A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer
Phase: PHASE3
Conditions: Metastatic Non-Small Cell Lung Cancer
Sponsor: Eli Lilly and Company

Protocol I4T-MC-JVCY(f) 
 
A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination with 
Ramucirumab or Placebo in Previously Untreated Patients with EGFR Mutation-Positive 
Metastatic Non-Small Cell Lung Cancer 
 
NCT02411448 
Approval Date: 23-Apr-2018 

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1.
Protocol I4T-MC-JVCY(f)
A Multicenter, Randomized, Double-Blind Study of Erlotinib 
in Combination with Ramucirumab or Placebo in Previously 
Untreated Patients with EGFR Mutation-Positive Metastatic 
Non-Small Cell Lung 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), 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)
Study I4T-MC-JVCY is a multicenter, randomized, double-blind, Phase 3 study that will 
compare the efficacy and safety of treatment with erlotinib (150 mg daily) and ramucirumab 
(10 mg/kg every 2 weeks) versus erlotinib (150 mg daily) and placebo (10 mg/kg every 
2 weeks) in previously untreated patients with EGFR mutation-positive metastatic NSCLC.  
Treatment will continue until disease progression, unacceptable toxicity, or another 
permitted reason for study discontinuation.  This Phase 3 part (Part B) is preceded by a 
Phase 1b part (Part A) to assess the safety and tolerability for the combination of 
ramucirumab plus erlotinib.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on:  11 December 2014
Amendment (a) Electronically Signed and Approved by Lilly on:  30 October 2015
Amendment (b) Electronically Signed and Approved by Lilly on:  17 February 2016
Amendment (c) Electronically Signed and Approved by Lilly on: 27 April 2016
Amendment (d) Electronically Signed and Approved by Lilly on: 07 March 2017
Amendment (e) Electronically Signed and Approved by Lilly on: 23 August 2017
Amendment (f) Electronically Signed and Approved on approval date provided below.
Approval Date: 23-Apr-2018 GMT

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2. Synopsis
Study Rationale
Inhibition of angiogenesis is considered a promising approach to the treatment of cancer and 
vascular endothelial growth factor (VEGF) family members are important regulators of 
angiogenesis.  Ramucirumab (LY3009806) is a recombinant human monoclonal antibody that 
specifically binds to the extracellular domain of VEGF Receptor 2 (VEGFR-2) with high 
affinity.  REVEL (Study I4T-MC-JVBA), a Phase 3 study of ramucirumab plus docetaxel in the 
treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) 
with progression after platinum-based chemotherapy, demonstrated a statistically significant and 
clinically meaningful improvement in overall survival (OS), and statistically significant 
treatment effects were observed across efficacy endpoints of progression-free survival (PFS) and 
objective response rate (ORR).  Improvement in disease control rate (DCR) was also observed, 
and the favorable effect of ramucirumab-docetaxel combination on OS and PFS was 
demonstrated for all major prognostic subgroups.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs; for example, 
erlotinib, gefitinib, and afatinib) significantly prolong progression-free survival in patients with 
EGFR mutation-positive advanced NSCLC when compared with platinum-based chemotherapy 
doublets; hence, these EGFR TKIs have become the standard of care in countries where 
approved.  The rationale for such treatment is supported by the results of studies such as BR.21, 
EURTAC, OPTIMAL, IPASS, and LUX-Lung 3.
Recently, ATLAS, BeTa, and JO25567 trials reported that the combination of the antiangiogenic 
agent bevacizumab in combination with the EGFR TKI erlotinib provided additional PFS and 
OS benefit in the subgroup of patients with EGFR mutations.  The ATLAS study results 
(bevacizumab plus erlotinib vs. bevacizumab plus placebo after chemotherapy with 
bevacizumab) demonstrated that the subgroup of patients with EGFR mutations (n = 52) had 
improved/longer duration of PFS and OS in the bevacizumab plus erlotinib arm as compared to 
the bevacizumab plus placebo arm (hazard ratio [HR] = 0.44 and 0.46, respectively).  The BeTa 
trial (erlotinib plus bevacizumab vs. erlotinib plus placebo) showed that OS favored erlotinib 
plus bevacizumab in the subgroup of patients with EGFR mutations (n = 30).  The median OS 
was not reached (95% confidence interval [CI]:  22.6, not reached) in the erlotinib plus 
bevacizumab arm (n = 12) and 20.2 months (95% CI:  16.4, 31.1), in the erlotinib arm, with 
HR = 0.44 (95% CI:  0.11, 1.67); however, the results should be interpreted with caution based 
on the small number of patients and the wide 95% CI for the HR.  A randomized Phase 2 study 
(JO25567) in 154 first-line patients with EGFR mutation-positive NSCLC randomized 1:1 to 
receive erlotinib with or without bevacizumab showed a statistically significant PFS 
improvement in the erlotinib plus bevacizumab arm (16.0 months) as compared to the erlotinib 
monotherapy arm (9.7 months) (HR = 0.54).  The DCR was 99% in the bevacizumab plus 
erlotinib arm versus 88% in the erlotinib arm.  The treatment effect was observed across both 
EGFR mutation types (exon 19 deletion [median PFS 18.0 vs. 10.3 months; HR = 0.41, 

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p=0.0011] and L858R mutation [numerically longer but not significant median PFS 13.9 vs. 
7.1 months; HR = 0.67, p=0.1653]).
This JVCY study is being conducted globally to determine whether an EGFR-TKI (erlotinib) in 
combination with ramucirumab as compared to EGFR-TKI (erlotinib) in combination with 
placebo would improve efficacy outcomes in previously untreated patients with EGFR mutation-
positive NSCLC.
Clinical Protocol Synopsis:  Study I4T-MC-JVCY
Name of Investigational Product:  Ramucirumab (LY3009806)
Title of Study:  A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination with Ramucirumab or 
Placebo in Previously Untreated Patients with EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer
Number of Planned Patients:
Part A (Phase 1b)
Entered:  20
Enrolled:  at least 12
Part B (Phase 3)
Entered:  550
Enrolled/Randomized:  450
Phase of Development:  3
Length of Study (Part A and Part B, excluding the Continued Access Period):  Approximately 61 months
Planned first patient visit:  APR 2015
Planned last patient visit:  MAY 2020 (Part B)
Planned analyses:
Analysis 1 (Part A, dose-limiting toxicity [DLT] evaluation):  After 6 patients enrolled from Japan and 6 patients 
enrolled from North America and/or Europe have completed 2 treatment cycles
Endpoint:  DLTs
Analysis 2 (Part B, Interim Safety):  After approximately 50 randomized patients have completed at least 3 cycles 
of treatment or discontinued from all study therapies due to any reason prior to 3 cycles
Endpoint:  Safety
Analysis 3 (Part B, Interim Futility):  Approximately 107 PFS events
Endpoint:  PFS and safety
Analysis 4 (Part B Primary PFS Analysis):  Approximately 270 PFS events
Endpoint:  PFS (Primary) and other secondary and exploratory objectives
Analysis 5 (Part B, Final Overall Survival):  Approximately 300 OS events
Endpoint:  OS (Secondary)
Additional safety reviews will be conducted approximately twice a year after the first interim safety analysis until 
primary PFS analysis.  The frequency of safety reviews could be reduced to once a year after the primary PFS 
analysis or earlier based on IDMC recommendation.

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Objectives
Part A Objective:
The primary objective of Part A is to assess the safety and tolerability of ramucirumab when administered in 
combination with erlotinib as therapy in previously untreated patients with EGFR mutation-positive metastatic 
NSCLC.
Part B:
Primary Objectives:
The primary objective of Part B is to compare PFS of ramucirumab administered in combination with erlotinib versus 
placebo in combination with erlotinib as therapy in previously untreated patients with EGFR mutation-positive 
metastatic NSCLC.
Secondary Objectives:
The secondary objectives of Part B of the study are:

Safety and toxicity profile

Overall Survival (OS)

Objective response rate (ORR) (complete response [CR] + partial response [PR])

Disease control rate (DCR) (CR + PR + stable disease [SD])

Duration of response (DOR)

Pharmacokinetics (PK) and immunogenicity of ramucirumab

Patient-reported outcomes (using Lung Cancer Symptom Scale [LCSS] and EuroQol 5-dimension, 5-level 
questionnaire [EQ-5D-5L])
Exploratory Objectives:
The exploratory objectives of Part B of the study are as follows:

Assessment of the association between biomarkers and clinical outcome

Comparison of progression-free survival 2 (PFS2) between treatment arms
The exploratory objectives in only the gefitinib/osimertinib cohort in Addendum 9, conducted in the 
East-Asian region including Japan, are as follows:

to evaluate the efficacy (for example, 1-year PFS rate) and safety of ramucirumab when administered in 
combination with gefitinib in previously untreated patients with EGFR mutation-positive metastatic 
NSCLC, in the East-Asian region including Japan

to evaluate the efficacy and safety of ramucirumab when administered in combination with osimertinib 
in patients with T790M-positive metastatic NSCLC whose disease has progressed on ramucirumab plus 
gefitinib in this study, in the East-Asian region including Japan

to assess PK and immunogenicity of ramucirumab

to assess patient-reported outcomes (using LCSS and EQ-5D-5L)

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Study Design:  This is a Phase 1b/3 study of previously untreated patients with metastatic EGFR mutation-positive 
NSCLC.  The Phase 1b single-arm and open-label part (Part A) will assess the safety and tolerability of the 
recommended dose for the Phase 3 part (Part B) where ramucirumab (10 mg/kg every 2 weeks) will be administered 
in combination with erlotinib (150 mg daily).  The target enrollment is 12 patients in Part A.  Patients will be enrolled 
in 1 of 2 cohorts (Cohort 1 will include 6 patients from Japan and Cohort 2 will include 6 patients from North 
America and/or Europe).  Part A patients may be enrolled concurrently into selected cohorts.  The Phase 3 dose will 
be selected based on the Phase 1b outcome.  Note: On 16 December 2015, the Assessment Committee reviewed the 
safety data for the Phase 1b portion (Part A) and recommended to initiate the randomized Phase 3 portion of the 
study (Part B) with ramucirumab at 10 mg/kg every 2 weeks.  Part B randomization will proceed after the completion 
of Part A DLT assessment.  The decision on the final dose for Part B (Phase 3) will be communicated to the 
investigative sites after the completion of DLT assessment.  The Phase 3, randomized, double-blinded portion of the 
trial will compare the efficacy and safety of ramucirumab in combination with erlotinib versus placebo in 
combination with erlotinib.  Approximately 450 patients will be randomized evenly between the 2 treatment arms 
using the following stratification factors:

EGFR mutation (exon 19 deletion vs. exon 21 [L858R] substitution mutation)

Gender (male vs. female)

Region (East Asia vs. other)

EGFR testing method (Therascreen® [Qiagen] and Cobas® [Roche] vs. other PCR and sequencing-based 
methods)
Treatment in Parts A (ramucirumab plus erlotinib) and B (ramucirumab/placebo plus erlotinib) will continue until 
disease progression, unacceptable toxicity, or another permitted reason for study discontinuation.  The study 
treatment in this protocol is considered ramucirumab or placebo in combination with erlotinib, or any component of 
the combination.
Diagnosis and Main Criteria for Inclusion and Exclusions:  The study will enroll male or female patients, 
18 years of age or older (20 years of age or older in Japan and Taiwan).  Main inclusion criteria include: metastatic 
NSCLC patients who are eligible for first-line treatment with erlotinib based on previously documented evidence of 
tumors that have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, ECOG PS ≤1.  Key exclusion 
criteria include:  patients with known T790M mutation; metastatic CNS lesions; ophthalmologic abnormalities; 
active interstitial lung disease; and any prior systemic chemotherapy for advanced or metastatic NSCLC, including 
prior TKI therapy for any stage.
Test Product, Dosage, and Mode of Administration:
Ramucirumab:  injection for intravenous (IV) use, supplied in sterile, preservative-free single-use vials containing 
500 mg of ramucirumab, at a final concentration of 10 mg/mL in a histidine based formulation (10mM histidine, 
75mM sodium chloride, 133mM glycine, and 0.01% polysorbate 80 at a pH of 6.0), administered as an IV infusion at 
a dose of 10 mg/kg every 2 weeks.  The infusion should be delivered over approximately 60 minutes on Day 1 of 
each cycle.  The infusion rate should not exceed 25 mg/min.
Placebo:  injection for IV use, supplied in single-use 50-mL vials containing histidine buffer only.  Since 
investigators and ancillary medical personnel will be blinded to the assignment of ramucirumab or placebo, the 
volume of placebo to be administered will be calculated as if it were ramucirumab formulated at 10 mg/mL and will 
be administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks.
Reference Therapy, Dose, and Mode of Administration:
Erlotinib: 150 mg taken orally once daily.
Planned Duration of Treatment:
A treatment cycle will be defined as 2 weeks.  Patients will be treated until there is radiographic or symptomatic 
progressive disease (PD) (symptomatic PD should be objectively confirmed radiographically), toxicity requiring 
cessation, withdrawal of consent from further study treatment or study participation, or until other discontinuation 
criteria are met.
Criteria for Evaluation:
Efficacy:
Part A:  Efficacy data will not be collected during the conduct of Part A; however, the same baseline tumor 
assessments, including gadolinium-enhanced MRI of the CNS, required for Part B will also apply for Part A, and will 
be performed prior to study enrollment.  Investigators are required to follow institutional guidelines for regular 
follow-up for the disease under treatment to assess the disease response to the study treatment.
Part B:  Efficacy assessments will be performed only for patients enrolled in Part B.

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Tumor measurements:  Investigators will read and perform tumor assessments for response according to Response 
Evaluation Criteria In Solid Tumors Version 1.1 guidelines.  Despite any treatment delays, imaging must be 
performed every 6 weeks (±7 days) following first dose of study therapy, and after 72 weeks while on study, imaging
will be performed every 12 weeks (±7 days) until documented objective PD.  If a patient discontinues treatment due 
to objective disease progression, one additional tumor scan will be collected at the 30-day short-term follow-up visit
unless the patient has received additional anticancer therapy prior to this visit. Thereafter, radiologic tests are no 
longer required.  Imaging requirements include computed tomography (CT) scan or magnetic resonance imaging 
(MRI) of chest and abdomen including both adrenal glands, with pelvic imaging performed if clinically indicated.  It 
is recommended that CT imaging of the abdomen/pelvis be performed with intravenous contrast.  If this is not 
feasible/advisable secondary to hypersensitivity or other conditions, then gadolinium-enhanced MRI is preferred.  
For patients with known serious allergic reactions to CT contrast material, contrast-enhanced MRI of the 
chest/abdomen/pelvis is encouraged.  A gadolinium-enhanced MRI of the CNS will be performed at baseline prior to 
randomization for all patients (per exclusion criterion regarding CNS metastases).  While on study, a gadolinium-
enhanced MRI of the CNS should be performed if clinically indicated to assess disease progression.

PFS is defined as the time from the date of randomization to the date of radiographically documented PD based 
on investigator assessment, or the date of death due to any cause, whichever is first.

OS is defined as the time from the date of randomization to the date of death from any cause.

ORR is defined as the proportion of randomized patients achieving a best overall response of PR or CR.

DCR is defined as the proportion of randomized patients achieving a best overall response of PR, CR, or SD.

DOR is defined from the date of first documented CR or PR (responder) 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, then the patient will be censored at the last evaluable tumor assessment.
Safety:
Part A:
Safety will be evaluated based on reported adverse events (AEs), clinical laboratory assessments, vital signs, and 
physical examinations.  DLT definitions include:

Grade 4 anemia

Grade ≥ 3 thrombocytopenia

Grade ≥ 3 febrile neutropenia

Grade 4 neutropenia lasting > 7 days

Elevated urine protein of ≥3 g/24 hour

Grade 4 or refractory hypertension 

Grade ≥ 3 nonhematologic toxicity excluding electrolyte abnormality or Grade 3 skin rash
DLTs will be assessed during the first 2 cycles of treatment (DLT Assessment Period).  Safety data throughout the 
Part A will be evaluated based on reported AEs, clinical laboratory assessments, vital signs, and physical 
examinations as outlined in the body of the protocol.
Part B:
Safety will be evaluated based on reported AEs, clinical laboratory assessments, vital signs, and physical 
examinations.  Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA™) 
and graded using the National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0 
(NCI-CTCAE v4.0).  Clinical laboratory toxicity will also be graded using NCI-CTCAE criteria v4.0.
Health Outcomes:
All Part B patients will undergo assessment for symptoms, quality of life, and health status using the LCSS, a 
self-administered, lung cancer-specific questionnaire instrument, and the EuroQol EQ-5D-5L.  Patients will complete 
the instruments at baseline, at Cycle 2, thereafter at every other cycle, and at the 30-day short-term follow-up visit.
Immunogenicity:
Serum samples will be analyzed for antibodies to ramucirumab on all Part B patients at baseline, at specified time 
points during treatment (Cycle 1 Day 1 and Cycle 4 Day 1), and at the 30-day short-term follow-up visit.  In the event 
of an infusion-related reaction (IRR), blood samples will be collected for both PK and immunogenicity analysis as 
close to the onset of the reaction as possible, at the resolution of the event, and 30 days following the event.

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before completing 2 cycles due to a DLT.  The recommended dose of ramucirumab plus erlotinib for Phase 3 (Part B) 
will be decided based on the rules established in advance.  Patients may continue study treatment after the DLT 
period until disease progression, development of unacceptable toxicity, noncompliance or withdrawal of consent by 
the patient, or investigator decision.
Part B (Phase 3):  All safety summaries and analyses will be based on the Safety Population, defined as all 
randomized patients receiving any quantity of study treatment in Part B.  Patients will be grouped according to 
treatment received in Cycle 1.
Interim safety analyses will be conducted by the IDMC several times during the course of the study.  It will occur 
after approximately 50 treated patients have completed 3 cycles of treatment or discontinued from all study therapies 
due to any reasons prior to 3 cycles, thereafter at the other interim analyses, including, if not limited to, 
approximately twice a year.
Safety analyses will include the incidence and percentage of patients with at least 1 occurrence of a preferred term, 
by maximum CTCAE grade (v4.0) during the study treatment period or within 30 days after the decision is made to 
discontinue study treatment.  Additionally, the following safety-related outcomes will be summarized:

study treatment discontinuations due to AEs

deaths during the study treatment period or within 30 days after the decision is made to discontinue study 
treatment

adverse events (AEs), treatment emergent AEs (TEAEs), serious adverse events (SAEs) during the study 
treatment period or within 30 days after the decision is made to discontinue study treatment

hospitalizations and transfusions during the study treatment period or within 30 days after the decision is 
made to discontinue study treatment
Health Outcomes:
For all Part B patients in the ITT population (censoring patients with no baseline data), time to deterioration (TtD) for 
each LCSS item is defined as the time from the date of randomization to the date of the first 15-mm increase from 
baseline (or censored at date of last assessment).  TtD will be analyzed using the Kaplan-Meier method and 
treatments will be compared using a Cox regression model to generate an HR.  LCSS data will also be analyzed with 
repeated measures.  EQ-5D-5L data will be summarized descriptively for each assessment period.
Pharmacokinetics/Immunogenicity:
Pharmacokinetics
Ramucirumab: Cmin and concentrations at 1 hour post end of infusion (approximately Cmax) will be summarized by 
descriptive statistics.  Additional analysis utilizing the population PK approach may also be conducted if deemed 
appropriate.
Immunogenicity
Incidence of anti-ramucirumab antibodies will be tabulated.  Correlation to ramucirumab drug level, activity, and 
safety will be assessed, as appropriate.
Exploratory Outcomes:
Translational Research
Translational research will be performed to analyze relevant biomarkers and to correlate them to clinical outcome.
PFS2
The time to PFS2 event will be analyzed with the Kaplan-Meier method by treatment groups, along with a summary 
of associated statistics (for example, median survival time and survival rates, including the corresponding two-sided 
95% CIs).

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3. Table of Contents
A Multicenter, Randomized, Double-Blind Study of Erlotinib 
in Combination with Ramucirumab or Placebo in Previously 
Untreated Patients with EGFR Mutation-Positive Metastatic 
Non-Small Cell Lung Cancer
Section
Page
1.
Protocol I4T-MC-JVCY(f)  A Multicenter, Randomized, Double-
Blind Study of Erlotinib in Combination with Ramucirumab or 
Placebo in Previously Untreated Patients with EGFR Mutation-
Positive Metastatic Non-Small Cell Lung Cancer................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................9
4.
Abbreviations and Definitions...........................................................................................17
5.
Introduction ......................................................................................................................23
5.1.
Ramucirumab Background...........................................................................................23
5.2.
Use of Tyrosine Kinase Inhibitors in NSCLC...............................................................25
5.3.
Rationale for Selection of Ramucirumab Dose Regimen 
(10 mg/kg on Day 1 Every 2 Weeks)............................................................................27
6.
Objectives.........................................................................................................................30
6.1.
Primary Objective ........................................................................................................30
6.2.
Secondary Objectives...................................................................................................30
6.3.
Exploratory Objectives.................................................................................................31
7.
Study Population...............................................................................................................32
7.1.
Inclusion Criteria..........................................................................................................32
7.2.
Exclusion Criteria ........................................................................................................35
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................37
7.3.
Discontinuation............................................................................................................38
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................38
7.3.2.
Discontinuation of Study Treatment.....................................................................39
7.3.2.1.
Ramucirumab/Placebo....................................................................................39
7.3.2.2.
Erlotinib .........................................................................................................40
7.3.2.3.
All Study Treatment .......................................................................................41
7.3.3.
Discontinuation from the Study Participation .......................................................42
7.3.4.
Patients Who Are Lost to Follow-Up....................................................................43
7.3.5.
Discontinuation of Study Sites .............................................................................43
7.3.6.
Discontinuation of the Study................................................................................43

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8.
Investigational Plan...........................................................................................................44
8.1.
Summary of Study Design............................................................................................44
8.1.1.
Part A (Phase 1b) .................................................................................................48
8.1.1.1.
Baseline and Study Treatment Period Assessments.........................................48
8.1.1.2.
Postdiscontinuation Follow-up Period Assessment .........................................49
8.1.1.3.
Study Completion and End of Trial.................................................................49
8.1.1.4.
Study Duration ...............................................................................................49
8.1.2.
Part B (Phase 3) ...................................................................................................49
8.1.2.1.
Baseline and Study Treatment Period Assessments.........................................49
8.1.2.2.
Postdiscontinuation Follow-Up Period Assessments .......................................51
8.1.2.3.
Study Completion and End of Trial.................................................................51
8.1.2.4.
Study Duration ...............................................................................................52
8.1.3.
Continued Access Period......................................................................................52
8.1.4.
Committees..........................................................................................................54
8.2.
Discussion of Design and Control ................................................................................54
9.
Treatment..........................................................................................................................55
9.1.
Treatments Administered .............................................................................................55
9.1.1.
Premedication ......................................................................................................58
9.1.1.1.
Premedication Prior to Infusion of Ramucirumab or 
Placebo...........................................................................................................58
9.1.1.2.
Premedication Prior to Erlotinib .....................................................................58
9.2.
Materials and Supplies .................................................................................................58
9.2.1.
Study Drugs .........................................................................................................58
9.2.1.1.
Ramucirumab .................................................................................................58
9.2.1.2.
Placebo...........................................................................................................59
9.2.1.3.
Erlotinib .........................................................................................................59
9.2.2.
Storage and Preparation........................................................................................59
9.2.2.1.
Ramucirumab/Placebo Storage and Preparation..............................................59
9.2.2.2.
Erlotinib Storage and Preparation ...................................................................60
9.3.
Method of Assignment to Treatment ............................................................................60
9.4.
Selection and Timing of Doses.....................................................................................60
9.4.1.
Dose-Limiting Toxicities in Part A.......................................................................61
9.4.2.
Dose Delays or Dose Modifications .....................................................................62
9.4.2.1.
Ramucirumab or Placebo................................................................................62
9.4.2.1.1.
Dose Delays (Delays for Subsequent Cycles) for 
Ramucirumab/Placebo ..............................................................................62
9.4.2.1.2.
Dose Modifications for Ramucirumab/Placebo .........................................63
9.4.2.1.2.1.
Infusion-Related Reactions .................................................................65

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9.4.2.1.2.2.
Hypertension.......................................................................................66
9.4.2.1.2.3.
Thromboembolic Events .....................................................................66
9.4.2.1.2.4.
Bleeding (Hemorrhagic) Events ..........................................................67
9.4.2.1.2.5.
Gastrointestinal Perforation.................................................................67
9.4.2.1.2.6.
Fistula.................................................................................................67
9.4.2.1.2.7.
Proteinuria ..........................................................................................68
9.4.2.1.2.8.
Congestive Heart Failure in Patients Who 
Received Ramucirumab Drug Product in 
Combination with Mitoxantrone or Following 
Prior Anthracycline Therapy ...............................................................68
9.4.2.1.2.9.
Surgery and Impaired Wound Healing ................................................69
9.4.2.1.2.10.
Liver Failure, Other Significant Liver Injury in 
Patients with Child-Pugh Class B Cirrhosis, or 
Cirrhosis (Any Degree) and a History of Hepatic 
Encephalopathy or Clinically Meaningful Ascites ...............................69
9.4.2.1.2.11.
Reversible Posterior Leukoencephalopathy 
Syndrome............................................................................................69
9.4.2.2.
Erlotinib .........................................................................................................70
9.4.2.2.1.
Dose Delays and Dose Modifications for Erlotinib....................................70
9.5.
Blinding .......................................................................................................................72
9.5.1.
Emergency Unblinding ........................................................................................73
9.5.2.
Inadvertent Unblinding ........................................................................................73
9.6.
Concomitant Therapy...................................................................................................73
9.6.1.
Supportive Care ...................................................................................................74
9.6.1.1.
Antidiarrheal Agents.......................................................................................74
9.6.1.2.
Antiemetic Agents..........................................................................................74
9.6.1.3.
Analgesic Agents............................................................................................74
9.6.1.4.
Appetite Stimulants ........................................................................................74
9.6.1.5.
Granulocyte-Colony Stimulating Factors (G-CSF)..........................................74
9.6.1.6.
Erythroid Growth Factors ...............................................................................75
9.6.1.7.
Bisphosphonate Usage....................................................................................75
9.6.2.
Prohibited and Restricted Concomitant Therapy...................................................75
9.6.2.1.
CYP3A4 Inducers or Strong Inhibitors ...........................................................75
9.6.2.2.
Anticoagulants................................................................................................75
9.6.2.3.
H2-Receptor Antagonists and Antacids ...........................................................75
9.6.2.4.
Proton Pump Inhibitors...................................................................................76
9.6.3.
Other Study Conditions:  Surgery and Palliative 
Radiotherapy (or Equally Considered Procedure) During 
Study Treatment Phase.........................................................................................76
9.7.
Treatment Compliance .................................................................................................76

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10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................77
10.1. Efficacy Measures........................................................................................................77
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................77
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................78
10.1.3.
Primary Efficacy Measure....................................................................................78
10.1.4.
Secondary Efficacy Measures...............................................................................78
10.2. Health Outcome/Quality of Life Measures ...................................................................79
10.2.1.
Patient-Reported Outcomes..................................................................................79
10.2.1.1.
Lung Cancer Symptom Scale (LCSS).............................................................79
10.2.1.2.
EQ-5D-5L ......................................................................................................80
10.2.2.
Resource Utilization.............................................................................................80
10.3. Safety Evaluations........................................................................................................80
10.3.1.
Adverse Events ....................................................................................................81
10.3.1.1.
Serious Adverse Events ..................................................................................82
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................83
10.3.2.
Safety Monitoring ................................................................................................83
10.3.3.
Complaint Handling.............................................................................................84
10.4. Sample Collection and Testing.....................................................................................85
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................85
10.4.2.
Samples for Translational Research......................................................................85
10.4.2.1.
Blood Sample for Plasma Collection...............................................................86
10.4.2.2.
Whole Blood Sample for DNA Collection......................................................86
10.4.2.3.
Mandatory Tumor Tissue Samples..................................................................87
10.4.2.4.
Collection Procedures for Translational Research...........................................87
10.4.3.
Samples for Immunogenicity Research.................................................................87
10.4.4.
Samples for Ramucirumab Drug Concentration 
Measurements Pharmacokinetics..........................................................................88
10.5. Appropriateness of Measurements................................................................................88
11.
Data Quality Assurance.....................................................................................................89
11.1. Data Capture System....................................................................................................89
12.
Sample Size and Statistical Methods .................................................................................90
12.1. Determination of Sample Size ......................................................................................90
12.2. Statistical and Analytical Plans.....................................................................................90
12.2.1.
General Considerations ........................................................................................90
12.2.1.1.
Analysis Populations ......................................................................................91

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12.2.2.
Patient Disposition...............................................................................................91
12.2.3.
Patient Characteristics..........................................................................................91
12.2.4.
Concomitant Therapy...........................................................................................91
12.2.5.
Postdiscontinuation Therapy ................................................................................92
12.2.6.
Treatment Compliance .........................................................................................92
12.2.7.
Primary Outcome and Methodology.....................................................................92
12.2.7.1.
Part A.............................................................................................................92
12.2.7.2.
Part B .............................................................................................................92
12.2.8.
Secondary Outcome and Methodology.................................................................94
12.2.8.1.
Overall Survival .............................................................................................94
12.2.8.2.
Objective Response Rate and Disease Control Rate ........................................94
12.2.8.3.
Duration of Response .....................................................................................94
12.2.9.
Sensitivity Analyses.............................................................................................95
12.2.10. Pharmacokinetic and Immunogenicity Analyses...................................................95
12.2.11. Progression-Free Survival 2 .................................................................................95
12.2.12. Translational Research Analyses..........................................................................96
12.2.13. Health Outcome/Quality of Life Analyses............................................................96
12.2.13.1. LCSS..............................................................................................................96
12.2.13.2. EQ-5D-5L:  Health State Utilities...................................................................97
12.2.13.3. Resource Utilization .......................................................................................97
12.2.14. Safety Analyses....................................................................................................97
12.2.14.1. Part A.............................................................................................................97
12.2.14.2. Part B .............................................................................................................97
12.2.15. Subgroup Analyses ..............................................................................................97
12.2.16. Interim Analyses..................................................................................................98
12.2.16.1. Part A.............................................................................................................99
12.2.16.2. Part B .............................................................................................................99
13.
Informed Consent, Ethical Review, and Regulatory Considerations ................................100
13.1. Informed Consent.......................................................................................................100
13.2. Ethical Review...........................................................................................................100
13.3. Regulatory Considerations .........................................................................................100
13.3.1.
Investigator Information.....................................................................................101
13.3.2.
Protocol Signatures ............................................................................................101
13.3.3.
Final Report Signature .......................................................................................101
14.
References ......................................................................................................................102

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List of Tables
Table
Page
Table JVCY.1.
Part A Treatment Regimen/Dosing Schedule ..........................................56
Table JVCY.2.
Part B Treatment Regimen/Dosing Schedule ..........................................57
Table JVCY.3.
Ramucirumab/Placebo Dose Reduction Schedule ...................................63
Table JVCY.4.
Ramucirumab/Placebo Dose Modification Table ....................................65
Table JVCY.5.
Erlotinib Dose Reduction Schedule ........................................................70
Table JVCY.6.
Erlotinib Dose Modification Table..........................................................71
Table JVCY.7.
Secondary Efficacy Endpoints................................................................79
Table JVCY.8.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........81
Table JVCY.9.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival.......................................................................93

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List of Figures
Figure
Page
Figure JVCY.1.
Predicted Cmin,ss following different dose regimens. ................................29
Figure JVCY.2.
Illustration of study design for Clinical Protocol I4T-MC-JVCY. ...........46
Figure JVCY.3.
Study period and continued access period diagram. ................................52

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JVCY Part A Study Schedule .................................................107
Attachment 2.
Protocol JVCY Part B Study Schedule..................................................116
Attachment 3.
Protocol JVCY Clinical Laboratory Tests.............................................126
Attachment 4.
Protocol JVCY Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality .........................................................................................127
Attachment 5.
Protocol JVCY Study Procedures .........................................................128
Attachment 6.
Protocol JVCY Creatinine Clearance Formula and NYHA 
Classification........................................................................................131
Attachment 7.
Protocol JVCY RECIST Criteria 1.1.....................................................132
Attachment 8.
Protocol JVCY Part B Pharmacokinetic, Immunogenicity, and 
Translational Research Sampling Schedule...........................................139
Attachment 9.
Protocol JVCY CYP3A4 Modulators ...................................................141
Attachment 10.
Protocol JVCY NCI-CTCAE v4.0 Infusion-Related Reactions and 
Dosing Algorithm for Proteinuria .........................................................142
Attachment 11.
Protocol JVCY Amendment (f) Summary A Multicenter, 
Randomized, Double-Blind Study of Erlotinib in Combination 
with Ramucirumab or Placebo in Previously Untreated Patients 
with EGFR Mutation-Positive Metastatic Non-Small Cell Lung 
Cancer..................................................................................................144

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4. Abbreviations and Definitions
Term
Definition
AC
Assessment Committee
AE
adverse event
Any new untoward medical occurrence or worsening of preexisting medical condition 
in a patient or clinical investigation subject administered a pharmaceutical product and 
that does not necessarily have a causal relationship with this treatment.  An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASBI
Average Symptom Burden Index
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
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 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.
BIRC
Blinded Independent Radiological Review Committee
BP
blood pressure
BSC
best supportive care
CHF
congestive heart failure
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
collection database
A computer database where clinical trial data are entered and validated.

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compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
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.
continued access 
period
The period between study completion and end of trial during which patients on study 
treatment who continue to experience clinical benefit and no undue risks may continue 
to receive study treatment until one of the criteria for discontinuation is met. 
CR
complete response
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
CT
computed tomography
cycle
A cycle in this trial is considered to be 2 weeks (14 days ± 3 days).
DCR
disease control rate
DCSI
Development Core Safety Information
DLT
dose-limiting toxicity
DOR
duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
EGFR mutation-
positive
EGFR mutation-positive includes exon 19 deletions or exon 21 (L858R) substitution 
mutations. 
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been deemed eligible and have been assigned to a treatment.
Part A (Phase 1b):  Enroll
Part B (Phase 3):  Enroll/Randomize

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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.
FFPE
formalin-fixed paraffin embedded
FSH
follicle-stimulating hormone
GCP
good clinical practice
G-CSFs
granulocyte-colony stimulating factors
GI
Gastrointestinal
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
ILD
interstitial lung disease
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.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.  Investigational product (IP) includes a product 
with a marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from the 
authorized form,
2.
used for an unauthorized indication, or 
3.
used to gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.

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IRR
infusion-related reaction
ITT
intention-to-treat
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IUD
intrauterine contraceptive device
I.V.
intravenous(ly)
IWRS
interactive web-response system
LCSS
Lung Cancer Symptom Scale
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.
LIRC
Lilly Internal Review Committee
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimal important difference
MRI
magnetic resonance imaging
NCI-CTCAE v4.0
National Cancer Institute Common Terminology Criteria for Adverse Events Version 
4.0 (v4.0 includes all of the minor versions [4.0x] generally typographical changes)
NSAIDs
non-steroidal anti-inflammatory drugs
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 study drugs are 
targeted
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PFS2
progression-free survival 2

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PK
Pharmacokinetics
PR
partial response
PRO/ePRO
patient-reported outcome/electronic patient-reported outcome
PS
performance status
PT
Preferred Term
PTT
partial thromboplastin time
QoL
quality of life
randomize/
randomization
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
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, blood 
draws).  For this type of screening, informed consent for these screening procedures 
and/or tests shall be obtained; this consent may be separate from obtaining consent for 
the study.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SMD
Senior Management Designee
SpO2
peripheral capillary oxygen saturation
study completion
This study will be considered complete after final analysis of overall survival is 
performed.
study drug, study 
treatment, or study 
therapy
ramucirumab/placebo and erlotinib, or any component of the combination
SUSARs
suspected unexpected serious adverse reactions

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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.
TPO
third-party organization
TtD
time to deterioration
TTP
time to progression
UA
Urinalysis
ULN
upper limits of normal
US
United States
VAS
visual analogue scale
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event

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A Multicenter, Randomized, Double-Blind Study of Erlotinib 
in Combination with Ramucirumab or Placebo in Previously 
Untreated Patients with EGFR Mutation-Positive Metastatic 
Non-Small Cell Lung Cancer
5. Introduction
5.1.
Ramucirumab Background
One promising approach to the treatment of cancer is inhibition of angiogenesis.  Investigators 
have identified a number of growth factors as positive regulators of angiogenesis, including 
members of the vascular endothelial growth factor (VEGF) family.  VEGF-A is one of several 
related cytokines and is distinct in that it acts as an endothelial cell-specific mitogen and is the 
growth factor most extensively studied and most consistently up-regulated in conditions 
associated with angiogenesis.  VEGF-A binds with high affinity to 2 structurally similar tyrosine 
kinase receptors, VEGF Receptor 1 and VEGF Receptor 2, which are both expressed on tumor 
vasculature.  Inhibition of the VEGF Receptor 2 signaling pathway has been investigated via a 
number of approaches, including anti-VEGF antibodies, anti-VEGF Receptor 2 antibodies, and 
small molecule tyrosine kinase inhibitors (TKIs) targeting the receptor; these approaches have 
been shown to inhibit new blood vessel formation and tumor growth in a variety of animal 
models.  Therapeutic agents that interfere with the function of VEGF and its receptors represent 
efficacious approaches to antiangiogenic and antitumor therapy.
Significant tumor growth inhibition has been observed with DC101, a rat monoclonal antibody 
(mAb) targeting murine VEGF Receptor 2, in multiple in vivo models across a broad range of 
doses (Skobe et al. 1997; Prewett et al. 1999; Bruns et al. 2000).  
 
 
  
The affinity of DC101 for murine VEGF Receptor 2 is approximately 6- to 9-fold lower than the 
affinity of ramucirumab for the human VEGF Receptor 2 (Zhu et al. 2003; data on file, notebook 
BE01241-012); however, clinical inhibition of cancer growth has frequently proven more 
difficult than inhibition of human tumor growth in many murine models.
Clinical activity was seen early in the development of ramucirumab.  In Phase 1 studies, 
ramucirumab has been generally well tolerated and exhibited preliminary evidence of antitumor 
activity in patients with solid tumors.  The maximum tolerated dose (MTD) of ramucirumab was 
identified as 13 mg/kg when given once weekly in the Phase 1 dose-escalation study, 
Study I4T-IE-JVBM (JVBM).  Preliminary activity was observed across a range of doses, 
including the 2-mg/kg dose.  Every-2-week (6 to 10 mg/kg) and every-3-week (15 to 20 mg/kg) 
dose regimens were evaluated in an additional dose-ranging study, I4T-IE-JVBN (JVBN).  No 
MTD was identified for every-2-week or every-3-week dosing; all dose regimens were well 
tolerated, and preliminary evidence of clinical efficacy was observed across a range of 
dose/schedule cohorts.
CCI

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Ramucirumab (IMC-1121B, LY3009806, CYRAMZATM) is a human receptor-targeted mAb that 
specifically binds to VEGF Receptor 2.  Phase 1 studies and initial Phase 2 studies investigating 
ramucirumab drug product (DP; hereafter referred to as ramucirumab) have provided 
information regarding safety and tolerability at clinically relevant doses, with preliminary 
evidence of clinical efficacy in a variety of human cancers.
Recently, a Phase 3 study (Study I4T-IE-JVBD; REGARD) indicated ramucirumab monotherapy 
following disease progression on initial therapy could improve overall survival (OS; median 5.2 
months vs. 3.8 months, hazard ratio [HR] = 0.776, 95% confidence interval [CI]:  0.603, 0.998, 
p=0.0473) and progression-free survival (PFS; median 2.1 months vs. 1.3 months, HR = 0.483, 
95% CI:  0.376, 0.620, p<0.0001) as compared with placebo and best supportive care (BSC) in 
patients with advanced gastric cancer.  Consequently, in April 2014, ramucirumab (trade name 
CYRAMZATM) was approved by the US Food and Drug Administration (FDA) for use as a 
single-agent treatment in patients with advanced gastric cancer in the second-line setting.
RAINBOW (Study I4T-IE-JVBE) was a global, randomized, double-blind, placebo-controlled 
Phase 3 study that compared the use of ramucirumab plus paclitaxel versus placebo plus 
paclitaxel in the treatment of patients with advanced (metastatic or locally advanced, 
unresectable disease) gastric or gastroesophageal adenocarcinoma following first-line platinum-
and fluoropyrimidine-containing therapy with or without an anthracycline (epirubicin or 
doxorubicin).  RAINBOW met its primary endpoint of OS and demonstrated a statistically 
significant and clinically meaningful improvement in OS and PFS in patients treated with 
ramucirumab plus paclitaxel compared with those treated with placebo plus paclitaxel.  
Additionally, consistent significant improvements were observed across all other efficacy 
endpoints:  time to progression (TTP), objective response rate (ORR), and disease control rate 
(DCR).
REVEL (Study I4T-MC-JVBA) was a global, randomized, placebo-controlled, double-blind 
Phase 3 study that compared the use of ramucirumab plus docetaxel versus placebo plus 
docetaxel in the treatment of patients with locally advanced or metastatic non-small cell lung 
cancer (NSCLC) with progression after platinum-based chemotherapy.  REVEL was the first 
study to demonstrate a statistically significant and clinically meaningful improvement in OS for 
a novel agent in combination with a standard chemotherapy in advanced NSCLC patients with 
progression after platinum-based chemotherapy.
ROSE (Study I4T-IE-JVBC) was a multicenter, global, randomized, double-blind study of 
ramucirumab with docetaxel v/s placebo and docetaxel in patients with previously untreated 
human epidermal growth factor receptor 2-negative, unresectable, locally recurrent or metastatic 
breast cancer.  The PFS endpoint was not met.  While the direction of the HR favored the 
ramucirumab arm, the p-value did not meet the prespecified two-sided 0.05 statistical 
significance level.
REACH (Study I4T-IE-JVBF) was a global, randomized, double-blind Phase 3 study of
ramucirumab plus best supportive care compared to placebo and BSC as a second-line treatment 
in patients with hepatocellular carcinoma who have been previously treated with sorafenib in the 

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first-line setting.  REACH did not meet its primary endpoint of OS; although the OS results 
favored the ramucirumab arm, they were not statistically significant.  Encouraging single-agent 
ramucirumab activity was observed, with meaningful improvements in key secondary endpoints 
of PFS, ORR, and TTP.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of ramucirumab may be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to the ramucirumab may be found in Section 7 
(Development Core Safety Information) of the IB.  Information on serious adverse events 
(SAEs) expected in the study population independent of drug exposure and that will be assessed 
by the sponsor in aggregate, periodically during the course of the study, may be found in 
Section 6 (Effects in Humans) of the IB.
5.2.
Use of Tyrosine Kinase Inhibitors in NSCLC
Epidermal growth factor receptor (EGFR) TKIs (for example, erlotinib and gefitinib) 
significantly prolong PFS in patients with advanced EGFR mutation-positive NSCLC when 
compared with placebo or platinum-based chemotherapy doublets; hence, these EGFR TKIs 
have become the standard of care in countries where approved.  The rationale for such treatment 
is supported by the results of studies such as BR.21 (Shepherd et al. 2005) and IPASS (Mok et al. 
2009).
Despite currently available options in NSCLC, there continues to be a need for new first-line 
treatment options with improved efficacy, without adding significant toxicity for those patients 
with EGFR mutation-positive NSCLC.  BR.21 and IPASS studies demonstrated a higher benefit 
with EGFR TKI in patients with EGFR mutation-positive NSCLC subgroup of study population 
(Shepherd et al. 2005; Mok et al. 2009).  LUX-Lung3 study demonstrated prolongation of PFS 
with afatinib when compared with standard doublet chemotherapy in patients with EGFR
mutations positive advanced lung adenocarcinoma (Sequist et al 2013).  EURTAC study, a 
randomized, multicenter, open-label trial, compared erlotinib (n=86) to platinum-based doublet 
chemotherapy (n=87) in patients with EGFR mutation-positive metastatic NSCLC.  The median 
PFS was 9.7 months (95% CI:  8.4, 12.3) in the erlotinib group, compared with 5.2 months 
(95% CI:  4.5, 5.8) in the standard chemotherapy group (HR = 0.37, 95% CI:  0.25, 0.54; 
p<0.0001) (Rosell et al. 2012).  OPTIMAL study, a multicenter, open-label, randomized, Phase 3 
study, compared erlotinib versus chemotherapy as first-line treatment for patients with advanced 
EGFR mutation-positive NSCLC.  Median PFS was significantly longer in erlotinib-treated 
patients than in those on chemotherapy (13.1 months [95% CI:  10.58, 16.53] vs. 4.6 months 
[95% CI:  4.21, 5.42] months; HR = 0.16, 95% CI:  0.10, 0.26; p<0·0001) (Zhou et al. 2011).
Several preclinical studies have shown that the VEGF and EGFR pathways are known to be
interrelated.  For example, cells with an EGFR mutation express higher levels of VEGF and 
VEGF is down regulated by EGFR inhibition (Byers and Heymach 2007).  In xenograft models, 
acquired resistance to cetuximab, a mAb targeting EGFR, was associated with increased VEGF 
levels and increased tumor angiogenesis in vivo (Viloria-Petit et al. 2001).  These studies suggest 
that dual blockade of the VEGF and EGFR pathways would be more effective than either 

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approach alone and may also have activity in tumors with acquired resistance to EGFR
inhibitors.  However, it is unknown whether this finding extends to resistance to EGFR TKIs.  In 
an experiment done in different cell lines, it was shown that dual inhibition of the EGFR and 
VEGF pathways did not only dramatically reduced endothelial cell proliferation but also 
abrogated primary and secondary resistance to EGFR TKIs (Naumov et al. 2009).
Recently reported results from several NSCLC clinical trials that include antiangiogenics in 
combination with TKIs have demonstrated that there is a significantly longer PFS and OS in the 
subgroup of patients with EGFR mutations, as compare to all-comers.
ATLAS was a second-line Phase 3 trial that randomized 1145 advanced NSCLC patients to 
receive bevacizumab plus placebo or bevacizumab plus erlotinib.  The median PFS was 
3.7 months in the placebo arm versus 4.8 months in the erlotinib arm (HR = 0.708; p < 0.001).  
The median OS was 13.3 versus 14.4 months, respectively, and was found to not be significant 
(HR = 0.917, p = 0.5341).  In the overall NSCLC patient population, the addition of erlotinib to 
bevacizumab improved PFS but not OS.  However, subgroup analyses demonstrated that patients 
with EGFR mutations (n=52) had a longer duration of PFS (HR = 0.44) in the erlotinib arm 
(n=27) versus the placebo arm (n=25) and OS results also showed a similar difference 
(HR = 0.46) (Johnson et al. 2013).
In the second-line Phase 3 BeTa trial, 636 patients with advanced NSCLC were randomized to 
receive erlotinib plus bevacizumab or erlotinib plus placebo.  The primary endpoint of OS was 
not found to be significant (9.3 months in the bevacizumab arm vs. 9.2 months in the placebo 
arm; HR=0.97).  Subgroup analysis of patients with EGFR mutation-positive status (n=30) 
suggested that OS favored bevacizumab (n=12; median OS Not Reached [22.6 - Not Reached]) 
in patients with EGFR mutations as compared to the control arm (n=18; 20.2 months [95% CI: 
16.4 - 31.1]) (HR = 0.44 [95% CI: 0.11 - 1.67]); however, the results should be interpreted with 
caution because of the small number of patients and the 95% CI for the HR were wide and 
overlapping (Herbst et al. 2011).
In the first-line Phase 2 JO25567 study, 154 Japanese patients with EGFR mutation-positive 
NSCLC were randomized 1:1 to receive erlotinib with or without bevacizumab.  Median PFS 
was 16.0 months in the erlotinib in combination with bevacizumab arm and 9.7 months in the 
erlotinib arm (HR, 0.54; 95% CI: 0.36, 0.79; log-rank p = 0.0015).  In the EGFR exon 19 
deletion subgroup, the median PFS in the erlotinib plus bevacizumab arm was 18.0 months and 
in the erlotinib arm was 10.3 months.  In the L858R subgroup, median PFS was 13.9 months for 
the combination and 7.1 months for erlotinib alone.  The DCR was 99% in the bevacizumab plus 
erlotinib arm versus 88% in the erlotinib arm (Kato et al. 2014; Seto et al. 2014).
In these 3 clinical trials, the combination of bevacizumab and erlotinib in patients with advanced 
NSCLC demonstrated that this regimen (antiangiogenic agent + EGFR TKI) was well tolerated 
and the safety profile was acceptable.

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5.3.
Rationale for Selection of Ramucirumab Dose Regimen 
(10 mg/kg on Day 1 Every 2 Weeks)
Ramucirumab administered at 10 mg/kg on Day 1 on an every-2-week schedule will be 
examined in both portions of this study.  This dose regimen of ramucirumab is different 
compared to the REVEL study.  In REVEL, conducted in a second-line NSCLC setting, 
ramucirumab was administered at a dose of 10 mg/kg every 3 weeks.  Exposure-response 
(efficacy/safety) findings from Phase 3 ramucirumab trials, REGARD, RAINBOW, and REVEL, 
and pharmacokinetic (PK) simulations were used to guide the dose selection in this JVCY study.
Efficacy
Exposure-efficacy response analyses performed on data obtained from REGARD, RAINBOW, 
and REVEL demonstrated that an increase in exposure is associated with improvement in 
efficacy in terms of both OS and PFS.
The following 4 exposure measures were tested, and the findings were consistent for all of them:

minimum concentration after first dose administration,

minimum concentration at steady state (Cmin,ss),

maximum concentration at steady state, and

average concentration at steady state.
In REGARD (n=72 [number of patients with evaluable PK data]), patients with greater-than-
median ramucirumab exposure demonstrated longer OS and PFS and significantly better 
treatment effects (smaller HR) as compared to patients with less than median ramucirumab 
exposure.
In RAINBOW (n=321 [number of patients with evaluable PK data]), patients with ramucirumab 
exposure greater-than-median (in the 3rd and 4th quartile groups) were associated with longer 
OS and PFS and significantly better treatment effects (smaller HR) as compared to patients with 
ramucirumab exposure lower than median (in the 1st and 2nd quartile groups).
In REVEL (n=376 [number of patients with evaluable PK data]), significantly longer OS and 
PFS favoring ramucirumab were generally observed in the highest exposure quartile group (the 
4th group), while marginal increases on OS and PFS were observed in other exposure quartile 
groups.
Safety
Weekly doses of ramucirumab ranging from 2 to 16 mg/kg were evaluated in Phase 1 Study 
JVBM.  An MTD for weekly dosing was identified as 13 mg/kg every week.  Every-2-week (6 to 
10 mg/kg) and every-3-week (15 to 20 mg/kg) dose regimens were evaluated in an additional 
dose-ranging study (Study JVBN).  All dose regimens in Study JVBN were well tolerated and no 
MTD was identified in this study.
The same ramucirumab dose regimen (8 mg/kg every 2 weeks) was used in REGARD and 
RAINBOW.  REGARD demonstrated a well-tolerated safety profile in the gastric cancer 

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monotherapy setting.  Due to the low incidence of hypertension and neutropenia, no 
safety-exposure relationship was identified.  In RAINBOW, ramucirumab in combination with 
paclitaxel was also well tolerated in patients with gastric cancer, with manageable AEs.  An 
increasing ramucirumab exposure was correlated with increased incidence of Grade ≥3
hypertension, neutropenia, and leukopenia. Of note, there were no Grade 4 or 5 hypertension 
events in RAINBOW.  Hypertension was managed primarily by the use of standard 
antihypertensive medication.  Neutropenia and leukopenia are known risks with paclitaxel 
treatment.  Overall, the safety profile of ramucirumab plus paclitaxel was largely consistent with 
the safety profiles of the individual treatment components and the combination revealed no 
unexpected safety findings.
The safety profile observed in REVEL was consistent with the safety profile for ramucirumab 
established in gastric cancer (REGARD and RAINBOW), as well as the established safety 
profile for docetaxel, and was manageable in the NSCLC population.  An increasing 
ramucirumab exposure was correlated with increased incidence of Grade ≥3 hypertension and 
febrile neutropenia.  Of note, there were no Grade 4 or 5 hypertension events in REVEL.  
Hypertension was managed primarily by the use of standard antihypertensive medication.  In 
addition, incidence of febrile neutropenia appeared to reach plateau at the third exposure quartile.
These exposure-efficacy and exposure-safety data indicate that there is an opportunity to further 
enhance efficacy of ramucirumab while maintaining an acceptable safety profile.  Based on PK 
simulation, a dose regimen of 10 mg/kg on Day 1 every 2 weeks was selected for Study JVCY 
for the following reasons:

This dose regimen may produce Cmin,ss that is higher than the 4th Cmin,ss quartile 
obtained from 10 mg/kg every-3-week regimen in REVEL, in at least 70% of the 
patient population (Figure JVCY.1) and is therefore expected to produce better 
clinical efficacy outcomes relative to the 10-mg/kg every-3-week regimen.

It is expected that ramucirumab-related AEs in the NSCLC indication may not be 
significantly increased using the selected ramucirumab dose of 10 mg/kg every 2 
weeks, since the selected dose for Study JVCY is still approximately 60% lower 
than the maximum tolerated weekly dose identified in the Phase 1 dose-escalation 
study, Study JVBM (13 mg/kg weekly).

The ramucirumab exposure distribution of the 10-mg/kg every-2-week regimen 
significantly overlaps with that of the 8-mg/kg every-2-week regimen studied in 
REGARD and RAINBOW.

In addition, an early safety lead-in portion of the study (Part A described in 
Section 8.1.1) will be performed to mitigate any potential risk, since the selected 
ramucirumab dosing schedule and combination therapy for Study JVCY are 
different from what was studied in REVEL.
Part A (Phase 1b) is being conducted to assess the safety and tolerability of ramucirumab 
administered at 10 mg/kg every 2 weeks in combination with erlotinib administered daily at 
150 mg. In the event that dose-limiting toxicities (DLTs) are reported to occur in this patient 
population at the prescribed ramucirumab dose, the Phase 3 starting dose could be determined to 

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be 8 mg/kg every 2 weeks, depending on the nature of the DLTs and the recommendations from 
the Assessment Committee (AC).  If that is the case, the recommendation for the dosing level 
may be modified for the Phase 3 part of the trial.
This early safety assessment will ensure the higher ramucirumab dose regimen of 10 mg/kg 
every 2 weeks can still maintain an acceptable safety profile in combination with erlotinib in 
NSCLC patients.  Based upon the review of the early safety analysis, study modifications may be 
warranted.
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 JVCY.1.
Predicted Cmin,ss following different dose regimens.
In summary, the dosing regimen of ramucirumab 10 mg/kg on Day 1 every 2 weeks in 
combination with erlotinib is anticipated to produce a favorable benefit-risk profile in patients 
with EGFR mutation-positive metastatic NSCLC.
The Assessment Committee reviewed the safety data for the Phase 1b portion (Part A) and 
recommended to initiate the randomized Phase 3 portion of the study (Part B) with ramucirumab 
at 10 mg/kg every 2 weeks.

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6. Objectives
6.1.
Primary Objective
The study is divided into 2 parts.  Part A is the Phase 1b portion of the trial and Part B is the 
Phase 3 portion of the trial.  Once the Assessment Committee (AC) has completed the DLT 
assessment for Part A, the outcome of those results will confirm the Part B dose and Part B 
enrollment will proceed.  The objective(s) for each part are as follows:
Part A:  The objective of Part A is to assess the safety and tolerability of ramucirumab when 
administered in combination with erlotinib as therapy in previously untreated patients with 
EGFR mutation-positive metastatic NSCLC.
Part B:  The primary objective of Part B is to compare the PFS of ramucirumab administered in 
combination with erlotinib versus placebo in combination with erlotinib in previously untreated 
patients with EGFR mutation-positive metastatic NSCLC.
6.2.
Secondary Objectives
Secondary objectives of Part B are to compare ramucirumab administered in combination with 
erlotinib versus placebo administered in combination with erlotinib for:

safety and toxicity profile

overall survival (OS)

objective response rate (ORR) (complete response [CR] + partial response [PR])

disease control rate (DCR) (CR + PR + stable disease [SD])

duration of response (DOR)

pharmacokinetics (PK) and immunogenicity of ramucirumab 

patient-reported outcomes (using Lung Cancer Symptom Scale [LCSS] and EuroQol 
5-dimension, 5-level questionnaire [EQ-5D-5L])

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6.3.
Exploratory Objectives
The exploratory objectives of Part B of the study are as follows:

to assess the association between biomarkers and clinical outcome.

to compare progression-free survival 2 (PFS2) between treatment arms.
The exploratory objectives in only the gefitinib/osimertinib cohort in Addendum 9, conducted in 
the East-Asian region including Japan, are as follows:

to evaluate the efficacy (for example, 1-year PFS rate) and safety of ramucirumab when 
administered in combination with gefitinib in previously untreated patients with EGFR
mutation-positive metastatic NSCLC, in the East-Asian region including Japan

to evaluate the efficacy and safety of ramucirumab when administered in combination 
with osimertinib in patients with T790M-positive metastatic NSCLC whose disease has 
progressed on ramucirumab plus gefitinib in this study, in the East-Asian region 
including Japan

to assess PK and immunogenicity of ramucirumab

to assess patient-reported outcomes (using LCSS and EQ-5D-5L)
There are no secondary or exploratory objectives planned for Part A in this study.

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7. Study Population
The study will enroll male or female patients, 18 years of age or older (20 years of age or older 
in Japan and Taiwan), who are diagnosed with EGFR mutation-positive (exon 19 deletions or 
exon 21 [L858R] substitution mutations) metastatic NSCLC who will be treated for their disease 
for the first time.  Patients with known T790M mutation will be excluded from study 
participation.
All patients meeting the eligibility requirements will be considered for enrollment regardless of 
race, religion, or gender.  The investigator or the Sponsor will not grant exceptions to eligibility 
criteria.
Patients who do not meet the criteria for participation within the 21-day screening period (screen 
failure) may be rescreened.  Note that repeating laboratory tests during the 21-day screening 
period does not constitute rescreening.  Screening laboratory tests may not be repeated more than 
twice in order to meet eligibility during the 21-day screening period.  If a repeat screening 
laboratory value meets eligibility, it is recommended that the test is rechecked to confirm 
stability.
Patients may be considered for rescreening after discussion with the Medical Monitor or 
designee.  Individuals may be rescreened up to 3 times.  Each time rescreening is performed, the 
patient must sign a new informed consent form (ICF) and will be assigned a new identification 
number.  In addition, laboratory criteria eligibility must be confirmed with new labs for each new 
re-screening period.  The maximum duration of time between re-screenings should be 28 days.
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria
prior to enrollment:
[1]
The patient has given their written informed consent to participate in the study 
and is amenable to compliance with protocol schedules and testing.
[2]
Males or females:  aged ≥18 years, ≥20 years in Japan and Taiwan at the time of 
study entry.
[3]
The patient has cytologically or histologically confirmed diagnosis of Stage IV 
NSCLC as defined by the American Joint Committee on Cancer Staging Criteria 
for Lung Cancer (AJCC 7th edition 2009) (Edge et al. 2009).

Patients with recurrent metastatic disease are permitted to enter the study as 
long as the adjuvant or neo-adjuvant therapy was completed at least 12 
months prior to the development of metastatic disease.  However, prior 
adjuvant or neo-adjuvant therapy is not required.

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[4]
The patient must be eligible for first-line treatment with erlotinib based on 
previously documented evidence of tumor that has EGFR exon 19 deletion or 
exon 21 (L858R) substitution mutation.
[5]
The patient consents to submit an archived formalin-fixed paraffin embedded 
(FFPE) Stage IV NSCLC tissue sample for assessment of biomarkers unless 
restricted per local regulations.  Archived NSCLC tissue samples derived from
other than Stage IV disease may be acceptable, based on approval by Lilly CRP;
For patients who do not submit Stage IV disease tissue samples, a plasma sample 
for disease characterization is required unless restricted by local regulations.  
Once consented, availability of an adequate tumor tissue sample or any necessary 
plasma sample is required for study eligibility.  
Note:  This tissue sample collection is not mandatory for patients enrolled in Part A.
[6]
The patient has at least one or more measurable lesion attributed to NSCLC at the 
time of study entry, documented by computed tomography (CT) scan or magnetic 
resonance imaging (MRI), as defined by the Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 (Attachment 7).
[7]
The patient is able to swallow tablets.
[8]
The patient has Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) of 0 or 1 at study entry (Attachment 5).
[9]
Prior radiation therapy is allowed:

For local palliation or prevention of symptoms (such as pain, bleeding, or 
obstruction) where at least 7 days have elapsed from last radiation treatment prior to 
enrollment (and provided that 25% or less of total bone marrow had been irradiated).

If the patient has completed palliative thoracic radiotherapy 28 days before 
enrollment.
[10] The patient has adequate hematologic and organ function, defined as:

Absolute neutrophil count (ANC) ≥1.5 x 109/L, hemoglobin ≥9.0 g/dL, and platelets 
≥100 x 109/L

Total bilirubin less than or equal to the upper limit of normal value (ULN), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN, or 
≤5 x ULN if the transferase elevation is due to liver metastases

The patient has a calculated creatinine clearance (CrCl) ≥50 mL/min per the 
Cockcroft-Gault formula (see Attachment 6).  If the value is below this parameter, 
then a 24-hour urine collection should be done to rectify or ratify the estimated 
creatinine clearance.

The patient has an adequate coagulation function as defined by International 
Normalized Ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 x ULN, and partial 
thromboplastin time (PTT/aPTT) ≤1.5 x ULN.  Patients who are on low molecular 

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weight heparin (LMWH) are eligible; whereas, patients receiving warfarin should be 
switched to LMWH as per institutional guidelines, and should have achieved stable 
coagulation profile prior to enrollment.  Note that a patient with a venous thrombosis 
is permitted to enroll provided that the patient is clinically stable, asymptomatic, and 
adequately treated with anticoagulants at the discretion of the investigator.

The patient’s urinary protein is ≤1+ on dipstick or routine urinalysis (UA).  If urine 
dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine must be 
collected and must demonstrate <1000 mg (< 1 g) of protein in 24 hours to allow 
participation in the study.
[11] Eligible patients of reproductive potential (both sexes) must agree to use 
adequate contraceptive methods (hormonal or barrier methods) during the study 
period and for at least 12 weeks after the last dose of study therapy. Eligible 
female patients of childbearing potential must have a negative serum pregnancy 
test within 7 days before enrollment.

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 (IUDs), sexual abstinence, or a vasectomized partner.  
For patients using a hormonal contraceptive method, information regarding 
the product under evaluation and its potential effect on the contraceptive 
should be addressed.

Men who are sterile (including vasectomy confirmed by post-vasectomy 
semen analysis) or who agree to use a reliable method of birth control and to 
not donate sperm during the study and for at least 12 weeks following the last 
dose of ramucirumab or country requirements, whichever is longer.

Women who agree to use a reliable method of birth control, or are not of 
child-bearing potential due to surgical sterilization (at least 6 weeks following 
surgical bilateral oophorectomy with or without hysterectomy or tubal 
ligation) confirmed by medical history or due to menopause, are eligible.  A 
“menopausal woman” is a woman meeting either of the following criteria:
o
Spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications during the 
amenorrhea that induced the amenorrhea (for example, oral contraceptives, 
hormones, gonadotropin releasing hormone, antiestrogens, selective 
estrogen receptor modulators, or chemotherapy).
o
Spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone (FSH) level >40 mIU/mL.
[12] The patient has resolution to Grade ≤1 (except alopecia), by the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
v4.0, of all clinically significant toxic effects of prior locoregional therapy, 
surgery, or other anticancer therapy.

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[13] The patient has a life expectancy of at least 3 months and, in the judgment of the 
investigator, will be able to complete at least 2 cycles of treatment.
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria prior to 
enrollment:
[14] The patient has known T790M EGFR mutation.
[15] The patient has known leptomeningeal carcinomatosis, uncontrolled/unstable 
spinal cord compression, or brain metastases.
[16] The patient has undergone major surgery within 28 days or subcutaneous venous 
access device placement within 7 days prior to enrollment.  Furthermore, any 
patient with postoperative bleeding complications or wound complications from 
a surgical procedure performed in the last 2 months will be excluded.
[17] The patient has pleural effusion, pericardial fluid, or ascites requiring drainage 
every other week or more frequently.
[18] The patient has superior vena cava syndrome.
[19] The patient has clinically relevant congestive heart failure (New York Heart 
Association [NYHA] II-IV; see Attachment 6) or symptomatic or poorly 
controlled cardiac arrhythmia.
[20] The patient has a serious illness or medical condition that would compromise 
their safety or impair their ability to comply with the protocol’s requirements, 
including, but not limited to, the following:

Severely immunocompromised patients (other than that related to the use of 
corticosteroids) including patients known to be HIV positive

Hepatic Impairment:

Severe liver cirrhosis Child-Pugh Class B (or worse) 

Cirrhosis with a history of hepatic encephalopathy 

Clinically meaningful ascites resulting from cirrhosis and requiring ongoing 
treatment with diuretics and/or paracentesis.

Patients with a history of hepatorenal syndrome should also be excluded.

Previous or concurrent malignancy except for basal or squamous cell skin cancer
(non-melanoma) and/or pre-invasive carcinoma of the cervix, mucosal 
gastrointestinal (GI) or uterine carcinoma, or other solid tumors treated curatively and 
without evidence of recurrence for at least 3 years prior to enrollment.

Known allergy or hypersensitivity reaction to any of the treatment components.

The patient has a known history of active drug abuse.

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
History of uncontrolled heredity or acquired thrombotic disorder.

The patient has had a serious or non-healing wound, ulcer, or bone fracture within 
28 days prior to enrollment.

Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or 
secondary effects of cancer that induce a high medical risk and/or make assessment of 
survival uncertain.

Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and in 
the judgment of the investigator would make the patient ineligible for entry into this 
study.
[21] The patient has uncontrolled hypertension defined as systolic blood pressure 
>150 mmHg or diastolic blood pressure >90 mmHg despite standard medical 
management.
[22] The patient is being treated with CYP3A4 inducers or strong inhibitors (see 
Attachment 9 for the list).
[23] The patient is receiving chronic therapy with nonsteroidal anti-inflammatory 
agents (NSAIDs; for example, indomethacin, ibuprofen, naproxen, or similar 
agents) or other antiplatelet agents (for example, clopidogrel, ticlopidine, 
dipyridamole, or anagrelide) within 7 days prior to first dose of study 
treatment. Aspirin use at doses up to 325 mg/day is permitted.
[24] The patient has a history of gross hemoptysis (defined as the presence of 
≥1/2 teaspoon of gross blood) within 2 months prior to enrollment.
[25] The patient has significant bleeding disorders, vasculitis, or experienced 
Grade 3/4 GI bleeding within 3 months prior to enrollment.
[26] The patient has radiologically documented evidence of major blood vessel 
invasion or encasement by cancer.
[27] The patient has radiographic evidence of intratumor cavitation, regardless of 
tumor histology.
[28] The patient has a history of GI perforation, peptic ulceration, diverticular disease,
and/or fistulae within 6 months prior to enrollment.
[29] The patient has a bowel obstruction, history or presence of inflammatory 
enteropathy or extensive intestinal resection (for example, hemicolectomy or 
extensive small intestine resection with chronic diarrhea), Crohn's disease, 
ulcerative colitis, or chronic diarrhea.
[30] The patient has experienced any arterial thrombotic event, including myocardial 
infarction, unstable angina, cerebrovascular accident, or transient ischemic 
attack, within 6 months prior to enrollment.

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[31] The patient has any known significant ophthalmologic abnormalities of the 
surface of the eye.  The use of contact lenses is not recommended during the 
study.
[32] The patient requires daily use of prescription or over-the-counter proton pump 
inhibitors (such as Nexium® [esomeprazole magnesium] or Prilosec®
[omeprazole]).
[33] The patient is currently enrolled in a clinical trial involving an investigational 
product (IP) or non-approved use of a drug or device (other than the study drugs 
used in this study), or concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study.  Patients 
participating in surveys or observational studies are eligible to participate in this 
study.
[34] The patient received his/her last dose of nonapproved use of a drug or device in a 
clinical trial within 30 days before the date of enrollment.
[35] The patient had any prior anticancer therapy for Stage IIIB/IV NSCLC (for 
example, chest radiotherapy, systemic chemotherapy [including TKIs], 
immunotherapy, or biological therapy).
Patients who received adjuvant therapy are permitted to enter the study as 
long as the adjuvant therapy was completed at least 12 months prior to the 
development of recurrent metastatic disease.  However, prior adjuvant therapy 
is not required.
[36] The patient has any evidence of clinically active interstitial lung disease.  
Asymptomatic patients with chronic, stable, radiographic changes are eligible.
[37] The patient has 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.
[38] The patient has SpO2 < 94 (room air).
[39] The patient is pregnant or breastfeeding.
7.2.1.Rationale for Exclusion of Certain Study Candidates
The exclusion criteria have been carefully selected by the Sponsor to ensure their ethical and 
scientific acceptability, and to help establish specificity of the patient population for both 
efficacy and safety analyses.
Exclusion Criteria [16], [20], [21], [23], [24], [25], [26], [27], [28], [29], and [30] are written for 
patient safety based on what is known about the side effect profile of an antiangiogenic agent 
such as ramucirumab.  Exclusion Criteria [31] and [36] are written for patient safety based on 
what is known about the side effect profile of TKI such as erlotinib.  Exclusion Criteria [17], 
[18], and [19] are written in the interest of patient’s overall safety.  Exclusion Criteria [14], [15], 
[35], [37], and [38] are written to maintain the specificity of the patient population intended for 

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enrollment and analyses.  Exclusion Criteria [22], [32], [33], and [34] are written to ensure that 
both erlotinib and ramucirumab are novel treatments, so that treatment safety and efficacy are 
not confounded by prior exposure and known treatment failure.  Exclusion Criterion [39] is 
based on the lack of experience with use of ramucirumab among women who are either pregnant 
or lactating.
7.3.
Discontinuation
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
All patients who discontinue, regardless of whether or not they received study treatment, will 
have procedures performed as shown in the Study Schedule (Attachment 1 or Attachment 2).
Patients who are discontinued from the study treatment will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1 or Attachment 2).
If a patient withdraws informed consent from continuing in the study participation, he or she 
must not be contacted unless he or she has explicitly provided permission and consent.  Lilly 
may continue to use previously collected medical research data prior to the withdrawal, 
consistent with the original authorization.
7.3.1.Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the Sponsor must be 
notified.  If the Sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the Sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without study treatment.  Inadvertently enrolled 
patients may be maintained in the study and on study drugs when the Lilly CRP agrees with the 
investigator that it is medically appropriate for that patient.  The patient may not continue in the 
study with or without study treatment if the Lilly CRP does not agree with the investigator’s 
determination.  The investigator must obtain documented approval from the Lilly CRP to allow 
the inadvertently enrolled patient to continue in the study with or without study treatment.
The patient may continue to receive study treatment if all of the following conditions are met:

The Lilly CRP or clinical research scientist (CRS) determines that no effective alternative 
therapy exists

The Lilly CRP or CRS and the investigator agree there is no safety concern meriting 
discontinuance of study drugs, and

In the opinion of the investigator, the patient is receiving benefit.

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7.3.2. Discontinuation of Study Treatment
Patients who discontinue study treatment will continue to be followed for survival until study 
completion.
7.3.2.1.
Ramucirumab/Placebo
The investigator will discontinue a patient from ramucirumab/placebo for any of the following 
reasons:

The patient requests to be withdrawn from ramucirumab/placebo (‘Patient Decision to 
Discontinue’ or ‘Patient Withdraws’ per electronic case report form [eCRF]).

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient) considered by the investigator to be attributed to 
ramucirumab/placebo.

Any Grade 4 nonhematologic toxicity considered by the investigator to be attributed to 
ramucirumab/placebo (Section 9.4.2.1.2).

A Grade 3 or 4 infusion-related reaction (IRR) that in the opinion of the investigator is 
considered to be attributed to ramucirumab/placebo (see Section 9.4.2.1.2.1).

Grade 4 hypertension or persistent/recurrent hypertension that is refractory (see 
Section 9.4.2.1.2.2).

A Grade 3 or 4 arterial thromboembolic event (ATE; see Section 9.4.2.1.2.3.1).

A Grade 3 or 4 venous thromboembolic event (VTE) that is considered by the 
investigator to be life-threatening, or symptomatic and cannot be adequately treated by 
anticoagulation therapy (see Section 9.4.2.1.2.3.2).

Any pulmonary embolism/deep vein thrombosis that intensifies during anticoagulant 
therapy

A Grade 3 or 4 bleeding or hemorrhagic event (see Section 9.4.2.1.2.4)

Hemoptysis that exceeds the severity grade present at baseline (see Section 9.4.2.1.2.4)

Event of a GI perforation (see Section 9.4.2.1.2.5)

A confirmed occurrence of a gastrointestinal or non-GI fistula (see Section 9.4.2.1.2.6)

Proteinuria level is >3 g/24 hours, or there is a third occurrence of proteinuria 
≥2 g/24 hours, or the proteinuria level does not return to <2 g/24 hours within 2 weeks of 
dose delay (see Section 9.4.2.1.2.7 and proteinuria algorithm in Attachment 10)

Any Grade 3-4 events consistent with congestive heart failure (CHF; see 
Section 9.4.2.1.2.8)

A persistence of impaired wound healing (for example, wounds could generate 
significant morbidity to the patient) greater than 28 days after suspension of 
ramucirumab/placebo therapy (see Section 9.4.2.1.2.9)

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
A new occurrence of hepatic encephalopathy and/or hepatorenal syndrome resulting from 
liver cirrhosis (see Section 9.4.2.1.2.10)

The diagnosis of reversible posterior leukoencephalopathy syndrome (RPLS) is 
confirmed (see Section 9.4.2.1.2.11).

Any event that would warrant the dose of ramucirumab/placebo to be modified for a 
higher number of times then permitted in the protocol (see Section 9.4.2.1.2).

Any event that would warrant ramucirumab/placebo to be held for >2 consecutive cycles 
(missing 2 consecutive doses).  In situations where >2 consecutive doses have been 
missed, events related to the missed doses have resolved, and there is evidence of 
ongoing disease control, continuation of ramucirumab/placebo may be considered and 
must be discussed with the Sponsor Physician or designee.
Patients who are discontinued from ramucirumab/placebo will continue to be in the study, and 
may be further treated with erlotinib.
7.3.2.2.
Erlotinib
The investigator will discontinue a patient from erlotinib for any of the following reasons:

The patient requests to be withdrawn from erlotinib (‘Patient Decision to Discontinue’ or 
‘Patient Withdraws’ per eCRF).

The investigator decides that the patient should be discontinued from erlotinib, according 
to the local practice and approved product information.

If the patient does not tolerate at least the 50-mg daily erlotinib dose.

If the investigator decides to discontinue erlotinib therapy, due to the patient having had a 
2-week delay in this therapy because of an erlotinib-related toxicity (an additional 1-week 
delay may be permitted per Section 9.4.2.2.1).

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient) that in the opinion of the investigator is considered to be 
attributed to erlotinib.

If interstitial lung disease is confirmed.  The patient should be treated appropriately.

If liver function tests demonstrate severe abnormal laboratory results (Table JVCY.6).

If the patient experiences GI perforation; severe bullous, blistering, or exfoliation skin 
conditions; corneal perforation or sever ulceration.

Patient compliance with erlotinib will be assessed at each visit (refer to Section 9.7).  
Patients who are consistently out of the compliance range may be discontinued.  A Lilly 
representative should be contacted upon the second instance of treatment noncompliance.
Patients who are discontinued from erlotinib will continue to be in the study and may be further 
treated with ramucirumab/placebo.  Conditions that might cause erlotinib discontinuation should 
be treated appropriately per standard of care.  In addition, discontinuation of erlotinib in the 
setting of AEs and guidelines for treatment management are detailed in Section 9.4.2.2.

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7.3.2.3.
All Study Treatment
The investigator will withdraw a patient who continues in the study from all study treatment 
(ramucirumab/placebo plus erlotinib) for the following reasons:

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.

Investigator decision:
o
The investigator decides that the patient should be discontinued from the study 
treatment.
o
If the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study treatment occurs prior to introduction of the new 
agent.

Patient decision:
o
The patient requests to be withdrawn from the study treatment.  If the patient 
withdraws consent to treatment, he or she may still enter short- and/or long-term 
follow-up if follow-up consent is not withdrawn.  It should be clarified with the 
patient and documented in the patient’s file whether follow-up information on 
tumor assessment, antitumor therapies, and survival can be still obtained, and if 
so, to what extent.  Investigations scheduled for the post-discontinuation 
follow-up period should be carried out as much as possible.

Sponsor decision:
o
Lilly stops the study or stops patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP).

Radiographic progressive disease or symptomatic progressive disease (PD).  If patient 
experiences symptomatic deterioration and progression is suspected, every attempt 
should be made to confirm PD radiographically as per RECIST criteria prior to/soon after 
the patient’s discontinuation from the study treatment.

If a patient deteriorates to an ECOG PS of ≥3, all study treatments are to be discontinued.  
In case of PS deterioration of <3, disease progression should be ruled out.

An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient) or any study treatment-related event that is deemed life-
threatening, regardless of NCI-CTCAE, v4.0 grade, and that in the opinion of the 
investigator cannot be attributed to a specific study agent.  For example:
o
In case of an SAE or a clinically significant laboratory value, appropriate 
measures are to be taken. The Sponsor or its designee is to be alerted 
immediately in the event of an SAE (Section 10.3).

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o
An intercurrent illness or changes in the patient’s condition that render the patient 
unsuitable for further treatment.

Occurrence of pregnancy during treatment.

Patient’s significant noncompliance with this study protocol.  Patients who miss 
appointments shall be contacted by site personnel to determine the reason for the missed 
appointment and to try to reschedule the appointment.  The date(s) the patient was 
contacted and the type of contact used should be recorded in the study documentation.
The patient in Part A experiences a DLT in Cycle 1 or Cycle 2 (see Section 9.4.1).
After termination of study treatment, the patient will be treated as clinically indicated by the 
investigator or referring physician.  All patients should be followed until resolution or 
stabilization of any SAE or study drug-related toxicities resolve, stabilize, return to baseline, or 
are deemed irreversible.
If a patient is discontinued from all study treatment:

The reason(s) for discontinuation should be documented in the patient’s medical record 
and eCRF.

A follow-up evaluation should be performed 30 days (±3 days) after the decision is made 
to discontinue study treatment, as described in the Study Schedule (Attachment 1 or 
Attachment 2).  In addition, patients with unresolved study treatment-related toxicities
will be followed at regularly scheduled intervals (as determined by the investigator) until
these toxicities resolve, stabilize, return to baseline, or are deemed irreversible.

For patients who discontinue for reasons other than PD, radiographic assessments should 
continue as scheduled (every 6 weeks [±7 days] following the first dose of study drug,
and after 72 weeks while on study, imaging will be performed every 12 weeks [±7 days]) 
until objective radiographic evidence of PD.
Follow-up evaluations should be performed as described in Attachment 1 or Attachment 2.  All 
patients will be followed for survival at regularly scheduled intervals (every 3 months ± 14 
days), for as long as the patient remains alive, or until study completion, whichever comes first, 
as defined in Section 8.1.2.3.
7.3.3.Discontinuation from the Study Participation
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 becomes pregnant during the study.  See Section 10.3.1 regarding reporting 
requirements on fetal outcome and breastfeeding.

The patient or the patient’s designee (for example, parents or legal guardian) requests that 
the patient be withdrawn from the study.

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 GCP.

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7.3.4.Patients Who Are Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and 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.  Each failed attempt to contact the patients should be documented in 
the source document.
Site personnel, or an independent third party, will attempt to collect the vital status (that is, alive 
or dead) for all enrolled patients who are lost to follow-up, including enrolled patients who do 
not receive study treatment, within legal and ethical boundaries.  Site personnel, or an 
independent third party, may search public sources for vital status information.  If the patient's 
vital status is determined, the vital status will be documented and the patient will not be 
considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.
7.3.5.Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.6.Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.

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8. Investigational Plan
8.1.
Summary of Study Design
Study I4T-MC-JVCY (JVCY) is a Phase 1b/3 design to treat previously untreated patients with 
EGFR mutation-positive metastatic NSCLC.
The Phase 1b part (Part A) of Study JVCY is single-arm and open-label, where the objective is to 
assess the safety and tolerability of the recommended Phase 3 (Part B) dose of ramucirumab 
administered at 10 mg/kg every 2 weeks in combination with daily oral dose of erlotinib at 
150 mg/day.  In Part A, the target enrollment is 12 patients, where patients will be enrolled into 
1 of 2 cohorts:  Cohort 1 will include 6 patients from Japan and Cohort 2 will include 6 patients 
from North America and/or Europe.  Part A patients may be enrolled concurrently into selected 
cohorts.
Part B will proceed after the completion of the DLT assessment in Part A.
The Phase 3 part (Part B) of Study JVCY is a multicenter, randomized, double-blind study that 
will compare the efficacy and safety of treatment with erlotinib (150 mg daily) plus ramucirumab 
(10 mg/kg every 2 weeks) (Arm A) versus erlotinib (150 mg daily) plus placebo (10 mg/kg 
every 2 weeks) (Arm B) in previously untreated patients with EGFR mutation-positive 
metastatic NSCLC.
The ramucirumab/placebo starting dose for Part B will be 10 mg/kg every 2 weeks unless, during 
Part A, the combination therapy (ramucirumab 10 mg/kg every 2 weeks + erlotinib 150 mg every 
day) is not tolerated.  Following DLT review in Part A, the AC may recommend adopting 
8 mg/kg every 2 weeks as starting dose for ramucirumab in Part B.  After the AC 
recommendations are made, a notification letter will be sent to investigative sites to inform the 
starting dose for ramucirumab for Part B.  Refer to Section 9.2.2 for preparation of first and 
subsequent dosing details.
Approximately 450 patients will be randomized evenly between the 2 treatment arms using the 
following stratification factors:

EGFR mutation (exon 19 deletion vs. exon 21 [L858R] substitution mutation) 

Gender (male vs. female)

Region (East Asia vs. other)

EGFR testing method (Therascreen® [Qiagen] and Cobas® [Roche] vs. other PCR and 
sequencing-based methods)
The chosen stratification factors have been identified as variables with the potential influence on 
the primary objective of PFS.  The patients with EGFR mutations benefit from targeted therapy 
whether it is exon 19 deletion or exon 21 substitution mutation; however, the degree of benefit 
may differ based on the type of mutation (Seto et al. 2014).  Gender is linked with prognosis; 
therefore, this is included as a stratification factor (Ou et al. 2009; Siddiqui et al. 2010).  The 
other stratification factor included in the study is region due to the potential regional 
heterogeneity of standards of care.  EGFR testing methods are considered as one of the key 

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stratification factors given that the existing heterogeneity in testing methods may increase the 
enrollment of patients with false positive EGFR mutations.
Treatment in Parts A and B will continue until disease progression, unacceptable toxicity, or 
another permitted reason for study discontinuation.  The study treatment in this protocol is 
considered ramucirumab in combination with erlotinib, or any component of the combination.
The duration of a cycle in this study is defined as 2 weeks (14 days ±3 days).  The windows 
during the treatment cycles and at other times defined in this protocol allow for the 
accommodation of scheduling conflicts, such as holidays, weekends, bad weather, or other 
unforeseen circumstances, and will not be considered a protocol deviation.
Figure JVCY.2 illustrates the study design.

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Abbreviations: D/C = discontinuation; ECOG PS = Eastern Cancer Oncology Group 
performance status; EGFR = epidermal growth factor receptor; NSCLC = non-small 
cell lung cancer; q2w = every 2 weeks.
Note:  If, in Part A, the combination therapy is not tolerated and the dose for 
ramucirumab is determined to be 8 mg/kg every 2 weeks based on the Assessment 
Committee recommendation, then the ramucirumab/placebo dose level for Part B will 
start at 8 mg/kg every 2 weeks.  Patients in Part A will continue to receive study 
treatment until disease progression, unacceptable toxicity, or other reasons for 
discontinuation; however, efficacy or survival data will not be collected.  
Note: On 16 December 2015, the Assessment Committee reviewed the safety data for 
the Phase 1b portion (Part A) and recommended to initiate the randomized Phase 3 
portion of the study (Part B) with ramucirumab at 10 mg/kg every 2 weeks.
Figure JVCY.2.
Illustration of study design for Clinical Protocol I4T-MC-JVCY.
Terms used to describe the periods during the study are defined below:

Baseline Period:  begins when the ICF (study entry) is signed and ends at the first dose 
of study treatment (or at discontinuation, if no treatment is given).

Study Period:  begins at the first dose of study treatment and ends at study completion.  
The study period does not include the continued access period.

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o
Study Treatment Period:  begins at the first dose of study treatment and ends 
when the patient and the investigator agree that the patient will no longer continue 
any study treatment.  The date of this agreement is to be reported on the eCRF as 
the Date of Discontinuation from all study treatment.

DLT Assessment Period for Part A: begins at the first dose of study 
treatment and ends at the end of the second cycle.
o
Post-discontinuation Follow-Up Period:  begins the day after the patient and the 
investigator agree that the patient will no longer continue any study treatment.

Short-term follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue any study treatment and lasts 
approximately 30 days (±3 days).  The short-term follow-up visit occurs at 
or near the end of the follow-up period (±3 days).

Long-term follow-up (Part B only) begins the day after short-term follow-
up is completed, and imaging continues to be collected every 6 weeks 
(± 7 days); after 72 weeks while on study, imaging will be performed 
every 12 weeks (±7 days) until PD.  For patients who discontinue study 
treatment for reasons other than radiographically documented PD, tumor 
response will continue to be evaluated according to the protocol schedule, 
except when not feasible in the opinion of the investigator due to patient’s 
clinical status.  Once radiographic assessments are no longer performed, 
the patient will be followed every 3 months (±14 days) until death, study 
completion, or withdrawal from study participation.  The long-term 
follow-up consists of follow-up for survival and/or PFS2.  During the 
long-term follow-up period, only SAEs that are related to protocol 
procedures or any component of study treatment will be collected.  In 
addition to the collection of SAEs during long-term follow-up, the 
investigator should report any SAEs they learn of after the long-term 
follow-up (see Section 10.3.1.1), if investigator considers it related to 
study treatment or protocol procedure.

Continued Access Period:  begins after study completion and ends at the end of trial.  
During the continued access period, patients on study treatment who continue to 
experience clinical benefit and no undue risks may continue to receive study treatment 
until one of the criteria for discontinuation is met.  The continued access period includes 
continued access follow-up.  Refer to Section 8.1.3 for more details.
o
Continued access follow-up:  begins the day after the patient and the investigator 
agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 30 days (± 3 days).  The continued access follow-
up visit occurs at or near the end of the continued access follow-up period 
(±3 days).

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8.1.1. Part A (Phase 1b)
The Phase 1b part is single arm to determine the recommended dose for Phase 3 part.  Two 
cohorts of patients will be enrolled to assess the safety and tolerability of ‘ramucirumab 
10 mg/kg q2w + erlotinib 150 mg daily’.  It is estimated that up to 20 patients will be entered into 
Part A to achieve at least 12 evaluable patients (6 patients in Cohort 1 enrolled from Japan and 
6 patients in Cohort 2 enrolled from North America and/or Europe).
8.1.1.1.
Baseline and Study Treatment Period Assessments
Baseline radiographic assessment of disease will be performed within 28 days prior to 
enrollment; first treatment will be administered within 7 days following enrollment.  Imaging 
requirements include CT scan or MRI of chest and abdomen including both adrenal glands, with 
pelvic imaging performed if clinically indicated.  It is recommended that CT imaging of the 
abdomen/pelvis be performed with intravenous (I.V.) contrast.  If this is not feasible/advisable 
secondary to hypersensitivity or other conditions, then contrast-enhanced MRI is preferred.  For 
patients with known serious allergic reaction(s) to CT contrast material, a contrast-enhanced 
MRI of the chest/abdomen/pelvis is encouraged.  A gadolinium-enhanced MRI of the CNS will 
be performed at baseline prior to enrollment for all patients (per Exclusion Criterion [15] 
regarding CNS metastases).  While on study, a gadolinium-enhanced MRI of the CNS should be 
performed if clinically indicated to assess disease progression.  Patients will receive any 
necessary premedication (see Section 9.1.1) prior to the infusion of study therapy at each 
treatment cycle.  A treatment cycle will be defined as 2 weeks (14 days ± 3 days) and includes 
the period of treatment with erlotinib given on Day 1 in combination with ramucirumab.  The 
start of treatment will be considered Cycle 1 Day 1 (C1D1) or the day that the first dose of any 
study treatment is administered.
Following administration of premedication (see Section 9.1.1), the patients in Part A will receive 
the following:

Ramucirumab on Day 1 of every 2-week cycle, administered as an I.V. infusion 
over approximately 60 minutes followed by a 1-hour observation period.  If there 
is no evidence of an IRR after the initial and second infusions of ramucirumab, no 
observation period is required for subsequent treatment cycles (in the event an 
IRR occurs thereafter, then the 1-hour observation should be reinstituted).

Erlotinib tablets orally every day.  On Day 1 of each cycle, patients will receive 
erlotinib after completion of ramucirumab infusion (after the observation period 
post ramucirumab infusion).
Administration of study treatment will occur as described in Section 9.1.
Criteria for starting the next cycle are defined in Section 9.4.2.1.1.
At least 6 patients from each of the 2 cohorts will be treated with ramucirumab and erlotinib.  
The DLT Assessment Period will be through 2 treatment cycles, Cycles 1 and 2 (totaling 
approximately 4 weeks).  Delays of study treatment administration (within 3 days) are permitted 
in the DLT Assessment Period of Part A due to any reasons.

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A DLT-evaluable patient is considered to be one who either completed 2 cycles of treatment or 
discontinued from study treatment or study participation before completing 2 cycles due to a 
DLT.
A DLT-non-evaluable patient is considered one who experienced disease progression, was
noncompliance, or discontinued for reasons other than AEs within the first 2 cycles of treatment.  
Any patient who discontinued from the study before completing safety monitoring for the DLT 
Assessment Period for any other reason than DLT will be considered non-evaluable for DLT 
assessment. Additional patients may be enrolled as replacements for non-evaluable patients.
The DLT definitions and rules are listed in Section 9.4.1.
Efficacy data will not be collected during the conduct of Part A.  Investigators are required to 
follow institutional guidelines for regular follow-up for the disease under treatment to assess the 
disease response to the study treatment.
8.1.1.2.
Postdiscontinuation Follow-up Period Assessment
Patients may continue on study treatment after the DLT Assessment Period until one of the 
following is reached:  disease progression, development of unacceptable toxicity, noncompliance 
or withdrawal of consent by the patient, or investigator decision.  Adverse event (AE) 
information will be collected until at least 30 days after the decision is made to discontinue study 
treatment.  After the 30-day short-term follow-up visit, only new and ongoing SAEs deemed 
related to study treatment will be collected.
8.1.1.3.
Study Completion and End of Trial
The objective of Part A is to assess the safety and tolerability of ramucirumab when administered 
in combination with erlotinib.  Part A completion is considered when the DLT assessment has 
been completed.  Patients may continue to receive study treatment per investigators discretion.  
The end of trial occurs after study completion and after the last patient has discontinued all study 
treatment and completed any applicable continued access follow-up.
8.1.1.4.
Study Duration
The duration of the Phase 1b portion of the study from study entry to the completion of the DLT 
Assessment Period is estimated to be approximately 6 months.
8.1.2.Part B (Phase 3)
Part B will start once the Part A DLT Assessment Period for all evaluable patients has concluded 
and the dose recommendations have been made.  After the AC recommendations are made, a 
notification letter will be sent to investigative sites to inform the starting dose for ramucirumab 
for Part B.
8.1.2.1.
Baseline and Study Treatment Period Assessments
Baseline radiographic assessment of disease will be performed within 28 days prior to 
randomization; first treatment will be administered within 7 days of enrollment (also within 3 
days of randomization).  Imaging requirements include CT scan or MRI of chest and abdomen 
including both adrenal glands, with pelvic imaging performed if clinically indicated.  It is 

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recommended that CT imaging of the abdomen/pelvis be performed with I.V. contrast.  If this is 
not feasible/advisable secondary to hypersensitivity or other conditions, then contrast-enhanced 
MRI is preferred.  For patients with known serious allergic reaction(s) to CT contrast material, a 
contrast-enhanced MRI of the chest/abdomen/pelvis is encouraged.  A contrast-enhanced MRI of 
the CNS will be performed at baseline prior to randomization for all patients in Part B.  Scans 
performed prior to the date of consent may be used provided they are within 28 days of 
randomization.  While on study, a gadolinium-enhanced MRI of the CNS should be performed if 
clinically indicated to assess disease progression.  Patients in both arms will receive any 
necessary premedication (see Section 9.1.1) prior to the infusion of study therapy at each 
treatment cycle.
A treatment cycle will be defined as 2 weeks (14 days ± 3 days) in each arm and include the 
period of treatment with erlotinib given on Day 1 in combination with either ramucirumab or 
ramucirumab placebo.  The start of treatment will be considered C1D1 or the day that the first 
dose of any study treatment is administered.
Following administration of premedication (see Section 9.1.1) patients in Arm A will receive:

Ramucirumab on Day 1 of every 2-week cycle as an I.V. infusion over 
approximately 60 minutes, followed by a 1-hour observation period.  If there is no 
evidence of an IRR after the initial and second infusions of ramucirumab, no 
observation period is required for subsequent treatment cycles (in the event an 
IRR occurs thereafter, then the 1-hour observation should be reinstituted).

Erlotinib tablets orally every day.  On Day 1 of each cycle, patients will receive 
erlotinib after completion of ramucirumab infusion (after the observation period 
post ramucirumab infusion).
Following administration of premedication (see Section 9.1.1) patients in Arm B will receive:

Placebo on Day 1 of every 2-week cycle as an I.V. infusion over approximately 
60 minutes, followed by a 1-hour observation period.  If there is no evidence of an 
IRR after the initial and second infusions of ramucirumab placebo, no observation 
period is required for subsequent treatment cycles (in the event an IRR occurs 
thereafter, then the 1-hour observation should be reinstituted).

Erlotinib tablets orally every day.  On Day 1 of each cycle, patients will receive 
erlotinib after completion of placebo infusion (after the observation period post 
ramucirumab/placebo infusion).
Administration and dosing of all therapeutic products will occur as described in Section 9.1.
Criteria for starting the next cycle are defined in Section 9.4.2.1.1.  Dose reductions for 
ramucirumab/placebo will be made in the event of specific treatment-related AEs, as described in 
Section 9.4.2.1.2.  Supportive care guidelines are detailed in Section 9.6.1.  No dose escalations 
or re-escalations for ramucirumab/placebo are permitted.
Patients will undergo radiographic assessment of disease status (CT or MRI) according to 
RECIST v. 1.1, every 6 weeks (± 7 days), as calculated from the first dose of study therapy

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regardless of treatment delay or omissions, and after 72 weeks while on study, imaging will be 
performed every 12 weeks (±7 days) until there is radiographic documentation of PD.  If a 
patient discontinues treatment due to objective disease progression, one additional tumor scan 
will be collected at the 30-day short-term follow-up visit unless the patient has received 
additional anticancer therapy prior to this visit. Thereafter, radiologic tests are no longer 
required (Attachment 2).
Patients in both arms will be treated until there is radiographic or symptomatic PD (symptomatic 
PD should be objectively confirmed radiographically), toxicity requiring cessation of treatment, 
withdrawal of consent from further study treatment or study participation, or until other 
discontinuation criteria are met.  For patients who discontinue treatment for any reason other 
than radiographically documented PD (for example, symptomatic deterioration), radiographic 
assessments should continue as scheduled every 6 weeks (± 7 days) following the first dose of 
study therapy, and after 72 weeks while on study, imaging will be performed every 12 weeks (±7
days) until objective radiographic evidence of PD.  Follow-up will continue as long as the patient 
is alive, the patient requests not to be followed for survival, or until study completion as defined 
in Section 8.1.2.3.
Following all study treatment discontinuation, follow-up information regarding further 
anticancer treatment and survival status will be collected every 3 months (± 14 days).
8.1.2.2.
Postdiscontinuation Follow-Up Period Assessments
If a patient discontinues treatment due to objective disease progression, one additional tumor 
scan will be collected at the 30-day short-term follow-up visit unless the patient has received 
additional anticancer therapy prior to this visit. Thereafter, radiologic tests are no longer 
required (Attachment 2).
Adverse event (AE) information will be collected until at least 30 days after the decision is made 
to discontinue from all study treatment.  After the 30-day short-term follow-up visit, only new 
and ongoing SAEs deemed related to study treatment will be collected.
8.1.2.3.
Study Completion and End of Trial
The primary objective is investigator-assessed PFS.  When approximately 270 PFS events have 
occurred among the study population, there will be a database lock to report the primary 
objective of the study.
Figure JVCY.3 is a diagram of the study period and continued access period.  This study will be 
considered complete (that is, the scientific evaluation will be complete [study completion]) 
following the final analysis of OS, as determined by Lilly.  Investigators will continue to follow 
the study schedule for all patients until notified by Lilly that study completion has occurred.  
“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient, 
including patients participating in the continued access period, if applicable.
Upon study completion, investigators and patients may be unblinded to study treatment
assignment.

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After study completion, all patients who are on study treatment and who are eligible for 
continued access will be unblinded.  Patients receiving study treatment and experiencing ongoing 
clinical benefit and no undue risks may continue to receive study treatment in the continued 
access period until one of the criteria for discontinuation is met (see Section 7.3).  During the 
continued access period, placebo will no longer be administered, therefore patients in erlotinib 
plus placebo arm may continue on erlotinib as monotherapy, and crossover will not be permitted.  
Lilly will notify investigators when the continued access period begins.  Refer to Section 8.1 for 
continued access design.
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
During the continued access period, all AEs, SAEs, and study treatment exposure will be 
reported on the eCRF.  Serious adverse events will also be reported to Lilly Global Patient Safety 
(see Section 10.3.1).  In the event that an SAE occurs, Lilly may request additional information 
(such as local laboratory results, concomitant medications, and hospitalizations) in order to 
evaluate the reported SAE.  Blood samples for PK and immunogenicity analysis will be collected 
only in the event of an IRR.
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly
will not routinely collect the results of these assessments.
Once patients have entered the continued access period, the sponsor may allow patients to enroll 
in a ramucirumab “rollover” protocol to provide long-term continued access for patients enrolled 
in this study.

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8.1.4. Committees
The following committees will be established to evaluate or patients’ safety or efficacy of the 
study treatment.  There will be charters for these committees to follow.
Assessment Committee (AC)
The Assessment Committee (AC) will be established as a Lilly internal safety review committee 
independent from the study team for Part A (Phase 1b) of the study and will follow an approved 
AC Charter.  The AC will evaluate DLT analysis and communicate back to the study team about 
dosing decisions.
Independent Data Monitoring Committee (IDMC)
The Independent Data Monitoring Committee (IDMC) will be established to conduct interim 
analyses as specified in Section 12.2.16.2 and will follow an approved IDMC charter.  The 
IDMC will communicate back to Lilly Senior Management Designee (SMD) about their 
assessment.
Lilly Internal Review Committee (LIRC)
The Lilly Internal Review Committee (LIRC) will propose actions back to the study team based 
upon the IDMC’s recommendation and LIRC assessment, if necessary.
Blinded Independent Radiological Review Committee (BIRC)
The Blinded Independent Radiographic Review Committee (BIRC) will review the CT scans and 
MRI scans for tumor assessments from all patients.  Details will be described in the statistical 
analysis plan (SAP).
8.2.
Discussion of Design and Control
Part A (Phase 1b) is single-arm and open-label; there is no randomization and no control arm.
Part B is a randomized, double-blind, placebo-controlled, Phase 3 portion of this study.  
Randomization minimizes systematic bias in the selection and assignment of patients to study 
treatment and provides justification for inferential statistical methods to be used on data from this 
study.  Using an appropriate concurrent control arm enables direct statistical estimation of 
benefits and harms due to study treatment and minimizes bias in the assessment and 
interpretation of observed treatment effects.  Patients will be stratified for factors thought to be 
associated with clinical outcomes to further reduce the potential for bias and improve the power 
of the analyses.
Investigational treatment administration in this study is double-blind; that is, patients, 
investigational sites, and the Sponsor study team do not have immediate access to treatment 
assignments for any patients.  This design feature minimizes potential bias due to knowledge of 
patient’s treatment during evaluation of study endpoints, at the patient level or aggregated across 
patients.

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9. Treatment
9.1.
Treatments Administered
The following treatments will be administered in Part A (Phase 1b) of the study:

Ramucirumab (10 mg/kg) will be administered as an I.V. infusion over approximately 
1 hour on Day 1 of each cycle (14 days [±3 days]); erlotinib (150 mg) will be taken orally 
once daily.
The following treatments will be administered in Part B (Phase 3) of the study:

Experimental Arm A:  ramucirumab (10 mg/kg) will be administered as an I.V. infusion 
over approximately 1 hour on Day 1 of each cycle (14 days [±3 days]); erlotinib (150 mg) 
will be taken orally once daily.

Control (Placebo) Arm B:  placebo (10 mg/kg) will be administered as an I.V. infusion 
over approximately 1 hour on Day 1 of each cycle (14 days [±3 days]); erlotinib (150 mg) 
will be taken orally once daily.
The ramucirumab/placebo starting dose for Part B will be 10 mg/kg every 2 weeks unless, during 
Part A, the combination therapy (ramucirumab 10 mg/kg every 2 weeks + erlotinib 150 mg every 
day) is not tolerated.  Following DLT review in Part A, the AC may recommend adopting 
8 mg/kg every 2 weeks as starting dose for ramucirumab in Part B.  After the AC 
recommendations are made, a notification letter will be sent to investigative sites to inform the 
starting dose for ramucirumab for Part B.  Refer to Section 9.2.2 for preparation of first and 
subsequent dosing details.
The first administration of study treatment will be performed no more than 7 days after 
enrollment (and also within 3 days of randomization in Part B).  On Day 1 of each cycle, patients 
must receive ramucirumab or placebo before they take erlotinib.  Erlotinib will be taken after the 
observation period (whenever instituted) and once a day thereafter.  Scheduled clinic visits will 
be approximately every 14 days and will occur on the days that the patients receive 
ramucirumab/placebo.
Patients will receive ramucirumab or placebo every 14 days (±3 days) until disease progression, 
the development of unacceptable toxicity, noncompliance or withdrawal of consent by the 
patient, or investigator decision.
Table JVCY.1 and Table JVCY.2 show the treatment regimens for Part A and Part B, 
respectively, of this study.

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Table JVCY.1.
Part A Treatment Regimen/Dosing Schedule
Study Drug
Dose
Route
Timing
Ramucirumaba
10 mg/kg
I.V.
approximately 1 hour infusion Day 1 of each cycle
1-hour observation periodb
followed by
Erlotinibc
150 mg
PO
Daily
Abbreviations:  I.V. = intravenous; PO = orally.
a
Premedication is required prior to infusion of ramucirumab.  Recommended premedication agents include 
histamine H1 antagonists such as diphenhydramine hydrochloride (or equivalent).  Additional premedication 
may be provided at the investigator’s discretion.  Premedication must be provided in the setting of a prior 
Grade 1-2 infusion-related reaction, as detailed in Section 9.4.2.1.2.1.  All premedication administered must be 
adequately documented in the electronic case report form.
b A 1-hour observation period is required after the administration of the first and second doses of ramucirumab.  If 
there is no evidence of an infusion-related reaction during the initial 2 cycles of ramucirumab, then no 
observation period is required for subsequent treatment cycles.  In the event an infusion-related reaction occurs 
thereafter, then the 1-hour observation period should be reinstituted.
c
Erlotinib will be taken after the observation period (if instituted), subsequent to the completion of the 
ramucirumab infusion on Day 1 and once a day thereafter.  Refer to Section 9.4 for further instructions on taking 
erlotinib.

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Table JVCY.2.
Part B Treatment Regimen/Dosing Schedule
Study Drug
Dose
Route
Timing
Ramucirumaba
10 mg/kg
I.V.
approximately 1 hour infusion Day 1 of each 
cycle
ARM A
1-hour observation 
periodb followed by
Erlotinibc
150 mg
PO
daily
OR
Placeboa
10 mg/kg
I.V.
approximately 1 hour infusion Day 1 of each 
cycle
ARM B
1-hour observation 
periodb followed by
Erlotinibc
150 mg
PO
daily
Abbreviations:  I.V. = intravenous; PO = orally.
a
Premedication is required prior to infusion of ramucirumab or placebo.  Recommended premedication agents 
include histamine H1 antagonists such as diphenhydramine hydrochloride (or equivalent).  Additional 
premedication may be provided at the investigator’s discretion.  Premedication must be provided in the setting of 
a prior Grade 1-2 infusion-related reaction, as detailed in Section 9.4.2.1.2.1.  All premedication administered 
must be adequately documented in the electronic case report form.
b A 1-hour observation period is required after the administration of the first and second doses of 
ramucirumab/placebo.  If there is no evidence of an infusion-related reaction during the initial 2 cycles of 
ramucirumab/placebo, then no observation period is required for subsequent treatment cycles.  In the event an 
infusion-related reaction occurs thereafter, then the 1-hour observation period should be reinstituted.
c
Erlotinib will be taken after the observation period (if instituted), subsequent to the completion of the 
ramucirumab/placebo infusion on Day 1 and once a day thereafter.  Refer to Section 9.4 for further instructions 
on taking erlotinib.
Any measurements used to determine ramucirumab/placebo dose should be taken at each cycle, 
and dose should be recalculated if needed.  Refer to Section 9.2.2 for ramucirumab/erlotinib dose 
preparation details.
Dose reductions of study drugs will be made in the event of specific treatment-related AEs, as 
described in Section 9.4.2.1.2.  Supportive care guidelines are detailed in Section 9.6.1 and 
prohibited and restricted concomitant therapies are detailed in Section 9.6.2.
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 patient/legal representative,

verifying that instructions are followed properly,

maintaining accurate records of study treatment dispensing and collection,

and returning all unused medication to Lilly or its designee at the end of the study.

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9.2.1.2.
Placebo
  
All excipients used for the manufacture of placebo are of pharmacopeial grade.  No animal-
derived components are used in the manufacture of placebo excipients.
9.2.1.3.
Erlotinib
Erlotinib is a commercially available product.  Investigators should consult the manufacturer`s 
instructions for erlotinib for complete prescribing information and follow institutional procedures 
for the administration of erlotinib, including testing for EGFR mutation status.  The specific 
mutation(s) identified and the name of the test method used to document evidence of EGFR
mutation positivity will be documented in the eCRF.
9.2.2.Storage and Preparation
9.2.2.1.
Ramucirumab/Placebo Storage and Preparation
Refer to the IB or CYRAMZA package insert (or Summary of Product Characteristics [SPC]) for 
detailed information for ramucirumab storage and preparation.  Ramucirumab placebo should be 
stored and prepared according to the same guidelines as used for ramucirumab.
Aseptic technique must be used when preparing and handling ramucirumab/placebo for infusion.  
Patients will receive ramucirumab/placebo by I.V. infusion over approximately 1 hour at 
10 mg/kg every 14 days (± 3 days) in the absence of disease progression or other discontinuation 
criteria.  The first dose of ramucirumab/placebo is dependent upon the patient’s baseline body 
weight in kilograms.  Patients should be weighed at the beginning of each cycle.  Subsequent 
doses of ramucirumab/placebo must be recalculated if there is a ≥10% change (increase or 
decrease) in body weight from the last dose calculation; subsequent doses may be recalculated if 
there is a <10% change (increase or decrease) in body weight from the last dose calculation.  For 
patients undergoing repeated palliative drainage procedures to remove pleural or peritoneal fluid, 
dry weight will be defined as weight obtained after the drainage procedure and before fluid 
reaccumulation.  In such circumstances, dry weight will be used for dose calculation, if obtained 
within 30 days prior to dose.  If no recent dry weight is available, actual weight will be used.
Ramucirumab is compatible with common infusion containers.  The use of a low protein-binding 
0.22-micron in–line filter is required, unless local requirements specify otherwise. Based on the 
calculated volume of ramucirumab, add (or remove from pre-filled [with 0.9% normal saline] I.V 
infusion container) a sufficient quantity of sterile normal saline (0.9% weight/volume) to the 
container to make the total volume 250 mL.  For dose volumes greater than 250 mL, the addition 
of sterile normal saline is not required.  Do not use dextrose-containing solutions.  The container 
should be gently inverted to ensure adequate mixing.  The infusion should be delivered via 
infusion pump in approximately 60 minutes.  The infusion rate should not exceed 25 mg/minute.  
Infusions of duration longer than 60 minutes are permitted in specific circumstances (that is, for 
CCI

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larger patients in order to maintain an infusion rate that does not exceed 25 mg/minute, or in the 
setting of prior ramucirumab IRR); the infusion duration must always be accurately recorded.  
The infusion set must be flushed post infusion with sterile 0.9% normal saline equal to or greater 
than infusion set hold-up volume to ensure delivery of the calculated dose.
CAUTION:  Infusion-related reactions may occur during or following ramucirumab 
administration (see Section 9.4.2.1.2.1 for a definition of Grade 3 and 4 IRRs).  During the 
administration of ramucirumab/placebo, patients should be in an area with resuscitation 
equipment and treatments necessary for advanced life support and cardiopulmonary 
resuscitation, such as bronchodilators, vasopressor agents (for example, epinephrine), oxygen, 
glucocorticoids, antihistamines, I.V. fluids, and so forth.  A 1-hour observation period is required 
after the administration of the first and second doses of ramucirumab/placebo.  If there is no 
evidence of an IRR during the initial 2 cycles of ramucirumab/placebo, then no observation 
period is required for subsequent treatment cycles.  In the event an IRR occurs thereafter, then 
the 1-hour observation period should be reinstituted.
9.2.2.2.
Erlotinib Storage and Preparation
Refer to the most recent version of the erlotinib (TARCEVA®) package insert or SPC for storage 
guidance.
9.3.
Method of Assignment to Treatment
Upon completion of all screening evaluations to confirm a patient’s eligibility, the site will 
register the patient by the Interactive Web Response System (IWRS), which is web-based and 
accessible 24 hours a day.  The IWRS registration consists of assigning the patient a unique 
study identification number for all patients (Parts A and B) and patients in Part B will be 
randomized into 1 of the 2 treatment arms on a 1:1 basis.
The IWRS will assign Part B patients to treatment arms according to a stratified method of 
randomization (that is, independent randomization within each of 16 strata, or cells), defined by 
all 16 combinations of the following 4 prognostic factors:

EGFR mutation (exon 19 deletion vs. exon 21 [L858R] substitution mutation)

Gender (male vs. female)

Region (East Asia vs. other)

EGFR testing method (Therascreen® [Qiagen] and Cobas® [Roche] vs. other PCR and 
sequencing-based methods)
Once the patient is registered through the IWRS, he/she is considered to be enrolled in the study.
9.4.
Selection and Timing of Doses
Patients in Part A will receive ramucirumab with erlotinib.  Patients in Part B will be randomly 
assigned to receive either ramucirumab plus erlotinib or placebo plus erlotinib (see Section 8.1).  
Study drug will be administered as shown in Section 9.1.
Ramucirumab/placebo will be administered over a 1-hour I.V. infusion on Day 1 of each cycle at 
a dose of 10 mg/kg.  The Phase 3 dose will be selected based on the Phase 1b outcome.

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The ramucirumab/placebo starting dose for Part B will be 10 mg/kg every 2 weeks unless, during 
Part A, the combination therapy (ramucirumab 10 mg/kg every 2 weeks + erlotinib 150 mg every 
day) is not tolerated.  Following DLT review in Part A, the AC may recommend adopting 
8 mg/kg every 2 weeks as starting dose for ramucirumab in Part B.  If this AC recommendation 
comes, a notification letter will be sent to the sites of this change prior to starting treatment in the 
Phase 3.  Refer to Section 9.2.2 for preparation of first and subsequent dosing details. Erlotinib 
will be administered orally as a once daily dose of 150 mg.  On the day of the I.V. infusion with 
either ramucirumab or placebo, erlotinib should be taken after the observation period (when 
instituted) or after the infusion.  It is recommended that tablets should be taken on an empty 
stomach with up to 200 mL of water, either 1 hour before or 2 hours after food intake.  Refer to 
Section 9.6.2 for details on prohibited and restricted therapies while on erlotinib that effect 
erlotinib plasma concentrations (such as CYP3A4 inducers and inhibitors, H2-receptor 
antagonists and antacids, and proton pump inhibitors).  Patient compliance with erlotinib self-
administration will be assessed at the beginning of each cycle.
A patient may continue to receive study treatment every 14 days (±3 days) until disease 
progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent 
by the patient from further study treatment, investigator decision, or until he or she meets 1 or 
more of the specified reasons for discontinuation (as described in Section 7.3).
9.4.1.Dose-Limiting Toxicities in Part A
DLT definitions include:

Grade 4 anemia

Grade ≥ 3 thrombocytopenia

Grade ≥ 3 febrile neutropenia

Grade 4 neutropenia lasting > 7 days

Elevated urine protein of ≥3 g/24 hours

Grade 4 or refractory hypertension (refer to Section 9.4.2.1.2.2)

Grade ≥ 3 nonhematologic toxicity excluding electrolyte abnormality or Grade 3 skin 
rash
A patient who either completed Cycle 2 or discontinued from study treatment or study 
participation before completing 2 cycles due to a DLT would be considered DLT-evaluable.  The 
recommended dose of ramucirumab in the Part B population will be decided based on the 
following rules:

If the proportion of patients experiencing DLT is < 33% (0 or 1 patient with any DLTs) 
for DLT-eligible patients from each of the cohorts during the first 2 cycles, the 
ramucirumab starting dose in Part B will be 10 mg/kg every 2 weeks.

If the proportion of patients experiencing DLTs is ≥ 33% (2 or more patients with any
DLTs) for DLT-eligible patients from any of the cohorts during the first 2 cycles, the 
ramucirumab starting dose in Part B will depend on AC recommendation.

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Upon review of safety data, AC may recommend one of the following:

To start enrollment in Part B with the starting dose of 10 mg/kg every 2 weeks

To enroll 3 additional patients at 10 mg/kg every 2 weeks and reassess the dose 
tolerability once these additional 3 patients complete the DLT Assessment Period

To start enrollment in Part B with the starting dose of 8 mg/kg every 2 weeks

To stop the study
The confirmed dose for Part B may be applied to Part A at investigator discretion.
9.4.2.Dose Delays or Dose Modifications
The timing of starting next cycle will be 14 days (± 3 days) from the last administration of 
ramucirumab/placebo.
If patients meet the discontinuation criteria for ramucirumab/placebo and continue on erlotinib 
only, the patients still follow the study schedule with a 14-day (± 3 days) cycle, based on the last 
dose of ramucirumab/placebo.
9.4.2.1.
Ramucirumab or Placebo
9.4.2.1.1.
Dose Delays (Delays for Subsequent Cycles) for 
Ramucirumab/Placebo
To start next ramucirumab/placebo dosing, the following criteria must be fulfilled:

Total bilirubin ≤ ULN

AST and ALT ≤2.5 x ULN, or ≤5 x ULN if the transaminase elevation is due to liver 
metastases

ANC ≥1.5 × 103/µL (≥1.5 × 109/L), platelets ≥100 × 103/µL (≥100 × 109/L)

Ramucirumab/placebo-related AEs that are NCI-CTCAE, v4.0 Grade <2 or equivalent
severity to baseline (except for alopecia; for hypertension, see Section 9.4.2.1.2.2, and for 
proteinuria, see Section 9.4.2.1.2.7).
Patients not meeting the criterion for total bilirubin may be allowed to continue treatment with 
ramucirumab or placebo in specific cases (for example, Gilbert’s syndrome) after the Lilly CRP 
and investigator agree that it is medically appropriate for these patients.  The decisions and 
supporting rationale must be documented in writing.
For patient and study site convenience and safety, treatment decisions will be based upon results 
of tests performed locally.  For dosing decisions, bilirubin, AST, and ALT will be required to be 
collected locally and centrally; ANC and platelets will be collected locally.  The duplicate test 
results obtained locally will not be collected on the eCRF, unless it impacts treatment decision, 
in which case the critical finding should be documented in the appropriate eCRF as part of the 
rationale for dose modification.  Discrepancies between the local and central laboratory that may 
have an impact on treatment decisions will not be considered protocol violations.

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Part A:
During the DLT Assessment Period, if these criteria listed above are not met, the ramucirumab 
dose for Cycle 2 can be delayed for up to 3 days.  Thereafter, a delay of up to 2 weeks is 
permitted to allow for recovery from these criteria.  The erlotinib treatment should be continued 
during the delay of ramucirumab if the patient does not meet the criteria of delay and/or 
discontinuation for erlotinib dosing per package insert (refer to Section 9.4.2.2.1).  If a delay of 
>2 cycles (missing 2 consecutive doses or >42 days have lapsed since last ramucirumab 
infusion) due to unresolved toxicity is necessary, ramucirumab should be discontinued.  The 
erlotinib treatment should be continued, with the patient remaining in the study, if clinically 
indicated.
Part B:
If the criteria listed above are not met, the next ramucirumab/placebo dosing should be delayed 
for up to 2 weeks to allow for recovery.  The erlotinib treatment should be continued during the 
delay of ramucirumab/placebo if the patient does not meet the criteria of delay and/or 
discontinuation for erlotinib dosing per package insert (refer to Section 9.4.2.2.1).  If a delay of 
>2 cycles (missing 2 consecutive doses or >42 days have lapsed since last ramucirumab 
infusion) due to unresolved toxicity is necessary, ramucirumab/placebo should be discontinued.  
The erlotinib treatment should be continued, with the patient remaining in the study, if clinically 
indicated.  Ramucirumab/placebo should be continued until PD, at the discretion of the 
investigator, in the event that erlotinib is discontinued.
9.4.2.1.2.
Dose Modifications for Ramucirumab/Placebo
The starting dose in Part B will be based upon the results of Part A.  Based on the starting dose 
outlined in Part B, one of the following 2 dose modification dosing schemas in Table JVCY.3
would be applicable:
Table JVCY.3.
Ramucirumab/Placebo Dose Reduction Schedule
Starting Dose
Dose Level -1
Dose Level -2 
Dose Level -3
10 mg/kg
8 mg/kg
6 mg/kg
5 mg/kg
8 mg/kg
6 mg/kg
5 mg/kg
Not applicable
Dose modifications (for those evaluable patients outside of the DLT Assessment Period in Part A 
and all patients in Part B) are permitted for ramucirumab/placebo in the setting of 
non-life-threatening and reversible Grade 3 clinical AEs (for example, fever) considered to be at 
least possibly related to ramucirumab/placebo and that resolve to Grade ≤1 or pretreatment 
baseline within 1 treatment cycle (approximately 2 weeks).
If a Grade 4 AE occurs and is deemed at least possibly related to ramucirumab/placebo, then 
ramucirumab/placebo should be discontinued except in the specific case of Grade 4 fever or 
Grade 4 laboratory abnormalities.  If Grade 4 fever or laboratory abnormalities resolve to 
Grade ≤1 or pretreatment baseline within 1 treatment cycle (approximately 2 weeks), treatment 
with ramucirumab/placebo may be continued at the discretion of the investigator.  In these 

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settings, ramucirumab/placebo may be re-administered at starting dose.  If a second instance of 
such an event occurs, ramucirumab/placebo should be subsequently re-administered at a Dose 
Level -1.  A second dose reduction to Dose Level -2 is permitted for this level of event (Grade 3 
or 4 event).  If the starting dose is 10 mg/kg, then a third dose reduction to Dose Level -3 is 
permitted in the event that additional postponement of ramucirumab/placebo is required.  If the 
dose of ramucirumab/placebo is reduced because of potentially related AEs, subsequent dose 
increases are not permitted.
Patients who enter the study with symptoms or laboratory values equivalent to NCI-CTCAE, 
v4.0 Grade 1 or 2 AEs should not have dose reductions related to the persistence or mild 
worsening of those symptoms or laboratory values; dose reductions may be warranted if 
worsening of symptoms or laboratory values is clinically significant in the opinion of the 
investigator.
Note that this section of the protocol pertains only to general dose modifications for 
ramucirumab/placebo.  Specific AEs requiring dose modifications are outlined below, and 
include:

Infusion-Related Reactions

Hypertension

Proteinuria

Thromboembolic Events

Bleeding/hemorrhage Events

GI Perforations

RPLS

CHF

Fistula Formation

Surgery and Impaired Wound Healing

Liver Injury/Failure
Table JVCY.4 shows the dose-modification criteria and guidelines for management of common 
ramucirumab/placebo toxicities.

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Table JVCY.4.
Ramucirumab/Placebo Dose Modification Table
Event and 
Gradea
Specifics
Ramucirumab/Placebo 
Dose Modifications
Guidelines for Management
IRR Events
Grades 1 or 2
Reduce the infusion rate by 
50% for the duration of the 
infusion and all subsequent 
infusions
Grade 1: reduce rate and monitor 
for worsening of condition.
Grade 2: stop infusion; treat with 
dexamethasone (or equivalent) and 
acetaminophen; resume at 50% 
infusion rate once resolved to 
Grade ≤1; and monitor for 
worsening of condition.
Premedicate with dexamethasone 
(or equivalent) and acetaminophen 
prior to each subsequent
ramucirumab/placebo infusion.
Grade 3 or 4
Discontinue
Hypertension
Grade 1-3
Asymptomatic
Maintain dose level
Manage with antihypertensive 
therapy as clinically indicated, per 
institutional guidelines
Symptomatic
Hold until resolution 
Manage with antihypertensive 
therapy as clinically indicated, per 
institutional guidelines
Grade 4 or refractory
Discontinue
Proteinuria
Urine Protein Level: Refer to Attachment 10 for Detailed Proteinuria Algorithm
Grades 2 or 3b
>3 g/24 hours or in the 
setting of nephrotic 
syndrome
Discontinue
2-3 g/24 hours
Hold dose
Reassess at next cycle
Discontinue after second 
consecutive occurrence
<2 g/24 hours
Maintain dose at first 
occurrence
Reduce dose thereafter
Abbreviation:  IRR = infusion-related reaction.
a
National Cancer Institute-Common Terminology Criteria for Adverse Events v4.0 (NCI 2009).
b If urine protein remains elevated at ≥ 2 g/24 hour for 2 consecutive cycles, then discontinue 
ramucirumab/placebo.
9.4.2.1.2.1.
Infusion-Related Reactions
Any treatment-related, infusion-related reactions (IRRs) are defined according to the NCI-
CTCAE v4.0 definition (section “General disorders and administration site conditions”).  
Symptoms occurring during or following infusion of ramucirumab/placebo may also be defined 
according to AE categories such as allergic reaction, anaphylaxis, or cytokine release syndrome 
(NCI-CTCAE, v4.0 section “Immune system disorders”).  In the setting of symptoms occurring 

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during or following infusion of ramucirumab/placebo, investigators are encouraged to use the 
AE term IRR and any additional terms (including those not listed here) that best describe the 
event.  These reactions should be graded as shown in Attachment 10.
As with other monoclonal antibodies, IRRs were reported in clinical trials with ramucirumab, 
with the majority of events occurring during or following a first or second ramucirumab infusion.  
It is thus required that patients are premedicated prior to each administration of 
ramucirumab/placebo. Recommended agents include histamine H1 antagonists such as 
diphenhydramine hydrochloride.  Monitor patients during the infusion for signs of 
hypersensitivity reactions with resuscitation equipment readily available.  Symptoms included 
rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, 
wheezing, hypoxia, and paresthesia.  In severe cases, symptoms included bronchospasm, 
supraventricular tachycardia, and hypotension.
Reduce the infusion rate of ramucirumab/placebo by 50% for the duration of the infusion and all 
subsequent infusions (the infusion duration should not exceed approximately 2 hours) for Grade 
1 IRRs; monitor the patient for worsening of condition.  If a patient experiences a Grade 2 IRR: 
stop the infusion; treat with dexamethasone (or equivalent) and acetaminophen; resume the 
infusion at 50% of the prior rate once the IRR has resolved or decreased to Grade 1 (the infusion 
duration should not exceed approximately 2 hours; all subsequent infusions should be 
administered at 50% infusion rate); and monitor the patient for worsening of condition.  For 
patients who have previously experienced a Grade 1 or 2 infusion reaction, also premedicate 
with dexamethasone (or equivalent) and acetaminophen prior to each ramucirumab/placebo 
infusion.
Immediately and permanently discontinue ramucirumab/placebo for Grade 3 or 4 IRRs.
9.4.2.1.2.2.
Hypertension
An increased incidence of severe hypertension was reported in patients receiving ramucirumab 
as compared to placebo.  In most cases, hypertension was controlled using standard 
antihypertensive treatment.
Pre-existing hypertension should be controlled before starting ramucirumab/placebo treatment.  
Monitoring of blood pressure (BP) is recommended during therapy.
Temporarily suspend ramucirumab/placebo for severe hypertension until controlled with medical 
management.  Permanently discontinue ramucirumab/placebo if medically significant 
hypertension cannot be controlled with antihypertensive therapy.
Patients whose hypertension is poorly controlled for > 4 weeks (>160 mm Hg systolic or 
>100 mm Hg diastolic) despite appropriate oral medication (>2 oral agents at maximum tolerated 
dose) is considered refractory.  The patient will be discontinued from ramucirumab/placebo.  
Treatment with erlotinib may be continued, if appropriate in the opinion of the investigator.
9.4.2.1.2.3.
Thromboembolic Events
9.4.2.1.2.3.1.
Arterial Thromboembolic Events

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Serious, sometimes fatal arterial thromboembolic events (ATEs), including myocardial 
infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, have been reported in 
clinical trials.  Permanently discontinue ramucirumab/placebo in patients who experience a 
severe (Grade 3 or 4) ATE.
9.4.2.1.2.3.2.
Venous Thromboembolic Events
Venous thromboembolic events (VTEs) are associated with cancer; however, the incidence of 
VTEs likely varies depending on the type of cancer, stage, and intensity of imaging.  
Additionally, VTEs have been associated with some antiangiogenic therapy, although the 
incidence varies depending on the type of therapy, use of concomitant chemotherapy agents, and 
specific disease state.  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.
Most VTEs lack early warning signs; therefore, awareness and prompt treatment is important, 
especially in those patients with risk factors and/or previous history of VTEs (Chen and Cleck 
2009; Suter and Ewer 2013).
Ramucirumab/placebo therapy should be discontinued in the event of any Grade 3/4 VTE that is 
considered by the investigator to be life threatening, or symptomatic and not adequately treated 
by anticoagulation therapy.  At the investigator’s discretion, ramucirumab/placebo therapy may 
be continued in the setting of an incidentally diagnosed, asymptomatic deep vein thrombosis or 
pulmonary embolism, or following a symptomatic deep vein thrombosis or pulmonary embolism 
when symptoms have resolved with the institution of anticoagulation therapy.  
Ramucirumab/placebo should also be discontinued in the setting of a deep vein thrombosis or 
pulmonary embolism that occurs or intensifies while the patient is receiving therapeutic 
anticoagulation therapy.
9.4.2.1.2.4.
Bleeding (Hemorrhagic) Events
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding.  Severe GI hemorrhages, including fatal events, have been reported in patients with 
gastric cancer treated with ramucirumab in combination with paclitaxel.
Permanently discontinue ramucirumab/placebo in patients who experience Grade 3 or 4 
bleeding.
9.4.2.1.2.5.
Gastrointestinal Perforation
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of GI 
perforations.  Permanently discontinue ramucirumab/placebo in patients who experience GI 
perforations.
9.4.2.1.2.6.
Fistula
Gastrointestinal and non-GI fistula formation have been associated with other antiangiogenic 
agents, including bevacizumab and sunitinib (Kamba et al. 2007).  Some fistulas can be resolved 

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with surgical procedures; however, fistulas can be fatal.  The impact on the quality of life of 
having a fistula varies according to the location and extent of the fistula (Chen and Cleck 2009).
Patients may be at increased risk for the development of fistula when treated with ramucirumab.  
Ramucirumab/placebo treatment should be discontinued in patients who develop fistula.
9.4.2.1.2.7.
Proteinuria
Proteinuria is an adverse effect for all therapies targeting the VEGF/VEGF Receptor 2 pathway.  
Proteinuria has been associated with ramucirumab in clinical studies.  The majority of events 
were Grade 1-2.
Refer to Attachment 10 for a detailed schema of the dosing algorithm for proteinuria.
Monitoring for the development or worsening of proteinuria during ramucirumab/placebo 
therapy is advised.  Delay ramucirumab/placebo therapy if the urine protein level is 2 to 
3 g/24 hours.  Reinitiate ramucirumab/placebo at a reduced dose of Dose Level -1 once the urine 
protein returns to <2 g/24 hours.  If the protein level 2-3 g/24 hours reoccurs, interrupt 
ramucirumab/placebo and reduce the dose to Dose Level -2 once the urine protein level returns 
to <2 g/24 hours.  A third dose reduction to Dose Level -3 (if applicable) is permitted in the 
event that urine protein level elevates to ≥2 g/24 hours after the second dose reduction, and then 
returns again to <2 g/24 hours after a temporary discontinuation.  In the event that the urine 
protein continues to be elevated at the lowest dose, then the ramucirumab/placebo will be 
permanently discontinued.  Permanently discontinue ramucirumab/placebo for urine protein level 
of ≥2 g/24 hours is sustained for 2 consecutive cycles or for urine protein level >3 g/24 hours or 
in the setting of nephrotic syndrome.
9.4.2.1.2.8.
Congestive Heart Failure in Patients Who Received Ramucirumab Drug 
Product in Combination with Mitoxantrone or Following Prior Anthracycline 
Therapy 
An increased risk of CHF has been associated with some antiangiogenic therapeutic agents, 
particularly in patients with metastatic breast cancer previously treated with anthracyclines or 
with other risk factors for CHF, including prior radiotherapy to the left chest wall.  A small 
number of CHF events (including fatal) were also reported in patients who had received 
ramucirumab after prior treatment with anthracyclines in the Phase 2 and Phase 3 studies.
While the mechanism of action is currently unknown, based on the safety data received to date it 
is likely that treatment with ramucirumab enhances the cardiotoxicity associated with 
mitoxantrone and has the potential to enhance cardiotoxicity of other agents within the 
anthracycline/anthracenedione class of chemotherapy medications.
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 pre-existing coronary artery disease or CHF.  Patients with symptomatic CHF, 
unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia should not be 

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enrolled in clinical trials with ramucirumab.  Ramucirumab/placebo should be discontinued in 
the event of any Grade 3-4 events consistent with CHF.
9.4.2.1.2.9.
Surgery and Impaired Wound Healing
The impact of ramucirumab has not been evaluated in patients with serious or non-healing 
wounds.  In a study conducted in animals, ramucirumab did not impair wound healing.  
However, since ramucirumab is an antiangiogenic therapy and may have the potential to 
adversely affect wound healing, ramucirumab treatment should be withheld for at least 4 weeks 
prior to scheduled surgery.  Note:  Central venous line replacement, such as a Hickman line, 
should not be consider a significant surgery and would not require discontinuation of 
ramucirumab.
If a patient develops wound healing complications during therapy, delay ramucirumab/placebo 
until the wound is fully healed.  Should the wound persist beyond 2 cycles (28 days*), 
permanently discontinue ramucirumab/placebo.
* This 28-day time period is approximate and begins on the day that the next cycle of 
ramucirumab/placebo should have been administered but was withheld specifically for toxicity.
9.4.2.1.2.10.
Liver Failure, Other Significant Liver Injury in Patients with Child-Pugh 
Class B Cirrhosis, or Cirrhosis (Any Degree) and a History of Hepatic 
Encephalopathy or Clinically Meaningful Ascites
Liver failure or other significant liver injury events, such as hepatic encephalopathy, have been 
observed in patients receiving ramucirumab.  Patients with the following conditions should not 
be enrolled in clinical trials with ramucirumab:  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.  “Clinically meaningful ascites” is defined as ascites 
resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
Ramucirumab/placebo should be discontinued in the event of any new occurrence of hepatic 
encephalopathy and/or hepatorenal syndrome resulting from liver cirrhosis.
9.4.2.1.2.11.
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical and radiologic 
syndrome typically consisting of reversible cortical neurological dysfunction and brain-imaging 
findings of subcortical edema involving the posterior circulation, particularly the occipital lobes 
(Hinchey et al. 1996).  The symptoms of RPLS most often include generalized seizures, 
headache, delirium, and cortical blindness, although these may vary significantly and 
occasionally include focal neurological deficits (Hinchey et al. 1996; Garg 2001; Lee et al. 
2008).  Magnetic resonance imaging (MRI) represents the most reliable method for the diagnosis 
(Lee et al. 2008).  Clinical symptoms and MRI abnormalities usually recover within days to 
weeks with proper management, although permanent neurologic dysfunction has been reported 
(Hinchey et al. 1996; Tajima et al. 1999; Garg 2001; Lee et al. 2008).

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Based on the Ramucirumab IB (Version 11.0), across the clinical program, 2 blinded cases of 
RPLS have been reported.  Both cases occurred in the ongoing double-blind, randomized, 
placebo-controlled Phase 3 Study I4T-MC-JVBB (IMCL CP12-0920) evaluating FOLFIRI in 
combination with ramucirumab versus FOLFIRI in combination with placebo for patients with 
metastatic colorectal cancer.
Reversible posterior leukoencephalopathy syndrome should be identified and treated promptly in 
order to minimize potential for permanent neurological damage.  Treatment encompasses careful 
control of BP, withdrawal of potentially causative medication, and administration of 
anticonvulsant agents to those experiencing seizures (Stott et al. 2005).
If the diagnosis of RPLS is confirmed, ramucirumab/placebo should be permanently 
discontinued.
9.4.2.2.
Erlotinib
Refer to the most recent version of the erlotinib (TARCEVA®) package insert or SPC.
9.4.2.2.1.
Dose Delays and Dose Modifications for Erlotinib
Patients receiving ramucirumab or placebo plus erlotinib can have the erlotinib dose reduced if 
the toxicity is specifically attributable to erlotinib at the discretion of the investigator per the 
package insert or SPC.  Patients may continue treatment with ramucirumab/placebo if they are 
discontinued from erlotinib.
Patients should be treated following the recommendations, warnings and precautions given for 
erlotinib in the package insert or SPC of erlotinib.  
The daily dose of erlotinib will be decreased in 50-mg decrements to a minimum dose of 50 mg 
daily (Table JVCY.5).  Re-escalation of erlotinib dosing is allowed at the investigator’s 
discretion.  Dose reductions must be documented within the current cycle so that treatment 
compliance can be determined.
Table JVCY.5.
Erlotinib Dose Reduction Schedule
Starting Dose
First Reduction
Second Reduction 
150 mg/day
100 mg/day
50 mg/day
Table JVCY.6 shows the dose modification criteria and guidelines for management of common 
erlotinib toxicities.

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Table JVCY.6.
Erlotinib Dose Modification Table
Event and Gradea
Erlotinib Dose Modifications
Guidelines for Management
Pulmonary Events
All grades (acute onset of new or 
progressive pulmonary symptoms such as 
dyspnea, cough, or fever)
Interrupt, pending the diagnostic 
evaluation; if ILD is diagnosed, 
discontinue study treatment and 
institute appropriate treatment.  If 
ILD is ruled out, resume erlotinib at
same dose.
Diarrhea
Grade 1
None
Consider loperamide: 4 mg at first onset, 
followed by 2 mg every 2 to 4 hours 
until diarrhea-free for 12 hours
Grade 2
Reduce if diarrhea persists over 48 to 
72 hours despite optimal medical 
management
Manage as for Grade 1
Grade 3 or any grade unresponsive to 
loperamide, or diarrhea that causes 
dehydration
Interrupt until resolution to Grade ≤1 
and restart at next reduced dose; do 
not re-escalate
Manage as for Grade 1
Grade 4
Discontinue erlotinib treatment 
Manage as for Grade 1
Rash
Tolerable rash (Grade 2 or 3)
None 
Any of the following: minocycline, 
topical tetracycline, topical clindamycin, 
topical silver sulfadiazine, 
diphenhydramine, oral prednisone (short 
course)
Intolerable rash
Consider interruption or dose 
reduction if unresponsive to 
symptomatic management.
Manage as for Grade 1
Grade 4
Discontinue erlotinib treatment
Manage as for Grade 1
Severe Hepatitis, Liver Failure, Liver 
Dysfunction
Hold erlotinib administration.  If 
event does not improve significantly 
or resolve within 3 weeks, then 
discontinue erlotinib.
Supportive care as appropriate
Abnormal Liver Function Test (hepatitis 
without liver failure)
Grade 1 (>ULN - 3.0xULN)
Erlotinib administration can continue 
at same dose.
Supportive care as appropriate
Grade 2 (>3.0xULN - 5.0xULN)
Hold erlotinib up to 3 weeks.  If 
event resolves to Grade < 1 during 
this period, then resume erlotinib at 
the same dose.
Supportive care as appropriate
Grade 3 (>5.0xULN - 20.0xULN)
Hold erlotinib up to 3 weeks.  If 
event resolves to Grade < 1, then 
resume erlotinib at a dose reduced by 
50 mg.
Supportive care as appropriate
Grade 4 (>20.0xULN)
Discontinue erlotinib.
Supportive care as appropriate
Abbreviations:  ILD = interstitial lung disease; ULN = upper limit of normal.
a
National Cancer Institute-Common Terminology Criteria for Adverse Events v4.0 (NCI 2009).

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In addition to the common erlotinib toxicities in Table JVCY.6, if a patient experiences other 
Grade 3 or 4 events that are considered at least possibly related to erlotinib, erlotinib 
administration may be omitted for up to 2 weeks.  If patient could not restart erlotinib at that
point, a discussion between the investigator and Lilly CRP must occur to assess if erlotinib dose 
delay can be extended for another week.

If the event resolves to ≤ Grade 1 or baseline, the patient may restart erlotinib treatment 
at a reduced dose (see Table JVCY.5).

If the event has not resolved to ≤ Grade 1 or baseline within 2 weeks, or another AE 
occurs during therapy at the reduced dose, a second dose reduction is permitted at the 
investigator’s discretion.

If the patient does not tolerate at least the 50-mg daily erlotinib dose, erlotinib must be 
discontinued.
9.5.
Blinding
Part B is a double-blind study.
To preserve the blinding of the study, a minimum number of Sponsor or designee personnel will 
see the randomization table and treatment assignments before the study is complete.  Individuals 
(IWRS, clinical trials materials management, and data management personnel) validating the 
database do not have access to aggregate summary reports or statistics.
Upon overall study completion (see Section 8.1.2.3), investigators may unblind patients to study 
treatment assignment.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from study treatment.  In cases where there are ethical reasons to have the 
patient remain on study treatment, the investigator must obtain specific approval from a Sponsor 
physician or designee for the patient to continue on study treatment.
Patient-level unblinded data will not be shared with sites until the study is completed.  Treatment 
assignment will be scrambled in the reporting database until the database lock for data analysis.  
This will ensure that unblinded aggregate efficacy and safety results are not available until the 
time of final data analysis.
For this study, the following roles will be permitted to access unblinded data for interim analyses 
of safety and/or futility: IDMC members, select group of programmers/statistician performing 
interim analyses, and GPS.  Access to unblinded data/documents will be controlled by restricting 
access to the data/documents in Lilly/TPO’s data and statistical warehouse.  Any changes to this 
unblinding plan may be described in a protocol amendment, the SAP, and/or a separate 
unblinding plan document.  Interim analyses for safety and futility will be conducted, using 
unblinded data, under the guidance of an Independent Data Monitoring Committee.  See 
Section 12.2.16 for further details.

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9.5.1.Emergency Unblinding
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP prior to unblinding 
a patient’s treatment assignment unless this could delay emergency treatment of the patient.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.
Emergency unblinding for AEs must be performed through the IWRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  The 
occurrence of an SAE should not routinely precipitate the immediate unblinding of a study 
therapy or study treatment label.  Study treatment is not to be unblinded for progressive disease. 
All unblinding events are recorded and reported by the IWRS.
9.5.2.Inadvertent Unblinding
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur.  A double-blind study design is 
known to be imperfect in the oncolytic setting because the potential for individual unblinding 
exists due to treatment-related signs and symptoms.  If an investigator, site personnel performing 
assessments, or patient is unblinded, the unblinding will not be sufficient cause (in and of itself) 
for that patient to be discontinued from study treatment or excluded from any safety or efficacy 
analyses.
Additionally, there may be ethical reasons to have the patient remain on the study treatment.  For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications and its indication must be captured at each visit in the eCRF.  Concomitant 
medications and supportive care therapies must also be documented at the time of 
discontinuation and at the 30-day short-term follow-up visit.
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment.
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to all patients on this trial.  Supportive care measures may include but 
are not limited to antidiarrheal agents, antiemetic agents, opiate and nonopiate analgesic agents, 
appetite stimulants, and granulocyte and erythroid growth factors, bisphosphonate usage.  Details 
of interventions (for example, medications such as sedatives, antibiotics, analgesics, 
antihistamines, steroids, or erythroid-stimulating agents), procedures (for example, paracentesis 

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or thoracentesis), or blood products (for example, blood cells, platelets, or fresh frozen plasma 
transfusions) should be recorded in the eCRFs.  Appropriate management of hypersensitivity 
reactions is described in Section 9.4.2.1.2.1.  Guidelines regarding the use of other specific 
supportive care agents are presented below.
Prohibited and restricted concomitant therapies are listed in Section 9.6.2 may include CYP3A4 
inducers or strong/moderate inhibitors, H2-receptor antagonists and antacids, and proton pump 
inhibitors.  Section 9.6.3 lists other study conditions during the study treatment period.
Additional concurrent chemotherapy, radiation therapy, biologic response modifiers, or other 
investigational agents may not be administered to patients on this study.
9.6.1.Supportive Care
9.6.1.1.
Antidiarrheal Agents
In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, loperamide, 
octreotide, and other antidiarrheals.  If diarrhea is severe (that is, requires I.V. hydration) and 
associated with fever or severe (Grade 3 or 4) neutropenia with nausea and vomiting, the patient 
should be considered for hospitalization for appropriate treatment.  Refer to the TARCEVA 
package insert and Section 9.4.2.2.1 for erlotinib dose delays and modifications for guidance.
9.6.1.2.
Antiemetic Agents
The use of antiemetic agents is permitted during this study and at the discretion of the 
investigator.  However, it is recommended to follow the guidelines of the Multinational 
Association of Supportive Care in Cancer and American Society of Clinical Oncology (ASCO); 
dexamethasone may be sufficient, but 5-HT3 antagonists and NK1 antagonists may be used (Kris 
et al. 2006; Gralla et al. 2010).
9.6.1.3.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.  Aspirin use at doses 
up to 325 mg/day is permitted.
The chronic use of NSAIDs is discouraged except at the discretion and responsibility of the 
investigator after careful assessment of the individual bleeding risk of the patient.
9.6.1.4.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.  Acceptable 
agents include, but are not limited to, megestrol acetate and dronabinol.
9.6.1.5.
Granulocyte-Colony Stimulating Factors (G-CSF)
The use of G-CSF is permitted during this clinical trial at the discretion of the investigator.  
G-CSF or similar agents are strongly recommended following Grade 3 or 4 neutropenia of 
duration >5 days or following any incidence of febrile neutropenia (ANC <1.0 × 103/µL 
[1.0 × 109/L] with a single temperature ≥38.3°C or a sustained temperature of ≥38.0°C for 
>1 hour).

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9.6.1.6.
Erythroid Growth Factors
The use of erythroid-stimulating factors (for example, erythropoietin) is permitted at the 
discretion of the investigator based on ASCO and FDA guidelines (Rizzo et al. 2008; FDA 
2009).
9.6.1.7.
Bisphosphonate Usage
Bisphosphonates are permitted for use by patients on this study.  However, there is a known 
increased risk for osteonecrosis of the jaw with long-term use of these treatments, especially in 
the setting of invasive dental procedures.  Thus, for any patients who are on bisphosphonate 
therapy whether on study or not, it is important that patients observe good oral hygiene, undergo 
regular dental examination, and avoid invasive dental procedures while on bisphosphonate 
therapy when possible.
9.6.2.Prohibited and Restricted Concomitant Therapy
Patients are not permitted to use any anticancer therapy (other than the study treatments) during 
the study period, from enrollment until completion of treatment period.
9.6.2.1.
CYP3A4 Inducers or Strong Inhibitors
There are potential interactions between erlotinib and CYP3A4 inhibitors and CYP3A4 
promoters.  Drugs that induce CYP3A4, such as rifampicin or phenytoin, may reduce the effects 
of erlotinib through increased erlotinib metabolism and decreased plasma concentrations.  
Conversely, CYP3A4 inhibitors, such as itraconazole and ketoconazole, may increase the effects 
of erlotinib through decreased erlotinib metabolism and increased plasma concentrations.  
Therefore, use of alternative treatments without CYP3A4 inducing or strong inhibiting activity is 
required whenever possible (Attachment 9). If an alternative treatment is unavailable, the dose 
of erlotinib should be adjusted according to the package insert or SPC when CYP3A4 inducers 
or strong inhibitors must be used.
9.6.2.2.
Anticoagulants
Further INR elevations and/or bleeding events have been reported in patients taking warfarin 
whilst on erlotinib therapy.  If a patient requires anticoagulation therapy after randomization, the 
use of low molecular weight heparin is required.
9.6.2.3.
H2-Receptor Antagonists and Antacids
Drugs affecting gastric pH decrease erlotinib plasma concentrations.
As per the TARCEVA® package insert, if the use of an H2-receptor antagonist (such as 
Tagamet® [cimetidine] or Zantac® [ranitidine]) is required, erlotinib should be taken 10 hours 
after and 2 hours before the dosing of the H2-receptor antagonist.
Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, if an 
antacid (such as Tums® [calcium carbonate]) is necessary, dosing with an antacid should be 
separated by at least 4 hours prior to or after dosing with erlotinib.

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9.6.2.4.
Proton Pump Inhibitors
Drugs affecting gastric pH decrease erlotinib plasma concentrations.
Concomitant use of erlotinib with proton pump inhibitors is prohibited.
9.6.3.Other Study Conditions:  Surgery and Palliative Radiotherapy (or 
Equally Considered Procedure) During Study Treatment Phase
If any surgery should be required during the study (palliative surgery or medically indicated by
the investigator), the patient should undergo radiologic evaluation before surgery for 
documentation of disease status.  Elective, nonemergent surgery is strongly discouraged during 
study participation.  The time of study treatment interruption before surgery should be at least 
28 days following the last dose of ramucirumab/placebo.  Patients may resume all study 
treatment no less than 28 days following surgery, provided there has been adequate recovery in 
the opinion of the investigator.  Following surgery, radiological evaluation of disease is required 
prior to resumption of ramucirumab/placebo.
Patients undergoing surgery before PD should be followed up by imaging every 6 weeks 
(±7 days), and after 72 weeks while on study, imaging will be performed every 12 weeks (±7
days) until radiographically documented PD.
Palliative radiation therapy is permitted, after discussion with and agreement of the Lilly 
CRP/CRS or designee, for irradiating small areas of painful metastases that cannot be managed 
adequately using systemic or local analgesics; such areas must not constitute PD or meet 
RECIST criteria for PD.  Any symptomatic deterioration or clinical disease progression 
requiring, in the opinion of the investigator, other forms of specific antitumor therapy will be 
cause for discontinuation of study therapy.
9.7.
Treatment Compliance
Ramucirumab/placebo will be administered intravenously only at the investigational sites by the 
authorized study personnel.  As a result, treatment compliance is ensured.
Patient compliance with erlotinib will be assessed at Day 1 of each cycle by direct questioning, 
review of diary, and counting returned tablets.  Deviations from the prescribed dosage regimen 
should be recorded in the “Study treatment: modifications” form.  For patients who are 
significantly noncompliant (<70% or >130% of expected study drug taken in a visit interval, or 
missed 7 consecutive dose in a visit interval), investigative sites must counsel patients on the 
importance of study drug compliance and drug accountability.  A patient will be considered 
significantly noncompliant if he or she is judged by the investigator to have intentionally or 
repeatedly taken more/less than the prescribed amount of medication.  Patients who are 
consistently out of the compliance range may be discontinued.  A Lilly representative should be 
contacted upon the second instance of treatment noncompliance.

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10.Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.  
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
study schedule (Attachment 1 and Attachment 2).
10.1. Efficacy Measures
The patient has at least one or more measurable lesion attributed to NSCLC at the time of study 
entry.  Disease assessment will be undertaken at baseline (scans performed prior to the date of 
consent may be used provided they are within 28 days of enrollment) and then every 6 weeks 
(±7 business days) as calculated from the first dose of study therapy, and after 72 weeks while on 
study, imaging will be performed every 12 weeks (±7 days).  The imaging method used at 
baseline must be used consistently for tumor assessment.
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment
Computed tomography (CT), including spiral CT, scans and MRI are the preferred methods of 
measurement.  Imaging requirements include CT scan or MRI of chest and abdomen including 
both adrenal glands, with pelvic imaging performed if clinically indicated.  A gadolinium-
enhanced MRI of the CNS will be performed at baseline prior to randomization for all patients.
Efficacy data will not be collected during the conduct of Part A; however, the same baseline 
tumor assessments, including gadolinium-enhanced MRI of the CNS, required for Part B will 
also apply for Part A, and will be performed prior to study enrollment.  Investigators are required 
to follow institutional guidelines for regular follow-up for the disease under treatment to assess 
the disease response to the study treatment.
For Part B, the method of tumor assessment used at baseline must be used consistently 
throughout the study. Patients must be enrolled with at least one measurable disease based on 
RECIST, version 1.1.  Disease assessment will be undertaken at baseline (within 28 days prior to 
randomization and may be prior to consent) and then every 6 weeks (±7 days) as calculated from 
the first dose of study therapy, and after 72 weeks while on study, imaging will be performed 
every 12 weeks (±7 days).  Patients will be evaluated for response according to RECIST, v 1.1 
guidelines (Eisenhauer et al. 2009).
During the continued access period, efficacy assessments (frequency and type of assessments) 
will be at the discretion of the investigator, based on the standard of care, and these data will not 
be collected or analyzed.
See further details for timing of imaging studies in Attachment 1, Attachment 2, Attachment 5,
and Attachment 7.

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10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1 or Attachment 2).
For those patients who discontinue one or both study treatment(s) without objectively measured 
PD, the investigative sites will continue to monitor patients and periodically evaluate tumor 
response every 6 weeks (±7 days) as calculated from the first dose of study therapy, and after 
72 weeks while on study, imaging will be performed every 12 weeks (±7 days) by the same 
method used at baseline and throughout the study until the patient has objective disease 
progression, or until final analysis of overall survival.  In the Part B phase of this randomized 
trial where progression is the primary endpoint, confirmation of response is not required.  If a 
patient discontinues treatment due to objective disease progression, one additional tumor scan 
will be collected at the 30-day short-term follow-up visit unless the patient has received 
additional anticancer therapy prior to this visit. Thereafter, radiologic tests are no longer 
required. The patient will be followed up approximately every 3 months (14 days) until the 
patient’s death or overall study completion, whichever occurs first.
Patients who are responding to study treatment but discontinued due to criteria other than PD, 
should have scheduled tumor assessment before the initiation of additional anticancer therapy.  
However, initiation of new therapy should not be delayed solely to confirm response.
After final analysis of OS, during the Continued Access Period, efficacy assessments (frequency 
and type of assessments) will be at the discretion of the investigator, based on the standard of 
care.
Lilly will continue to collect survival and PFS2 data through study completion but may reduce 
data collection for other efficacy data.  Lilly will notify investigators when this reduced data 
collection can begin.  Although it is not mandatory, PFS2 based on radiographic assessment is 
recommended.
10.1.3.
Primary Efficacy Measure
The progression-free survival (PFS) time is measured from the date of randomization to the date 
of radiographic documentation of progression (as defined by RECIST v. 1.1) based on 
investigator assessment, or the date of death due to any cause, whichever is earlier.  Patients who 
have neither progressed nor died will be censored at the day of their last radiographic tumor 
assessment.  The detailed censoring rules are described in the SAP.
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  An independent review of imaging scans will be performed by BIRC, 
where an audit of the scans will be conducted to verify the investigator-assessed PFS.
10.1.4.
Secondary Efficacy Measures
The following secondary efficacy measures (Table JVCY.7) will be collected at the times shown 
in the Study Schedule (Attachment 1 or Attachment 2).

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Table JVCY.7.
Secondary Efficacy Endpoints
Endpoint
Definition
Overall Survival (OS)
OS is defined as the time from the date of randomization until the date 
of death from any cause.  If the patient was alive at the end of the 
follow-up period (or was lost to follow-up), OS data will be censored 
for analysis on the last date the patient was known to be alive.
Objective Response Rate (ORR)
ORR is defined as the proportion of randomized patients achieving a 
best overall response of PR or CR.
Disease Control Rate (DCR)
DCR is defined as the proportion of randomized patients achieving a 
best overall response of PR or CR or SD.
Duration of Response (DOR)
DOR is defined from the date of first documented CR or PR 
(responder) 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, then the patient will be 
censored at the last evaluable tumor assessment.
Abbreviations:  CR = complete response; DCR = disease control rate; DOR = duration of response; OS = overall
survival; PR = partial response; SD = stable disease.
10.2. Health Outcome/Quality of Life Measures
10.2.1.
Patient-Reported Outcomes
All patients for whom there is a validated translation in which the patient is fluent will undergo 
assessment for symptoms, quality of life (QoL), and health status using the patient-reported 
LCSS and the EuroQol EQ-5D-5L.  It is recommended that the instruments be administered 
together and in sequential order, with the LCSS presented first, followed by presentation of the 
EQ-5D-5L. Patients will complete the instruments according to the Study Schedule 
(Attachment 1 or Attachment 2).  Patients will complete the instruments at baseline, at Cycle 2, 
thereafter at every other cycle, and at the 30-day short-term follow-up visit.  On days that the 
patient receives ramucirumab/placebo, assessments will be completed prior to treatment 
administration and before any extensive contact and consultation with the clinician/study 
investigator in regards to the disease assessments.
10.2.1.1. Lung Cancer Symptom Scale (LCSS)
Disease-related symptoms and QoL will be assessed with the self-administered LCSS (Hollen et 
al. 1994).  The LCSS is a validated and reliable instrument to assess lung cancer-specific 
symptoms and their impact on QoL.  The LCSS consists of 9 items:  6 questions focused on lung 
cancer symptoms (appetite loss, fatigue, cough, shortness of breath, blood in sputum, and pain) 
plus 3 global items (symptom distress, difficulties with daily activities, and quality of life).  Each 
item is assessed on a 100-mm visual analogue scale (VAS), with 0 representing no symptoms or 
better QoL.  From the 9 items on the LCSS, the Average Symptom Burden Index (ASBI; mean 
of 6 symptom-specific items) and LCSS total score (mean of all 9 items) will be calculated for 
each patient at each assessment.  For a given assessment, if any of the contributing items have 
not been completed, the ASBI and the LCSS total score will not be calculated.  For each patient 
and any particular scale, the minimal important difference (MID) from baseline is defined as 
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Each of the 9 scales and 2 summary scores at each assessment time point will be compared to its 
baseline value and be categorized using the MID as follows:

Deterioration:  defined as an increase of 15 mm or more.

Improvement:  defined as a decrease of 15 mm or more.

Stable:  defined as no change or increase/decrease < 15 mm
The best response across all time points will be obtained for each of the 11 scores by 
categorizing the best score as deterioration, improvement, or stable.  The worst response will be 
similarly obtained by categorizing the worst score.
10.2.1.2. EQ-5D-5L
The EQ-5D-5L (Janssen et al. 2008; van Hout et al. 2012) is a standardized instrument for use 
across diseases as a measure of self-reported health status.  Specifically, this questionnaire is 
included in this trial to evaluate health-state utilities associated with advanced lung cancer.  
These utility measures are an important input for economic evaluations concerning the value of 
treatment interventions.
The EQ-5D-5L consists of 2 parts.  In the first part, patients will complete the 5-dimension 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), 5-level (no 
problem, slight, moderate, severe, or extreme problem) assessment.  The responses to the 
5 dimensions are combined into an index score where 0 represents death and 1 represents perfect 
health.  The second part is a VAS that allows patients to rate their present health condition.  
Possible scores range from 0 (worst imaginable health state) to 100 (best imaginable health 
state).
10.2.2.
Resource Utilization
Investigators will be asked to document the use of BSC measures, concomitant medications, 
transfusions, and treatment-related hospitalization days.  Such assessments are to be taken 
throughout the study through the 30-day short-term postdiscontinuation follow-up visit.
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, or that caused the patient to discontinue 
before completing the study.  The patient should be followed until the event is resolved, 
stabilized, returned to baseline, deemed irreversible, or otherwise explained.  Frequency of 
follow-up evaluation is left to the discretion of the investigator.

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The timing of all safety evaluations is shown in the Study Schedule (Attachment 1 or 
Attachment 2).  Table JVCY.8 presents a summary of AE and SAE reporting guidelines.  
Table JVCY.8 also shows which database or system is used to store AE and SAE data.
Table JVCY.8.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study treatment
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study treatment that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1.
Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.  After the ICF is signed, site personnel will record the occurrence and nature of any 
AEs and any change in the preexisting condition(s).  Patients will be evaluated for AEs at each 
visit and will be instructed to call their physician to report any AEs between visits.  Lack of drug 
effect is not an AE in clinical trials, because the purpose of the clinical trial is to establish drug 
effect.  All AEs related to protocol procedures are reported to Lilly or its designee via eCRF.  In 
addition, all AEs occurring after the patient receives the first dose of study treatment must be 
reported to Lilly or its designee via eCRF.  Investigators will be instructed to report to Lilly or its 
designee their assessment of the potential relatedness of each AE to protocol procedure and/or 
study treatment via eCRF.  Any clinically significant findings from ECGs, labs, vital sign 
measurements, and other procedures that result in a diagnosis should be reported as adverse 
events to Lilly or its designee via eCRF.

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Cases of pregnancy that occur during maternal or paternal exposures to or up to 12 weeks after 
the last dose of study treatment should be reported as an SAE.  Data on fetal outcome and breast-
feeding are collected for regulatory reporting and drug safety evaluation.
The NCI-CTCAE v4.0 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 eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

Death

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Initial or prolonged inpatient hospitalization

Congenital anomaly/birth defect

Considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed informed consent and has 
received study treatment.  If a patient experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will not be reported as serious unless the investigator 
feels the event may have been caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  If study site 
personnel contact Lilly or its designee by telephone regarding an SAE, study site personnel must 
also immediately provide official notification on study-specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
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Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study treatment.
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, if an investigator becomes aware of an SAE 
occurring after the patient’s participation in the trial has ended, and the investigator believes that 
the SAE is related to a protocol procedure or study treatment, the investigator should report the 
SAE to the sponsor, and the SAE will be entered in the Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
10.3.1.2. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information (DCSI) in the IB and that the investigator identifies 
as related to the study treatment or study procedure.  United States 21 CFR 312.32 and European 
Union Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national 
regulatory requirements in participating countries require the reporting of SUSARs.  Lilly has 
procedures that will be followed for the recording and expedited reporting of SUSARs that are 
consistent with global regulations and associated detailed guidances.
10.3.2.
Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP 
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review:

Trends in safety data

Laboratory analytes

Adverse events including monitoring of adverse events of special interest

If during treatment, a patient experiences either:
o
elevated ALT >5× ULN and elevated total bilirubin >2× ULN or 
o
elevated ALT >8× ULN (regardless of bilirubin level), 
then clinical and laboratory monitoring should be initiated by the investigator.  

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
For patients entering the study with ALT >3× ULN, monitoring should be triggered at 
ALT >5× ULN.

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests.  See Attachment 4.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring committee (an advisory group for this 
study formed to protect the integrity of data; refer to Section 12.2.16) can conduct additional 
analyses of the safety data.
For the purpose of this study, in which survival is an important secondary efficacy endpoint, all 
deaths and SAE reports will be reviewed in a blinded manner by Lilly during the clinical trial.  
These reports will be reviewed to assure completeness and accuracy but will not be unblinded to 
Lilly during the clinical trial.  If a death or other clinical AE is deemed serious, unexpected, and 
related to study treatment, only Lilly Global Patient Safety representatives external to the study 
team will be unblinded for regulatory reporting and safety monitoring purposes.  These measures 
will preserve the integrity of the data collected during this trial and minimize any potential for 
bias while providing for appropriate safety monitoring.
Unblinding of groups of cases is required to make a determination that the group of cases 
represents a suspected adverse reaction for the purpose of expedited reporting in some countries 
or situations.  Such unblinding is performed by Lilly Global Patient safety personnel external to 
the study to ensure the blinding integrity of the study.
10.3.3.
Complaint Handling
Lilly collects product complaints on study drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and to facilitate process and product improvements.
Complaints related to unblinded comparator drugs or concomitant drugs are reported directly to 
the manufacturers of those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or its designee will be reported.
The investigator or his/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.

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10.4. Sample Collection and Testing
Attachment 1 lists the schedule for Part A sample collections in this study and Attachment 2 lists 
the schedule for Part B.
Attachment 3 lists the specific tests that will be performed for this study and whether these will 
be performed at a central and/or local laboratory.  For patient and study site convenience and 
safety, treatment decisions will be based upon results of tests performed locally.  For dosing 
decisions, bilirubin, AST, and ALT will be required to be collected locally and centrally.  The 
duplicate test results obtained locally will not be collected, unless it impacts treatment decision, 
in which case the critical finding should be documented in the appropriate eCRF as part of the 
rationale for dose modification.  Discrepancies between the local and central laboratory that may 
have an impact on treatment decisions will not be considered protocol violations.
Attachment 4 lists tests that may be obtained in the event of a treatment-emergent hepatic 
abnormality.
Attachment 8 provides a summary of the sampling time points for PK analyses during the study.
10.4.1.
Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2.
Samples for Translational Research
Required samples for biomarker and pharmacogenetics research to be collected from all patients 
in this study, unless restricted per local regulations, are the following:

plasma samples from whole blood (mandatory for Parts A and B; see Section 10.4.2.1
and Section 10.4.2.3.

whole blood sample for DNA collection (mandatory for Parts A and B; see 
Section 10.4.2.2)

archived tumor tissue (mandatory for Part B only; see Section 10.4.2.3); 
 
 
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Mandatory FFPE tissue provided should be from the Stage IV NSCLC diagnosis and, ideally, not 
from an earlier staging.  However, for patients in Part B, archived NSCLC tissue samples derived 
from other than Stage IV disease may be acceptable, based on approval by Lilly CRP.
10.4.2.1. Blood Sample for Plasma Collection
 
 
For patients who do not submit Stage IV disease tissue samples, a plasma sample for disease 
characterization is required for patients entering the study at baseline and, if not provided at 
baseline for patients ongoing at the time of amendment d, may be requested during the treatment 
period.
10.4.2.2. Whole Blood Sample for DNA Collection
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations allow, a blood sample will be collected for pharmacogenetic analysis.  Sampling for 
such analysis will be a one-time collection, as noted in the Study Schedule (Attachment 1 or 
Attachment 2).  Variable response to ramucirumab and erlotinib may be due to genetic 
determinants that impact drug absorption, distribution, metabolism and excretion, the mechanism 
of action of the drug, the availability of receptors, the disease etiology and/or the disease subtype 
itself.
 
In the event of an unexpected AE or the observation of an unusual response, the samples may be 
genotyped and analysis may be performed to evaluate genetic association with response to 
ramucirumab and/or erlotinib.  These investigations may include focused candidate gene studies 
or, if appropriate, genome-wide association studies may be performed to identify regions of the 
genome associated with the variability observed in drug response.  Samples will only be used for 
investigations related to disease, cancer-related conditions, and drug under study in the context 
of this clinical program.
They will not be used for broad exploratory unspecified disease or population genetic analysis.  
Pharmacogenetic data will not be provided back to the investigator or the patient except where 
required by local law.
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10.4.2.3. Mandatory Tumor Tissue Samples
Once the patient consents, collection of archived tumor tissue is mandatory for entry on Part B of 
this study.  Submission of archived tumor tissue is highly encouraged for Part A but is not 
mandatory.  If the mandatory archived tumor tissue is not collected during the baseline period, at 
any time during the study, tumor tissue should be provided from patients who consent to provide 
tissue.  Fresh tissue is not required.  Previously archived Stage IV NSCLC tissue from the initial 
diagnosis may be used; for patients in Part B, archived NSCLC tissue samples derived from 
other than Stage IV disease may be acceptable, based on approval by Lilly CRP.  Due diligence
should be used to make sure that tumor specimen (not a normal adjacent or a tumor margin 
sample) is provided.  Pathology notes accompanying archival tissue may also be requested (de-
identified and translated).  
 
 
 
 
 
.  The paraffin-embedded whole blocks will be sectioned 
and sent back to the site.  Partial blocks and slides will not be returned.
10.4.2.4. Collection Procedures for Translational Research
Plasma samples for biomarker research, whole blood samples for DNA, and tumor tissue 
samples will be collected at the times specified in the Study Schedule (Attachment 1 or 
Attachment 2).  Translational research samples will be stored at a facility chosen by the Sponsor 
or designee.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study treatment.
Patients will not receive results of these investigations except where required by local law.  
Samples will be destroyed according to a process consistent with local regulation.  Stored 
samples will retain the patient identifier (for example, the trial patient number) and will not be 
stored indefinitely.
Supplies required for the collection and shipment of the patients’ stored samples will be supplied 
by the central laboratory vendor.  Sample handling and shipment to the central laboratory will 
occur per instructions provided to the study site.
10.4.3.
Samples for Immunogenicity Research
Blood samples will be collected on all patients to determine antibody production against 
ramucirumab at baseline (BEFORE the first infusion of ramucirumab/placebo on C1D1).  For 
patients in Part B, additional blood samples for immunogenicity testing will be collected 
BEFORE the infusion of ramucirumab/placebo on C4D1, and at the 30-day short-term follow-up 
visit (as noted in Attachment 8).
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In the event of an IRR, blood samples will be collected for both immunogenicity and PK analysis 
as close to the onset of the reaction as possible, at the resolution of the event, and 30 days 
following the event.  To interpret the results of immunogenicity, a sample to measure the 
concentration of ramucirumab in the blood is also collected at the same time point (as noted in 
Section 10.4.4).
Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies in 
the presence of the ramucirumab.  Antibodies may be further characterized and/or evaluated for 
their ability to neutralize the activity of ramucirumab.
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.
10.4.4.
Samples for Ramucirumab Drug Concentration 
Measurements Pharmacokinetics
Whole blood samples will be collected for all patients in Part B and processed as serum, as 
specified in the Part B Schedule for Ramucirumab/Placebo Pharmacokinetic, Immunogenicity, 
and Translational Research Sampling Schedule (Attachment 8).
In either Part A or Part B, in the event of an IRR, with the immunogenicity sample, blood 
samples will be collected to determine serum ramucirumab concentrations, as described in 
Section 10.4.3.
Serum concentrations of ramucirumab will be assayed using validated methods.  These samples 
will be analyzed at laboratories designated by the sponsor.
The PK samples will be stored at a facility designated by the Sponsor.  The remaining sample 
materials collected for PK may be pooled and used for exploratory metabolism and other 
exploratory PK/pharmacodynamic work as deemed appropriate.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalytical samples collected to measure ramucirumab concentration will be retained for a 
maximum of 1 year following last patient visit for the study.
10.5. Appropriateness of Measurements
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials.

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

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12.Sample Size and Statistical Methods
12.1. Determination of Sample Size
Part A: 
At least 12 previously untreated patients with EGFR mutation-positive metastatic NSCLC will 
be enrolled and treated with ramucirumab plus erlotinib.
Part B:
The primary objective of this study is to compare ramucirumab plus erlotinib versus placebo plus 
erlotinib in terms of PFS in previously untreated patients with EGFR mutation-positive 
metastatic NSCLC.  The study will enroll approximately 450 patients in 1:1 randomization.  The 
primary analysis will be performed after approximately 270 PFS events have occurred (40% 
censoring rate).
An interim futility analysis was conducted at 114 investigator-assessed PFS events (data cutoff 
date 16 October 2017) and the IDMC recommended the trial continue without modification. A 
nominal alpha <0.00001 was spent in order to maintain type-I error.  Assuming an HR of 0.71, 
this sample size yields at least 80% statistical power to detect superiority of the ramucirumab 
plus erlotinib arm over the placebo plus erlotinib arm, with the use of a 1-sided log-rank test and 
a type I error of 0.02499.  If the true median PFS for the placebo plus erlotinib arm is 11 months, 
then the HR of 0.71 amounts to an approximate 4.5-month improvement in median PFS for the 
ramucirumab plus erlotinib arm under an additional assumption of exponential survival 
distribution.
12.2. Statistical and Analytical Plans
12.2.1.
General Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all CIs will 
be given at a 2-sided 95% level, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Before unblinding of the aggregate 
database, minor modifications or clarifications to the data analysis methods may be described 
and justified in the statistical analysis plan (SAP).
The assumptions for each statistical method may be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.

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12.2.1.1. Analysis Populations
The following populations will be defined for this study:
Intention-to-Treat Population:  This population is defined as all patients who will be 
randomized (enrolled) to study treatment during Part B.  Patients will be grouped according to 
randomized treatment.  This population will be used for all baseline, efficacy, and PRO analyses.

Part A Safety Population:  all patients enrolled in Part A and received at least 1 dose of 
any study treatment

Part A DLT-evaluable Population:  patients that either completed 2 cycles of treatment 
or discontinued from study treatment or study participation before completing 2 cycles 
due to a DLT would be considered DLT-evaluable.  See Section 9.4.1 for detailed DLT 
definition.

Part B Safety Population:  all enrolled (randomized) patients that received at least 
1 dose of any study treatment in Part B.  Patients will be grouped according to treatment 
received in Cycle 1.  The Part B safety population will be used for all dosing/exposure, 
AEs, and resource utilization analyses.
All the analyses for Part A and B will be conducted separately, unless otherwise stated.  
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset ITT 
population in Part B from whom a valid assay result (according to laboratory guideline) has been 
obtained.
12.2.2.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  A summary of all important protocol deviations will be provided.
12.2.3.
Patient Characteristics
Patient characteristics will include a summary by treatment arm of the following:

Patient demographics

Baseline disease characteristics

Preexisting conditions

Baseline prognostic factors for NSCLC
Other patient characteristics will be summarized as deemed appropriate.
12.2.4.
Concomitant Therapy
Concomitant medications will be summarized by treatment arm for the safety population.

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12.2.5.
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, for the Part B ITT population.
12.2.6.
Treatment Compliance
The number of dose omissions, reductions, and delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients per treatment arm.
Treatment compliance information for erlotinib will be collected on the eCRF by direct 
questioning, review of diary, and/or counting returned tablets at each visit and the number of 
tablets taken relative to the number expected to be taken will be summarized.
12.2.7.
Primary Outcome and Methodology
12.2.7.1. Part A
Primary objective of Part A is to assess the safety and tolerability of ramucirumab when 
administered in combination with erlotinib.
Safety and tolerability will be assessed based on the DLT-evaluable population.  The number of 
patients who experienced any DLT will be presented based on DLT-evaluable population.  All 
other safety analyses will be performed using the Part A Safety population.
12.2.7.2. Part B
The primary endpoint of Part B of this study is investigator-assessed PFS.  Patients who have 
neither progressed nor died will be censored at the day of their last radiographic tumor 
assessment.  The detailed censoring rules are described in 9.

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Table JVCY.9.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Rule
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no 
death 
Date of Randomization
Censored
3
No documented progression and no 
death (with a post-baseline tumor 
assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew 
consent from study participation) 
before documented progression or 
death 
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented 
progression 
Date of death 
Progressed
7
Documented progression or death 
after missing ≥2 consecutive 
post-baseline tumor assessments
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later
Censored
8
New anticancer treatment started and 
no tumor progression or death within 
14 days
Date of adequate tumor assessment 
prior to start of new anticancer 
treatment +14 days or date of 
randomization, whichever is later
Censored
Note:  Progression-free survival and associated outcome is determined by the earliest of the dates above, if more 
than 1 situation applies.
The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the PFS curves as 
well as PFS rates at every 3 months for each treatment group.  These rates will be compared 
based on a normal approximation for the difference between the rates.  The comparison of the 
PFS curves between treatment groups will be conducted by a stratified log-rank test with 
following stratification variables as the primary analysis:

EGFR mutation (exon 19 deletion vs. exon 21 [L858R] substitution mutation) 

Gender (male vs. female)

Region (East Asia vs. other)

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
EGFR testing method (Therascreen® [Qiagen] and Cobas® [Roche] vs. other PCR and 
sequencing-based methods)
The stratified Cox proportional hazard model (Cox 1972) with assigned treatment as the only 
covariate will be used to estimate the HR and corresponding 95% CI for the primary analysis.  
All randomized patients, according to the ITT principle, will be included in the analysis of this 
endpoint.
12.2.8.
Secondary Outcome and Methodology
The secondary objectives of the study for Part B are listed in Section 6.2.
12.2.8.1. Overall Survival
The treatment regimens will be compared in terms of OS; however, multiple postprogression 
anticancer treatments are expected, which will dilute the treatment effect in OS.  In addition, 
unequal treatment after progression is expected to obscure any effect of ramucirumab plus 
erlotinib relative to erlotinib plus placebo.
The primary analysis of PFS described in Section 12.2.7.2 will also be performed in an 
analogous fashion for OS.
One interim analysis and a final analysis for OS may be performed in this study.  A hierarchical 
testing procedure will be employed to test OS.  The OS will be tested only if PFS is significant.  
If PFS is not significant after the primary analysis for PFS is performed, OS will not be 
statistically evaluated.
The interim OS analysis may be performed at the time of primary PFS analysis (approximately 
270 PFS events) and the final analysis may be conducted later with the aim of providing as much 
information as possible on OS.  This final analysis of OS will be performed when OS data are 
relatively mature (approximately 300 OS events and 35% censoring).  The 1-sided type I error 
rate will be controlled at 2.5% by using a Haybittle Peto type spending function (p-value bound 
0.0001 at the interim analysis).
If it is determined that an additional interim analysis would provide further scientifically 
meaningful characterization of OS, then an additional interim analysis could be performed prior 
to the final analysis.
12.2.8.2. Objective Response Rate and Disease Control Rate
The ORR and DCR of each treatment arm will be calculated as defined by RECIST v1.1.  The 
ORR with 95% CI observed in each treatment group will be summarized and compared using the 
Cochran-Mantel-Haenszel test adjusting for the randomization strata.
12.2.8.3. Duration of Response
The survival curves and median with 95% CI will be estimated using the Kaplan-Meier 
methodology and will be compared using Cox regression model and log-rank test.  The analysis 
is for responders only.

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12.2.9.
Sensitivity Analyses
Sensitivity analyses will be undertaken for calculation of the primary endpoint in order to 
evaluate the robustness of the analysis.
Sensitivity analyses will include analyses using unstratified log-rank test and Cox models, the 
per-protocol population, including both radiographic and clinical progressions as PFS events, 
and analyses applying alternative PFS censoring rules (for example, post-discontinuation 
systemic anticancer therapy, missing tumor assessment, missing 2 or more tumor assessments 
prior to PD/death or lost to follow up, etc.; more details will be specified in the SAP).
In addition, a PFS analysis based on BIRC review will be conducted.  Discordance statistics, 
such as those defined by the Pharmaceutical Research and Manufacturers of America 
methodology (Amit et al. 2011) will also be calculated.  These analyses will be conducted on all 
patients.
Additional sensitivity analyses may be specified in the SAP.
12.2.10.
Pharmacokinetic and Immunogenicity Analyses
Pharmacokinetics:
Ramucirumab: Cmin and concentrations at 1 hour post end of infusion (approximately maximum 
concentration [Cmax]) will be summarized by descriptive statistics.  Additional analysis utilizing 
the population PK approach may also be conducted if deemed appropriate.  Relationships 
between ramucirumab exposure and measures of efficacy and safety will be explored.  Details 
will be described in the SAP.
Immunogenicity:
Incidence of anti-ramucirumab antibodies will be tabulated.  Correlation to ramucirumab drug 
level, activity, and safety will be assessed, as appropriate.
In the event of an infusion-related reaction, the immunogenicity and ramucirumab serum 
concentrations will be tabulated.
A limited number of pre-identified individuals may gain access to the limited unblinded data, as 
specified in the unblinding plan, prior to the interim or final database lock, in order to initiate the 
final population pharmacokinetic/pharmacodynamic model development processes for interim or 
final analyses.  Information that may unblind the study during the analyses will not be reported 
to study sites or blinded study team until the study has been unblinded.
12.2.11.
Progression-Free Survival 2
PFS2 is defined as the time from randomization to second disease progression (defined as 
objective radiological or symptomatic progression after the start of additional systemic 
anticancer treatment), or death from any cause, whichever occurs first. If the patient is alive at 
the cutoff for analysis and a second disease progression has not been observed, PFS2 data will be 
censored on the last date the patient was known to be alive.

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
The analysis of PFS2 will be based on stratified log-rank test, stratified by 
randomization strata (IWRS).  PFS2 median with 95% CI and survival curves for 
each treatment group will be estimated using Kaplan-Meier method (Kaplan and 
Meier 1958).  The HR will be estimated using a stratified Cox regression model, 
stratified by randomization strata (IWRS). 

An additional sensitivity analysis may be explored in which an event is defined as 
discontinuation of second-line treatment, second disease progression, or death from 
any cause, whichever occurs first.  Other sensitivity analyses may be specified in the 
SAP.
12.2.12.
Translational Research Analyses
Biomarker results for translational research will be summarized, and will be analyzed for 
correlations with clinical outcomes.
12.2.13.
Health Outcome/Quality of Life Analyses
For each instrument, percentage compliance will be calculated as the number of completed 
assessments divided by the number of expected assessments (that is, patients still on study).  
Percentage compliance will be summarized by treatment arm for each assessment period and 
overall.  Reasons for noncompliance will be described.
12.2.13.1.LCSS
The LCSS assessments will be used primarily to calculate time to deterioration (TtD) for each of 
the 9 items, ASBI, and LCSS total score as defined in Section 10.2.1.  TtD for each LCSS score 
is defined as the time from the date of randomization until the date of the first ≥15-mm increase 
from baseline (de Marinis et al. 2008).  Alternative definitions of minimally important 
differences may be explored as needed.  Patients without deterioration will be censored on the 
date of the patient’s last LCSS assessment.

The Kaplan-Meier method will be used to estimate parameters for time-to-
event analyses on each treatment group.  Kaplan-Meier curves by treatment 
arm may be produced.

Hazard ratios will be estimated using stratified Cox proportional hazards 
models with assigned treatment as the only covariate, reported with 2-tailed 
95% CIs.  These Cox models should be stratified identically to the stratified 
log-rank tests.  

The LCSS data will be summarized descriptively by baseline and cycle.  For 
each patient, the maximum change (improvement or deterioration) over 
baseline score will be calculated for each of the scores.  Data on maximum 
change (improvement or deterioration separately) will be compared 
statistically between study treatment arms for each of the scores using analysis 
of covariance (using only baseline score as a covariate) and the Mann-
Whitney-Wilcoxon test.

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12.2.13.2.EQ-5D-5L:  Health State Utilities
Descriptive statistics (Herdman et al. 2011) for the 5 dimensions, index, and VAS will be 
calculated for each assessment period.
12.2.13.3.Resource Utilization
Hospitalizations, transfusions, and concomitant medications during the study treatment period or 
during the 30-day short-term follow-up period will be summarized by treatment group.
12.2.14.
Safety Analyses
12.2.14.1.Part A
Safety analysis will be performed in DLT-evaluable patients (refer to Section 9.4.1) for the AEs 
reported during the DLT Assessment Period.  The number of patients who experienced any DLT 
will be presented based on all DLT-evaluable patients (DLT population).
All other safety analyses will be performed using the safety population.  The safety data 
collected in Part A will not be combined with the safety data in Part B.
12.2.14.2.Part B
All patients enrolled in the study and treated with at least 1 dose of study treatment will be 
evaluated for safety.  Safety analyses will include summaries of the incidence of AEs by 
maximum NCI-CTCAE v 4.0 grade that occur during the study treatment period or within 
approximately 30 days after the decision is made for discontinuation from study treatment.  
Additionally, the following safety-related outcomes will be summarized:

Study treatment discontinuations due to AEs

Deaths during the study treatment period or within 30 days after the decision is made to 
discontinue study treatment

AEs, TEAEs, and SAEs during the study treatment period or within 30 days after the 
decision is made to discontinue study treatment

Hospitalizations and transfusions during the study treatment period or within 30 days 
after the decision is made to discontinue study treatment

Select concomitant medications, including growth factors (erythroid growth factors, 
G-CSF, granulocyte-macrophage colony-stimulating factor), antiemetics, CYP3A4 
inducers and inhibitors, and antibiotics, during the study treatment period or within 
30 days after the decision is made to discontinue study treatment.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline.
12.2.15.
Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for each of following potential prognostic 
subgroup variables:

all baseline stratification factors

age (<65 years vs. ≥65 years)

age (<70 years vs. ≥70 years)

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
smoking history (ever vs. never smoker)

performance status (0 vs. 1)

initial stage at diagnosis (Stage IV vs. other)
Tobacco product smoking history will be collected.  The definition of ‘ever smoker’ includes 
those who smoked ≥100 cigarettes, cigars, or pipefuls in his/her lifetime and the definition of 
‘never smoker’ is one who smoked <100 cigarettes, cigars, or pipefuls in his/her lifetime.
If a category of subgroup variable consists of fewer than 5% of randomized patients, then 
analysis within that category may be omitted.
Analyses will be done within subgroup and, separately, across subgroups with a test of 
interactions of subgroups with treatment performed.
Other subgroup analyses may be performed as deemed appropriate.  If any safety analyses 
described in Section 12.2.14 identify important imbalances between arms, subgroup analyses of 
these endpoints may be performed.
 
  Details of the analyses will be 
described in the SAP.
12.2.16.
Interim Analyses
Two independent committees will be formed to review the interim data and provide guidance to 
the study team, as described in Section 8.1.4.
The AC, which is internal to Lilly and independent of the JVCY study team, is responsible for 
reviewing the DLT analysis of Part A and providing consultation recommendation to the study 
team with regards to the starting dose of Part B (refer to Section 9.4.1), if needed after the 
completion of Part A.
The IDMC is responsible for providing external oversight for Part B of JVCY study 
independently of Lilly.
In general, the planned analyses include the following: 

Analysis 1 (Part A; DLT evaluation):  after the 6 patients enrolled from Japan and 
6 patients enrolled from North America and/or Europe have completed 2 treatment cycles
Endpoint:  DLTs

Analysis 2 (Part B, Interim Safety):  after approximately 50 randomized patients have 
completed 3 cycles of treatment or discontinued from all study therapies due to any 
reason prior to 3 cycles
Endpoint:  Safety profile

Analysis 3 (Part B, Interim Futility):  approximately 107 PFS events
Endpoint:  PFS and safety profile

Analysis 4 (Part B, Primary PFS):  approximately 270 PFS events
Endpoint:  PFS (Primary) and other secondary and exploratory objectives
CCI

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
Analysis 5 (Part B, Final Overall Survival):  approximately 300 OS events
Endpoint:  OS (Secondary)
Additional safety reviews will be conducted approximately twice a year after the first interim 
safety analysis until primary PFS analysis.  The frequency of safety reviews could be reduced to 
once a year after the primary PFS analysis or earlier based on IDMC recommendation.
12.2.16.1.Part A
The DLT evaluation will be performed once all DLT-evaluable patients have completed 2 cycles 
of treatment or discontinued from the study treatment or study participation due to a DLT during 
the first 2 cycles.  The evaluation will be based on the safety data reported during the first 
2 cycles of treatment in this population.  The AC is responsible for reviewing the DLT analysis 
of Part A and providing recommendation to the study team when requested by the study team.
12.2.16.2.Part B
An IDMC review will be performed after the first 50 treated patients completed 3 cycles or 
discontinued from all study therapies due to any reason prior to 3 cycles. The safety data will be 
reviewed by IDMC.
There will be no prespecified rules for stopping the trial due to safety concerns.  The IDMC 
members will review unblinded safety data at each interim analysis to determine whether there 
are sufficient safety concerns to justify the termination of study treatment and/or enrollment.
A futility and safety interim analysis will be performed after approximately 107 investigator-
assessed PFS events were observed.  Futility for the interim analysis will be determined in terms 
of PFS.  The futility rule will be based on stratified log-rank test.  As guidance, an IDMC may 
recommend stopping the trial for futility if the p-value of the stratified log-rank test for PFS is 
>0.39 (this corresponds to approximately a HR >0.95 under a Cox PH model).  The stopping 
guidance should be viewed as only guidance, not the absolute rules.
The IDMC will be instructed to engage the Lilly SMD, who may subsequently convene a Lilly 
Internal Review Committee to propose actions based upon the IDMC’s recommendation.
Only the IDMC are authorized to evaluate unblinded interim futility and safety analyses; 
however, unblinding of groups of cases is required to make a determination that the group of 
cases represents a suspected adverse reaction for the purpose of expedited reporting in some 
countries or situations.  Such unblinding is performed by Lilly Global Patient safety personnel 
external to the study to ensure the blinding integrity of the study.  Study sites will receive 
information about interim results ONLY if they need to know for the safety of their patients.
Unblinding details are specified in the blinding section of the protocol (Section 9.5).  If changes 
to the unblinding plan occurred after protocol approval, they may be described in either a 
protocol amendment, the unblinding plan section of the SAP, or in a separate unblinding plan 
document.

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13.Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or, 
where permitted by local law or regulation, by the patient's legal representative.  This includes 
obtaining the appropriate signatures and dates on the ICF prior to the performance of any 
protocol procedures and prior to the administration of study treatment.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at the investigative sites.  
All ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline 
on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites.
The study site’s ERBs should be provided with the following:

The current IB or package labeling and updates during the course of the study

The ICF

Relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

ICH GCP Guideline (E6)

Applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).

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

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independent central review of progression in cancer clinical trials: results from a meta-
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Bruns CJ, Liu W, Davis DW, Shaheen RM, McConkey DJ, Wilson MR, Bucana CD, Hicklin DJ, 
Ellis LM. Vascular endothelial growth factor is an in vivo survival factor for tumor 
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Byers LA, Heymach JV. Dual targeting of the vascular endothelial growth factor and epidermal 
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Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev 
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Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
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Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;74(2):187-220.
de Marinis F, Pereira JR, Fossella F, Perry MC, Reck M, Salzberg M, Jassem J, Peterson P, 
Liepa AM, Moore P, Gralla RJ. Lung Cancer Symptom Scale outcomes in relation to standard 
efficacy measures: an analysis of the phase III study of pemetrexed versus docetaxel in 
advanced non-small cell lung cancer. J Thorac Oncol. 2008;3(1):30-36.
Dodd LE, Korn EL, Freidlin B, Jaffe CC, Rubinstein LV, Dancey J, Mooney MM. Blinded 
independent central review of progression-free survival in phase III clinical trials: important 
design element or unnecessary expense? J Clin Oncol. 2008;26(22):3791–3796.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging 
Handbook: From the AJCC Cancer Staging Manual. 7th ed. NY: Springer; 2009.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
[FDA] Food and Drug Administration. Guidance for Industry. Erythroid-stimulating factors. 
Available at: 
http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders
/ucm109375.htm. Accessed September 16, 2014.
Garg RK. Posterior leukoencephalopathy syndrome. Postgrad Med J. 2001;77(903):24-28.
Gralla RJ, Roila F, Tonato M, Herstedt J, Aapro M, et al; for the ESMO/MASCC Guidelines 
Working Group. Guideline update for MASCC and ESMO in the prevention of chemotherapy-
and radiotherapy-induced nausea and vomiting: results of the Perugia consensus 
conference. Ann Oncol. 2010;21(suppl 5):v232-v243.

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Attachment 1.Protocol JVCY Part A Study Schedule

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Attachment 2.Protocol JVCY Part B Study Schedule

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Attachment 3.Protocol JVCY Clinical Laboratory Tests
Hematology
a:
Clinical Chemistry
c:
Whole Blood Concentrations of the following:
Serum Concentrations of the following:
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total bilirubind
Mean cell volume (MCV)
Direct bilirubind
Mean cell hemoglobin concentration (MCHC)
Alkaline phosphatase
Leukocytes (WBC)
Alanine aminotransferase (ALT)d
Neutrophils
Aspartate aminotransferase (AST)d
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatinine
Eosinophils
Uric acid
Basophils
Calcium
Platelets
Glucose, random
Albumin
Coagulation Testa,b:
Chloride
Prothrombin time (PT or INR)
Total protein
Partial thromboplastin time (PTT or aPTT)
Lactate dehydrogenase
Magnesium
Pregnancy Test (WOCBP only)a:
Phosphorus
Serum (baseline only) or urine
HgbA1c (to be collected at baseline and short-term follow-up)
Thyroid Tests
c:
TSH and free T4 (to be collected at baseline and 
short-term follow-up)
Urinalysisa:
Routine dipstick measurements, and if clinically indicated, 
microscopic analysis.  If urine dipstick or routine analysis 
indicates proteinuria ≥2+ at evaluations, a 24 hour urine 
collection (to assess protein) must be obtained.
Exploratory Biomarker Testsc:
Follicle Stimulating Hormone
a:
Refer to Section 10.4.2
FSH
Otherc
Tissue testa:
Anti-ramucirumab antibody 
EGFR mutation
Ramucirumab concentrations in serum
Abbreviations:  ALT = alanine aminotransferase; aPTT = activated partial prothrombin time; AST = aspartate aminotransferase; 
eCRF = electronic case report form; INR = international normalized ratio; PT = prothrombin time; PTT = partial prothrombin time; RBC = red 
blood cells; WBC = white blood cells; WOCBP = women of child-bearing potential.
a
Assayed by local or investigator-designated laboratory.  For hematology, if a manual differential is not able to be performed, then an 
automated differential will be acceptable.  Serum pregnancy test in WOCBP will be done at baseline, thereafter serum or urine pregnancy test 
will be required (minimum sensitivity 25 IU/L or equivalent units of beta human chorionic gonadotropin [β HCG]).  Pregnancy test results will 
not be collected on the eCRF.  If the urine pregnancy test is positive, confirm with a serum pregnancy test.  A baseline FSH test for eligibility will 
only be performed on women who have had spontaneous amenorrhea for 6-12 months prior to study entry.  For the EGFR mutation status, sites 
will enter on the eCRF the specific mutation(s) identified and the name of the test method used to document evidence of EGFR mutation 
positivity.
b
For both prothrombin time and partial thromboplastin, whichever lab for each is selected at baseline should be followed throughout the study.
c
PGx and ‘Other’ samples will be assayed by a sponsored-designated laboratory.  Serum chemistry and thyroid tests will be assayed centrally.  
Thyroid tests (TSH and free T4) and HgbA1c will be collected at baseline and at the short-term follow-up visit.
d
For dosing decisions, bilirubin and AST/ALT are required to be collected locally and centrally.

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Attachment 4.Protocol JVCY Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa, b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK 
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; IgG =immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 5.Protocol JVCY Study Procedures
Informed Consent
Written informed consent will be given by each patient prior to undergoing study-specific 
evaluations and prior to receiving treatment.
Demography
Date of birth, sex, and race/ethnicity.  Demographic data are collected to demonstrate that a trial 
population is representative of the to-be-treated population considered for regulatory approval.  
The representativeness could be, to a large degree, determined by race.
Medical History
Past and current medical conditions and treatments, current medications, medications taken 
within 30 days prior to enrollment, date of diagnosis, histopathological or cytological 
confirmation of malignancy, prior cancer therapy (surgery, radiotherapy, chemotherapy regimen, 
and any targeted therapy agents, maintenance therapy) including reason for discontinuation of 
the previous anticancer therapy.  Any preexisting toxicity (e.g., Grade 1 fatigue) should be 
documented and recorded at this time.
Physical Examination
Complete Physical Examination - height (pretreatment only) and weight.
ECOG Performance Status – according to the ECOG PS criteria given in the table below.
ECOG Performance Status Scale
Grade
Description
0
Fully active, able to carry out 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 housework, office work).
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
Source:  Oken et al. 1982.
Toxicity/AE - Assessment including NCI-CTCAE v4.0 grade
Vital Signs - Measurements include temperature, pulse rate, respiratory rate, and blood pressure.

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Clinical Tests
Laboratory Parameters – see Attachment 3.
Pregnancy Test –Women of child bearing potential (WOCBP) includes any female who has 
experienced menarche and who has not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal 
(defined as amenorrhea ≥12 consecutive months; or women on hormone replacement therapy 
[HRT] with documented serum follicle-stimulating hormone [FSH] level ≥40 mIU/mL).  Even 
women who are using oral, implanted, or injectable contraceptive hormones or mechanical 
products, such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) 
to prevent pregnancy, who are practicing abstinence, or whose partner is sterile (for example, 
vasectomy), should be considered to be of childbearing potential.
Other Tests
Electrocardiogram (ECG) – to be obtained at screening/baseline (≤ 21 days prior to enrollment), 
within 72 hours prior to treatment on Day 1 of Cycle 3, Cycle 5, and every 2 cycles thereafter 
(and if clinically indicated), at the discontinuation of chemotherapy, at the discontinuation of 
ramucirumab/placebo, and at the short-term follow-up visit.
Echocardiogram or Multiple Gated Acquisition Scan (MUGA) - to be obtained at 
screening/baseline (≤ 21 days prior to enrollment) and at the short-term follow-up visit.
Efficacy Assessments
Imaging Studies:
Imaging methods will be employed consistently during the course of each patient’s evaluation 
during the study (for example, patients who have abdominal MRI as a baseline exam should 
continue to have abdominal MRI assessments as a means of determining response/progression).

CT scan or MRI of chest and upper abdomen including both adrenal glands are 
required, with pelvic imaging performed if clinically indicated.  Disease should be 
captured and metastases identified at baseline (within 28 days prior to 
enrollment).  Subsequently, imaging studies required to investigate known disease 
should be repeated every 6 weeks ±7 days (as calculated from the first dose of 
study therapy) following the first dose of study therapy and despite any treatment 
delays, after 72 weeks while on study, imaging must be performed every 12 
weeks (±7 days).  It is recommended that CT imaging of the abdomen/pelvis be 
performed with IV contrast.  If this is not feasible/advisable secondary to 
hypersensitivity or other conditions, then contrast-enhanced MRI is preferred.  
For patients with known serious allergic reactions to CT contrast material, a 
contrast-enhanced MRI of the chest/abdomen/pelvis is encouraged.

A gadolinium-enhanced MRI of the CNS will be performed at pretreatment.  
While on study, a gadolinium-enhanced MRI of the CNS may be performed if 
clinically indicated.

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
Bone scans and positron emission tomography (PET) scans may be performed if 
clinically indicated, but may not be used to measure target lesions.  Abnormal 
findings on bone scans at baseline that are suggestive or compatible with metastatic
disease to the bone require radiographic confirmation (with plain films, CT, or MRI).
Radiographic scans will be collected locally and stored centrally.  An independent review 
of all scans may be considered following the completion of the study.
Health Outcome/Quality of Life Measures: see Section 10.2
Other Study Procedures (see Sections 10.4.2, 10.4.3, and 10.4.4)
Translational Research
Immunogenicity Research
Pharmacokinetic Assessment
Postdiscontinuation Follow-Up Period:
The postdiscontinuation follow-up period includes the 30-day short-term follow-up and long-
term follow-up visits, and will continue until death or study completion.
Short-Term Follow-Up:
The short-term follow-up period begins on the day after the patient and the investigator agree to 
discontinue the patient from the treatment portion of the trial and lasts approximately 30 days 
(±3 days).
For patients who stop treatment for reasons other than PD, imaging studies with tumor 
measurements/disease response assessments should continue to be performed every 6 weeks 
(± 7 days), after 72 weeks while on study, imaging must be performed every 12 weeks (±7 days) 
until documentation of radiographic PD.
Adverse events occurring during this period will be documented and reported according to 
Section 10.3.1.
Long-Term Follow-Up:
After the 30-day follow-up, only new and ongoing serious adverse events (SAEs) deemed related 
to study treatment will be collected.
Patients will be contacted every 3 months (± 14 days) to obtain information about survival status 
and detailed information on any subsequent systemic anticancer therapy and disease progression 
(for patients not having a radiographic progression).  Follow-up will continue as long as the 
patient is alive, or until study completion as defined in Section 7.3.

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Attachment 6.Protocol JVCY Creatinine Clearance Formula 
and NYHA Classification
Note:  This formula is to be used for calculating creatinine clearance (CrCl).  
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.
New York Heart Association (NYHA) Classification
Functional Capacity
Class I. Patients with cardiac disease but without resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II. Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III. Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV. Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
Source: The Criteria Committee of the New York Heart Association. (1994). Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. pp. 253–256.

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CCI

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g
The postdiscontinuation follow-up begins on the day after the patient and the investigator agree that the patient will no longer 
continue study treatment.  The short-term 30-day follow-up visit occurs at or near the end of the short-term follow-up period.
h
When a patient discontinues ramucirumab/placebo or ramucirumab/placebo and erlotinib, PK/IG serum and plasma samples 
will be collected 30 (±10) days thereafter.  If a patient continues to take erlotinib after discontinuation of 
ramucirumab/placebo, additional PK/IG serum and plasma samples are NOT required after erlotinib discontinuation. 

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Attachment 10.
Protocol JVCY NCI-CTCAE v4.0 Infusion-
Related Reactions and Dosing Algorithm for Proteinuria
Adverse 
Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Infusion-
related 
reaction
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
nonsteroidal 
anti-inflammatory drugs 
[NSAIDs], narcotics, 
I.V. fluids); prophylactic 
medications indicated for 
≤ 24 h
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Allergic 
reaction
Transient flushing 
or rash, drug fever 
<38°C (<100.4°F); 
intervention not 
indicated
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics); 
prophylactic medications 
indicated for ≤ 24 h
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
-
-
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like 
substances from mast cells, causing a hypersensitivity immune response.  Clinically, it presents with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness and may lead to death.
Cytokine 
release 
syndrome
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤ 24 h
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Life-threatening 
consequences; 
pressor or 
ventilator 
support 
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by 
the release of cytokines from the cells.

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Attachment 11.
Protocol JVCY Amendment (f) Summary A 
Multicenter, Randomized, Double-Blind Study of Erlotinib 
in Combination with Ramucirumab or Placebo in 
Previously Untreated Patients with EGFR Mutation-Positive 
Metastatic Non-Small Cell Lung Cancer
Overview
Protocol I4T-MC-JVCY(e), A Multicenter, Randomized, Double-Blind Study of Erlotinib in 
Combination with Ramucirumab or Placebo in Previously Untreated Patients with EGFR 
Mutation-Positive Metastatic Non-Small Cell Lung Cancer, has been amended.  The new 
protocol is indicated by amendment (f) and will be used to conduct the study in place of any 
preceding version of the protocol.
This amendment reflects revised statistical assumptions for both the control and the experimental 
arms.  Accordingly, the number of PFS events required to perform the primary analysis has been 
updated from approximately 320 events to approximately 270 events.  The following provides 
the rationale for the revised assumptions:
The performance of the control arm has been reassessed based on data from recent first-line 
erlotinib trials in patients with EGFR mutation-positive NSCLC (Soria et al. 2018), 
meta-analysis (Lee et al. 2017) and real-world evidence (Okamoto et al. 2018).  These data show 
that the erlotinib control arm may perform better than the initially-assumed median PFS of 
9.5 months.  As a result, the median PFS assumption for the control arm was increased to 
11 months.  Additionally, recent positive data from the Phase 1b part (Part A) of this study have 
shown a median PFS of 17.1 months (Reck et al. 2017).  Consequently, the median PFS 
assumption for the experimental arm was increased from approximately 13 months to 
15.5 months.  Under the assumption of exponential PFS, this translates to an HR of 0.71, and
therefore the HR has been reduced to reflect the revised statistical assumptions from 0.72 to 0.71.
Additionally, this amendment removes the interim PFS efficacy analysis that was to occur at 
approximately 224 PFS events because the FDA recommended not to perform this interim 
analysis as it may not provide an accurate or reproducible estimate of treatment benefit.
The combined impact of (i) reducing the target HR to 0.71, (ii) having previously passed the 
futility analysis, and (iii) having removed the planned efficacy interim analysis resulted in the 
reduction in the number of PFS events needed for primary analysis from approximately 320 to
approximately 270.
This amendment also aligns the Part C exploratory objectives in Section 6.3 with Addendum 9.  
Furthermore, an additional PFS censoring rule (starting new anticancer treatment and no tumor 
progression or death) was added to Table JVCY.9 to align with other ramucirumab Phase 3 
studies. As the censoring rule for new anticancer therapy was added to Table JVCY.9, the PFS 

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sensitivity analyses 1 and 3 in Section 12.2.9 no longer apply. The current text was simplified 
and additional PFS sensitivity analyses were added to further evaluate the robustness of the 
primary analysis.  The PFS analysis based on BIRC review will be conducted on all patients 
instead of a subset of patients.  Other clarifications or corrections were made for consistency.
The following section shows all changes included in this protocol amendment.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Where existing language is underlined, additions have been identified by the use 
of double underscore.
Synopsis
Length of Study (Part A and Part B, excluding the Continued Access Period):  Approximately 61 months
Planned first patient visit:  APR 2015
Planned last patient visit:  MAY 2020 (Part B)
Planned analyses:
Analysis 1 (Part A, dose-limiting toxicity [DLT] evaluation):  After 6 patients enrolled from Japan and 6 patients 
enrolled from North America and/or Europe have completed 2 treatment cycles
Endpoint:  DLTs
Analysis 2 (Part B, Interim Safety):  After approximately 50 randomized patients have completed at least 3 cycles 
of treatment or discontinued from all study therapies due to any reason prior to 3 cycles
Endpoint:  Safety
Analysis 3 (Part B, Interim Futility):  Approximately 107 PFS events
Endpoint:  PFS and safety
Analysis 4 (Part B, Interim Efficacy):  Approximately 224 PFS events
Endpoint:  PFS, OS, and safety
Analysis 5 4 (Part B Primary PFS Analysis):  At least 320 Approximately 270 PFS events
Endpoint:  PFS (Primary) and other secondary and exploratory objectives
Analysis 6 5 (Part B, Final Overall Survival):  Approximately 300 OS events
Endpoint:  OS (Secondary)
Additional safety reviews will be conducted approximately twice a year after the first interim safety analysis until 
primary PFS analysis.  The frequency of safety reviews could be reduced to once a year after the primary PFS 
analysis or earlier based on IDMC recommendation.
Exploratory Objectives:
The exploratory objectives of Part B of the study are as follows:

Assessment of the association between biomarkers and clinical outcome

Comparison of progression-free survival 2 (PFS2) between treatment arms
The exploratory objectives in only the gefitinib/osimertinib cohort in Japan (Addendum 9), conducted in the 
East-Asian region including Japan, are as follows: 

to evaluate the efficacy (for example, 1-year PFS rate) and safety of ramucirumab when administered in 
combination with gefitinib in previously untreated Japanese patients with EGFR mutation-positive 
metastatic NSCLC, in the East-Asian region including Japan

to evaluate the efficacy and safety of ramucirumab when administered in combination with osimertinib 
in Japanese patients with T790M-positive metastatic NSCLC and who were previously treated with 
whose disease has progressed on ramucirumab plus gefitinib in this study, in the East-Asian region 
including Japan

to assess PK and immunogenicity of ramucirumab

to assess patient-reported outcomes (using LCSS and EQ-5D-5L)
Statistical Methods:
Part B:
Approximately 450 patients will be randomized through an interactive web response system (IWRS).  At 

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randomization, patients will be stratified as stated above in the study design.
A 3 look group sequential design on the primary endpoint of PFS will be conducted, with 1 interim futility analysis, 
1 interim efficacy analysis, and primary PFS analysis occurring at approximately 107 PFS events, approximately 
224 PFS events, and approximately 320 PFS events, respectively.  A Gamma family with parameter 0.5 was used to 
calculate the futility bound (non binding approach).  A spending function in rho family with parameter 16 was used 
to derive the efficacy bound to maintain the cumulative one sided type I error 0.025.  An interim futility analysis 
(Analysis 3 above) was conducted at 114 investigator-assessed PFS events (data cutoff date 16 October 2017) and the 
IDMC recommended to continue the trial without modification.  A nominal alpha <0.00001 was spent in order to 
maintain type-I error.  Assuming an HR of 0.72 0.71, this design yields at 80% statistical power to detect superiority 
of the ramucirumab plus erlotinib arm over placebo plus erlotinib arm with the use of a 1-sided log-rank test and a 
type I error rate of 0.025 0.02499.
4.
Abbreviations and Definitions
study completion
This study will be considered complete after final evaluation analysis of overall survival 
is performed.
6.3.
Exploratory Objectives
The exploratory objectives in only the gefitinib/osimertinib cohort in Japan (Addendum 9), 
conducted in the East-Asian region including Japan, are as follows:

to evaluate the efficacy (for example, 1-year PFS rate) and safety of ramucirumab when
administered in combination with gefitinib in previously untreated Japanese patients with 
EGFR mutation-positive metastatic NSCLC, in the East-Asian region including Japan

to evaluate the efficacy and safety of ramucirumab when administered in combination
with osimertinib in Japanese patients with T790M-positive metastatic NSCLC and who 
were previously treated with whose disease has progressed on ramucirumab plus gefitinib 
in this study, in the East-Asian region including Japan

to assess PK and immunogenicity of ramucirumab

to assess patient-reported outcomes (using LCSS and EQ-5D-5L)
8.1.2.3.
Study Completion and End of Trial
The primary objective is investigator-assessed PFS., and when there are at   When approximately 
320 270 PFS events have occurred among the study population, there will be a database lock to 
report the primary objective of the study.
Figure JVCY.3 is a diagram of the study period and continued access period.  This study will be 
considered complete (that is, the scientific evaluation will be complete [study completion]) 
following the final evaluation analysis of OS, as determined by Lilly.  Investigators will continue 
to follow the study schedule for all patients until notified by Lilly that study completion has 
occurred.  “End of trial” refers to the date of the last visit or last scheduled procedure for the last 
patient, including patients participating in the continued access period, if applicable.

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using unblinded data, under the guidance of an Independent Data Monitoring Committee.  See 
Section 12.2.16 for further details.
12.1.
Determination of Sample Size
Part B:
The primary objective of this study is to compare ramucirumab plus erlotinib versus placebo plus 
erlotinib in terms of PFS in previously untreated patients with EGFR mutation-positive 
metastatic NSCLC.  The study will enroll approximately 450 patients in 1:1 randomization.  The 
primary analysis will be performed after approximately 320 270 PFS events have occurred 
(approximately 30%  40% censoring rate).  An interim futility analysis will be conducted after 
approximately 107 PFS events and an interim efficacy analysis will be conducted after 
approximately 224 PFS events.
An interim futility analysis was conducted at 114 investigator-assessed PFS events (data cutoff 
date 16 October 2017) and the IDMC recommended the trial continue without modification.  A 
nominal alpha <0.00001 was spent in order to maintain type-I error.  Assuming an HR of 0.72 
0.71, this sample size yields at least 80% statistical power to detect superiority of the 
ramucirumab plus erlotinib arm over the placebo plus erlotinib arm, with the use of a 1-sided 
log-rank test and a type I error of 0.025 0.02499.  If the true median PFS for the placebo plus 
erlotinib arm is 9.5 11 months, then the HR of 0.72 0.71 amounts to an approximate 3.5 4.5-
month improvement in median PFS for the ramucirumab plus erlotinib arm under an additional 
assumption of exponential survival distribution.

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12.2.7.2.
Part B
Table JVCY.9.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Rule
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no 
death 
Date of Randomization
Censored
3
No documented progression and no 
death (with a post-baseline tumor 
assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew 
consent from study participation) 
before documented progression or 
death 
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented 
progression 
Date of death 
Progressed
7
Documented progression or death 
after missing ≥2 consecutive 
post-baseline tumor assessments
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later
Censored
8
New anticancer treatment started and 
no tumor progression or death within 
14 days
Date of adequate tumor assessment 
prior to start of new anticancer 
treatment +14 days or date of 
randomization, whichever is later
Censored
Note:  Progression-free survival and associated outcome is determined by the earliest of the dates above, if more 
than 1 situation applies.
A group sequential design on the primary endpoint of PFS will be conducted, with 1 interim 
futility analysis, 1 interim efficacy analysis, and primary PFS analysis occurring at 
approximately 107 PFS events, approximately 224 PFS events, and approximately 320 PFS 
events, respectively (Table JVCY.10).
An interim futility analysis will be conducted after approximately 107 investigator assessed PFS 
events (approximately 33%).  A non-binding approach with gamma family of beta spending 
function (gamma=0.5) will be used to calculate the futility bound.  A nominal alpha <0.00001 
will be spent in order to maintain type-I error.

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An interim efficacy analysis will be conducted after approximately 224 investigator assessed
PFS events.  A spending function in rho family with parameter 16 was used to derive the efficacy
bound to maintain the cumulative one sided type I error 0.025.
All the testing boundaries will be adjusted based on actual number of events at each analysis, 
according to the alpha spending functions.
If statistical significance is not declared at the interim PFS analysis, the primary PFS analysis 
will be performed after approximately 320 investigator assessed PFS events have been observed 
based on investigator assessment.
Table JVCY.10.
Property of the Design for PFS
Information 
Fraction
Cumulative 
PFS Events
Cumulative 
Alpha Spent
Cumulative 
Beta Spent
Boundary Reject of H0
Boundary Futility
33%
107
<0.00001
0.078
NA
>0.39 (~ HR >0.95)
70%
224
0.00008
0.078
<0.00008 (~HR <0.6)
NA
100%
320
0.025
0.199
<0.025
NA
Abbreviations:  HR = hazard ratio; NA = not applicable; PFS = progression free survival.
The stratified Cox proportional hazard model (Cox 1972) with assigned treatment as the only 
covariate will be used to estimate the HR and corresponding 95% CI for the primary analysis.  All 
randomized patients, according to the ITT principle, will be included in the analysis of this endpoint.  
Additionally, the un stratified Cox regression model will be employed.
12.2.8.1.
Overall Survival
Up to a total of 2 One interim analyseis and a final analysis for OS may be performed in this 
study.  A hierarchical testing procedure will be employed to test OS.  The OS will be tested only 
if PFS is significant.  If PFS is not significant after the primary analysis for PFS is performed, 
OS will not be statistically evaluated.
The first interim OS analysis will be performed at the time of the PFS interim efficacy analysis 
(approximately 224 PFS events).  A second analysis will may be performed at the time of 
primary PFS analysis (approximately 320 270 PFS events) and the last final analysis will may be 
conducted somewhat later with the aim of providing as much information as possible on OS.  
This last evaluation of the additional final analysis of OS data collected after the primary PFS 
analysis will be performed when OS data are relatively mature (approximately 300 OS events 
and 35% censoring).  The 1-sided type I error rate will be controlled at 2.5% by using a 3 look 
Haybittle Peto type spending function (p-value bound 0.0001 at the interim analyseis).
If it is determined that an updated additional interim analysis would provide additional further 
scientifically meaningful characterization of OS, then an updated additional interim analysis will 
could be performed at an additional time point prior to the final analysis.

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12.2.9.
Sensitivity Analysies
Sensitivity analyses will be undertaken for calculation of the primary endpoint in order to 
evaluate the robustness of the analysis.
The following sensitivity analyses will be performed for PFS: 
Progression Free Survival Sensitivity Analysis 1 (censoring for receiving subsequent systemic 
anticancer therapy):  if a patient is initiated on another anticancer therapy prior to objective 
progression, including any postdiscontinuation treatment systemic therapy, radiotherapy, or 
surgical intervention, PFS will be censored at the date of the last complete objective progression
free disease assessment before initiation of the new therapy, regardless of whether or not this 
patient subsequently had objective progression or died.
Progression Free Survival Sensitivity Analysis 2 (censoring for missing two consecutive 
scheduled assessments):  if a patient misses at least 2 consecutive scheduled disease assessments 
prior to objective progression, then the PFS time will be censored at the last objective 
progression-free disease assessment prior to the missed assessments, regardless of whether or not 
this patient subsequently had objective progression or died.
Progression Free Survival Sensitivity Analysis 3 (censoring for any of above 2 sensitivity 
analyses):  if a patient has any of the scenarios outlined for sensitivity analyses 1 through 2 prior 
to objective progression, then the PFS time will be censored at the last objective progression free 
disease assessment date prior to the earliest occurrence of any of these scenarios, regardless of 
whether or not this patient subsequently had objective progression or died.
Sensitivity analyses will include analyses using unstratified log-rank test and Cox models, the 
per-protocol population, including both radiographic and clinical progressions as PFS events, 
and analyses applying alternative PFS censoring rules (for example, post-discontinuation 
systemic anticancer therapy, missing tumor assessment, missing 2 or more tumor assessments 
prior to PD/death or lost to follow up, etc.; more details will be specified in the SAP).
In addition, a PFS analysis based on BIRC review will be conducted.  Discordance statistics, 
such as those defined by the Pharmaceutical Research and Manufacturers of America 
methodology (Amit et al. 2011) will also be calculated.  These analyses will be conducted on a 
randomly selected subset of patients to evaluate the presence of investigator bias with the 
intention of evaluating the reliability of the treatment effect based on investigator assessment.  
Details concerning the size of the subset of patients and decision rules for conducting a central 
review of all patients will be described in a separate SAPall patients.
Additional sensitivity analyses may be specified in the SAP.
12.2.16.
Interim Analyses
In general, the planned analyses include the following: 

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
Analysis 1 (Part A; DLT evaluation):  after the 6 patients enrolled from Japan and 
6 patients enrolled from North America and/or Europe have completed 2 treatment cycles
Endpoint:  DLTs

Analysis 2 (Part B, Interim Safety):  after approximately 50 randomized patients have 
completed 3 cycles of treatment or discontinued from all study therapies due to any 
reason prior to 3 cycles
Endpoint:  Safety profile

Analysis 3 (Part B, Interim Futility):  approximately 107 PFS events
Endpoint:  PFS and safety profile

Analysis 4 (Part B, Interim Efficacy):  approximately 224 PFS events
Endpoint:  PFS, OS, and safety profile

Analysis 5 4 (Part B, Primary PFS):  at least 320 approximately 270 PFS events
Endpoint:  PFS (Primary) and other secondary and exploratory objectives

Analysis 6 5 (Part B, Final Overall Survival):  approximately 300 OS events
Endpoint:  OS (Secondary)
12.2.16.2.
Part B
An efficacy interim analysis will be performed after approximately 224 investigator assessed
PFS events were observed.  Interim efficacy analysis will be conducted for PFS.  The stopping 
rule will be based on stratified log rank test.  As guidance, an IDMC may recommend stopping 
the trial for efficacy if the p value of the stratified log rank test for PFS is <0.00008 (this 
corresponds to approximately an HR <0.6 under a Cox PH model). The stopping guidance 
should be viewed as only guidance, not the absolute rules.  The interim efficacy analysis will be 
conducted to provide early efficacy information and could potentially result in early 
communication with regulatory agencies.  The IDMC will be instructed to engage the Lilly 
SMD, who may subsequently convene a Lilly Internal Review Committee to propose actions 
based upon the IDMC’s recommendation.
Only the IDMC are authorized to evaluate unblinded interim efficacy futility and safety analyses; 
however, unblinding of groups of cases is required to make a determination that the group of 
cases represents a suspected adverse reaction for the purpose of expedited reporting in some 
countries or situations.  Such unblinding is performed by Lilly Global Patient safety personnel 
external to the study to ensure the blinding integrity of the study.  Study sites will receive 
information about interim results ONLY if they need to know for the safety of their patients.

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the previous anticancer therapy.  Any preexisting toxicity (e.g., Grade 1 fatigue) should be 
documented and recorded at this time.

Leo Document ID = 717002c8-2f9c-43d2-842a-04ab8753853d
Approver: 
Approval Date & Time: 23-Apr-2018 20:10:22 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 23-Apr-2018 20:10:22 GMT
Signature meaning: Approved
PPD
PPD