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 Addendum I4T-MC-JVCY (9) 
 
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: 15-Aug-2017 

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1. Protocol Addendum I4T-MC-JVCY(9)
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 addendum 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 (FOIA) 
Exemption 4. 
Ramucirumab (LY3009806)
This addendum is to be performed in addition to all procedures required by 
Protocol I4T-MC-JVCY or any subsequent amendments to that protocol.
Eli Lilly and Company
Indianapolis, Indiana 46285, USA
Protocol Addendum (9) Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 15-Aug-2017 GMT

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2. Table of Contents
Protocol Addendum I4T-MC-JVCY(9)
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 Addendum I4T-MC-JVCY(9) 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.
Table of Contents................................................................................................................2
3.
Rationale for Addendum .....................................................................................................6
4.
Protocol Additions ..............................................................................................................7
5.
References ........................................................................................................................32

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List of Tables
Table
Page
Table JVCY(9).1.
Treatment Regimens/Dosing Schedule in Period 1 of Part C.....................20
Table JVCY(9).2.
Treatment Regimens/Dosing Schedule in Period 2 of Part C.....................20
Table JVCY(9).3.
Gefitinib Dose Modification .....................................................................24
Table JVCY(9).4.
Osimertinib Dose Modifications ...............................................................26

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List of Figures
Figure
Page
Figure JVCY(9).1.
Illustration of study design for Clinical Protocol I4T-MC-JVCY 
in Part C. .......................................................................................................14
Figure JVCY(9).2.
Study period and continued access period diagram for Part C..............19

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List of Attachments 
Attachment
Page
Part C Attachment 1.
Protocol JVCY Part C Study Schedule ................................................34
Part C Attachment 2.
Protocol JVCY Part C Pharmacokinetic, Immunogenicity, and 
Translational Research Sampling Schedule....................................................52

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3. Rationale for Addendum
This addendum adds a cohort of patients (Part C) to the main protocol (I4T-MC-JVCY [JVCY]), 
and will only be applicable to sites in Japan.
Part C is an open-label, 2-period, single-arm, exploratory study.  The purpose of this addendum 
is to provide the evaluation of the efficacy and safety of ramucirumab when administered in
combination with gefitinib in previously untreated Japanese patients with epidermal growth 
factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC)
(Period 1), and of ramucirumab when administered in combination with osimertinib in Japanese
patients with T790M-positive metastatic NSCLC and who were previously treated with 
ramucirumab plus gefitinib in this study (Period 2).

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4. Protocol Additions
The following sections describe the additions to Protocol JVCY that are applicable to this 
addendum. 
All sections of Protocol JVCY apply to this addendum, except as described in this addendum.  
All protocol references to randomization, the independent data monitoring committee, or 
treatment with erlotinib and placebo do not apply to this addendum.
5.2.  Use of Tyrosine Kinase Inhibitors in NSCLC
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (for example, 
erlotinib and gefitinib) significantly prolong progression-free survival (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).
Data from 2 recent Japanese Phase 3 trials (NEJ002 and WJTOG3405) have shown that first-line
treatment with gefitinib resulted in significantly improved PFS times in patients with advanced 
or recurrent NSCLC with EGFR mutations compared with platinum-based doublet chemotherapy
(Mitsudomi et al. 2010; Inoue et al. 2013). In the NEJ002 study, median PFS values on gefitinib
therapy versus carboplatin-paclitaxel chemotherapy were:  10.8 versus 5.4 months (hazard ratio 
[HR] = 0.322, 95% confidence interval [CI]:  0.236, 0.438; p<0.001).  In the WJTOG3405 study, 
the gefitinib group had significantly longer median PFS compared with the cisplatin-docetaxel 
group (9.2 months [95% CI:  8.0, 13.9] vs. 6.3 months [95% CI:  5.8, 7.8]; HR = 0.489, 95% CI:  
0.336, 0.710; log-rank p<0.0001).  Similar results have been observed in subgroup analyses of 
the IPASS study in which gefitinib monotherapy resulted in significantly longer PFS than 
platinum-based doublet chemotherapy in chemonaïve, East Asian patients with advanced non-
squamous NSCLC and EGFR mutations (9.5 vs. 6.3 months, HR = 0.48; 95% CI:  0.36, 0.64;
p<0.001 [Mok et al. 2009; Govindan 2010]). Concurrently with the PFS advantage provided by 
gefitinib in patients with an EGFR mutation, the IPASS trial showed significantly shorter PFS 
(HR = 2.85, 95% CI: 2.05, 3.98; p<0.001) in gefitinib-treated patients with wild-type EGFR.
This result indicates that patients in whom an EGFR mutation has been identified will benefit 
most from first-line therapy with gefitinib. The recent real-world clinical practice data in Japan 
showed 56.1% of patients with advanced/recurrent NSCLC and EGFR mutation were treated 
with gefitinib as the first-line treatment (Inoue et al. 2016).
Osimertinib (AZD9291) is a novel, third-generation, and irreversible EGFR TKI with selectivity 
against mutant versus wild-type forms of EGFR.  Osimertinib is a mono-anilino-pyrimidine 
compound that is structurally and pharmacologically distinct from all other TKIs, including 
another third-generation compound, rociletinib (CO-1686) (Cross et al. 2014).
Osimertinib (TAGRISSO®, PI) 80 mg once-daily tablet has been recently approved in the United 
States and European Union for the treatment of patients with metastatic EGFR T790M mutation-
positive NSCLC, who have progressed on or after EGFR TKI therapy.

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Osimertinib potently inhibits EGFR phosphorylation in activating mutations and resistance cell 
lines in vitro, with much less activity against wild-type EGFR lines.
Preclinical data comparing efficacy of afatinib+cetuximab (A+C) and osimertinib showed that 
both A+C and osimertinib inhibited proliferation of T790M-positive cells in long-term (10-day) 
growth inhibition assays, but osimertinib induced more growth inhibition than A+C (Meador et 
al. 2015).  Moreover, xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo 
sensitivity to osimertinib, but osimertinib-resistant cell lines demonstrated cross-resistance to 
A+C.  Interestingly, addition of cetuximab to osimertinib did not confer additive benefit in any 
preclinical disease setting.
Available data from a Phase 1 clinical trial with osimertinib reveal high response rates in patients 
with EGFR TKI resistance whose tumors harbored EGFR-T790M (objective response rate 
[ORR] 61%; 95% CI:  52, 70), and lower response rates in patients whose tumors lacked EGFR-
T790M (ORR 21%; 95% CI:  12, 34).  The median PFS was 9.6 months (95% CI:  8.3, not 
reached) in EGFR T790M-positive patients and 2.8 months (95% CI:  2.1, 4.3) in EGFR T790M-
negative patients.  The most common adverse events (AEs) were diarrhea (47%), rash (40%), 
nausea (22%), and decreased appetite (21%) (Jänne et al. 2015).
Due to its margin of potency between T790M mutant EGFR and wild-type EGFR, the incidence 
and severity of wild-type EGFR AEs (for example, rash and diarrhea) appear to be lower than 
those observed with first- and second-generation EGFR TKIs.
The combination of an EGFR TKI and an antiangiogenic agent has shown promising efficacy
improvement without significant additional toxicity.  Recently, ATLAS (Johnson et al. 2013) 
and BeTa (Herbst et al. 2011) trials reported that the combination of bevacizumab with erlotinib 
provided additional PFS and overall survival (OS) benefit in the subgroup of patients with EGFR
mutations.  In addition, the JO25567 study showed statistically significant improvement in PFS 
(erlotinib plus bevacizumab vs erlotinib alone, HR = 0.54 [95% CI:  0.36, 0.79]; log-rank test 
p=0.0015) (Seto et al. 2014).  Similarly, BELIEF, which is a single-arm Phase 2 study of first-
line erlotinib plus bevacizumab in patients with EGFR-mutant NSCLC, showed that for all 109 
patients, the 1-year PFS is 55.6% (95% CI:  44.7, 66.6), with a median of 13.6 months, while for 
patients with T790M-positive NSCLC determined pretreatment by a sensitive method, 1-year 
PFS is 60.2% (95% CI:  45.6, 74.8) with a median of 15.4 months (Stahel et al. 2015).
6.3.  Exploratory Objectives
The exploratory objectives of Part C of study 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

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 ramucirumab plus gefitinib in this study 

to assess pharmacokinetics (PK) and immunogenicity of ramucirumab

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
to assess patient-reported outcomes (using Lung Cancer Symptom Scale and EuroQol 5 
dimension, 5-level questionnaire)
7.1.  Inclusion Criteria
All inclusion criteria included in the main protocol are applicable to patients participating in Part 
C Period 1, except where noted below.
[4]
Criterion is applicable only for patients enrolled in Part A and Part B.
[5]
Criterion is applicable only for patients enrolled in Part B.  An archived formalin-
fixed paraffin embedded Stage IV NSCLC tissue sample collection is optional
for patients enrolled in Part C.
The following additional inclusion criterion applies to patients participating in Part C Period 1:
[40] The patient must be eligible for first-line treatment with gefitinib for Period 1 of 
Part C based on previously documented evidence of tumor that has EGFR exon 
19 deletion or exon 21 (L858R) substitution mutation.
7.3.2.  Discontinuation of Study Treatment
7.3.2.1.  Ramucirumab

Any event that would warrant ramucirumab to be held for >2 consecutive cycles (missing 
2 consecutive doses), except in the transition between Periods 1 and 2 of Part C.  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 may be considered and must be discussed with the Sponsor Physician or 
designee.
Patients who are permanently discontinued from ramucirumab due to AEs should be excluded 
from Period 2 of Part C.
7.3.2.4.  Gefitinib
The investigator will discontinue a patient from gefitinib for any of the following reasons:

The patient requests to be withdrawn from gefitinib (“Patient Decision to Discontinue” or 
“Patient Withdraws” per electronic case report form [eCRF]).

The investigator decides that the patient should be discontinued from gefitinib, according 
to the local practice and approved product information.

If the investigator decides to discontinue gefitinib therapy, due to the patient having had a 
3-week delay in this therapy because of an gefitinib-related toxicity.

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 gefitinib.

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
If interstitial lung disease is confirmed, the patient should be treated appropriately.

If liver function tests demonstrate severe abnormal laboratory results. (Table JVCY(9).3)

If the patient experiences gastrointestinal (GI) perforation; severe bullous, blistering, or 
exfoliation skin conditions; corneal perforation or severe ulceration.

Patient compliance with gefitinib will be assessed at each visit (refer to Section 7.6).  
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 gefitinib will continue to be in the study and may be further 
treated with ramucirumab.  Conditions that might cause gefitinib discontinuation should be 
treated appropriately per standard of care.  In addition, discontinuation of gefitinib in the setting 
of AEs and guidelines for treatment management are detailed in Section 9.4.2.3.
7.3.2.5.  Osimertinib
The investigator will discontinue a patient from osimertinib for any of the following reasons:

The patient requests to be withdrawn from osimertinib (“Patient Decision to Discontinue”
or “Patient Withdraws” per eCRF).

The investigator decides that the patient should be discontinued from osimertinib, 
according to the local practice and approved product information.

If the investigator decides to discontinue osimertinib therapy, due to the patient having 
had a 3-week delay in this therapy because of an osimertinib-related toxicity.

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 osimertinib.

If interstitial lung disease is confirmed, the patient should be treated appropriately.

If electrocardiogram (ECG) tests demonstrate severe corrected QT interval (QTc)
prolongation results (Table JVCY(9).4).

If the patient experiences GI perforation; severe bullous, blistering, or exfoliation skin 
conditions; corneal perforation or severe ulceration.

Patient compliance with osimertinib will be assessed at each visit (refer to Section 7.6).  
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 discontinue osimertinib may continue treatment with ramucirumab.  Conditions 
that might cause osimertinib discontinuation should be treated appropriately per standard of care.  
In addition, discontinuation of osimertinib in the setting of AEs and guidelines for treatment 
management are detailed in Section 9.4.2.4.

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7.3.2.6.  All Study Treatment for Part C
The investigator will withdraw a patient from all study treatment (ramucirumab plus gefitinib 
and ramucirumab plus osimertinib) 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’s 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’s 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’s 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.

Radiographic progressive disease (PD) or symptomatic PD.  If patient experiences 
symptomatic deterioration and progression is suspected, every attempt should be made to 
confirm PD radiographically as per Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria prior to/soon after the patient’s discontinuation from the study 
treatment.
Gefitinib:  For patients whose disease has progressed in Part C Period 1, gefitinib may be 
continued at the discretion of the investigator, provided that the patient can still benefit 
from the treatment. Patients who continue on gefitinib after disease progression cannot 
continue onto Period 2.
Ramucirumab:  For patients whose disease has progressed in Part C Period 1, treatment 
with ramucirumab will continue into Period 2. For patients who are not eligible to 
continue onto Period 2, ramucirumab should be discontinued.

If a patient deteriorates to an Eastern Cooperative Oncology Group performance status 
(ECOG PS) of ≥3, all study treatments are to be discontinued.  In case of PS deterioration 
of <3, disease progression should be ruled out.

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
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 the National Cancer Institute-Common Terminology Criteria 
for Adverse Events version 4.0 (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 serious adverse event (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).
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.
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 (Part C Attachment 1).  
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 Part C Attachment 1.  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 8.1.5.4.
8.1.  Summary of Study Design
Part C of Study JVCY is an open-label, 2-period, single-arm, multicenter, exploratory study.  
Period 1 will evaluate the efficacy and safety of treatment with gefitinib (250 mg daily) plus 

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ramucirumab (10 mg/kg every 2 weeks) in previously untreated Japanese patients with EGFR
mutation-positive metastatic NSCLC.  Period 2 will evaluate the efficacy and safety of treatment 
with osimertinib (80 mg daily) plus ramucirumab (10 mg/kg every 2 weeks) in Japanese patients 
with T790M- positive metastatic NSCLC and who were previously treated with ramucirumab
plus gefitinib in this study.
Part C will enroll approximately 100 patients.
The study treatment in Part C is considered to be ramucirumab in combination with gefitinib
(Period 1) and ramucirumab in combination with osimertinib (Period 2) or any component of the 
combination.
Patients in Part C will receive ramucirumab 10 mg/kg every 2 weeks, in combination with 
gefitinib (Period 1; Figure JVCY(9).1).  Ramucirumab and gefitinib treatment will continue until 
disease progression, development of unacceptable toxicity, or any other discontinuation criteria 
are met.  For patients whose disease has progressed in Part C Period 1, gefitinib may be 
continued at the discretion of the investigator, provided that the patient can still benefit from 
treatment.  Patients continuing on gefitinib following disease progression cannot continue onto 
Period 2.  For patients whose disease has progressed in Part C Period 1, treatment with 
ramucirumab will continue into Period 2.  For patients who are not eligible to continue onto 
Period 2, ramucirumab should be discontinued.  
Screening period for Period 2 begins 1 day after that the patient signs his or her informed consent 
to participate in Period 2.  Patients who meet continuation criteria for Period 2 will receive 
ramucirumab 10 mg/kg every 2 weeks in combination with osimertinib (Period 2;
Figure JVCY(9).1).  Patients who do not meet continuation criteria of Period 2 (see Section 
8.1.5.2.1) within 12 weeks from decision of study treatment discontinuation of Period 1 should 
be discontinued from study.
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(9).1 for Part C illustrate the study design.

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Abbreviations: D/C = discontinuation; ECOG PS = Eastern Cooperative Oncology 
Group performance status; EGFR = epidermal growth factor receptor; MRI = magnetic 
resonance imaging; NSCLC = non-small cell lung cancer; PFS = progression-free 
survival; q2w = every 2 weeks; TKI = tyrosine kinase inhibitor.
Figure JVCY(9).1.
Illustration of study design for Clinical Protocol I4T-MC-JVCY in 
Part C.
8.1.5.  Part C (Exploratory study)
8.1.5.1.  Baseline and Study Treatment Period Assessments
Baseline radiographic assessment of disease will be performed within 28 days in both Periods 1 
and 2 prior to enrollment.  For Period 1, first dose of any study treatment will be administered 
within 7 days of enrollment assigning a patient to the treatment.  Imaging requirements include 
computed tomography (CT) scan or magnetic resonance imaging (MRI) of the 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 (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 reaction(s) to CT 
contrast material, a contrast-enhanced MRI of the chest/abdomen/pelvis is encouraged.  A 
contrast-enhanced MRI of the central nervous system (CNS) will be performed at baseline prior 
to first dose of any study treatment for all patients in Part C (per Exclusion Criterion [15] 

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regarding CNS metastases).  Scans performed prior to the date of consent may be used provided 
they are within 28 days of first dose of any study treatment.  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) in both Periods 1 and 2, and 
include the period of treatment with gefitinib in Period 1 or osimertinib in Period 2 given on 
Day 1 in combination with ramucirumab.  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 will receive:

Ramucirumab on Day 1 of every 2-week cycle as an IV infusion over 
approximately 60 minutes, followed by a 1-hour observation period.  If there is no 
evidence of an infusion-related reaction (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).

Gefitinib tablets in Period 1 or osimertinib tablets in Period 2 orally every day.  
On Day 1 of each cycle, patients will receive gefitinib or osimertinib after 
completion of the ramucirumab infusion (after the observation period post 
ramucirumab infusion).
Administration and dosing of all therapeutic products will occur as described in Section 9.1.
The criteria for starting the next cycle are defined in Section 9.4.2.1.1.  Dose reductions for 
ramucirumab 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 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
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 in Period 1 and does not 
continue onto Period 2, 1 additional tumor scan will be collected at the short-term follow-up visit 
unless the patient has received additional anticancer therapy or study treatment prior to this visit.  
Thereafter, radiologic tests are no longer required (Part C Attachment 1).
For Period 1, patients 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 whose disease has progressed in Part C Period 1, 
gefitinib may be continued at the discretion of the investigator, provided that the patient can still 
benefit from the treatment.  Patients on gefitinib cannot continue onto Period 2.  For patients 
whose disease has progressed in Part C Period 1, treatment with ramucirumab will continue into 

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Period 2.  For patients who are not eligible to continue onto Period 2, ramucirumab should be 
discontinued.  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, death, start of Period 2.  Long-term 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 8.1.5.4.
During the screening period for Period 2, radiographic assessment should be completed as part of 
the baseline assessment of Period 2 within 28 days prior to enrollment of Period 2.
For Period 2, radiographic assessments are to be performed every 6 weeks (±7 days) following
enrollment of Period 2 for the 72 weeks, and every 12 weeks (±7 days) thereafter, even if 
treatment is delayed, until there is radiographic documentation of PD.  Further radiographic 
assessments after treatment discontinuation will not be required for patients who discontinue for 
reasons other than radiographically documented PD to commence alternative treatment.
Following all study treatment discontinuation, follow-up information regarding further 
anticancer treatment and survival status will be collected every 3 months (± 14 days).
8.1.5.2.  Screening Period for Period 2
The screening period for Period 2 begins one day after the patient signs his or her informed 
consent to participate in Period 2. Patients who meet continuation criteria of Period 2 can start 
administration of study treatment of Period 2 (see Section 8.1.5.2.1).  Patients who do not meet 
continuation criteria of Period 2 within 12 weeks from a first PD after study treatment of Period
1 should be discontinued from the study.  Patients who will start next treatment other than Period
2 treatment or decide not to move to Period 2 must be followed for 30 days (±7 days) after the 
decision is made that the patient will be discontinued from the study. 
8.1.5.2.1.  Continuation criteria for Part C Period 2:  Transition from Period 1 
(Ramucirumab/Gefitinib) to Period 2 (Ramucirumab/Osimertinib)
Patients who meet continuation criteria of Period 2 can continue into Period 2.  
Patient who hascontinued ramucirumab after disease progression should maintain the same 
schedule as Period 1.
Patients who do not meet the continuation criteria of Period 2 within 12 weeks from a first PD 
after study treatment of Period 1 should be discontinued from the study. 
If ramucirumab was permanently discontinued in Period 1 (i.e. toxicities/AEs), this patient 
cannot be included in Period 2.  
Ramucirumab can be administered once the patient has recovered from the prior toxicities/AEs. 
Osimertinib can be administered after continuation criteria are met.

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Those patients who do not meet discontinuation criteria (see Section 7.3) are eligible to be 
included in Period 2 only if they meet the following continuation criteria prior to study treatment 
in Period 2:
The patient has given their written informed consent to participate in Period 2 of 
the study and is amenable to compliance with protocol schedules and testing.
The patient has confirmed T790M-positive status using a test validated and 
performed locally after disease progression on gefitinib treatment received in 
Period 1 of the study.
The patient has serum albumin that is ≥25 g/L at the time of screening period for 
Period 2.
The patient has resolution to Grade ≤1 (except alopecia, hypertension), by the 
NCI-CTCAE, v4.0, of all clinically significant toxic effects in Period 1 of the 
study.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.
The patient did not permanently discontinue ramucirumab treatment prior to
Period 2 for a reason other than PD (that is, AE or toxicity).
The patient does not have superior vena cava syndrome.
The patient does not have any evidence of clinically active interstitial lung 
disease.  Asymptomatic patients with chronic, stable, radiographic changes are 
eligible.
The patient does not have preexisting idiopathic pulmonary fibrosis as evidenced 
by CT scan/X-ray at baseline; have or had any disease of acute lung injury, 
idiopathic pulmonary fibrosis, or pneumoconiosis evident on an X-ray; have or 
had any disease of radiation pneumonia or drug-induced pneumonia.
The patient does not have SpO2 <94 (room air).
The patient does not have any of the following cardiac abnormal findings:

Mean resting QTc >470 msec obtained from 3 ECGs, using the screening 
clinic ECG machine-derived QTc value

Any clinically important abnormalities in rhythm, conduction, or 
morphology of resting ECG; for example, complete left bundle branch 
block, third-degree heart block, or second-degree heart block

Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, 
family history of long QT syndrome or unexplained sudden death under 
40 years of age in first-degree relatives, or any concomitant medication 
known to prolong the QT interval

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
Have a history of any of the following conditions:  presyncope or syncope 
of either unexplained or cardiovascular etiology, ventricular arrhythmia 
(including but not limited to ventricular tachycardia and ventricular 
fibrillation), or sudden cardiac arrest
8.1.5.3.  Postdiscontinuation Follow-Up Period Assessments
If a patient discontinues treatment due to objective disease progression in Period 1 and does not 
continue onto Period 2, 1 additional tumor scan will be collected at the short-term follow-up visit 
unless the patient has received additional anticancer therapy or study treatment prior to this visit.  
Thereafter, radiologic tests are no longer required (Part C Attachment 1).
Adverse event information will be collected until at least 30 days after the decision is made to 
discontinue from all study treatments of Period 1 and those of Period 2.  After the short-term 
follow-up visit, only new and ongoing SAEs deemed related to study treatment will be collected.
8.1.5.4.  Study Completion and End of Trial
Figure JVCY(9).2 is a diagram of the study period and continued access period.  Study period of 
Part C will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) when study completion of Part B has occurred, or when OS events have occurred in 
half of the patients entered into Period 1, whichever comes later.  “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.
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.

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Abbreviation:  OS = overall survival.
Figure JVCY(9).2.
Study period and continued access period diagram for Part C.
8.1.5.5.  Study Duration
The duration in Part C from first patient treatment until last patient visit for PFS2 is 
approximately 55 months.
9.1.  Treatments Administered
Table JVCY(9).1 shows the treatment regimens in Period 1 of Part C.

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Table JVCY(9).1.
Treatment Regimens/Dosing Schedule in Period 1 of Part C
Study Drug
Dose
Route
Timing
Ramucirumaba
10 mg/kg
IV
Over 60 minutes infusion on Day 1 of each 2-week 
cycle
1-hour observation periodb
followed by
Gefitinibc
250 mg
PO
Daily
Abbreviations:  IV = 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 Grades 1 to 
2 infusion-related reaction, as detailed in Section 9.4.2.1.2.1. All premedications 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 if an infusion-related reaction occurs 
thereafter, then the 1-hour observation period should be reinstituted.
c
Gefitinib will be taken after the observation period (if reinstituted), 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 
gefitinib.
Table JVCY(9).2 shows the treatment regimens in Period 2 of Part C.
Table JVCY(9).2.
Treatment Regimens/Dosing Schedule in Period 2 of Part C
Study Drug
Dose
Route
Timing
Ramucirumaba
10 mg/kgb
IV
Over 60 minutes infusion on Day 1 of each 
2-week cycle
1-hour observation periodc
followed by
Osimertinibd
80 mg
PO
Daily
Abbreviations:  IRR = infusion-related reaction; IV = 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 Grades 1 to 
2 IRR, as detailed in Section 9.4.2.1.2.1.  All premedications administered must be adequately documented in the 
electronic case report form.  
b
Dose escalations are NOT allowed after dose reductions in Period 1.
c
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 IRR during the initial 2 infusions of ramucirumab, then no observation period is 
required for subsequent treatment cycles.  In the event if an IRR occurs thereafter, then the 1-hour observation 
period should be reinstituted.  Refer to Section 9.4.2.1.2.1 for further instructions in detail.
d
Refer to Section 9.4 for further instructions on taking osimertinib.

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9.1.1.  Premedication
9.1.1.3.  Premedication Prior to Gefitinib
Investigators should consult the manufacturer’s instructions for gefitinib for complete 
prescribing information (including warnings, precautions, contraindications, and adverse 
reactions) and follow institutional procedures for the administration of gefitinib.  All 
premedications administered must be adequately documented in the eCRF.
9.1.1.4.  Premedication Prior to Osimertinib
Investigators should consult the manufacturer’s instructions for osimertinib for complete 
prescribing information (including warnings, precautions, contraindications, and adverse 
reactions) and follow institutional procedures for the administration of osimertinib.  All 
premedications administered must be adequately documented in the eCRF.
9.2.  Materials and Supplies
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
Ramucirumab will be supplied to sites by Lilly.  Gefitinib and osimertinib may be supplied by 
the sites where commercially available or supplied to the sites by Lilly Japan.
9.2.1.  Study Drugs
9.2.1.4.  Gefitinib
Gefitinib is a commercially available product.  Investigators should consult the manufacturer’s 
instructions for gefitinib for complete prescribing information and follow institutional procedures 
for the administration of gefitinib, 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.
9.1.2.1.5.  Osimertinib
Osimertinib is a commercially available product.  Investigators should consult the 
manufacturer`s instructions for osimertinib for complete prescribing information and follow 
institutional procedures for the administration of osimertinib, including testing for T790M
mutation status.  The specific mutation(s) identified and the name of the test method used to 
document evidence of T790M mutation positivity will be documented in the eCRF.
9.2.2.  Storage and Preparation
9.2.2.3.  Gefitinib Storage and Preparation
Refer to the most recent version of the gefitinib (IRESSA®) package insert for storage guidance.
9.2.2.4.  Osimertinib Storage and Preparation
Refer to the most recent version of the osimertinib (TAGRISSO®) package insert for storage 
guidance.

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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 in Part C.
9.4.  Selection and Timing of Doses
For Part C, ramucirumab will be administered over a 1-hour IV infusion on Day 1 of each cycle
(every 2 weeks) at a dose of 10 mg/kg.
Gefitinib will be administered orally as a once-daily dose of 250 mg.  Refer to the most recent 
version of the gefitinib (IRESSA®) package insert for administration, and prohibited and 
restricted concomitant therapy.
Osimertinib will be administered orally as a once-daily dose of 80 mg.  Refer to the most recent 
version of the osimertinib (TAGRISSO®) package insert for administration, and prohibited and 
restricted concomitant therapy.
9.4.2.  Dose Delays or Dose Modifications
9.4.2.1.1.
Dose Delays (Delays for Subsequent Cycles) for Ramucirumab
Part C:
If the criteria listed above are not met, the next ramucirumab dosing should be delayed for up to 
2 weeks to allow for recovery.  The gefitinib and osimertinib treatment should be continued 
during the delay of ramucirumab if the patient does not meet the criteria of delay and/or 
discontinuation for gefitinib and osimertinib dosing per package insert (refer to Sections
9.4.2.3.1 and 9.4.2.4.1, respectively).  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, except in the transition between Periods 1 and 2 in Part C
regardless occurrence of AE.  The gefitinib and osimertinib treatment should be continued, with 
the patient remaining in the study, if clinically indicated.  For patients whose disease has 
progressed in Part C Period 1, treatment with ramucirumab will continue into Period 2.  For 
patients who are not eligible to continue onto Period 2, ramucirumab should be discontinued.
9.4.2.3.  Gefitinib
9.4.2.3.1.  Dose Delays and Dose Modifications for Gefitinib
Patients receiving ramucirumab plus gefitinib can withhold gefitinib for up to 3 weeks if the 
toxicity is specifically attributable to gefitinib at the discretion of the investigator per the package 
insert.  Patients may continue treatment with ramucirumab if they discontinue gefitinib.  For 
patients whose disease has progressed in Part C Period 1, gefitinib may be continued at the 
discretion of the investigator, provided that the patient can still benefit from treatment. Patients 
on gefitinib cannot continue onto Period 2.

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Patients should be treated following the recommendations, warnings, and precautions given for 
gefitinib in the package insert or the user guidance of gefitinib.  Patients also may refer to the 
following dose modification guidance in Table JVCY(9).3.

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Table JVCY(9).3.
Gefitinib Dose Modification
Event and Gradea
Gefitinib 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 ruled out, resume 
gefitinib treatment

If ILD is diagnosed, 
permanently discontinue 
study treatment and institute 
appropriate treatment
Gastrointestinal perforation
All grades
Interrupt, pending the diagnostic 
evaluation:

If gastrointestinal perforation 
is ruled out, resume gefitinib 
treatment

If gastrointestinal perforation 
is diagnosed, permanently 
discontinue study treatment 
and institute appropriate 
treatment
Diarrhea
Grade 1 or 2
None
Consider loperamide:  4 mg at first 
onset, followed by 2 mg every 2 to 4 
hours until diarrhea-free for 12 hours
Grade 3 or any grade unresponsive to 
loperamide, or diarrhea that causes 
dehydration
Interrupt until resolution to 
Grade ≤1 (up to 3 weeks) or 
baseline, and resume gefitinib 
treatment
Manage as for Grade 1; supportive 
care as appropriate (refer to 
Section 9.6.1.1)
Grade 4
Discontinue gefitinib treatment
Manage as for Grade 1; supportive 
care as appropriate (refer to 
Section 9.6.1.1)
Skin reaction
Tolerated rash (Grade 2 or 3)
None 
Any of the following: minocycline, 
topical tetracycline, topical 
clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral 
prednisone (short course)
Intolerated rash
Interrupt dosing, up to 3 weeks 
until be successfully managed 
followed by resuming of gefitinib 
treatment
Manage as for Grade 1
Grade 4
Discontinue gefitinib treatment
Manage as for Grade 1
Severe hepatitis, liver failure, liver 
dysfunction 
Interrupt dosing, up to 3 weeks 
until be successfully managed 
followed by restart of gefitinib 
treatment
Supportive care as appropriate

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Event and Gradea
Gefitinib Dose Modifications
Guidelines for Management
Abnormal liver function test
(hepatitis without liver failure)
Grade 1 (>ULN - 3.0×ULN)
Gefitinib treatment can be 
continued
Supportive care as appropriate
Grade 2 (>3.0×ULN - 5.0×ULN) or 
Grade 3 (>5.0×ULN - 20.0×ULN)
Interrupt until resolution to 
Grade ≤1 (up to 3 weeks) or 
baseline and restart gefitinib 
treatment
Supportive care as appropriate
Grade 4 (>20.0×ULN)
Discontinue gefitinib treatment
Supportive care as appropriate
Eye symptoms (such as pain)
Signs and symptoms of severe or 
worsening ocular disorders including 
keratitis
Interrupt gefitinib therapy, after 
symptoms and eye changes have 
resolved, the decision should be 
made concerning resume of 
gefitinib treatment
Removal of an aberrant eyelash if 
present
Persistent ulcerative keratitis
Discontinue gefitinib treatment
Abbreviations:  ILD = interstitial lung disease; ULN = upper limit of normal.
a
National Cancer Institute-Common Terminology Criteria for Adverse Events v4.0 (NCI 2009).
In addition to the common gefitinib toxicities in Table JVCY(9).3, if a patient experiences other 
Grade 3 or 4 events that are considered at least possibly related to gefitinib, gefitinib 
administration may be delayed for up to 3 weeks until resolution.  
If the event resolves to ≤Grade 1 or baseline, the patient may restart gefitinib treatment.
9.4.2.4.  Osimertinib
9.4.2.4.1.  Osimertinib Dose Adjustments, Delays, and Discontinuation
Patients should be treated following the recommendations, warnings, and precautions given for 
osimertinib in the package insert or the user guidance of osimertinib.  Patients may also refer to
the following dose modification guidance in Table JVCY(9).4.

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Table JVCY(9).4.
Osimertinib Dose Modifications
Target Organ
Adverse Reactiona
Osimertinib Dose Modification
Pulmonary
Interstitial lung disease 
(ILD)/pneumonitis
Permanently discontinue osimertinib
Cardiac
QTc interval greater than 500 msec on at 
least 2 separate ECGs
Withhold osimertinib until QTc interval is less 
than 481 msec or recovery to baseline if baseline 
QTc is greater than or equal to 481 msec, then 
resume at a 40-mg dose
QTc interval prolongation with 
signs/symptoms of life-threatening 
arrhythmia
Permanently discontinue osimertinib
Asymptomatic, absolute decrease in 
LVEF of 10% from baseline and below 
50%
Withhold osimertinib for up to 3 weeks
• If improved to baseline LVEF, resume
• If not improved to baseline, permanently 
discontinue
Symptomatic congestive heart failure
Permanently discontinue osimertinib
Other
Grade 3 or higher adverse reaction
Withhold osimertinib for up to 3 weeks
If improvement to Grades 0-2 within 
3 weeks
Osimertinib may be restarted at the same dose 
(80 mg) or a lower dose (40 mg)
If no improvement within 3 weeks
Permanently discontinue osimertinib
Abbreviations:  ECGs = electrocardiograms; LVEF = left ventricular ejection fraction; QTc = QT interval corrected 
for heart rate.
a
Adverse reactions graded by the National Cancer Institute-Common Terminology Criteria for Adverse Events 
version 4.0 (NCI CTCAE v4.0).
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 IV 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 IRESSA and 
TAGRISSO package insert and Sections 9.4.2.3.1 and 9.4.2.4.1 for gefitinib and osimertinib
dose delays and modifications for guidance.
9.6.2.  Prohibited and Restricted Concomitant Therapy
For Part C, refer to the IRESSA and TAGRISSO package insert for gefitinib and osimertinib 
prohibited and restricted concomitant therapy for guidance.
9.7.  Treatment Compliance
Patient compliance with gefitinib and osimertinib 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 

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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.
10.1.1.  Efficacy Assessments at Baseline and during Study Treatment
For Part C, the method of tumor assessment used at baseline must be used consistently 
throughout the study.  Patients must be enrolled with at least 1 measurable disease based on 
RECIST, version 1.1.  Disease assessment will be undertaken at baseline (within 28 days prior to 
enrollment) for each of Period 1 and Period 2 (if applicable), and then every 6 weeks (±7 days) 
as calculated from the first dose of study therapy for each of Period 1 and Period 2 (if 
applicable), 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).
10.4.2.  Samples for Translational Research
Required samples for biomarker and pharmacogenetic research to be collected from all patients 
in this study, unless restricted per local regulations, are the following:

plasma samples from the whole blood (mandatory for Part C; see Sections 10.4.2.1 and 
10.4.2.3)

whole blood sample for DNA collection (mandatory for Part C; see Section 10.4.2.2)

archived tumor tissue (optional for Part C; see Section 10.4.2.3) 
 
 
 
 
 
10.4.2.1.  Blood Sample for Plasma Collection
 
 
 
  Sampling timepoints are shown in the Study Schedule (Part C Attachment 1 and Part C 
Attachment 2).
CCI
CCI

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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 (Part C Attachment 
1).  Variable response to ramucirumab and gefitinib/osimertinib 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 gefitinib/osimertinib.  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.
10.4.2.3.  Tumor Tissue Samples
Submission of archived tumor tissue is highly encouraged for Part C but is not mandatory.  
Pathology notes accompanying archival tissue may also be requested (de-identified and 
translated).  
 
 
 
 
 
 The paraffin-embedded blocks will be sectioned and 
sent back to the site.  Slides will not be returned.
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 on C1D1).  For patients in 
CCI
CCI

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Part C, additional blood samples for immunogenicity testing will be collected BEFORE the 
infusion of ramucirumab on C4D1, and at the 30-day short-term follow-up visit (as noted in Part 
C Attachment 2). 
10.4.4.  Samples for Ramucirumab Drug Concentration Measurements Pharmacokinetics
Whole blood samples will be collected for all patients in Part C and processed as serum, as 
specified in the Part C Schedule for Ramucirumab Pharmacokinetic, Immunogenicity, and 
Translational Research Sampling Schedule (Part C Attachment 2).
In either Part C, 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.
12.1.  Determination of Sample Size
Part C:
Approximately, 100 previously untreated Japanese patients with EGFR mutation-positive 
metastatic NSCLC will be enrolled and treated with ramucirumab plus gefitinib.
A 1-year PFS rate for bevacizumab plus gefitinib in patients with EGFR mutation-positive 
metastatic NSCLC reported 56.7% (95% CI: 39.9, 70.5) (Ichihara et al. 2015).  Given an 
expected 1-year PFS rate of 55% for ramucirumab plus gefitinib, 96 patients are required to 
generate 1-year PFS rate estimate whose 95% confidence half-width is <10%.
12.2.1.1.  Analysis Populations

Part C ITT Population:  All patients who will be enrolled to study treatment during Part 
C.

Part C Safety Population:  All enrolled patients who received at least 1 dose of any study 
treatment in Part C.  The Part C safety population will be used for all dosing/exposure, 
AEs, and resource utilization analyses.  The safety summaries may be provided by 
period.
All the analyses for Part C will be conducted separately, unless otherwise stated.  
Pharmacodynamic and/or tailoring biomarker analyses will be based on the subset ITT 
population in Part C from whom a valid assay result (according to laboratory guideline) has been 
obtained.
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 gefitinib/osimertinib 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.

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12.2.7.  Primary Outcome and Methodology
12.2.7.3.  Part C
The primary endpoint of the exploratory Part C of Study JVCY is the investigator-assessed 1-
year PFS rate in Period 1. A 1-year PFS rate is defined as the cumulative proportion of patients 
who survived during the first year (that is, 1 year from enrollment) in the study without disease 
progression. 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 Table JVCY.9.  
Progression-free survival curves, the median with 95% CI, and survival rates at various time 
points including 1-year PFS rate will be estimated using Kaplan-Meier method (Kaplan and 
Meier 1958).
12.2.8.  Secondary Outcome and Methodology
12.2.8.4.  PFS2 in Periods 1 and 2 and PFS in Period 2
To define either of PFS2 in Periods 1 and 2 or PFS in Period 2, the second occurrence of PD 
should be judged. The baseline tumor measurement of the second occurrence of PD should be 
performed immediately before starting osimertinib treatment. Progression-free survival 2 in 
Periods 1 and 2 is defined as the duration from enrollment (assignment to treatment) to the 
second occurrence of PD. Progression-free survival in Period 2 is defined as the duration from a 
day with the baseline tumor measurement before osimertinib treatment to the second occurrence 
of PD. Progression-free survival curves, the median with 95% CI, and survival rates at various 
time points will be estimated using Kaplan-Meier method (Kaplan and Meier 1958).   
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 may be explored. Details 
will be described in the Statistical Analysis Plan.
12.2.14.  Safety Analyses
12.2.14.3.  Part C
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

I4T-MC-JVCY(9) Clinical Protocol Addendum
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
Adverse events, treatment-emergent adverse event (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, 
granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage CSF), 
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 TEAE is defined as an event that first occurred or worsened in severity after baseline.
12.2.16.  Interim Analyses
12.2.16.3.  Part C
The sponsor may analyze the data from Part C for reporting preliminary results to the regulatory 
authority, when the primary analysis for Part B is performed.
Trial Level Safety Review by Lilly Clinical Research Physician will periodically perform the 
safety monitoring for Part C every 6 months since first subject has been entered to treatment in 
Period 1.

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5. References
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, 
Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, 
Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, 
Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated 
resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046-1061.
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.
Govindan R. INTERESTing biomarker to select IDEAL patients for epidermal growth factor 
receptor tyrosine kinase inhibitors: yes, for EGFR mutation analysis, others, I PASS. J Clin 
Oncol. 2010;28(5):713-715.
Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, Vlahovic G, Soh CH, O’Connor 
P, Hainsworth J. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced 
non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-
blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846-1854.
Ichihara E, Hotta K, Nogami N, Kuyama S, Kishino D, Fujii M, Kozuki T, Tabata M, Harada D, 
Chikamori K, Aoe K, Ueoka H, Hosokawa S, Bessho A, Hisamoto-Sato A, Kubo T, Oze I, 
Takigawa N, Tanimoto M, Kiura K. A phase II trial of gefitinib in combination with 
bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating 
EGFR gene mutations: The Okayama Lung Cancer Study Group Trial 1001. J Thoracic Oncol. 
2015;10(3):486-491.
Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, 
Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Saijo Y, 
Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Updated overall survival 
results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for 
chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann 
Oncol. 2013;24(1):54-59.
Inoue A, Yoshida K, Morita S, Imamura F, Seto T, Okamoto I, Nakagawa K, Yamamoto N, 
Muto S, Fukuoka M. Characteristics and overall survival of EGFR mutation-positive non-
small cell lung cancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis 
for 1660 Japanese patients. Jpn J Clin Oncol. 2016;46(5):462-467.
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, 
Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, 
Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. 
N Engl J Med. 2015;372(18):1689-1699.
Johnson BE, Kabbinavar F, Fehrenbacher L, Hainsworth J, Kasubhai S, Kressel B, Lin CY, 
Marsland T, Patel T, Polikoff J, Rubin M, White L, Yang JC, Bowden C, Miller V. ATLAS: 
randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab 
therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for 

I4T-MC-JVCY(9) Clinical Protocol Addendum
Page 33
LY3009806
first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol.
2013;31(31):3926-3934.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53(282):457-481.
Meador CB, Jin H, de Stanchina E, Nebhan CA, Pirazzoli V, Wang L, Lu P, Vuong H, 
Hutchinson KE, Jia P, Chen X, Eisenberg R, Ladanyi M, Politi K, Zhao Z, Lovly CM, Cross 
DA, Pao W. Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung 
cancer. Mol Cancer Ther. 2015;14(2):542-552.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada 
H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu 
E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Oncology Group. Gefitinib 
versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring 
mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised 
phase 3 trial. Lancet Oncol. 2010;11(2):121-128.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, 
Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield 
EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. 2009. Published
date: May 29, 2009.
Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, 
Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, 
Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with 
advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): 
an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-1244.
Shepherd FA, Pereira JE, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, 
Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, 
Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of 
Canada Clinical Trials Group. Erlotinib in previously treated non–small-cell lung cancer. N 
Engl J Med. 2005;353(2):123-132.
Stahel RA, Dafni U, Gautschi O, Felip E, Curioni-Fontecedro A, Peters S, Massutí B, Cardenal 
F, Aix SP, Früh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, Carcereny E, 
Sanchez Ronco M, Molina MA, Rosell R. A phase II trial of erlotinib (E) and bevacizumab 
(B) in patients with advanced non-small-cell lung cancer (NSCLC) with activating epidermal 
growth factor receptor (EGFR) mutations with and without T790M mutation. The Spanish 
Lung Cancer Group (SLCG) and the European Thoracic Oncology Platform (ETOP) BELIEF 
trial. European Cancer Congress 2015. Abstract number: 3BA.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Part C Attachment 1.
Protocol JVCY Part C Study Schedule

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Study Schedule, Protocol I4T-MC-JVCY
Perform procedures as indicated.
Baseline Schedule (Period 1 in Part C)
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 21 days (except where noted)
Relative Day to Enrollment
≤21
≤14
Procedure 
Category
Protocol 
Section
Procedure
Comments
Study 
Entry/Enroll
ment
7
13.1
Informed Consent Form signed (prior to conducting any 
protocol-specific tests/procedures)
X
Obtain informed consent prior to any study-related procedures or 
evaluations.  The investigator or the Sponsor will not grant 
exceptions to eligibility criteria.
7.1, 7.2
Inclusion/Exclusion evaluation
X
All inclusion/exclusion criteria must be met for a patient to be 
considered eligible for study entry of Part C Period 1.  The 
patient will be enrolled via IWRS after meeting 
inclusion/exclusion criteria.
Medical 
History
10.3.1
Att. 5
Initial history (including smoking history)/preexisting 
conditions/disease characteristics
X
Any preexisting and pretreatment toxicity (treatment or disease 
related) should be documented and recorded as part of the 
pretreatment medical history, as well as smoking history.  
Disease characteristics at initial diagnosis and at study entry will 
be collected.
Att. 5
Demography
X
Date of birth, sex, and race/ethnicity will be collected at baseline.
Att. 5
Prior treatment therapy of underlying disease
X
Prior treatment includes any treatment for underlying disease, 
including maintenance therapy.  Start and stop dates should be 
documented as well.
Physical 
Examination
Att. 5
Physical examination (including height and weight)
X
Height measurements to be performed at baseline only.  A time 
window of -7 days is permitted for the C1D1 physical 
examination.
Att. 5
ECOG PS
X
A time window of -7 days is permitted for the C1D1 ECOG PS.
Att. 5
Vital signs
X
Includes blood pressure, pulse, respiratory rate, temperature, and 
SpO2.  The results of the SpO2 test will not be collected on the 
eCRF.
Concomitant 
Medications
9.6
Concomitant medications
X (within 30 days)
Concomitant medications will be recorded, including any taken 
within 30 days prior to start of study treatment.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Baseline Schedule (Period 1 in Part C)
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 21 days (except where noted)
Relative Day to Enrollment
≤21
≤14
Procedure 
Category
Protocol 
Section
Procedure
Comments
Laboratory/
Diagnostic 
Tests
7.1
Att. 3
Hematology (local)
X
Hematology will be collected for local laboratory testing.  If 
enrollment hematology profile is collected within 7 days of 
C1D1, the profile does not need to be repeated at C1D1. 
7.1
Att. 3
Serum chemistry including thyroid tests and HgbA1c
(central)
X
If enrollment chemistry profile is collected within 7 days of 
Day 1, Cycle 1, the profile does not need to be repeated at C1D1.  
Central chemistry laboratory results will be used to determine 
patient eligibility at baseline.  For dosing decisions, bilirubin and 
AST/ALT are required to be collected locally and centrally.  
Thyroid tests (TSH and free T4) and HgbA1c will be collected 
for safety monitoring and will be performed at a central lab.
7.1
Att. 3
Coagulation profile (local)
X
If enrollment coagulation bloodwork is collected within 7 days of 
C1D1, the profile does not need to be repeated.  Patients 
receiving warfarin should be switched to LMWH as per 
institutional guidelines, and have achieved stable coagulation 
profile prior to enrollment.
7.1
Att. 3
Att. 10
Urinalysis (local)
X
At baseline, dipstick measurements should be done within 7 days 
prior to C1D1.  If urine dipstick or routine analysis indicates 
proteinuria ≥2+, a 24-hour urine collection (to assess protein) 
must be obtained.
7.1
Att. 3
Att. 5
Pregnancy test (local)
X
At baseline, serum pregnancy testing for women of childbearing 
potential will be performed locally.  The results of this test will 
not be collected on the eCRF.
7.1
FSH (local)
X
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.
10.4.2.3
Tumor tissue
X
This tissue collection is for the evaluation of potential 
biomarkers.  Either archived tumor tissue or tissue from a recent 
biopsy may be submitted.  FFPE tissue provided should be from 
the Stage IV NSCLC diagnosis and not an earlier staging; 
Submission of archived tumor tissue is highly encouraged for 
Part C but is not mandatory.
10.4.2.3
Plasma sample (see comments) 
X
Unless restricted by local regulations, the plasma sample for 
disease characterization is required ONLY for patients who do 
not submit Stage IV disease tissue samples
7.1
Att. 5
Echocardiogram or MUGA
X
7.1
Att. 5
ECG (local)
X
A single ECG is to be obtained within 21 days prior to 
enrollment.  In the event the ECG is abnormal at baseline, a 
repeat confirmation triplicate ECG will be requested.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Baseline Schedule (Period 1 in Part C)
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 21 days (except where noted)
Relative Day to Enrollment
≤21
≤14
Procedure 
Category
Protocol 
Section
Procedure
Comments
Health 
Outcomes
10.2.1
PRO assessments (LCSS, EQ-5D-5L)
X
The instruments should be completed before any extensive 
contact and consultation which may bias patient responses.  It is 
recommended that the instruments be administered together, with 
the LCSS completed first, followed by the EQ-5D-5L.
Efficacy
Assessment
10.1.1
Att. 5
Att. 7
Imaging/tumor assessments (according to RECIST v1.1)
X (within 28 days)
Baseline radiological tumor assessment per RECIST version 1.1 
should be done during screening.  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 enrollment
for all patients.  Bone scans and PET scans may be performed if 
clinically indicated (refer to Attachment 5 for further details).  
All baseline radiological reports will be collected and sent to the 
central imaging vendor, preferably prior to C1D1.  For screening, 
scans performed prior to the date of consent may be used 
provided they are within 28 days of enrollment.
Patient Disposition
X
At the time that the patient is discontinued from study 
participation, information regarding the patient status will be 
collected.
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BL = baseline; C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = electronic case report form; EQ-5D-5L = EuroQoL 5 Dimensions 5 Levels; 
FFPE = formalin-fixed paraffin embedded; FSH = follicle-stimulating hormone; HgbA1c = glycated hemoglobin; IWRS = Interactive Web Response System; LCSS = Lung Cancer Symptom Scale; 
LMWH = low molecular weight heparin; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NSCLC = non-small cell lung cancer; PET = positron emission tomography; PRO = 
patient-reported outcome; RECIST = Response Evaluation Criteria In Solid Tumors; TSH = thyroid-stimulating hormone.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Study Schedule, Protocol I4T-MC-JVCY
Perform procedures as indicated.
Treatment Period Schedule (Period 1 in Part C)
Study Period
Treatment Period
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Visit
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination
Att. 5
Physical 
examination
(including weight)
X
X
X
X
X
X
X
X
X
Patients should be weighed at the beginning of each cycle.  Height 
measurements to be performed at baseline only.  After Cycle 1, a time 
window of -4 days is permitted for the Day 1 physical examination.
Att. 5
ECOG PS
X
X
X
X
X
X
X
X
X
Complete prior to treatment infusion.  After Cycle 1, a time window of -4
days is permitted for the Day 1 ECOG PS.  
Att. 5
Vital signs
X
X
X
X
X
X
X
X
X
Includes blood pressure, pulse, respiratory rate, and temperature.  To be 
obtained at every treatment visit, within 30 minutes prior to and after the 
completion of each infusion of ramucirumab.  If there is a post-infusion 
observation period, then vital signs measurements should also be obtained at 
the end of the observation period.  In the event of an infusion-related 
reaction, the respiration rate will be collected.
Laboratory/
Diagnostic 
Tests
Att. 3
Hematology (local)
X
X
X
X
X
X
X
X
Performed locally within 4 days prior to treatment on Day 1 of each cycle, 
after Cycle 1.  If results of the laboratory tests obtained at planned Day 1 of 
the next cycle require a delay in the start of the subsequent cycle, repeat 
laboratory tests should be obtained, as clinically indicated.  
Att. 3
Serum chemistry 
(selected tests 
local/central)
X
X
X
X
X
X
X
X
Performed centrally within 4 days prior to treatment on Day 1 of each cycle 
after Cycle 1.  For dosing decisions, bilirubin and AST/ALT are required to 
be collected locally and centrally.  If enrollment serum chemistry profile is 
collected within 7 days of C1D1, the profile does not need to be repeated.
Att. 3
Coagulation profile 
(local)
X
X
X
Performed locally within 4 days prior to treatment on Day 1 of the required 
cycle (after Cycle 1).  Beginning at Cycle 4, coagulation profile performed 
every 4 cycles or more frequently, as clinically indicated.  Coagulation 
parameters to be tested include INR or PT, and PTT/aPTT.
Att. 3
Att. 10
Urinalysis (local)
X
X
X
X
X
X
X
X
While a patient is being treated with ramucirumab, dipstick or routine 
analysis measurements should be done within 4 days prior to treatment at 
every cycle, after Cycle 1.  Results should be available at the time of the next 
dosing decision.  For further information on events of proteinuria, see Section  
9.4.2.1.2.7 and Attachment 10.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Treatment Period Schedule (Period 1 in Part C)
Study Period
Treatment Period
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Visit
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Procedure 
Category
Protocol 
Section
Procedure
Comments
Att. 3
Att. 5
Pregnancy test 
(local)
X
X
X
X
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of β-HCG).  Every 2 cycles (or per institutional guidelines, whichever is 
more frequent), pregnancy testing for women of childbearing potential will 
be performed locally (not collected on the eCRF).  If the urine pregnancy test 
is positive, confirm with a serum pregnancy test.
Att. 5
ECG (local)
X
X
X
X
Twelve-lead ECG within 4 days prior to treatment on C3D1, C5D1, and 
every 2 cycles thereafter (and if clinically indicated), at the discontinuation of 
gefitinib, at the discontinuation of ramucirumab, and at the short-term follow-
up.
10.4.3
10.4.4
Part C Att. 2
Immunogenicity
Refer to Part C Attachment 2 for timepoints.
Immunogenicity blood work to be collected BEFORE the first infusion of 
ramucirumab on C1D1 of treatment.  If a patient experiences an IRR to 
ramucirumab, blood samples for immunogenicity and PK analysis will be 
taken at the following time points:  (1) as soon as possible after the onset of 
the IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
10.4.4
Part C Att. 2
Pharmacokinetics
Refer to Part C Attachment 2 for timepoints.
10.4.2.2
Part C Att. 2
Whole blood sample
Refer to Part C Attachment 2 for timepoints.
Sample will be used for SNP and possible other translational research assays, 
as applicable.  It is highly recommended to draw the whole-blood sample 
prior to the first dose.  However, it can be collected later during the study if 
necessary.  Mandatory for Period 1 in Part C.
10.4.2.1
Part C Att. 2
Plasma sample 
Refer to Part C Attachment 2 for timepoints.
Plasma samples will be used for the analysis of circulating factors and will be 
collected prior to the infusion on C1D1, and on C4D1.  Mandatory for Period
1 in Part C.  

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Treatment Period Schedule (Period 1 in Part C)
Study Period
Treatment Period
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Visit
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Procedure 
Category
Protocol 
Section
Procedure
Comments
Health 
Outcomes
10.2.1
PRO assessments 
(LCSS, EQ-5D-5L)
X
X
X
X
X
The patient will undergo assessment for symptoms and QoL using the LCSS 
and the EQ-5D-5L at Cycle 2, thereafter at every other cycle.  The 
instruments should be completed before any extensive contact and 
consultation which may bias patient responses.  It is recommended that the 
instruments be administered together, with the LCSS completed first, 
followed by the EQ-5D-5L.
Efficacy
Assessment
10.1.1
Att. 5
Att. 7
Imaging/tumor 
assessments 
X
X
X
Disease assessment will be every 6 weeks (±7 days) as calculated from the 
first dose of study therapy, and after 72 weeks while on study, imaging must 
be performed every 12 weeks (±7 days).  The method used at baseline must 
be used consistently for tumor assessment.  CT scan or MRI of the chest and 
upper abdomen including both adrenal glands are required, with pelvic 
imaging performed if clinically indicated.  Bone scans and PET scans may be 
performed if clinically indicated (refer to Attachment 5 for further details).
Adverse Events 
Collection/
CTCAE 
Grading
10.3
Toxicity assessment
X
All AEs/SAEs will be followed for up to 30 days after the patient and 
investigator agree that the patient will no longer continue study treatment.
Concomitant 
Therapy
9.6
Concomitant 
medications
X
X
X
X
X
X
X
X
X
Concomitant medications will be recorded throughout the treatment period, 
including those taken during the 30 days after the last dose of all study 
treatment.
Premedication
9.1.1
Administer 
premedication (list 
on eCRF)
X
X
X
X
X
X
X
X
X
Refer Section 7.3 for discontinuation guidance and Section 9.4 for selection 
and timing of dosing.  First dose of any study treatment will be administered 
within 7 days of enrollment.  Gefitinib (250 mg) is self-administered per os
(by mouth) once daily.
Study 
Treatment
9.1
Administer 
ramucirumab
X
X
X
X
X
X
X
X
X
9.1
Administer gefitinib
X
X
X
X
X
X
X
X
X
Patient Disposition
X
At the time that the patient is discontinued from any component of the study 
treatment or Study Participation, information regarding the patient status will 
be collected.
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; β-HCG = beta-human chorionic gonadotropin; 
C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group
performance status; eCRF = electronic case report form; EQ-5D-5L = EuroQoL 5 Dimensions 5 Levels; INR = international normalized ratio; IRR = infusion-related reaction; LCSS = Lung Cancer 
Symptom Scale; MRI = magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetic; PT = prothrombin time; PTT = partial thromboplastin time; QoL = quality of life; 
SAE = serious adverse event; SNP = single nucleotide polymorphism.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Study Schedule, Protocol I4T-MC-JVCY
Perform procedures as indicated.
Post-Treatment Discontinuation Schedule (Period 1 in Part C)
Study Period
Post-discontinuation Follow-Up
Short-term follow-up
Long-term follow-up
Visit
801
802-8XX
Duration
30 ± 3 days
See footnote for duration
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination 
Att. 5
Physical examination
(including weight)
X
Att. 5
Vital signs
X
Includes blood pressure, pulse, respiratory rate, and temperature.
Att. 5
ECOG PS
X
Laboratory/
Diagnostic 
Tests
Att. 3
Hematology (local)
X
Hematology will be collected for local laboratory testing.
Att. 3
Serum chemistry including 
thyroid tests and HgbA1c 
(central)
X
Chemistry will be collected for central laboratory testing.
Att. 3
Coagulation profile (local)
X
Coagulation will be collected for local laboratory testing.
Att. 3
Att. 10
Urinalysis (local)
X
If urine dipstick or routine analysis indicates proteinuria ≥2+, a 24-hour urine 
collection (to assess protein) must be obtained.
Att. 3
Att. 5
Pregnancy test (local)
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of β-HCG).  If the urine pregnancy test is positive, confirm with a serum 
pregnancy test (pregnancy test results are not recorded on the eCRF).
Att. 5
Echocardiogram or MUGA
X
Att. 5
ECG (local)
X
A single ECG will be performed.  In the event the ECG is abnormal, a repeat 
confirmation triplicate ECG will be performed.
10.4.3
10.4.4
Part C 
Att. 2
Immunogenicity
Refer to Part C 
Attachment 2 for 
timepoints and 
additional notes.
Immunogenicity sample to be collected at the short-term follow-up.   
In the event of an IRR reaction, 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.  
Part C 
Att. 2
Pharmacokinetics
Refer to Part C 
Attachment 2 for 
timepoints and 
additional notes.
PK sample to be collected at the short-term follow-up.  In the event of an IRR 
reaction, 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.
10.4.2
Part C 
Att. 2
Plasma sample
X
The plasma samples will be used for the analysis of circulating proteins, to be 
collected at the short-term follow-up.
Health 
Outcomes
10.2.1
PRO assessments (LCSS, 
EQ-5D-5L)
X
The patient will undergo assessment for symptoms and QoL using the LCSS 
and the EQ-5D-5L.  The instruments should be completed before any 
extensive contact and consultation which may bias patient responses.  It is 
recommended that the instruments be administered together, with the LCSS 
completed first, followed by the EQ-5D-5L.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Post-Treatment Discontinuation Schedule (Period 1 in Part C)
Study Period
Post-discontinuation Follow-Up
Short-term follow-up
Long-term follow-up
Visit
801
802-8XX
Duration
30 ± 3 days
See footnote for duration
Procedure 
Category
Protocol 
Section
Procedure
Comments
Efficacy 
Assessments
Att. 5
Att. 7
Imaging/tumor assessments 
(every 6 weeks [ ±7 days], 
and after 72 weeks while on 
study, imaging must be 
performed every 12 weeks 
[±7 days])
X
X
For patients who discontinue study treatment without objectively measured 
PD, disease assessment will continue to be assessed every 6 weeks (±7 days) 
as calculated from the first dose of study therapy, and after 72 weeks while on 
study, imaging must be performed every 12 weeks (±7 days).  The method 
used at baseline must be used consistently for tumor assessment.  If a patient 
discontinues treatment due to objective disease progression in Period 1 and 
does not continue onto Period 2, 1 additional tumor scan will be collected at 
the short-term follow-up visit unless the patient has received additional 
anticancer therapy or study treatment prior to this visit.  Thereafter, radiologic 
tests are no longer required.
The long-term follow-up consists of follow-up for survival and/or PFS2.
10.2.1
Survival information and 
subsequent anticancer 
treatments
X
Patients will be followed for survival data and subsequent anticancer 
treatments will be collected after discontinuation of study drug at regularly 
scheduled intervals (every 3 months [± 14 days]) until death or study 
completion, whichever occurs first.  This follow-up might be a phone call to 
the patient, her/his family, or local doctor for the collection of survival data 
and subsequent antitumor therapies.
Adverse Events 
Collection/
CTCAE 
Grading
10.3
Toxicity assessment
X
X
All AEs/SAEs will be followed for up to 30 days after the patient and 
investigator agree that the patient will no longer continue study treatment.
Concomitant 
Medication 
Notation
9.6
Concomitant medications
X
Concomitant medications taken during the 30 days after the last dose of all 
study treatment will be recorded.
Patient Disposition
X
X
At the time that the patient is discontinued from Study Participation, 
information regarding the patient status will be collected.
Abbreviations:  AE = adverse event; β-HCG = beta-human chorionic gonadotropin; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = 
electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = electronic case report form; EQ-5D-5L = EuroQoL 5 Dimensions 5 Levels; IRR = infusion-related 
reaction; LCSS = Lung Cancer Symptom Scale; MUGA = multigated acquisition; PD = progressive disease; PFS2 = progression-free survival 2; PK = pharmacokinetic; PRO = patient-reported 
outcome; QoL = quality of life; SAE = serious adverse event.
Short-term follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts until the short-term follow-up visit is completed, 
approximately 30 days (±3 days) after the end of study treatment.
Long-term follow-up begins the day after short-term follow-up is completed and continues every 6 weeks (±7 days), and after 72 weeks while on study, imaging must be performed every 12 weeks (±7 
days) until PD, thereafter every 3 months (±14 days) until the patient’s death or overall study completion.  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.  Although it is not mandatory, PFS2, based on radiographic assessment, is recommended.  For patient to be entered into Period 2, the long-term follow-
up began after a short-term follow-up in Period 2 is completed.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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LY3009806
Study Schedule, Protocol I4T-MC-JVCY
Perform procedures as indicated.
Continued Access Period Schedule (Period 1 in Part C)
Study Period
Continued Access 
Treatment Period
Continued Access 
Follow-Up Period
Cycle
X-Y
Follow-up
Visit
501-5XX
901
Duration
1
30 ± 3 days
Procedure 
Category
Protocol 
Section
Procedure
Comments
Adverse Events 
Collection/CTCAE 
Grading
10.3
Toxicity assessment
X
X
All AEs/SAEs will be followed for up to 30 days after the patient 
and investigator agree that the patient will no longer continue 
study treatment.
Laboratory/Diagno
stic Tests
10.4.3
10.4.4
Part C 
Att. 2
Immunogenicity/PK
Only if applicable
If a patient experiences an IRR to ramucirumab, blood samples 
for immunogenicity and PK analysis will be taken at the 
following time points:  (1) as soon as possible after the onset of 
the IRR, (2) at the resolution of the IRR, and (3) 30 days after 
the IRR.  
Premedication
9.1.1
Administer premedication (list on eCRF)
X
Refer Section 7.3 for discontinuation guidance and Section 9.4
for selection and timing of dosing.  In the event of a medication 
error, investigative sites must inform Lilly within 24 hours of 
becoming aware of the error.  Gefitinib (250 mg) is self-
administered per os (by mouth) once daily.
Study Treatment
9.1
Administer ramucirumab
X
9.1
Administer gefitinib (daily)
X
Patient Disposition
X
X
At the time that the patient is discontinued from any component 
of the study treatment or study participation, information 
regarding the patient status will be collected.  Information 
regarding the patient status will also be collected at the continued 
access follow-up visit.  This follow-up might be a phone call to 
the patient, her/his family, or local doctor.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic case report form; IRR = infusion-related reaction; PK = pharmacokinetics; 
SAE = serious adverse event.
Continued access follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment in the continued access period, and lasts until the continued
access follow-up visit is completed, approximately 30 days (±3 days) later.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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LY3009806
Baseline Schedule (Period 2 in Part C)
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 21 days (except where 
noted)a
Relative Day to Enrollment
≤21
≤14
Procedure 
Category
Protocol 
Section
Procedure
Comments
Study 
Entry/Enroll
ment
8.1.5.2.1
13.1
Informed Consent Form signed (prior to conducting any 
protocol-specific tests/procedures for Period 2)
X
(allowable during 12 weeks after 
PD in Period 1)
Obtain informed consent prior to any study-related procedures or 
evaluations for entering Period 2.  The investigator or the 
Sponsor will not grant exceptions to eligibility criteria.
8.1.5.2.1
Continuation criteria evaluation
X
Patients who meet continuation criteria of Period 2 can continue 
into Part C Period 2
8.1.5.2.1
T790M test (local)
X
(allowable >21 days prior to 
starting treatment)
If the result of T790M has discrepancy between plasma and 
tissue, investigator use the result of tissue.
Physical 
Examination
Att. 5
Physical examination (including weight)
X
Height measurements to be performed at baseline only.  A time 
window of -7 days is permitted for the C1D1 physical 
examination.
Att. 5
ECOG PS
X
A time window of -7 days is permitted for the C1D1 ECOG PS.
Att. 5
Vital signs
X
Includes blood pressure, pulse, respiratory rate, temperature, and 
SpO2.  The results of the SpO2 test will not be collected on the 
eCRF.
Concomitant 
Medications
9.6
Concomitant medications
X (within 30 days)
Concomitant medications will be recorded, including any taken 
within 30 days prior to start of study treatment.
Laboratory/
Diagnostic 
Tests
Att. 3
Hematology (local)
X
Hematology will be collected for local laboratory testing.  If 
enrollment hematology profile is collected within 7 days of 
C1D1, the profile does not need to be repeated at C1D1. 
Att. 3
Serum chemistry including thyroid tests and HgbA1c
(central)
X
If enrollment chemistry profile is collected within 7 days of 
Day 1, Cycle 1, the profile does not need to be repeated at C1D1.  
Central chemistry laboratory results will be used to determine 
patient eligibility at baseline.  For dosing decisions, bilirubin and 
AST/ALT are required to be collected locally and centrally.  
Thyroid tests (TSH and free T4) and HgbA1c will be collected 
for safety monitoring and will be performed at a central 
laboratory.
Att. 3
Coagulation profile (local)
X
If enrollment coagulation bloodwork is collected within 7 days of 
C1D1, the profile does not need to be repeated.  Patients 
receiving warfarin should be switched to LMWH as per 
institutional guidelines, and have achieved stable coagulation 
profile prior to enrollment.
Att. 3
Att. 10
Urinalysis (local)
X
At baseline, dipstick measurements should be done within 7 days 
prior to C1D1.  If urine dipstick or routine analysis indicates 
proteinuria ≥2+, a 24-hour urine collection (to assess protein) 
must be obtained.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Baseline Schedule (Period 2 in Part C)
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 21 days (except where 
noted)a
Relative Day to Enrollment
≤21
≤14
Procedure 
Category
Protocol 
Section
Procedure
Comments
Att. 3
Att. 5
Pregnancy test (local)
X
At baseline, serum pregnancy testing for women of childbearing 
potential will be performed locally.  The results of this test will 
not be collected on the eCRF.
10.4.2.3
Plasma sample 
X
Required sample following gefitinib treatment prior to start of 
osimertinib treatment for all patients for disease characterization. 
Att. 5
Echocardiogram or MUGA
X
Att. 5
ECG (local)
X
A single ECG is to be obtained within 21 days prior to 
enrollment.  In the event the ECG is abnormal at baseline, a 
repeat confirmation triplicate ECG will be requested.
Health 
Outcomes
10.2.1
PRO assessments (LCSS, EQ-5D-5L)
X
The instruments should be completed before any extensive 
contact and consultation which may bias patient responses.  It is 
recommended that the instruments be administered together, with 
the LCSS completed first, followed by the EQ-5D-5L.
Efficacy
Assessment
10.1.1
Att. 5
Att. 7
Imaging/tumor assessments (according to RECIST v1.1)
X (within 28 days)
Baseline radiological tumor assessment per RECIST version 1.1 
should be done during screening.  CT scan or MRI of the 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 enrollment
for all patients.  Bone scans and PET scans may be performed if 
clinically indicated (refer to Attachment 5 for further details).  
All baseline radiological reports will be collected and sent to the 
central imaging vendor, preferably prior to C1D1.  For screening, 
scans performed prior to the date of consent may be used 
provided they are within 28 days of enrollment.
Patient Disposition
X
At the time that the patient is discontinued from study 
participation, information regarding the patient status will be 
collected.
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BL = baseline; C1D1 = Cycle 1 Day 1; CNS = central nervous system; CT = computed tomography; ECG = 
electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = electronic case report form; EQ-5D-5L = EuroQoL 5 Dimensions 5 Levels; HgbA1c = glycated 
hemoglobin; LCSS = Lung Cancer Symptom Scale; LMWH = low molecular weight heparin; MRI = magnetic resonance imaging; MUGA = multigated acquisition; PET = positron emission 
tomography; PRO = patient-reported outcome; RECIST = Response Evaluation Criteria In Solid Tumors; TSH = thyroid-stimulating hormone.
a
If a procedure item is done in Period 1 within the allowance of the baseline, the item does not need to be repeated at the baseline of Period 2.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Study Schedule, Protocol I4T-MC-JVCY
Perform procedures as indicated.
Treatment Period Schedule (Period 2 in Part C)
Study Period
Treatment Period
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Visit
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination
Att. 5
Physical 
examination
(including weight)
X
X
X
X
X
X
X
X
X
Patients should be weighed at the beginning of each cycle.  Height 
measurements to be performed at baseline only.  After Cycle 1, a time 
window of -4 days is permitted for the Day 1 physical examination.
Att. 5
ECOG PS
X
X
X
X
X
X
X
X
X
Complete prior to treatment infusion.  After Cycle 1, a time window of -4
days is permitted for the Day 1 ECOG PS.  
Att. 5
Vital signs
X
X
X
X
X
X
X
X
X
Includes blood pressure, pulse, respiratory rate, and temperature.  To be 
obtained at every treatment visit, within 30 minutes prior to and after the 
completion of each infusion of ramucirumab.  If there is a post-infusion 
observation period, then vital signs measurements should also be obtained at 
the end of the observation period.  In the event of an infusion-related 
reaction, the respiration rate will be collected.
Laboratory/
Diagnostic 
Tests
Att. 3
Hematology (local)
X
X
X
X
X
X
X
X
Performed locally within 4 days prior to treatment on Day 1 of each cycle, 
after Cycle 1.  If results of the laboratory tests obtained at planned Day 1 of 
the next cycle require a delay in the start of the subsequent cycle, repeat 
laboratory tests should be obtained, as clinically indicated.  
Att. 3
Serum chemistry 
(selected tests 
local/central)
X
X
X
X
X
X
X
X
Performed centrally within 4 days prior to treatment on Day 1 of each cycle 
after Cycle 1.  For dosing decisions, bilirubin and AST/ALT are required to 
be collected locally and centrally.  If enrollment serum chemistry profile is 
collected within 7 days of C1D1, the profile does not need to be repeated.
Att. 3
Coagulation profile 
(local)
X
X
X
Performed locally within 4 days prior to treatment on Day 1 of the required 
cycle (after Cycle 1).  Beginning at Cycle 4, coagulation profile performed 
every 4 cycles or more frequently, as clinically indicated.  Coagulation 
parameters to be tested include INR or PT), and PTT/aPTT.
Att. 3
Att. 10
Urinalysis (local)
X
X
X
X
X
X
X
X
While a patient is being treated with ramucirumab, dipstick or routine 
analysis measurements should be done within 4 days prior to treatment at 
every cycle, after Cycle 1.  Results should be available at the time of the next 
dosing decision.  For further information on events of proteinuria, see Section 
9.4.2.1.2.7 and Attachment 10.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Treatment Period Schedule (Period 2 in Part C)
Study Period
Treatment Period
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Visit
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Procedure 
Category
Protocol 
Section
Procedure
Comments
Att. 3
Att. 5
Pregnancy test 
(local)
X
X
X
X
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of β-HCG).  Every 2 cycles (or per institutional guidelines, whichever is 
more frequent), pregnancy testing for women of childbearing potential will 
be performed locally (not collected on the eCRF).  If the urine pregnancy test 
is positive, confirm with a serum pregnancy test.
Att. 5
ECG (local)
X
X
X
X
Twelve-lead ECG within 4 days prior to treatment on C3D1, C5D1, and 
every 2 cycles thereafter (and if clinically indicated), at the discontinuation of 
osimertinib, at the discontinuation of ramucirumab, and at the short-term 
follow-up.
Echocardiogram or
MUGA
X
X
X
Every 12 weeks from C1D1 or if clinically indicated.
10.4.3
10.4.4
Part C Att. 2
Immunogenicity
Refer to Part C Attachment 2 for timepoints.
Immunogenicity blood work to be collected BEFORE the first infusion of 
ramucirumab on C1D1 of treatment.  If a patient experiences an IRR to 
ramucirumab, blood samples for immunogenicity and PK analysis will be 
taken at the following time points:  (1) as soon as possible after the onset of 
the IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
10.4.4
Part C Att. 2
Pharmacokinetics
Refer to Part C Attachment 2 for timepoints.
10.4.2.2
Part C Att. 2
Whole blood sample
Refer to Part C Attachment 2 for timepoints.
Sample will be used for SNP and possible other translational research assays, 
as applicable.  It is highly recommended to draw the whole blood sample 
prior to the first dose.  However, it can be collected later during the study if 
necessary.  Mandatory for Period 2 in Part C.
10.4.2.1
Part C Att. 2
Plasma sample 
Refer to Part C Attachment 2 for timepoints.
Plasma samples will be used for the analysis of circulating factors and will be 
collected prior to the infusion on C1D1, and on C4D1.  Mandatory for Period
2 in Part C.  
Health 
Outcomes
10.2.1
PRO assessments 
(LCSS, EQ-5D-5L)
X
X
X
X
X
The patient will undergo assessment for symptoms and QoL using the LCSS 
and the EQ-5D-5L at Cycle 2, thereafter at every other cycle.  The 
instruments should be completed before any extensive contact and 
consultation which may bias patient responses.  It is recommended that the 
instruments be administered together, with the LCSS completed first, 
followed by the EQ-5D-5L.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Treatment Period Schedule (Period 2 in Part C)
Study Period
Treatment Period
Cycle (14-day 
cycle ± 3 days)
1
2
3
4
5
6
7
8
9-X
Visit
1
2
3
4
5
6
7
8
9-X
Relative Day 
within Dosing 
Cycle
1
1
1
1
1
1
1
1
1
Procedure 
Category
Protocol 
Section
Procedure
Comments
Efficacy
Assessment
10.1.1
Att. 5
Att. 7
Imaging/tumor 
assessments 
X
X
X
Disease assessment will be every 6 weeks (±7 days) as calculated from the 
first dose of study therapy in Period 2, and after 72 weeks while on study, 
imaging must be performed every 12 weeks (±7 days).  The method used at 
baseline must be used consistently for tumor assessment.  CT scan or MRI of 
chest and upper abdomen including both adrenal glands are required, with 
pelvic imaging performed if clinically indicated.  Bone scans and PET scans 
may be performed if clinically indicated (refer to Attachment 5 for further 
details).
Adverse Events 
Collection/
CTCAE 
Grading
10.3
Toxicity assessment
X
All AEs/SAEs will be followed for up to 30 days after the patient and 
investigator agree that the patient will no longer continue study treatment.
Concomitant 
Therapy
9.6
Concomitant 
medications
X
X
X
X
X
X
X
X
X
Concomitant medications will be recorded throughout the treatment period, 
including those taken during the 30 days after the last dose of all study 
treatment.
Premedication
9.1.1
Administer 
premedication (list 
on eCRF)
X
X
X
X
X
X
X
X
X
Refer Section 7.3 for discontinuation guidance and Section 9.4 for selection 
and timing of dosing.  First dose of any study treatment will be administered 
within 7 days of enrollment.  Osimertinib (80 mg) is self-administered per os
(by mouth) once daily.
Study 
Treatment
9.1
Administer 
ramucirumab
X
X
X
X
X
X
X
X
X
9.1
Administer 
osimertinib
X
X
X
X
X
X
X
X
X
Patient Disposition
X
At the time that the patient is discontinued from any component of the study 
treatment or Study Participation, information regarding the patient status will 
be collected.
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; β-HCG = beta-human chorionic gonadotropin; 
C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group
performance status; eCRF = electronic case report form; EQ-5D-5L = EuroQoL 5 Dimensions 5 Levels; IRR = infusion-related reaction; LCSS = Lung Cancer Symptom Scale; MRI = magnetic 
resonance imaging; PET = positron emission tomography; PK = pharmacokinetic; PT = prothrombin time; PTT = partial thromboplastin time; QoL = quality of life; SAE = serious adverse event; SNP = 
single nucleotide polymorphism.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Study Schedule, Protocol I4T-MC-JVCY
Perform procedures as indicated.
Post-Treatment Discontinuation Schedule (Period 2 in Part C)
Study Period
Post-discontinuation Follow-Up
Short-term follow-up
Long-term follow-up
Visit
801
802-8XX
Duration
30 ± 3 days
See footnote for duration
Procedure 
Category
Protocol 
Section
Procedure
Comments
Physical 
Examination 
Att. 5
Physical examination
(including weight)
X
Att. 5
Vital signs
X
Includes blood pressure, pulse, respiratory rate, and temperature.
Att. 5
ECOG PS
X
Laboratory/
Diagnostic 
Tests
Att. 3
Hematology (local)
X
Hematology will be collected for local laboratory testing.
Att. 3
Serum chemistry including 
thyroid tests and HgbA1c 
(central)
X
Chemistry will be collected for central laboratory testing.
Att. 3
Coagulation profile (local)
X
Coagulation will be collected for local laboratory testing.
Att. 3
Att. 10
Urinalysis (local)
X
If urine dipstick or routine analysis indicates proteinuria ≥2+, a 24-hour urine 
collection (to assess protein) must be obtained.
Att. 3
Att. 5
Pregnancy test (local)
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of β-HCG).  If the urine pregnancy test is positive, confirm with a serum 
pregnancy test (pregnancy test results are not recorded on the eCRF).
Att. 5
Echocardiogram or MUGA
X
Att. 5
ECG (local)
X
A single ECG will be performed.  In the event the ECG is abnormal, a repeat 
confirmation triplicate ECG will be performed.
10.4.3
10.4.4
Part C 
Att. 2
Immunogenicity
Refer to Part C 
Attachment 2 for 
timepoints and 
additional notes.
Immunogenicity sample to be collected at the short-term follow-up.   
In the event of an IRR reaction, 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.  
Part C 
Att. 2
Pharmacokinetics
Refer to Part C 
Attachment 2 for 
timepoints and 
additional notes.
PK sample to be collected at the short-term follow-up.  In the event of an IRR 
reaction, 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.
10.4.2
Part C 
Att. 2
Plasma sample
X
The plasma samples will be used for the analysis of circulating proteins, to be 
collected at the short-term follow-up
Health 
Outcomes
10.2.1
PRO assessments (LCSS, 
EQ-5D-5L)
X
The patient will undergo assessment for symptoms and QoL using the LCSS 
and the EQ-5D-5L.  The instruments should be completed before any 
extensive contact and consultation which may bias patient responses.  It is 
recommended that the instruments be administered together, with the LCSS 
completed first, followed by the EQ-5D-5L.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Post-Treatment Discontinuation Schedule (Period 2 in Part C)
Study Period
Post-discontinuation Follow-Up
Short-term follow-up
Long-term follow-up
Visit
801
802-8XX
Duration
30 ± 3 days
See footnote for duration
Procedure 
Category
Protocol 
Section
Procedure
Comments
Efficacy 
Assessments
Att. 5
Att. 7
Imaging/tumor assessments 
(every 6 weeks [±7 days], 
and after 72 weeks while on 
study, imaging must be 
performed every 12 weeks 
[±7 days])
X
X
For patients who discontinue study treatment without objectively measured 
PD, disease assessment will continue to be assessed every 6 weeks (±7 days) 
as calculated from the first dose of study therapy, and after 72 weeks while on 
study, imaging must be performed every 12 weeks (±7 days).  The method 
used at baseline must be used consistently for tumor assessment.  If a patient 
discontinues treatment due to objective disease progression, 1 additional 
tumor scan will be collected at the short-term follow-up unless the patient has 
received additional anticancer therapy prior to this visit.  Thereafter, radiologic 
tests are no longer required.
The long-term follow-up consists of follow-up for survival and/or PFS2.
10.1.2
Survival information and 
subsequent anticancer 
treatments
X
Patients will be followed for survival data and subsequent anticancer 
treatments will be collected after discontinuation of study drug at regularly 
scheduled intervals (every 3 months [± 14 days]) until death or study 
completion, whichever occurs first.  This follow-up might be a phone-call to 
the patient, her/his family, or local doctor for the collection of survival data 
and subsequent antitumor therapies.
Adverse Events 
Collection/
CTCAE 
Grading
10.3
Toxicity assessment
X
X
All AEs/SAEs will be followed for up to 30 days after the patient and 
investigator agree that the patient will no longer continue study treatment.
Concomitant 
Medication 
Notation
9.6
Concomitant medications
X
Concomitant medications taken during the 30 days after the last dose of all 
study treatment will be recorded.
Patient Disposition
X
X
At the time that the patient is discontinued from Study Participation, 
information regarding the patient status will be collected.
Abbreviations:  AE = adverse event; β-HCG = beta-human chorionic gonadotropin; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = 
electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = electronic case report form; EQ-5D-5L = EuroQoL 5 Dimensions 5 Levels; IRR = infusion-related 
reaction; LCSS = Lung Cancer Symptom Scale; MUGA = multigated acquisition; PD = progressive disease; PFS2 = progression-free survival 2; PK = pharmacokinetic; PRO = patient-reported 
outcome; QoL = quality of life; SAE = serious adverse event.
Short-term follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts until the short-term follow-up visit is completed, 
approximately 30 days (±3 days) after the end of study treatment.
Long-term follow-up begins the day after short-term follow-up is completed and continues every 6 weeks (±7 days), and after 72 weeks while on study, imaging must be performed every 12 weeks (±7 
days) until PD, thereafter every 3 months (±14 days) until the patient’s death or overall study completion.  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.  Although it is not mandatory, PFS2, based on radiographic assessment, is recommended.

I4T-MC-JVCY(9) Clinical Protocol Addendum
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Study Schedule, Protocol I4T-MC-JVCY
Perform procedures as indicated.
Continued Access Period Schedule (Period 2 in Part C)
Study Period
Continued Access 
Treatment Period
Continued Access 
Follow-Up Period
Cycle
X-Y
Follow-up
Visit
501-5XX
901
Duration
1
30 ± 3 days
Procedure 
Category
Protocol 
Section
Procedure
Comments
Adverse Events 
Collection/CTCAE 
Grading
10.3
Toxicity assessment
X
X
All AEs/SAEs will be followed for up to 30 days after the patient 
and investigator agree that the patient will no longer continue 
study treatment.
Laboratory/Diagno
stic Tests
10.4.3
10.4.4
Part C 
Att. 2
Immunogenicity/PK
Only if applicable
If a patient experiences an IRR to ramucirumab, blood samples 
for immunogenicity and PK analysis will be taken at the 
following time points:  (1) as soon as possible after the onset of 
the IRR, (2) at the resolution of the IRR, and (3) 30 days after 
the IRR.  
Premedication
9.1.1
Administer premedication (list on eCRF)
X
Refer Section 7.3 for discontinuation guidance and Section 9.4
for selection and timing of dosing.  In the event of a medication 
error, investigative sites must inform Lilly within 24 hours of 
becoming aware of the error.  Osimertinib (80 mg) is self-
administered per os (by mouth) once daily.
Study Treatment
9.1
Administer ramucirumab
X
9.1
Administer osimertinib (daily)
X
Patient Disposition
X
X
At the time that the patient is discontinued from any component 
of the study treatment or study participation, information 
regarding the patient status will be collected.  Information 
regarding the patient status will also be collected at the continued 
access follow-up visit.  This follow-up might be a phone call to 
the patient, her/his family, or local doctor.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic case report form; IRR = infusion-related reaction; PK = pharmacokinetics; 
SAE = serious adverse event.
Continued access follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment in the continued access period, and lasts until the continued
access follow-up visit is completed, approximately 30 days (±3 days) later.

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Part C Attachment 2.
Protocol JVCY Part C
Pharmacokinetic, Immunogenicity, and Translational 
Research Sampling Schedule
It is essential that the exact infusion start and stop times (actual clock readings), as well as 
infusion parameters (such as, type of infusion pump, flow rate settings) are recorded.  The exact 
time of collection of each venous blood sample will be based on the clock used to record 
infusion times.  It is essential that the PK blood samples not be withdrawn from the same site as 
the drug infusion.  Sample collection times may vary to within 1 to 1.5 hours after the end of 
ramucirumab infusion outlined in the PK sampling schedule.
Protocol I4T-MC-JVCY Schedule for Ramucirumab Pharmacokinetic, Immunogenicity, 
and Translational Research Sampling for Period 1 and Period 2 of Part C
Visit
Time
Serum 
Ramucirumab
PKa
Immuno-
genicitya
Tumor 
Tissue 
Collectionb
Plasma 
Whole 
Blood for 
DNA
Day 1 of 
Cycle 1
Predosec
X
X
X
Xd
Xe
1 hour after 
the end of 
ramuciruma
b infusion
X
Day 1 of 
Cycle 2
Predosef
X
Day 1 of 
Cycle 4
Predosef
X
X
X
Day 1 of 
Cycle 7
Predosef
X
Day 1 of Cycle
14
Predosef
X
1 hour after 
the end of 
ramuciruma
b infusion
X
30 (±10) days
after 
discontinuation 
of 
ramucirumabg,h
Anytime
X
X
X
Note:  It is essential that the draw dates and draw times are accurately recorded.
Abbreviations:  C1D1 = Cycle 1, Day 1; IG = immunogenicity; PK = pharmacokinetic(s).
a
In the event of an infusion-related reaction, 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.
b
Optional.  Refer to Section 10.4.2.3 for details on tumor tissue collection.
c
Prior to the first infusion (baseline; may be obtained within 14 days prior to the initial infusion of ramucirumab).

I4T-MC-JVCY(9) Clinical Protocol Addendum
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d
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 prior to Period 1., unless restricted by local regulations. For all patients continuing into 
Period 2 (regardless of whether a Stave IV disease tissue sample was provided), a plasma sample for updated disease 
characterization is required following gefitinib treatment prior to start of osimertinib treatment, unless restricted by local 
regulations. If a plasma sample for disease characterization is not collected during the baseline period, the plasma sample 
may be requested during the treatment period.    
e
Prior to first infusion on C1D1 preferred, otherwise later during the trial is acceptable.
f
Prior to ramucirumab infusion.
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 or ramucirumab and gefitinib/osimertinib, PK/IG serum and plasma samples will 
be collected 30 (±10) days thereafter.  If a patient continues to take gefitinib/osimertinib after discontinuation of ramucirumab, 
additional PK/IG serum and plasma samples are NOT required after gefitinib/osimertinib discontinuation.

Leo Document ID = aa7b7e36-c77a-41ad-9d8c-cc99497fe1b0
Approver: 
Approval Date & Time: 15-Aug-2017 15:38:40 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 15-Aug-2017 18:06:00 GMT
Signature meaning: Approved
PPD
PPD