treatment encompasses careful control of blood pressure, withdrawal of 
potentially causative medication, and administration of anticonvulsant agents to those 
experiencing seizures (Stott et al. 2005).
6.9.1.2.1.7.
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.  A small number of CHF events (including fatal) were 
also reported in patients who had received ramucirumab after prior treatment with anthracyclines 
in the Phase 2 and Phase 3 studies.
Patients with risk factors should be closely monitored for signs and symptoms of CHF.
Caution should be exercised when treating patients with clinically significant cardiovascular 
disease, such as preexisting coronary artery disease or CHF.  Ramucirumab should be 
discontinued in the event of any Grade 3 or 4 events consistent with CHF.
6.9.1.2.1.8.
Fistula Formation
Because fistula formation has been associated with antiangiogenic agents, patients may be at 
increased risk for the development of fistula when treated with ramucirumab.  Some fistulas can 
be resolved with surgical procedures; however, fistulas can be fatal.  The impact on the quality of 
life of having a fistula varies according to the location and extent of the fistula (Chen and Cleck 
2009).
6.9.1.2.1.9.
Surgery and Impaired Wound Healing
Because ramucirumab is an antiangiogenic therapy, it may have the potential to adversely affect 
wound healing.  Ramucirumab did not impair wound healing in a study conducted in animals; 
however, the impact of ramucirumab on serious or nonhealing wounds has not been evaluated in 
humans.
6.9.1.2.1.10. Liver Failure and Other Significant Liver Injury
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  Patients with 1) cirrhosis at a level of Child-Pugh 
Class B (or worse) or 2) cirrhosis (any degree) and a history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis should not be enrolled in clinical trials with 
ramucirumab.  “Clinically meaningful ascites” is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis.  See Site Guidance document for 
Hepatic Monitoring/Drug-Induced Liver Injury.
6.9.1.2.2. Supportive Care Agents for Ramucirumab- Guidelines
Supportive care measures may include but are not limited to antiemetic agents, opiate and 
nonopiate analgesic agents, appetite stimulants, and granulocyte and erythroid growth factors.  
Guidelines regarding the use of specific supportive care agents are presented below.

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6.9.1.2.2.1.
Antiemetic Agents
Although emesis is not an expected side effect of ramucirumab, the use of antiemetic agents is 
permitted at the discretion of the investigator.  Acceptable antiemetic agents include 5-HT3
receptor antagonists (for example, ondansetron), dopamine receptor antagonists (for example, 
metoclopramide), corticosteroids (for example, dexamethasone), and others.
6.9.1.2.2.2.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.  Opiate and 
nonopiate analgesic agents are permitted (including acetaminophen/paracetamol); however, use 
of NSAIDs and/or aspirin is restricted (Attachment 7).
6.9.1.2.2.3.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.  Examples
include megestrol acetate, dronabinol, and others.
6.9.1.2.2.4.
Granulocyte-Colony Stimulating Factors
The as-needed use of G-CSFs is permitted at the discretion of the investigator based on 
American Society of Clinical Oncology (ASCO) guidelines (Smith et al. 2006) (Attachment 7).
6.9.1.2.2.5.
Erythroid Growth Factors
The as-needed use of erythroid-stimulating factors (for example, erythropoietin) is permitted at 
the discretion of the investigator based on ASCO guidelines (Rizzo et al. 2008) (Attachment 7).
6.9.1.2.2.6.
Other Supportive Care Agents
The use of benzodiazepines, antidepressants, laxatives, and other agents that may be helpful in 
controlling disease-related symptoms are also permitted and encouraged, except as prohibited in
Attachment 7.
6.9.1.3. Supportive Care for Pembrolizumab
Supportive care guidelines for the management of specific AEs with potential immunologic 
etiology are outlined below. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Several courses of steroid 
tapering may be necessary, as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
pembrolizumab.
If after the evaluation the event is determined not to be related, the investigator does not need to 
follow the treatment guidance as outlined below.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 

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6.9.1.3.1. Pneumonitis - Pembrolizumab
Apply the following supportive care guidance for pneumonitis: 
For Grade 2 events, treat with systemic corticosteroids (prednisone 1 to 2 mg/kg/day or 
equivalent).  When symptoms improve to Grade 0-1, steroid taper should start and be continued 
over no less than 4 weeks.
For Grade 3-4 events, immediately treat with intravenous steroids (methylprednisolone 125 mg) 
followed by high-dose oral steroids (prednisone 1 to 2 mg/kg/day or dexamethasone 4 mg every 
4 hours).  Administer additional anti-inflammatory measures, as needed.
Add prophylactic antibiotics for opportunistic infections, in the case of prolonged steroid 
administration.
6.9.1.3.2. Diarrhea/Colitis - Pembrolizumab
Patients should be monitored carefully for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, and blood or mucus in stool, with or without fever) and of bowel perforation 
(such as peritoneal signs and ileus).

All patients who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis.

For Grade 2 diarrhea/colitis, administer oral corticosteroids (prednisone 1 to 
2 mg/kg/day or equivalent).

For Grade 3 or 4 diarrhea/colitis (or Grade 2 diarrhea), treat with intravenous steroids 
(methylprednisolone 125 mg) followed by high-dose oral steroids (prednisone 1 to 2 
mg/kg/day or dexamethasone 4 mg every 4 hours).

When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
6.9.1.3.3. Type 1 Diabetes Mellitus or Hyperglycemia - Pembrolizumab
For Grade 3-4 hyperglycemia or new onset type 1 diabetes mellitus (T1DM), including diabetic 
ketoacidosis (DKA) or ≥ Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA),supportive care guidance is as follows:

Insulin replacement therapy is recommended for T1DM and for Grade 3-4 hyperglycemia 
associated with metabolic acidosis or ketonuria.

Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.
6.9.1.3.4. Hypophysitis - Pembrolizumab
Apply the following supportive care guidance for hypophysitis:

For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered.

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
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered.
6.9.1.3.5. Hyperthyroidism or Hypothyroidism - Pembrolizumab
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Apply the 
following supportive care guidance:

Grade 2 hyperthyroidism events and Grade 2-4 hypothyroidism:
o
In hyperthyroidism, non-selective beta-blockers (for example, propranolol) are 
suggested as initial therapy.
o
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care.

Grade 3-4 hyperthyroidism 
o
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered.
6.9.1.3.6. Hepatic Events - Pembrolizumab
See Site Guidance Document for Hepatic Monitoring/Drug-Induced Liver Injury.  Apply the 
following supportive care guidance for hepatic events:

For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
o
Treat with IV or oral corticosteroids.

For Grade 3-4 events, treat with IV corticosteroids for 24 to 48 hours.

When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
6.9.1.3.7. Renal Failure or Nephritis - Pembrolizumab
Apply the following supportive care guidance for renal failure or nephritis:

For Grade 2 events, treat with corticosteroids.

For Grade 3-4 events, treat with systemic corticosteroids.

When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
6.10. Continued Access Period
The continued access period begins after study completion and ends at end of trial 
(Figure JVDF.2 and Section 4.4).
Attachment 1 presents the schedule of events, including AE/serious adverse event (SAE) data
collection and a continued access follow-up visit, to occur 30 days after discontinuation from the 

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continued access period or when the patient starts a new anticancer therapy, whichever happens 
first.
Patients receiving IPs and experiencing ongoing clinical benefit, without disease progression, 
and no undue risks may continue to receive IP after study completion in the continued access 
period until one of the criteria for discontinuation is met, including unacceptable toxicity or 
pregnancy (Section 7.1).  Patients may receive a maximum of 35 cycles (approximately 2 years)
of study treatment.
Lilly will notify investigators when the continued access period begins and ends.

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7.
Discontinuation Criteria
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
All enrolled patients who discontinue, regardless of whether or not they received IPs, will have 
procedures performed as shown in the Time and Events Table (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.1.
Discontinuation from Study Treatment
Patients are considered to have discontinued from study treatment when BOTH pembrolizumab 
and ramucirumab will no longer be administered.
Details regarding discontinuation due to an AE or due to pregnancy are found in Section 6.6, 
Section 8.2.1, and Section 8.2.1.2).  Patients will be discontinued from study treatment if they 
meet any of the following additional criteria:

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

The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication, discontinuation 
from the study occurs prior to introduction of the new agent.

The investigator decides that the patient should be discontinued from study treatment.

The patient requests that the patient be withdrawn from study treatment.

The patient is significantly noncompliant with study procedures and/or treatment.

disease progression (must be confirmed if patient is clinically stable [Section 8.1.1.3])

Discontinuation of treatment may be considered for patients who have attained a 
confirmed CR that have been treated for at least 24 weeks and had at least 2 cycles of 
study treatments beyond the date when the initial CR was declared.
7.1.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.  If the Sponsor or investigator identifies a 
patient who did not meet enrollment criteria and was inadvertently enrolled, a discussion must 
occur between the Sponsor CRP and the investigator to determine if the patient may continue in 
the study.  If both agree it is medically appropriate to continue, the investigator must obtain 
documented approval from the Sponsor CRP to allow the inadvertently enrolled patient to 
continue in the study with or without treatment with study drug(s).
7.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

The investigator decides that the patient should be discontinued from the study.

The patient requests that the patient be withdrawn from the study.

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
The patient becomes pregnant during the study. See Section 8.2.1.3 regarding reporting 
requirements on fetal outcome and breastfeeding.

Lilly stops the study or stops the patient’s participation in the study for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and good 
clinical practice (GCP).
7.2.1. Patients Who are Lost to Follow-Up
A patient will be considered lost to follow up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow.

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8.
Study Assessments and Procedures
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.
Study procedures assessments and their timing are described in the sections below and shown in 
the Time and Events Table (Attachment 1).
8.1.
Efficacy
8.1.1. Efficacy Assessments at Baseline and during Study Treatment
RECIST 1.1 (Attachment 6) will be applied as the primary measure for assessment of tumor 
response and date of disease progression.  Local tumor imaging (investigator assessment with 
site radiological reading) will be used.
Tumor imaging should be performed by CT, which is preferred for the majority of patients, as 
the more commonly used modality.  Magnetic resonance imaging (MRI) should only be used 
when CT is contraindicated or for imaging in the brain.  The same imaging technique should be 
used for a patient throughout the trial.  Imaging should include the chest, abdomen, and pelvis.
The subsections below describe in detail the tumor imaging and assessment measures at baseline 
and during study treatment (one or both study drugs, Section 4.1.3).
8.1.1.1. Baseline Tumor Imaging
Initial tumor imaging at screening must be performed within 21 days prior to the date of 
enrollment (assignment to treatment) or within 28 days of the first dose of study treatment.  The 
site study team must review screening images to confirm the patient has measurable disease per 
RECIST 1.1.
Scans performed as part of routine clinical management are acceptable for use as initial tumor 
imaging if they are of diagnostic quality and performed within protocol required time frame as 
described above.
8.1.1.2. Tumor Imaging During Study Treatment
During study treatment, tumor response will be assessed every 6 weeks (± 7 days) by 
investigator, with confirmatory assessment obtained at the next routine scheduled imaging 
time point (that is, after 6 weeks ±7 days).  After 24 weeks, tumor assessment will be conducted 
every 12 weeks (± 7 days).
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor imaging 
assessment not less than 4 weeks from the date the response was first documented.  The tumor 
imaging for confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response, or at the next scheduled scan (that is, 6 weeks + 7 days later), whichever 
is clinically indicated.
Continue to perform imaging until whichever of the following occurs first:

disease progression confirmed by the second radiographic exam

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
the start of new anticancer treatment

withdrawal of consent

death

end of trial
8.1.1.3. Immune-Related RECIST (irRECIST)
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  Standard RECIST may not provide an accurate response assessment 
of immunotherapeutic agents such as pembrolizumab.  Therefore, for Study JVDF, RECIST 1.1 
will be adapted to account for the unique tumor response characteristics seen with treatment of 
pembrolizumab (immune-related RECIST [irRECIST]).  irRECIST will be applied as detailed 
below for treatment-related decisions, and the resulting data will be included in the clinical
database.
If radiologic imaging verifies initial progressive disease (PD), tumor assessment should be 
repeated approximately 4 weeks later in order to confirm PD with the option of continuing study 
treatment per below while awaiting radiologic confirmation of progression.
If repeat imaging shows < 20% target lesion compared to nadir, stable or improved previous new 
lesion (if identified as cause for initial PD), and stable/improved non-target disease (if identified 
as cause for initial PD), treatment may be continued / resumed.
If repeat imaging confirms PD due to any of the scenarios listed below, patients will be 
discontinued from study treatment.  In determining whether or not the tumor burden has 
increased or decreased, site study team should consider all target lesions as well as non-target 
lesions (see Site Guidance Document for RECIST/irRECIST).
Scenarios where PD is confirmed at repeat imaging:

Target lesions remains ≥ 20% and at least 5-mm absolute increase compared to nadir.

Non-target disease resulting in initial PD is worse (qualitative).

New lesion resulting in initial PD is worse (qualitative).

Additional new lesion(s) since last evaluation
In patients who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a patient on study treatment until repeat imaging is obtained.  This 
clinical judgment decision should be based on the patient’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Patients may receive study
treatment while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria:

absence of signs and symptoms indicating disease progression

no decline in ECOG performance status

absence of rapid progression of disease

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
absence of progressive tumor at critical anatomical sites (for example, cord 
compression) requiring urgent alternative medical intervention
When feasible, patients should not be discontinued from study treatment until progression is 
confirmed by the second radiographic exam.  This allowance to continue treatment despite initial 
radiologic progression takes into account the observation that some patients can have a transient 
tumor flare in the first few months after the start of immunotherapy, but with subsequent disease 
response.  Patients who are deemed clinically unstable are not required to have repeat imaging 
for confirmation of PD.
Table JVDF.6 summarizes the guidance for imaging and treatment after the first radiologic 
evidence of PD.
Table JVDF.6.
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD
Repeat imaging 
approximately 4 
weeks later at site 
to confirm PD
May continue 
study treatment at 
the investigator’s 
discretion while 
awaiting 
confirmatory scan
Repeat imaging 
approximately 4 
weeks later to
confirm PD, per 
investigator 
discretion only
Discontinue 
treatment 
Repeat scan 
confirms PD
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A
Repeat scan shows 
SD, PR, or CR
Continue regularly 
scheduled imaging 
assessments every 
6 weeks 
Continue study 
treatment at the 
investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments every 
6 weeks 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion 
Abbreviations:  CR = complete response; N/A = not applicable; PD = progressive disease; PR = partial response; 
SD = stable disease.
NOTE: Discontinuation of study treatment may be considered for patients who have attained a confirmed CR that 
have been treated for at least 24 weeks with study treatment and had at least 2 treatment cycles beyond the date 
when the initial CR was declared.
In determining whether or not the tumor burden has increased or decreased, study site 
investigators should consider all target lesions as well as non-target lesions (see Procedure 
Manual).  Patients that are deemed clinically unstable are not required to have repeat tumor 
imaging for confirmation.  If radiologic progression is confirmed by subsequent scan, then the 
patient will be discontinued from study treatment.  If radiologic progression is not confirmed, 

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then the patient should resume or continue trial treatment and have their next tumor imaging 
according to the protocol schedule of every 6 weeks (± 7 days).
8.1.2. Efficacy Assessments during Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted per the Time and 
Events Table (Attachment 1).
Tumor assessments may continue for patients who are withdrawn from the study for reasons 
other than disease progression every 6 to 12 weeks depending on standard of care.
8.1.3. Efficacy Measures
The objective response rate (ORR) is the proportion of enrolled patients who have received 
any amount of either study drug, have at least 1 postbaseline tumor image, and achieve a best 
overall response of complete response (CR) or partial response (PR).  The ORR will be assessed 
based on RECIST 1.1 (Eisenhauer et al. 2009) and irRECIST.
Time-to-response (TTR) is the time from the date of first study treatment until the first 
evidence of a confirmed CR or PR, as defined in Section 8.1.1.3.
Duration of response (DoR) is defined only for responders (patients with a confirmed CR or 
PR).  It is measured from the date of first evidence of a confirmed 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.
Disease Control Rate (DCR) is defined as the proportion of enrolled patients who have a best 
overall response of CR, PR, or stable disease (SD).
Progression-free survival (PFS) is defined as the time from the date of first study treatment 
until the date of the first observed radiographically documented PD or death due to any cause, 
whichever is earlier.  The censoring is taken in the following order:
-
if a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the enrollment date, regardless of whether or not objectively determined 
disease progression or death has been observed for the patient; otherwise,
-
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 complete 
objective progression-free disease assessment date.
TTR, DoR, DCR, and PFS will be assessed based on RECIST 1.1.  Exploratory analysis of TTR, 
DoR, and PFS may be conducted using irRECIST.
Overall survival (OS), including 1- and 2- year survival rates, is determined from the date of 
first study treatment until death due to any cause.  If the patient was alive at the data inclusion 
cutoff date for the analysis (or was lost to follow-up), OS will be censored on the last date the 
patient was known to be alive.

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8.1.4. Appropriateness of Measurements
The measures used in this study are consistent with those used in most conventional oncology 
trials.
8.2.
Safety
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, 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.
The timing of all safety evaluations is shown in the Time and Events Table (Attachment 1).  
Table JVDF.7 presents a summary of AE and SAE reporting guidelines and shows which
database or storage system is used.

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Table JVDF.7.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to 
be Reporteda
Collection 
Databaseb
Lilly 
Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol 
procedures
x
X
Study treatment period
All AEs
x
All SAEs
x
X
Short-term postdiscontinuation follow-up (30 days)
All AEs
x
All SAEs
x
X
Long-term postdiscontinuation period
Through post-discontinuation follow-up visit (90 days)
All SAEs
x
X
Additional long-term discontinuation follow up (every 90 
days to study completion) 
All SAEs related to 
protocol procedures or 
IP
x
X
Continued access period
All AEs
x
All SAEs
x
X
Continued access follow-up (30 days; or sooner, to occur 
when patient begins a new anti-cancer therapy)
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 or 
IP that the investigator 
becomes aware of
X
Abbreviations:  AEs = adverse events; CRF = case report form; IP = Investigational Product (ramucirumab or 
pembrolizumab); SAEs = serious adverse events.
a
Although not strictly adverse events, pregnancy and breastfeeding are reported as SAEs.  The reporting period 
starts after receiving IP(s) and ends 120 days after discontinuing study treatment or 30 days following cessation 
of treatment if the patient initiates new anticancer therapy, whichever is earlier.
b CRF collection guidelines will be followed.
8.2.1. Adverse Events
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), labs, vital sign 
measurements, or other procedures that result in a diagnosis should be reported to Lilly or its 
designee.
After the informed consent form (ICF) is signed, 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.  Site personnel will record the occurrence 
and nature of any AEs and any change in the preexisting condition(s).  Progression of the cancer 
under study is not considered an adverse event unless it is considered to be drug-related by the 
investigator.  All AEs related to protocol procedures are reported to Lilly or its designee.

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In addition, all AEs occurring after the patient receives the first dose of IP must be reported to 
Lilly or its designee via CRF.
Investigators should report to Lilly or its designee their assessment of the potential relatedness of 
each AE to protocol procedure or IP via CRF.
The investigator decides whether he or she interprets the observed AEs as reasonably possibly 
related to disease, to the study regimen, study procedure, or other concomitant treatment or 
pathologies. To assess the relationship of the AE to the IP, the following is defined:
Reasonably Possibly Related: Reasonable possibility that there is a cause and effect 
relationship between the IP, study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
NCI-CTCAE v 4.0 will serve as the reference document for choosing appropriate terminology 
for, and grading the severity of, all AEs and other symptoms.  For AEs without matching 
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 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) dictionary.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.
8.2.1.1. Reporting Ramucirumab Adverse Events of Special Interest and 
Pembrolizumab Events of Clinical Interest
8.2.1.1.1. Infusion-Related Reactions-Ramucirumab and Pembrolizumab
Any treatment-related IRRs are defined according to the CTCAE Version 4.0 definition (General 
Disorders and Administration Site Conditions).  Symptoms occurring during or following 
infusion of investigational therapy may also be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome (Immune System Disorders).  In the 
setting of symptoms occurring during or following infusion of investigational therapy, 
investigators are encouraged to use the AE term “infusion-related reaction” and any additional 
terms (including those not listed here) that best describe the event.
8.2.1.1.2. Adverse Events of Special Interest- Ramucirumab
Section 6.9.1.2.1 describes supportive care measures for each ramucirumab AESI.  
Table JVDF.3 presents the dose-modification guidelines for ramucirumab AESIs.  Contact the 
Lilly CRP if questions arise concerning AESIs.

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8.2.1.1.3. Events of Clinical Interest- Pembrolizumab
The 2 categories of ECIs include:
1. an overdose of pembrolizumab (≥1000 mg [5 times the dose]) not associated with clinical 
symptoms or abnormal laboratory results. 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal (ULN) and an elevated total bilirubin lab value that is greater than or equal to 2X 
ULN and, at the same time, an alkaline phosphatase lab value that is less than 2X ULN, 
as determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing. Please refer to the Site Guidance Document for Drug-induced Liver Injury.
ECIs identified from the date of first dose through 90 days following discontinuation of study 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever is earlier, need to 
be reported to the Sponsor (ECIs that are SAEs are reported within 24 hours, per 
Section 8.2.1.2).
8.2.1.2. Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason, including, but not limited 
to: 
o
Is a new cancer (that is, not a condition under study.  NOTE: metastases are not 
considered to be a new cancer). 
o
Is associated with an overdose (as defined in Section 8.2.1.1.3 for pembrolizumab 
and greater than the appropriate absolute dose based on the patient’s weight as 
specified in Section 6.1.1).
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 IP and ends 90 days following cessation of treatment, or 30 days following cessation of 
treatment if the patient initiates new anticancer therapy, whichever is earlier.   If a patient 
experiences an SAE after signing informed consent, but prior to receiving IPs, the event will not 
be reported as serious unless the investigator feels the event may have been caused by a protocol 
procedure. 
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a Sponsor-approved method.  If study site 

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personnel contact Lilly or its designee by telephone regarding an SAE, study site personnel must 
also immediately provide official notification on study-specific SAE forms.
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.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the IPs.
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, if an investigator becomes aware of an SAE 
occurring after the patient’s participation in the trial has ended, and the investigator believes that 
the SAE is related to a protocol procedure or IPs, the investigator should report the SAE to the 
Sponsor, and the SAE will be entered in the Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the Sponsor in aggregate periodically during the course of the trial may be 
found in the pembrolizumab and ramucirumab IBs.
8.2.1.3. Pregnancy
Cases of pregnancy that occur during maternal or paternal exposures to IPs (ramucirumab or 
pembrolizumab) should be reported within 24 hours.  Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, congenital abnormality, 
fetal death, intrauterine death, miscarriage and stillbirth, or other disabling or life-threatening 
complication to the mother or newborn must be reported as AEs.  Data on fetal outcome 
(including and breastfeeding) are collected for regulatory reporting and drug safety evaluation.  
The following additional measures will be taken in the case of pregnancy:

A patient who becomes pregnant will be immediately removed from the study.

It is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a patient (spontaneously reported to them) that occurs during the trial or 
within 120 days of completing the trial or 30 days following cessation of treatment if the 
patient initiates new anticancer therapy, whichever is earlier.

All patients who become pregnant must be contacted by the site at least monthly and the 
patient’s status documented to the completion/termination of the pregnancy; the 
investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.
8.2.1.4. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information in the IB and that the investigator identifies as 

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related to the IPs or study procedure.  United States 21 CFR 312.32 and European Union Clinical 
Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and associated detailed guidances.
8.2.2. Other Safety Measures
8.2.2.1. Electrocardiograms
For each patient, 12-lead digital ECGs will be collected according to the Time and Events Table 
(Attachment 1) as single ECGs for overread.  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 a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.
The investigator (or qualified designee) must document his/her review of the ECG printed at the 
time of evaluation.  Local ECG findings at baseline and end of treatment, and any on study 
clinically significant abnormal findings, will be reported into the electronic CRF (eCRF) and any 
alert reports.
8.2.2.2. Echocardiogram or Multiple-Gated Acquisition Scan
An echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan will be performed 
according to the Time and Events Table (Attachment 1).  Additional evaluations are not required 
but should be performed in the setting of cardiac symptoms, at the discretion of the investigator.
Patients will undergo baseline left ventricular ejection fraction (LVEF) determination by ECHO 
or MUGA scan. This evaluation may be repeated at any time during the study if clinically 
indicated.
8.2.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.

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Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP 
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review:

trends in safety data

laboratory analytes (Attachment 3)

adverse events, including ramucirumab AESI and pembrolizumab ECI (Section 8.2.1.1).

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 may consult with the Lilly CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests.  See Site Guidance 
Document for Drug-Induced Liver Injury.
8.3.
Pharmacokinetics
Pharmacokinetic samples to determine ramucirumab PK will be collected as specified in
Attachment 2.
Blood samples will be drawn for all patients for the assessment of ramucirumab concentrations
in serum (also known as bioanalytical samples). Sampling times were selected to coincide with 
expected Cmax and Cmin and with consideration to draw minimum volume of blood from 
patients and ensuring that the patients do not to need to make an extra visit to provide these 
samples.
Instructions for the collection and handling of bioanalytical blood samples will be provided by 
the Sponsor.  The actual start and end date and time of ramucirumab infusion administration 
must be recorded on the eCRF.  The actual date and time that each bioanalytical blood sample 
was drawn must be recorded on the laboratory accession page after the sample is drawn.
Ramucirumab concentrations in bioanalytical serum samples will be measured using a validated 
assay methodology in a laboratory designated by the Sponsor.
Bioanalytical samples collected to measure ramucirumab concentration will be retained for a 
maximum of 1 year following last patient visit for the study.
8.4.
Biomarkers
Where local regulations and ethical review boards (ERBs) allow, these samples will be collected 
for biomarker research as discussed below and specified in the Sampling Schedule 
(Attachment 2).
All biomarker samples will be coded with the patient number.  These samples and any data 
generated can be linked back to the patient only by the investigator site personnel.  Samples will 
be destroyed according to a process consistent with local regulations.
It is possible that biomarker data for patients in the study has already been generated from 
samples that were collected and analyzed prior to enrolling in this trial. This may include data 

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generated from genetic analyses. If available, these data may be requested from medical records 
for use in the research described in Section 8.4.2.
8.4.1. Genetics
Whole Blood Sample for DNA Collection:
A whole blood sample will be collected for pharmacogenetic analysis where local regulations 
and ERBs allow.  These samples are not being collected to create a biobank for conducting 
unspecified disease or population genetic research either now or in the future.
Samples may be used to investigate variable response to study treatment and to investigate 
genetic variants thought to play a role in cancer. Assessment of variable response may include 
evaluation of AEs or differences in efficacy.  These studies may include but are not limited to the 
VEGF pathway and immunomodulatory mechanisms to evaluate their association with observed 
response to study treatment.
Samples will be retained for a maximum of 15 years after the last patient visit, or as local 
regulations and ERBs allow, for the study at a facility selected by the Sponsor.  This retention 
period enables use of new technologies, response to regulatory questions, and investigation of 
variable response that may not be observed until later in drug development or when the drug is 
commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, candidate gene studies, and epigenetic analyses.  
Regardless of the technology utilized, genotyping data generated will be used only for the 
specific research scope described in this section.
8.4.2. Tailoring and Pharmacodynamic Biomarkers
Samples will be collected for potential non-pharmacogenetic biomarker research. Samples will 
be collected at the times specified in the Schedule of Activities.
Samples may be used for research on the drug targets (PD-1 and VEGF Receptor 2), disease 
process, pathways associated with cancer, mechanism of action of ramucirumab and/or 
pembrolizumab, and/or research method or in validating diagnostic tools or assay(s) related to 
cancer.
Samples will be retained for a maximum of 15 years after the last patient visit, or as local 
regulations and ERBs allow, for the study at a facility selected by the Sponsor.  This retention 
period enables use of new technologies, response to regulatory questions, and investigation of 
variable response that may not be observed until later in drug development or when the drug is 
commercially available.
Required samples for biomarker research to be collected from all patients in this study as 
specified in the study schedule are the following:

EDTA plasma

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
peripheral mononuclear blood cells from whole blood

tumor tissue at baseline (see Inclusion Criterion [4] and the paragraph below). 
For the submission of baseline tumor tissue sample, formalin-fixed paraffin-embedded tumor 
tissue sample blocks are preferred.  If submitting unstained cut slides, freshly cut slides should 
be submitted to the testing laboratory within 7 days from when the slides are cut. In addition, all 
archival samples should be discussed with the Sponsor before submission.  A formalin-fixed 
paraffin-embedded tumor tissue block obtained within 3 months prior to enrollment and 
following most recent systemic treatment will be considered by the Sponsor.
Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following:

tumor tissue/biopsy that becomes available during the study treatment period
8.5.
Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine anti-drug antibody 
(ADA) production against ramucirumab.  The specific time points are listed in Attachment 2. 
Sample collection, storage, and shipment instructions for blood samples will also be provided in 
the Procedures Manual.
Pretreatment and post-treatment samples will be collected and assayed for the presence of ADA 
using an immunoassay.  The number and percentage of patients with positive antidrug response 
will be summarized. In the event of an IP- related infusion reaction, every effort should be made 
to collect a blood sample for anti-ramucirumab antibody determination, as well as a blood 
sample for ramucirumab serum concentration, as close to the onset of the reaction as possible, at 
the resolution of the event, and 30 days following the event.
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 to ramucirumab.  
The duration allows the Sponsor to respond to regulatory requests related to ramucirumab.
8.6.
Health Economic and Outcomes Research
This section is not applicable to this protocol.

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9.
Statistical Considerations and Data Analysis
9.1.
Determination of Sample Size
The primary objective for the DLT Phase 1a and Expansion Phase 1b is to evaluate safety and 
tolerability.  The sample size of Expansion Phase 1b was selected to allow adequate assessment 
of safety at the recommended doses for ramucirumab and pembrolizumab for each tumor type 
and dose schedule, separately.
The following sample sizes apply to each phase of the study:
Phase 1a Dose-Limiting Toxicity Observation: up to 12 DLT-evaluable patients
Phase 1b Expansion: 155 patients;

15 patients each for Gastric-GEJ (2nd - 3rd Line) Cohorts A and B (2nd - 3rd Line)

25 patients each for:
o
BTC (2nd - 3rd Line) Cohort A1
o
Gastric-GEJ (1st Line) Cohort A2
o
NSCLC (2nd - 4th Line) Cohort C
o
Urothelial (2nd - 4th Line) Cohort D 
o
NSCLC (1st Line) Cohort E
The primary objective of Study JVDF is the safety and tolerability of ramucirumab in 
combination with pembrolizumab.  During Expansion Phase 1b, 25 to 30 patients per tumor type 
will be treated, to provide a preliminary assessment of tumor response and an assessment of 
safety.  For each of the tumor types, the ORR values in the simulations are provided as a 
reference for estimation of statistical power rather than a basis of any decision criteria.  All 
efficacy endpoints will be utilized to determine next steps of development of the combination.
For Gastric-GEJ and BTC (2nd -3rd line), and NSCLC and Urothelial (2nd to 4th line), the null 
hypothesis is based on the assumption that the ORR is no greater than 10% to 15% and the target 
treatment effect (alternative response rate) of the combination treatment on ORR is greater than 
20% to 30%.  Based on these assumptions, a sample size of n=25 to 30 (n=30 for combined 
Gastric Cohorts A and B) provides statistical power of approximately 60% to 90%, with a 1-
sided 0.20 significance level (Table JVDF.8).

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Table JVDF.8.
Summary of Statistical Power for Overall Response Rates for 
NSCLC 2-4L, Bladder 2-4L, BTC 2-3L, and Gastric 2-3L 
NSCLC, Bladder, and BTC
Gastric (combined preliminary efficacy)
Low 
Case
High 
Case
Low 
Case
High 
Case
Low 
Case
High 
Case
Low 
Case
High
Case
N=25
N=25
N=25
N=25
N=30
N=30
N=30
N=30
Null response rate
10%
10%
15%
15%
10%
10%
15%
15%
Alternative 
response rate
20%
25%
25%
30%
20%
25%
25%
30%
Power 
57.9%
78.6%
62.2%
80.7%
74.5%
90.2%
65.2%
84.0%
Abbreviations:  BTC = biliary tract cancer; L = line; N = number of patients; NSCLC = non-small cell lung cancer.
Note:  Low case = 10% difference between alternative response rate and null response rate for overall response rate; 
High case = 15% difference between alternative response rate and null response rate for overall response rate.
For the first-line NSCLC and Gastric-GEJ, the null hypothesis is based on the assumption that 
the ORR is no greater than 30% to 35% and the target treatment effect (alternative response rate) 
of the combination treatment on ORR is greater than 45% to 55%.  Based on these assumptions, 
a sample size of n=25 provides statistical power of approximately 65% to 90%, with a 1-sided 
0.20 significance level (Table JVDF.9).
Table JVDF.9.
Summary of Statistical Power for Overall Response Rates for 
NSCLC 1L and Gastric 1L
NSCLC (1L) and Gastric (1L; combined preliminary efficacy)
Low Case
High Case
Low Case
High Case
N=25
N=25
N=25
N=25
Null response rate
30%
30%
35%
35%
Alternative 
response rate
45%
50%
50%
55%
Power 
75.8%
88.5%
65.5%
81.7%
Abbreviations:  1L = First-Line; N = number of patients; NSCLC = non-small cell lung cancer.
Note:  Low case = 15% difference between alternative response rate and null response rate for overall response rate; 
High case = 20% difference between alternative response rate and null response rate for overall response rate.
9.2.
General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly.
For the Phase 1a, a 3+3 design will be used to assess the safety of ramucirumab in combination 
with pembrolizumab (Section 6.1.1.1). Additional patients will be enrolled in a dosing schedule 
to achieve the minimum of 3 evaluable patients, if dropouts or dose interruptions or reductions occur 
that result in a patient being non-evaluable for DLTs. Data will be reviewed by dose schedule 
group (3 patients).

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The final analysis of safety and preliminary efficacy will occur approximately 2 years after the first 
patient received first study treatment. Separate interim analyses will occur after all patients in 
each cohort have completed approximately 24 weeks of study treatment or discontinued for any 
reason. Safety and preliminary efficacy will be analyzed separately for each cohort (details in 
Section 9.8).
Descriptive statistics will be derived where appropriate.  The rate of DLTs will be summarized 
by cohort; dose exposure and density for each study drug will be calculated by each cohort.
Pharmacodynamics/Biomarkers
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset of patients 
from the above cohorts from whom a valid assay result (according to laboratory guideline) has 
been obtained.
General
Additional details will be provided in a separate statistical analysis plan (SAP) for the study.  
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.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
9.3.
Patient Characteristics
Patient characteristics which will be summarized by cohort:

Patient demographics will be reported using descriptive statistics. Demographic data are 
collected and reported to demonstrate that a trial population represents the target patient 
population considered for regulatory approval.

Baseline disease characteristics will be summarized by presenting frequency counts and 
percentages (for example, for pathological diagnosis [histological or cytological] and 
disease stage).

A detailed description of patient disposition will be provided.  It will include a summary 
of the number and percentage of patients entered into the study, enrolled in the study, and 
treated as well as number and percentage of patients completing the study, or 
discontinuing (overall and by reason for discontinuation).

Disease-related therapies, including prior anticancer treatments, prior radiotherapies 
(such as type of therapy, regimen, and prior surgery)
Other patient characteristics will be summarized as deemed appropriate.
9.3.1. Concomitant Therapy
Concomitant medications will be summarized for the safety population.

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9.3.1.1. Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.
9.3.2. Treatment Compliance
The number of dose omissions, reductions, and delays, number of cycles received, and dose 
intensity will be summarized for all treated patients and for both study drugs.
9.4.
Efficacy Analysis: Phase 1b
The objective response rate and disease control rate, and the corresponding confidence interval,
will be provided by cohort (according to RECIST v1.1 and irRECIST). Time-to-event variables, 
such as time to response, duration of response, PFS, and OS will be estimated by Kaplan-Meier 
(1958) methodology by cohort.  Presentations of efficacy may include patients enrolled in DLT 
Phase 1a with the same tumor type and treatment schedule.
Individual changes in the tumor burden over time will be presented graphically within a tumor 
type (that is, Waterfall plots).  Subgroup analysis of interest will be further defined in the SAP. 
Association between tumor PD-L1 expression at baseline will also be correlated with clinical 
outcomes such as overall response rate, and further assessed and characterized by appropriate
statistics.
9.5.
Safety Analyses
All patients who receive at least 1 dose of ramucirumab or pembrolizumab will be evaluated for 
safety and toxicity.  Adverse event terms and severity grades will be assigned by the investigator 
using CTCAE, Version 4.0.
Safety analyses will include summaries of the following:

DLTs:  the number of patients who experienced any DLTs during Cycle 1 will be 
summarized by dose schedule in Phase 1a

AEs, including severity and possible relationship to study drug

AEs by MedDRA System Organ Class (SOC) by decreasing frequency of Preferred Term 
within SOC

Laboratory and nonlaboratory AEs by CTCAE term and maximum CTCAE grade 
(regardless of causality and at least possibly related to study treatment)
9.6.
Pharmacokinetic/Pharmacodynamic Analyses
The sampling schedule for drawing blood samples for ramucirumab PK is provided in
Attachment 2.  Serum concentrations of ramucirumab prior to infusion (Cmin) and at 1 hour after 
the end of the ramucirumab infusion (approximately maximum concentrations) will be 
summarized using descriptive statistics.
Population PK analyses for ramucirumab may be conducted using population PK approach.  The 
relationship between ramucirumab exposure and selected safety outcomes may be explored.

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9.7.
Other Analysis
9.7.1. Immunogenicity
Immunogenicity (anti-ramucirumab antibody) incidence will be tabulated, and correlation to 
ramucirumab drug level, activity, and safety will be assessed, as appropriate, respectively.  The 
measures that will be analyzed include baseline presence and level of ADA, treatment-emergent 
ADA, levels of neutralizing ADA, and incidence and levels of ADA related to IRRs.
9.7.2. Biomarker Analysis
Biomarkers will be summarized and assessed for correlations with clinical outcomes.  Biomarker 
relationships by tumor type, changes in biomarker levels over time, and differences among dose 
levels or exposure will be explored as possible.
9.8.
Interim Analyses
For Phase 1a, safety and PK data will be reviewed on a cohort-by-cohort basis during the study.  
The purpose of these data reviews is to evaluate the safety and tolerability for each dose schedule 
and determine if a DLT has been observed.  The investigators and the Lilly study team will 
evaluate the totality of data to determine whether or not to move into the Expansion Phase 1b.
Separate interim analyses will occur after all patients in each cohort have completed 
approximately 24 weeks of study treatment or discontinued for any reason.  The interim analyses 
may be combined if they are expected to occur within approximately a month, and interim 
analyses may also be combined with the ongoing trial-level safety review or annual safety review 
for annual safety update reporting.
An independent data monitoring committee may be initiated if one or more additional cohorts 
will be expanded to further explore safety and efficacy for the ramucirumab and pembrolizumab 
combination.

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10. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
10.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of 
investigational product.
10.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline 
on GCP.
The investigator must give assurance that the ERB was properly constituted and convened as 
required by ICH guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IBs and updates during the course of the study

ICF

relevant curricula vitae
10.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines
2) the ICH GCP Guideline [E6]
3) 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 the Sponsor will be assigned to a third-party organization.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data.
10.4. Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
10.5. Protocol Signatures
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
10.6. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.  The coordinating investigator will be the 
investigator with the most enrolled patients; if this investigator is unable to fulfill this function, 
another investigator will be chosen by the Sponsor.
The Sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
10.7. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Complaints related to unblinded concomitant drugs are reported directly to the manufacturers of 
those drugs/devices in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.8. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

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

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Attachment 1.Protocol JVDF Time and Events Tables

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Time and Events Table: Baseline, Study Treatment, and Postdiscontinuation Follow-Up Periods
Study Period
Notes
Baseline
(within 28 days prior 
to enrollment)
Treatment 
(21-day cycles)
±7 days
Postdiscontinuation 
Follow-Up
The first study treatment will be administered within 7 days 
following enrollment.
Postdiscontinuation follow-up begins when the decision is 
made that the patient will no longer continue study 
treatment.
Procedure
≤28 
days
≤21 
days
≤7 
days
Day 1
Day8
Short-Term 
Follow-Up 
Visit 
(30 ±7 days)
Long-Term 
Follow-Up 
Visit
(every 90 ±7 
days)
Day 8 procedures are only for Cohort A, A1, and A2
(Gastric-GEJ or BTC Ram 8 mg/kg, Days 1 and 8).
Long-term follow-up should be attempted at regularly 
scheduled intervals (every 90 days [±7 days]) until death, 
loss to follow-up, or study completion (whichever occurs 
first).
Informed consent
form (ICF)
X
Obtain ICF prior to any study-specific procedures.  If the 
ICF is revised during the course of the study, re-consenting 
of patients may be required if deemed necessary by Lilly or 
the ERB.
Inclusion/exclusion
criteria
X
Medical history
X
Including preexisting conditions and historical illnesses
ECG
X
X
Baseline, short-term follow–up, and when clinically 
indicated
Echocardiogram or 
MUGA scan
X
Baseline, and when clinically indicated
ECOG Performance 
Status
X
X
X
A time window of -3 days of Day 1 is permitted for the 
ECOG assessment.
Brain Scan
X
Baseline brain scan by CT or MRI for NSCLC patients and 
Urothelial patients only.  Refer to eligibility criteria.
Concomitant therapy
X
X
X
Concomitant medications will be recorded, including any 
taken within 30 days prior to enrollment and those taken 
during the 30 days after the last dose of study treatment.
Physical exam
X
X
X
A time window of ±3 days with respect to the other study 
visit procedures is permitted.

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Study Period
Notes
Baseline
(within 28 days 
prior to 
enrollment)
Treatment 
(21-day 
cycles)
Postdiscontinuation 
Follow-Up
The first study treatment will be administered within 7 days following 
enrollment.
Postdiscontinuation follow-up begins when the decision is made that the 
patient will no longer continue study treatment.
Procedure
≤28 
days
≤21 
days
≤7 
days
Day 
1
Day
8
Short-Term 
Follow-Up 
Visit 
(30 ±7 days)
Long-Term 
Follow-Up 
Visit
(every 90 ±7 
days)
Day 8 procedures are only for Cohort A, A1, and A2 (Gastric-GEJ or 
BTC Ram 8 mg/kg, Days 1 and 8).
Long-term follow-up should be attempted at regularly scheduled 
intervals (every 90 days [±7 days]) until death, loss to follow-up, or study 
completion (whichever occurs first).
Height, 
weight
X
X
Measure height at baseline only. Measure weight at the beginning of 
each cycle. Recalculate the ramucirumab dose if weight change is ≥10% 
compared to previous measurement(s).
Vital signs
X
X
X
For the first 2 ramucirumab infusions, measure blood pressure and pulse
as follows:  (i) within 15 minutes prior; (ii) after infusion completion; 
and (iii) at the end of the 1-hr post-infusion observation period.  Measure 
blood pressure and pulse prior to each subsequent ramucirumab infusion.  
Measure other vital signs as clinically indicated.
AE 
collection; 
CTCAE 
grading
X
During short-term follow-up, all AEs/SAEs will be collected.
At the 90-day long-term follow-up visit, all SAEs will be collected.  
Thereafter, during long-term follow-up, only SAEs that are related to 
study regimen or protocol procedures will be collected.

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Study Period
Notes
Baseline
(within 28 days 
prior to 
enrollment)
Treatment 
(21-day 
cycles)
Postdiscontinuation 
Follow-Up
The first study treatment will be administered within 7 days 
following enrollment.
Postdiscontinuation follow-up begins when the decision is made 
that the patient will no longer continue study treatment.
Procedure
≤28 
days
≤21 
days
≤7 
days
Day 
1
Day
8
Short-Term 
Follow-Up 
Visit 
(30 ±7 days)
Long-Term 
Follow-Up 
Visit
(every 90 ±7 
days)
Day 8 procedures are only for Cohort A, A1, and A2 (Gastric-GEJ 
or BTC Ram 8 mg/kg, Days 1 and 8).
Long-term follow-up should be attempted at regularly scheduled 
intervals (every 90 days [±7 days]) until death, loss to follow-up, or 
study completion (whichever occurs first).
Laboratory 
Assessment
Baseline laboratory assessments can be used for Cycle 1 Day 1 if 
the baseline assessments were performed within 7 days prior to 
Cycle 1 Day 1 and the results are deemed still clinically valid by 
the treating investigator. Starting with the second cycle, where 
required, labs are to be performed within 3 days prior to first day of 
each cycle.  More frequent assessment should be performed if 
clinically indicated.  Results of blood tests must be reviewed prior 
to start of cycle.  
Hematology
X
X
X
Local only.  Within 3 days prior to Day 1 of each cycle.
Chemistry
X
X
X
Local and central: Local chemistry laboratory testing will be used 
to determine patient eligibility and decisions for treatment.  
Central chemistry laboratory testing will be used for subsequent 
scheduled analyses.
Within 3 days prior to Day 1 of each cycle.
Urinalysis
X
X
X
Local only. Within 3 days prior to Day 1 of each cycle. 24-hr 
urine protein analysis if urine protein is ≥2+ at baseline, >2+ during 
study treatment.
T3, free T4, 
TSH
X
X
X
Central and local as needed. At baseline, within 3 days prior to 
Day 1 of Cycle 3, Day 1 of Cycle 6, and every 2 cycles thereafter; 
and more frequently if clinically indicated.
Coagulation
X
X
X
Local only. Within 3 days prior to Day 1 of every odd-numbered 
cycle.
Pregnancy test
X
X
Local only. Required for women of child-bearing potential. If 
required per local regulations and/or institutional guidelines, testing 
can occur at other times during the study treatment period.

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Study Period
Notes
Baseline
(within 28 days 
prior to enrollment)
Treatment 
(21-day 
cycles)
Postdiscontinuation 
Follow-Up
The first study treatment will be administered within 7 days 
following enrollment.
Postdiscontinuation follow-up begins when the decision is made 
that the patient will no longer continue study treatment.
Procedure
≤28 
days
≤21 
days
≤7 
days
Day 
1
Day
8
Short-Term 
Follow-Up 
Visit 
(30 ±7 
days)
Long-Term 
Follow-Up 
Visit
(every 90 ±7 
days)
Day 8 procedures are only for Cohort A, A1, and A2 (Gastric-GEJ 
or BTC Ram 8 mg/kg, Days 1 and 8).
Long-term follow-up should be attempted at regularly scheduled 
intervals (every 90 days [±7 days]) until death, loss to follow-up, 
or study completion (whichever occurs first).
Efficacy 
Assessment
Tumor imaging and 
assessment
X
X
X
X
Assessments previously obtained as part of routine clinical care 
may be used as the baseline assessment if performed within 
21 days prior to enrollment. Imaging is not required on Cycle 1 
Day 1.  SEE FOOTNOTE.
Survival information
X
X
Follow-up for the collection of survival data and subsequent 
anticancer treatments should be attempted at regularly scheduled 
intervals (every 90 days [±7 days]) for up to 2 years after patients 
receive the first dose.  This follow-up might be a phone call to the 
patient, her/his family, or local doctor.
Additional 
Analyses
Tumor tissue
X
New biopsy at baseline (recent to Cycle 1 Day 1) is required.  For 
first line NSCLC, PD-L1 >=1% is required.  Tumor tissue 
collection during the treatment period is optional, and can be 
provided if available, for example in case of a clinically-indicated 
biopsy.
Genetics Whole 
Blood Sample 
X
Collect 1 sample prior to treatment on Cycle 1 Day 1.
Biomarker
Pharmacokinetics
Immunogenicity
See Attachment 2.

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Study Period
Notes
Baseline
(within 28 days 
prior to enrollment)
Treatment 
(21-day 
cycles)
Postdiscontinuation 
Follow-Up
The first study treatment will be administered within 7 days 
following enrollment.
Postdiscontinuation follow-up begins when the decision is 
made that the patient will no longer continue study treatment.
Procedure
≤28 
days
≤21 
days
≤7 
days
Day 
1
Day
8
Short-Term 
Follow-Up 
Visit 
(30 ±7 days)
Long-Term 
Follow-Up 
Visit
(every 90 ±7 
days)
Day 8 procedures are only for Cohort A, A1, and A2 (Gastric-
GEJ or BTC Ram 8 mg/kg, Days 1 and 8).
Long-term follow-up should be attempted at regularly 
scheduled intervals (every 90 days [±7 days]) until death, loss 
to follow-up, or study completion (whichever occurs first).
Administration of 
Study Drugs
Administer ramucirumab first per the dose schedule to which 
the patient is allocated.  For first 2 cycles, implement a 1-hr 
observation period i) between ramucirumab and 
pembrolizumab administration, and ii) after pembrolizumab 
infusion.  For all cycles thereafter, no observation period will 
be required unless clinically indicated.
Administer 
Ramucirumab
BTC 8 mg/kg
X
X
Gastric-GEJ 
8 mg/kg
X
X
Gastric-GEJ 
10 mg/kg
X
NSCLC 10 mg/kg,
X
Urothelial 10 mg/kg
X
Administer 
Pembrolizumab
200 mg fixed
X

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Time and Events Table (concluded)
Abbreviations:  AE = adverse event; Att. = attachment; BTC = biliary tract cancer; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; ERB = ethical review board; Gastric-
GEJ= Gastric-Gastroesophageal Junction; ICF = informed consent form; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; NSCLC = 
non-small cell lung cancer; PD = progressive disease; Prot. Ref. = protocol reference; Ram = ramucirumab; SAE= serious adverse event; TSH = thyroid-
stimulating hormone.
FOOTNOTES Regarding Tumor Assessment:

During treatment cycles, perform tumor assessment and imaging as follows:  (i) every 6 weeks (±7 days) for the first 6 months after enrollment, and 
(ii) every 12 weeks (±7 days) thereafter.  Perform as scheduled even if study treatment is delayed, except when tumor assessment and imaging are not 
feasible in the opinion of the investigator because of the patient’s clinical status.

If radiologic imaging verifies initial progressive disease (PD), tumor assessment should be repeated approximately 4 weeks later in order to confirm PD 
with the option of continuing study treatment while awaiting radiologic confirmation of progression (Section 8.1.1.3).

During the short-term and long-term follow-up periods, for patients who discontinue study treatment without objectively measured PD, continue to 
perform tumor assessment and imaging every 6 to 12 weeks depending on standard of care.

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Time and Events Table: Continued Access Period
Continued Access Period
Notes
Continued 
Access
Treatment
(21-day cycles)
Continued 
Access 
Follow-Up
Day 1 and Day 8 assessments are performed only if study drug dosing is scheduled to occur on that 
day.
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient 
will no longer continue treatment in the continued access period and lasts approximately 30 days.
Efficacy assessments will be performed at the investigator’s discretion based on the standard of care.
Relative Day within a 
Cycle
Day 1
Day 8
Procedures
Weight
X
Administer 
Ramucirumab
BTC 8 mg/kg
X
X
Gastric-GEJ 8 mg/kg
X
X
Gastric-GEJ 10 mg/kg
X
NSCLC 10 mg/kg
X
Urothelial 10 mg/kg
X
Administer 
Pembrolizumab 
200 mg (fixed)
All treatment cohorts
X
AE Collection, 
CTCAE Grading
X
X
X
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly 
Safety System.  After the patient is no longer participating in the study (that is, no longer receiving 
study treatment and no longer in follow-up), only SAEs that the investigator is made aware of and are 
related to study regimen or protocol procedures will be collected.  
Immunogenicity and 
PK Sample
If a patient experiences an IRR to ramucirumab, blood samples for immunogenicity and PK analysis 
will be taken at the following time points:  (1) as soon as possible after the onset of the IRR, (2) at the 
resolution of the IRR, and (3) 30 days after the IRR.
Abbreviations:  AE = adverse event; BTC = biliary tract cancer; CTCAE = Common Terminology Criteria for Adverse Events; GEJ = gastroesophageal junction; 
IRR = infusion-related reaction; NSCLC = non-small cell lung cancer; PK = pharmacokinetics; SAE =serious adverse events.

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Attachment 2.Protocol JVDF Pharmacokinetic, 
Immunogenicity, and Biomarker Sampling Schedules
PK and immunogenicity (IK) samples will be collected for ramucirumab only, in both Phase 1a 
and Phase 1b portions of the study. Predose samples should be taken as close as possible to the 
start of first infusion, that is ramucirumab infusion, but can be drawn up to 1 hour (60 minutes) 
prior start of infusion, and exact clock reading should be recorded.  Postdose (post end-of-
infusion) samples for PK for ramucirumab should be drawn preferably at 1 hour (±15 minutes)
after the end of the ramucirumab infusion, and exact clock reading for the sample draw should be 
recorded.
Preferred time windows for each ramucirumab PK/IK sample collection are also provided in the 
tables in this section. While best effort should be done to draw the blood sample for 
ramucirumab PK/IK within the time window provided, it is more important to ensure predose 
sample is actually collected before the start of ramucirumab infusion and post-dose samples 
(post-end of infusion samples) are collected after ramucirumab infusion has actually completed.  
It is also equally important to record actual date and time of blood collection for ramucirumab 
PK/IK sample on the Requisition Form after drawing the sample (that is, do not record not 
planned time of collection). Sample collection for PK/IK must be from the opposite arm to that 
used for study drug infusion. If drug was administered via a central venous catheter, the sample 
collection should be from a different site.
In addition, if a patient experiences an infusion-related reaction (IRR), blood samples for anti-
ramucirumab antibody and PK should be drawn.  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.

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Table ATT.2.1.
Schedule 1 (Gastric GEJ Cohort A [2nd-3rd Line] and Gastric GEJ A2 [1st Line]; and BTC Cohort A1 [2nd-
3rd Line]):  Pharmacokinetic (PK), Immunogenicity (IK), and Biomarker Collection Timepoints for 
Ramucirumab for Schedule 1 Dosing Regimen (1h Infusion Ramucirumab followed by 0.5h Infusion 
Pembrolizumab on Day 1 and 1h Infusion Ramucirumab on Day 8, every 3 weeks)
Visit/Cycle Day
Study 
Day
Sample Time 
(relative to start 
of Ram 
infusion)
(HR:MIN)a
Ram PKf
(Serum)
Ram 
Immunogenicitye,f
(Serum)
Biomarker
EDTA
Plasma
PBMCs
Cycle 1 Day 1 (1-hr 
observation period between 
Ram and Pem infusions)
1
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X 
X
X
2.00 hr Postdose 
samplec,d 
X (collect approx. 1 hr after Ram 
infusion ends)
Cycle 1 Day 8 (Ram only)
8
0:00 hr Predose 
sampleb,d  
X (collect prior to start of infusion)
X
X
Cycle 2 Day 1 
22
0:00 hr Predose 
sampleb,d  
X (collect prior to start of first infusion)
X
X
X
Cycle 3 Day 1
43
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
Cycle 4 Day 1
64
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
X
Cycle 5 Day1
85
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
X
Cycle 7 Day 1
127
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
X
Cycle 7 Day 8 (Ram only)
134
0:00 hr Predose 
sampleb,d  
X (collect prior to start of infusion)
X
X
Cycle 9, Day 1 
169
0:00 hr 
Predoseb,d
X (collect prior to start of first infusion)
X
X
X
2:00 hr 
Postdosec,d
X (collect approx. 1 hr after Ram 
infusion ends )
30 days Post treatment DC
Anytimeg
X 
X
X
X

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Schedule 1 (Gastric GEJ Cohort A [2nd-3rd Line] and Gastric GEJ A2 [1st Line]; and BTC Cohort A1 [2nd-3rd Line]):  Pharmacokinetic (PK), 
Immunogenicity (IK), and Biomarker Collection Timepoints for Ramucirumab for Schedule 1 Dosing Regimen (1h Infusion Ramucirumab followed by 
0.5h Infusion Pembrolizumab on Day 1 and 1h Infusion Ramucirumab on Day 8, every 3 weeks) (concluded)
Note: Ram and Pem infusions are given every 3 weeks. 1-hr Ram infusion is given prior to half-hour Pem infusion. There is one-hour observation 
period (for infusion reactions) between Ram and Pem infusions at Cycle 1 Day 1 visit. Each cycle is a 21-day cycle.
Abbreviations: DC = Discontinuation; eCRF = electronic case report form; GEJ = gastroesophageal junction; IK = immunogenicity; IRR = infusion-related 
reaction; Pem = pembrolizumab; PMBC = peripheral blood mononuclear cells; PK = pharmacokinetics; Ram = ramucirumab.
a
All sample times are relative to start of first (Ram) infusion.
b Predose sample for Ram PK, IK, and biomarkers should be preferably collected within 1 hour prior to start of first infusion, and within 15 minutes of one 
another.
c
Two-hour sample for Ram PK should be preferably collected at 1 hr ±15 minutes from the end of Ram infusion.
d While best effort should be done to draw the blood sample for PK/IK within the time windows provided above, it is more important to ensure predose sample 
is actually collected before the start of first infusion and postdose samples are collected after the infusion has actually completed. It is also equally important 
to record ACTUAL date and time of blood collection for PK/IK sample on the Requisition Form AFTER drawing the sample and to accurately record the 
ACTUAL infusions start and end dates and times on the eCRF to be able to use the data for analyses.  Sample collection for PK/IK must be from the opposite 
arm to that used for study drug infusion. If drug was administered via a central venous catheter, the sample collection should be from a different site.
e
In the event of an IRR, blood samples will be collected for both PK and IK analysis at the following time points:  (i) as close as possible to the onset of the 
IRR, (ii) at the resolution of the IRR, and (iii) 30 days following the IRR.
f
Record ACTUAL date and time of blood collection for PK/IK sample on the Requisition Form AFTER drawing the sample.

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Table ATT.2.2.
Schedule 2 (Gastric-GEJ Cancer Patients Cohort B [2nd-3rd Line], NSCLC Cohort C [2nd-4th Line], 
Urothelial Cancer Cohort D [2nd-4th Line]**
, and NSCLC Cohort E [1st Line]): Pharmacokinetic (PK), 
Immunogenicity (IK), and Biomarker Collection Timepoints for Ramucirumab for Schedule 2 Dosing 
regimen (1h infusion Ramucirumab followed by 0.5h infusion Pembrolizumab on Day 1 every 
3 weeks)
Sample Time 
(relative to start 
of Ram 
infusion)
(HR:MIN)a
Biomarker Collection
Visit/Cycle Day
Study 
Day
Ram PK f 
(Serum)
Ram 
Immunogenicitye,f  
(Serum)
EDTA
Plasma
PBMCs
Cycle 1 Day 1 (1-hr 
observation period between 
Ram and Pem infusions)
1
0:00 hr Predose 
sampleb,d  
X (collect prior to start of first infusion)
X 
X
X
2.00 hr Postdose 
samplec,d
X (collect approx. 1 hr after Ram infusion ends)
Cycle 2 Day 1 
22
0:00 hr Predose 
sampleb,d  
X (collect prior to start of first infusion)
X 
X
X
Cycle 3 Day 1
43
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
Cycle 4 Day1
64
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
X
Cycle 5 Day 1
85
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
X
Cycle 7 Day 1
127
0:00 hr Predose 
sampleb,d
X (collect prior to start of first infusion)
X
X
X
Cycle 9 Day 1  
169
0:00 hr 
Predoseb,d
X (collect prior to start of first infusion)
X
X
X
2:00 hr 
Postdosec,d
X (collect approx. 1 hr after Ram infusion ends)
30 days Post treatment DC
Anytimef
X
X
X
X

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Schedule 2 (Gastric-GEJ Cancer Patients Cohort B [2nd-3rd Line], NSCLC Cohort C [2nd-4th Line], Urothelial Cancer Cohort D [2nd-4th Line]**, 
and NSCLC Cohort E [1st Line]): Pharmacokinetic (PK), Immunogenicity (IK), and Biomarker Collection Timepoints for Ramucirumab for Schedule 
2 Dosing regimen (1h infusion Ramucirumab followed by 0.5h infusion Pembrolizumab on Day 1 every 3 weeks) (concluded)
Notes: 
Ram and Pem infusions are given Q3W. 1-hr Ram infusion is given prior to half-hour Pem infusion. There is one hour observation period (for infusion 
reactions) between Ram and Pem infusions at Cycle 1 Day 1 visit. Each cycle is a 21-day cycle.
Abbreviations:  DC = Discontinuation; eCRF = electronic case report form; GEJ = gastroesophageal junction; IK = immunogenicity; IRR = infusion-related 
reaction; NSCLC = non-small cell lung cancer; Pem = pembrolizumab; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetics; 
Ram = ramucirumab.
a
All sample times are relative to start of first (Ram) infusion.
b
Predose sample for Ram PK, IK, and biomarkers should be preferably collected within 1 hour prior to start of first infusion, and within 15 minutes of one 
another.
c
Two-hour sample for Ram PK should be preferably collected at 1 hr ±15 minutes from the end of Ram infusion.
d
While best effort should be done to draw the blood sample for PK/IK within the time windows provided above, it is more important to ensure predose sample 
is actually collected before the start of first infusion and post dose samples are collected after the infusion has actually completed. It is also equally important 
to record ACTUAL date and time of blood collection for PK/IK sample on the Requisition Form AFTER drawing the sample and to accurately record the 
ACTUAL infusions start and end dates and times on the eCRF to be able to use the data for analyses.  Sample collection for PK/IK must be from the opposite 
arm to that used for study drug infusion. If drug was administered via a central venous catheter, the sample collection should be from a different site.
e
In the event of an IRR, blood samples will be collected for both PK and IK analysis at the following time points:  (i) as close as possible to the onset of the 
IRR, (ii) at the resolution of the IRR, and (iii) 30 days following the IRR. 
f
Record ACTUAL date and time of blood collection for PK/IK sample on the Requisition Form AFTER drawing the sample.

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Attachment 3.Protocol JVDF Clinical Laboratory Tests
Hematology-Local only
Clinical Chemistry-Local and Central a
Hemoglobin
Hematocrit
Erythrocyte count (RBC)
Leukocytes (WBC)
Absolute Neutrophil Count 
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Serum Concentrations of:
Sodium
Magnesium
Potassium
Total bilirubin
Direct bilirubin (if total bilirubin is above ULN)
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Blood urea nitrogen (BUN)
Creatinine
Uric acid
Calcium
Glucose, random
Albumin
Cholesterol
Creatine kinase (CK)
Chloride
Total protein
Phosphorus
Lactate dehydrogenase (LDH)
Thyroid Function Tests-Central Only
Thyroid-stimulating hormone (TSH)
Total triiodothyronine (T3)
Free tyroxine (T4)
Urinalysisb- Local Only
Protein
Specific gravity
Blood
Glucose
Pregnancy Test Urine or Serumc–Local Only
β-human chorionic gonadotropin (β-hCG)
Coagulation Testd Local Only
Prothrombin time (PT) /INR
Partial thromboplastin time (PTT) or activated PTT 
(aPTT)
Abbreviations:  INR= International Normalized Ratio; RBC = red blood cells; ULN = upper limit of normal; 
WBC = white blood cells.
a. Local chemistry laboratory testing will be used to determine patient eligibility and decisions for treatment.  
Central chemistry laboratory testing will be used for subsequent scheduled analyses.
b A microscopic exam is required for abnormal results.  If urinalysis indicates proteinuria ≥2+ at baseline or during 
the treatment period, a 24 hour urine collection (to assess protein) must be obtained.
c. Minimum sensitivity 25 IU/L or equivalent units of β-human chorionic gonadotropin (β-HCG), for women of 
childbearing potential (WOCBP).  If urine pregnancy results cannot be confirmed as negative, a serum pregnancy 
test will be required.
d. For both prothrombin time and partial thromboplastin time, the laboratory for each is selected at baseline, and 
should be followed during the study period.

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

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Attachment 5.Protocol JVDF Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.
For serum creatinine 
concentration in mg/dL:
CrCl =
(mL/min) 
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(mL/min)
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a
age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.

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Attachment 6.Protocol JVDF RECIST 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, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone Lesions:

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.

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Cystic Lesions:

Simple cysts should not be considered as malignant lesions (neither 
measurable nor nonmeasurable)

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability.  If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated at a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are non-measurable unless there has been demonstrated 
progression in the lesion.
Baseline Documentation of Target and 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. For Study 
JVDF (Section 8.1.1.3), total of 10 lesions (and a maximum of 5 lesions per organ) could be 
collected if clinically relevant.  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 as 1 liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 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 it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV 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 to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  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 when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or 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, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline that impacts the ability to 
make a reliable evaluation of response.
Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).

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Non-CR/ non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease: Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.)  Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline.
Table 1.
Time Point Response: Patients with Target (Non-target) 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.
Table 2 is to be used when patients have nonmeasurable disease only.

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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; SD = stable disease.
a
non-CR/non-PD is preferred over SD for nontarget disease.
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  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 response in clinical trials is to avoid overestimating 
the response rate observed.  The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur; assessment of 
nontargets is not required.
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required.  But, elimination of the requirement may 
increase the importance of central review to protect against bias, in particular of studies which 
are not blinded.
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 [first dose].
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).

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD).
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, 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 JVDF Restricted and Prohibited 
Concomitant Therapy
The table below describes medications, treatments, and drug classes restricted or prohibited, with 
exceptions and conditions for use during the study treatment period (there are no prohibited 
therapies during the follow- up period). Patients who, in the assessment by the investigator, 
require the use of any of the prohibited treatments for clinical management should be removed 
from the trial.  Patients may receive other supportive therapy or vaccinations that the investigator 
deems to be medically necessary.
Generally, medications or live vaccinations specifically prohibited in the exclusion criteria are 
not allowed during the ongoing trial.

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Therapy
As 
Needed
Chronic 
Use
Exceptions or Conditions for Use
Anti-platelet therapy
yes
no
Chronic use of aspirin up to 325 mg/day is permitted.
Anticoagulation therapy
no
Yes, with 
restrictions
At enrollment, patients on full-dose anticoagulation must be on 
a stable dose (minimum duration 14 days) of oral anticoagulant 
or low molecular weight heparin or similar agent.  If on 
warfarin, the patient must have an INR ≤ 3 and no active 
bleeding or pathological condition present that carries a high 
risk of bleeding (e.g., tumor involving major vessels or known 
varices).
Anti-cancer biological 
therapy
no
no
Chemotherapy
no
no
Colony-stimulating 
factors
yes
no
Follow local guidelines.
Erythroid growth factors
yes
no
Follow local guidelines.
Experimental medicines 
or investigational 
agents
no
no
Other than ramucirumab or pembrolizumab
Glucocorticoids
no
no
Systemic glucocorticoids are permitted to modulate symptoms 
from an event of suspected immunologic etiology.  The use of 
physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.  
Note:  Inhaled steroids are allowed for management of asthma.
Immunotherapy 
(including 
vaccinations)
no
no
Other than pembrolizumab OR inhaled steroids
Live vaccines are NOT allowed within 30 days prior to the first 
study treatment and while participating in the trial.  Examples of 
live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed. 
However, intranasal influenza vaccines (e.g., Flu - Mist®) are 
live attenuated vaccines, and are not allowed.
NSAIDs
yes
no
Chronic use of aspirin up to 325 mg/day is permitted.
In addition, in certain medical situations, NSAIDs may be the 
best treatment option (for example, for pain management). 
Increased risk of bleeding should be considered by the treating 
physician and the patient. 
Radiation therapy
no
no
Localized radiation therapy to a symptomatic, solitary lesion or 
to the brain may be allowed after consultation with the Sponsor.
Abbreviations:  INR = international normalized ratio; NSAIDs = nonsteroidal anti-inflammatory drugs.

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Attachment 8.Protocol JVDF Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
AE
Any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
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.
Cave,ss
average concentration at steady state
CHF
congestive heart failure
Cmax,ss
maximum concentration at steady state
Cmin,1
minimum concentration after first dose administration
Cmin,ss
minimum concentration at steady state

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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 (ramucirumab and/or pembrolizumab) 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/eCRF
case report form/electronic case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRP
clinical research physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician, or other medical officer.
CRS
clinical research scientist
CSFs
colony-stimulating factors
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
DCR
disease control rate
DKA
diabetic ketoacidosis
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECHO
echocardiogram
ECI
event of clinical interest

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ECOG PS
Eastern Cooperative Oncology Group performance status
end of trial
End of trial is after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up. 
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.
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.
EU
European Union
FOLFIRI
irinotecan, 5-fluorouracil, and folinic acid
FSH
follicle-stimulating hormone
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GEJ
gastroesophageal junction
GI
gastrointestinal
GM-CSF
granulocyte macrophage colony-stimulating factor
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IK
immunogenicity
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
INR
international normalized ratio

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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.
In this study, the IPs are ramucirumab and pembrolizumab. 
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
irRECIST
immune-related Response Evaluation Criteria In Solid Tumors
IV
intravenous
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.
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MMR
mismatch-repair
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition
NCI
National Cancer Institute

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non-investigational 
product (non-IP)
A non-investigational product (non-IP) is a product that is not being tested or used as a 
reference in the trial but is provided to patients and used in accordance with the 
protocol.
Examples of  non-IPs include the following:

Concomitant or rescue/escape medication for preventive, diagnostic, or therapeutic 
reasons

Concomitant or rescue/escape medication to ensure that adequate medical care is 
provided for the patient

A product used in accordance with the protocol to induce a physiological response.
NSAID
non-steroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PD-1
programmed death-1 T-cell co-receptor
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
randomize
the process of assigning patients to an experimental group on a random basis
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 analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event

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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.  
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SOC
system organ class
Study completion
This study will be considered complete after the final analysis and evaluation of the 
Phase 1b study endpoints is performed.
SUSAR
suspected unexpected serious adverse reactions
T1DM
type 1 diabetes mellitus
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
TSH
thyroid stimulating hormone
TTR
time to first response
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event

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Attachment 9.Protocol JVDF Amendment(b)
Summary An Open-Label, Multicenter, Phase 1 Study of 
Ramucirumab plus Pembrolizumab in Patients with Locally 
Advanced and Unresectable or Metastatic Gastric or 
Gastroesophageal Junction Adenocarcinoma, Non-Small 
Cell Lung Cancer, Transitional Cell Carcinoma of the 
Urothelium, or Biliary Tract Cancer
Overview
Protocol I4T-MC-JVDF, An Open-Label, Multicenter, Phase 1 Study of Ramucirumab plus 
Pembrolizumab in Patients with Locally Advanced and Unresectable or Metastatic Gastric or 
Gastroesophageal Junction Adenocarcinoma, Non-Small Cell Lung Cancer, or Transitional Cell 
Carcinoma of the Urothelium, has been amended.  The new protocol is indicated by 
amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Addition of title, rationale, study design, entry criteria, study procedures and statistical 
elements for 3 new Phase 1b expansion Cohorts, to include first-line Gastric-GEJ
(Schedule 1), first-line NSCLC patients (Schedule 2), and second or third line BTC
patients (Schedule 1).  At the time of this amendment, Phase 1A Schedule 1 DLT 
observation is ongoing; Phase 1A Schedule 2 DLT observation has been completed.  For 
first line Gastric/GEJ and first line NSCLC patients, more frequent tumor imaging 
schedule (every 4 weeks for the first 12 weeks) is required to monitor anti-tumor 
response to study treatment and initiate alternative treatment as determined by treating 
investigators.  

Clarifications and refinements, as follows:
o
The final analysis of safety and preliminary efficacy will occur approximately 
2 years after the first patient received first study treatment.  Separate interim 
analyses will occur after all patients in each cohort have completed 
approximately 24 weeks of study treatment or discontinued for any reason.  
Safety and preliminary efficacy will be analyzed separately for each cohort.  
Rationale: This change was implemented to harmonize the interim analysis and 
final analysis with the intent of the trial design.  There is no change to the study 
treatment duration for each individual patient (35 cycles, approximately 2 years).
o
In Inclusion Criterion [20], clarified that baseline tumor tissue samples must be 
evaluable, and elaborated on guidance regarding the submission of tumor tissue 
samples in Section 8.4.2. 

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o
The timing of the required 1-hour observation periods, to occur between 
ramucirumab and pembrolizumab administration *and* after pembrolizumab 
administration, for the first 2 cycles. Rationale: this change was implemented to 
ensure the consistent implementation of the 1-hour observation periods for 
Schedule 1 and Schedule 2 patients.
o
Two additional categories of events are to be reported as SAEs: 1) new cancers 
(exception: metastases of cancer under study), and 2) any event associated with 
an overdose of either study drug, as defined in Section 8.2.1.2.
o
For pembrolizumab, immune-related adverse events are no longer labeled as 
Events of Clinical Interest (ECIs).  Similarly, references in the protocol to the 
detailed Site Guidance Document for Events of Clinical Interest were removed.  
Two (2) categories of ECIs remain: overdose and abnormal liver function tests 
(as defined in Section 8.2.1.1.3). 
o
Pembrolizumab dose modification table “Note” was updated to specify that 
Grade 2 pneumonitis warrants permanent discontinuation of pembrolizumab (see 
“Note” in table footnote).
o
Pembrolizumab supportive care guidelines for Diarrhea/Colitis (Section 
6.9.1.3.2) were updated to eliminate any waiting period before beginning 
treatment for any Grade 2, 3, or 4 event. 

Other typographical, formatting errors or very minor clarifications (key examples below): 
o
The Introduction was updated to reflect current regulatory approval status for 
ramucirumab and pembrolizumab.
o
In Inclusion Criterion [7], to clarify that the screening period is 28 days.  
o
Exclusion Criterion [20], to allow seasonal flu vaccines that do not contain live 
virus. 
o
Dose management for ramucirumab in case of Grade 2 toxicity, investigator 
“may” reduce ramucirumab dose or discontinue ramucirumab.  See footnote b in 
Table JVDF.4.  
o
If radiologic imaging verifies initial progressive disease, tumor assessment 
should be repeated approximately (not “at least”) 4 weeks later to confirm PD. 
o
That “whole” blood sample is collected for pharmacogenetic analysis where 
local regulations and ERBs allow. 
o
That the overall response rates presented in the simulations represented by Table 
JVDF.8 and Table JVDF.9 are provided as a reference for estimation of 
statistical power rather than as a basis for any decision criteria.  
o
A baseline brain scan by CT or MRI was added in the schedule of events
(Attachment 1) to be consistent with inclusion criteria for NSCLC and urothelial 
cancer patients. 
o
Correction of formatting error in baseline biomarker samples collection for 
Schedule 1 patients (Attachment 2).  Baseline sample should be collected pre-
dose.

I4T-MC-JVDF(b) Clinical Protocol
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LY3009806
Note: Changes that are applied globally to the document were described above.  A brief section 
of text with strikethrough/underscore as an example of the type of change that occurs throughout 
the amended protocol is provided below.

Leo Document ID = 69a09e1c-a512-4680-baeb-60d497185cde
Approver: 
Approval Date & Time: 11-Feb-2016 18:54:03 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Feb-2016 20:23:25 GMT
Signature meaning: Approved
PPD
PPD