An Open-Label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination With Gemcitabine and Cisplatin in the First-Line Treatment of Patients With Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE1
Conditions: Squamous Non-small Cell Lung Cancer
Sponsor: Eli Lilly and Company

Protocol (e) I4X-JE-JFCM 
 
An Open-label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination with 
Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced (Stage IV) 
Squamous Non-Small Cell Lung Cancer (NSCLC) 
 
 
NCT01763788 
 
Approval Date: 12-Jun-2016 
 
 
 

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1.
Protocol I4X-JE-JFCM(e)
An Open-label, Multicenter, Phase 1b/2 Study to Evaluate 
Necitumumab in Combination with Gemcitabine and 
Cisplatin in the First-Line Treatment of Patients with 
Advanced (Stage IV) Squamous Non-Small Cell Lung 
Cancer (NSCLC)
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
Necitumumab (IMC-11F8; LY3012211), unless such persons are bound by a confidentiality 
agreement with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA)
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Necitumumab (IMC-11F8; LY3012211)
Gemcitabine (LY188011)
This is a Phase 1b/2 study in the first-line treatment of patients with advanced (Stage IV) 
Squamous Non-Small Cell Lung Cancer (NSCLC).  The study consists of a Phase 1b part 
and Phase 2 part.  The Phase 1b part is single arm, open-label, dose-escalation to 
determine the recommended dose for Phase 2 part.  The Phase 2 part is open-label, 
randomized study to evaluate efficacy and safety of necitumumab in combination with 
gemcitabine-cisplatin compared with gemcitabine-cisplatin alone.
Eli Lilly Japan K.K.
Kobe, Hyogo, Japan
Protocol Electronically Signed and Approved by Lilly: 05 Nov 2012
Amendment (a) Electronically Signed and Approved by Lilly: 19 Dec 2012
Amendment (b) Electronically Signed and Approved by Lilly: 03 Mar 2014
Amendment (c) Electronically Signed and Approved by Lilly: 22 Aug 2014
Amendment (d) Electronically Signed and Approved by Lilly: 06 Jan 2015
Amendment (e) Electronically Signed and Approved by Lilly 
on approval date provided below.
Approval Date: 12-Jun-2016 GMT

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2.
Synopsis
Study Rationale
Necitumumab (LY3012211; IMC-11F8) is a recombinant human monoclonal antibody (Mab) of 
the immunoglobulin G, subclass 1, that blocks the ligand binding site of the epidermal growth 
factor receptor (EGFR).  The EGFR is a member of the human EGFR family of tyrosine kinases.  
EGFR activation leads to stimulation of tyrosine kinase-dependent signal transduction pathways 
that can contribute to neoplastic transformation and tumor growth.  Inhibition of the EGFR 
pathway in cells can result in disruption of cell cycle progression and mitosis, and blocks the 
inhibitory effect on apoptosis.  Decreased angiogenesis may also occur as a result of EGFR 
inhibition through effects on angiogenic factor production.  
Necitumumab has shown in vivo antitumor activity against a variety of human xenograft tumors, 
including non-small cell lung cancer (NSCLC).  Phase 1 and 2 studies investigating 
necitumumab have provided information regarding safety and tolerability at clinically relevant 
doses, with preliminary evidence of clinical efficacy in a variety of human cancers.  
In clinical settings, the feasibility of administering EGFR-directed Mabs in combination with a 
standard platinum-based doublet in the first-line treatment of advanced NSCLC has been 
demonstrated in several randomized studies.  Two randomized Phase 3 studies were conducted 
with cetuximab in combination with either vinorelbine-cisplatin (FLEX; Pirker et al. 2009) or 
carboplatin-taxane (BMS-099; Lynch et al. 2010) as the chemotherapy backbone.  The addition 
of cetuximab to both regimens resulted in a statistically significant improvement in the best 
overall response rate (complete response [CR] partial response [PR]), but not in 
progression-free survival (PFS) in both studies.  In FLEX, a significant prolongation of overall 
survival (OS) with statistical significance was observed.  The analyses of both studies by 
histologic subtypes showed, that for cetuximab-containing regimens, a more pronounced trend in 
improvement of OS in squamous cell carcinoma (hazard ratio [HR] 0.80 [FLEX], HR 0.87 
[BMS-099]) than in adenocarcinoma (HR 0.94 [FLEX], HR 0.89 [BMS-099]) when compared to 
chemotherapy alone only.
According to current National Comprehensive Cancer Network (NCCN) guidelines, the 
combination chemotherapy of gemcitabine-cisplatin is a preferred regimen for patients with 
squamous cell NSCLC.  The data of treatment with combination chemotherapy suggest that 
patients with squamous histology may derive maximum benefit from a combination of biologic 
therapy with gemcitabine and cisplatin.  Gemcitabine is indicated in combination with cisplatin 
for the first-line treatment of patients with inoperable, locally advanced (Stage IIIa or IIIb), or 
metastatic (Stage IV) NSCLC, and has been shown to prolong survival.  Therefore 
chemobackbone of global Phase 3 study (CP11-0806) is gemcitabine-cisplatin. The primary 
objective of global Phase 3 study (CP11-0806) is to evaluate the OS in patients with Stage IV 
squamous NSCLC (per the American Joint Committee on Cancer [AJCC] Staging Manual, 
Seventh Edition) treated with necitumumab plus gemcitabine-cisplatin chemotherapy (Arm A) vs.
gemcitabine-cisplatin chemotherapy alone (Arm B) in the first-line metastatic setting.

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In this study, the efficacy of necitumumab in combination with gemcitabine-cisplatin 
chemotherapy will be evaluated in terms of OS in Japanese patient with advanced squamous 
NSCLC in Phase 2 part after confirming the tolerability of necitumumab in combination with 
gemcitabine-cisplatin chemotherapy in Phase 1b part.

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Clinical Protocol Synopsis:  Study I4X-JE-JFCM
Name of Investigational Product:  Necitumumab (LY3012211; IMC-11F8) and Gemcitabine (LY188011)
Title of Study:  An Open-label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination with 
Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced (Stage IV) Squamous Non-Small 
Cell Lung Cancer (NSCLC)
Number of Planned Patients:
Phase 1b Part
   Enrolled: 9 to 18
Phase 2 Part
   Enrolled: 190
   Randomized: 180 (up to 190 patients will be randomized)
Phase of Development: 
1b/2
Length of Study:
Planned first patient visit:  Dec 2012               Planned last patient visit:  Mar 2017
Planned interim analysis:  Planned interim analyses are performed to monitor the safety data.
Objectives:  
The primary objectives of this study are divided into two parts: the Phase 1b part and the Phase 2 part.
Phase 1b part: to investigate the safety and tolerability of necitumumab as measured by Dose-Limiting Toxicity 
(DLT), in combination with gemcitabine-cisplatin chemotherapy as first line treatment in patients with Stage IV 
squamous NSCLC and to determine the recommended dose for the subsequent Phase 2 study.
Phase 2 part: to evaluate the efficacy of necitumumab in combination with gemcitabine-cisplatin chemotherapy in 
terms of OS in patients with Stage IV squamous NSCLC in a first-line setting.
The secondary objectives of the study are:
Phase 1b part:

to investigate the safety profile as assessed by clinically significant events of necitumumab in combination 
with gemcitabine-cisplatin chemotherapy 

to investigate the anti-tumor effect.  

to assess pharmacokinetics (PK) of necitumumab, gemcitabine, and cisplatin  

to determine the immunogenicity of necitumumab
Phase 2 part:

to investigate the safety profile as assessed by clinically significant events of necitumumab in combination 
with gemcitabine-cisplatin chemotherapy 

to investigate PFS

to investigate objective response rate (ORR) 

to investigate time to treatment failure (TTF) 

to assess PK of necitumumab in combination with gemcitabine-cisplatin 

to assess Quality of Life (QOL; Patient-reported outcomes: PROs) using Lung Cancer Symptom Scale 
(LCSS) and EuroQol (EQ-5D)

to assess the relationship between EGFR protein expression (as measured by immunohistochemistry 
[IHC]) and each of several efficacy measures:  overall survival (OS), PFS, and best tumor response (ORR)

to determine the immunogenicity of necitumumab
Exploratory Objective is to further evaluate as follows:
Phase 1b/2 part:  to explore biomarkers including HER2 and HER3 protein expression (IHC), KRAS and 
EGFR mutation status, fragment C gamma receptor (FCγR) polymorphisms, and/or additional biomarkers of 
interest related to the necitumumab, gemcitabine, and cisplatin mechanism of action.

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Study Design:  This is a Phase 1b/2 study in the first-line treatment of patients with advanced (Stage IV) 
squamous NSCLC.  The study consists of a Phase 1b part and Phase 2 part.  The Phase 1b part is single arm, 
open-label, dose-escalation to determine the recommended dose for Phase 2 part.  The Phase 2 part is open-label, 
randomized study to evaluate efficacy and safety of necitumumab in combination with gemcitabine-cisplatin.  The 
target enrollment is 190 patients in Phase 2 part and patients will be randomly assigned on a 1:1 basis to 
necitumumab plus gemcitabine-cisplatin chemotherapy (Arm A) or gemcitabine-cisplatin chemotherapy alone 
(Arm B).  Randomization will be stratified by Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) (0 vs. 1) and gender (females vs. males).
Diagnosis and Main Criteria for Inclusion and Exclusions:
Key inclusion criteria at the time of enrollment (Phase 1b) or randomization (Phase 2)

Patient has histologically confirmed squamous NSCLC.

Patient has Stage IV NSCLC (based on the AJCC, Seventh Edition [Edge et al. 2009]).

Patients have measurable or nonmeasurable disease documented by computed tomography (CT) scan or 
magnetic resonance imaging (MRI) as defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 (Eisenhauer et al. 2009).

Patient has the ECOG PS of 0 or 1.  

The patient has not received prior anticancer therapy for NSCLC (eg, surgery, chest radiotherapy, 
systematic chemotherapy, and targeted therapy).

Patient has resolution to Grade 1 by the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) version 4.0, of all clinically significant toxic effects of prior therapy for 
other than NSCLC.
Test Product, Dosage, and Mode of Administration:  

Necitumumab is a sterile, preservative-free, intravenous (I.V.) infusion supplied in 50-mL vials containing 
16 mg/mL (800 mg/50 mL) of product, and administered over 50 minutes at a dose of 800 mg on Days 1 and 8 
of each 3-week cycle.

Gemcitabine is a lyophilized powder, I.V. infusion supplied in sterile vials containing 1 g as the hydrochloride 
salt (expressed as the free base), mannitol, and sodium acetate of product.  In the Phase 1b part, gemcitabine is
administered over approximately 30 minutes at a dose of 1000 or 1250 mg/m2 on Days 1 and 8 of each cycle 
for a maximum of 4 cycles.  In the Phase 2 part, gemcitabine is administered over approximately 30 minutes at 
a dose of 1250 mg/m2 on Days 1 and 8 of each cycle for a maximum of 4 cycles.
Reference Therapy, Dose, and Mode of Administration:  
Cisplatin, administered I.V. over approximately 120 minutes at a dose of 75 mg/m2 on Day 1 for a maximum of 
4 cycles.
Planned Duration of Treatment:  
Baseline period:  21 days
Treatment period: 21 days for a treatment cycle.  Necitumumab is administered on Days 1 and 8 of each 3-week 
cycle (21-day cycle), until the patient meets one or more of the discontinuation criteria.  Gemcitabine is 
administered on Days 1 and 8 of each 3-week cycle, and cisplatin is administered on Day 1 of each 3-week cycle, 
for a maximum of 4 cycles.
30-day safety follow-up period (post-discontinuation):  30 days
Long-term follow-up period (post-discontinuation):  Only new and ongoing serious adverse events (SAEs) deemed 
related to study treatment by the investigator will be collected every 90 days.
Study Completion: The point at which a 137 OS events (deaths) have been observed for final analysis
Study Extension:  Patients who are on study therapy at study completion may continue to receive study therapy in 
the extension phase until they meet the discontinuation criteria.

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Criteria for Evaluation:  
Efficacy:  
Overall Survival (OS): defined as the time from the date of randomization to the date of death from any cause.  
Patients who are alive at the time of study completion or are lost to follow-up will be censored at the time they 
were last known to be alive.  
Progression-Free Survival (PFS): defined as the time from the date of randomization until the date of 
radiographically documented progressive disease (PD) or death due to any cause, whichever is earlier.  
Time To Treatment Failure (TTF): defined as the time from the date of randomization until the date of the first 
observation of radiographically documented PD, death due to any cause, discontinuation of treatment for any 
reason, or initiation of new anticancer therapy.
Objective Response Rate (ORR): defined as the proportion of patients achieving a best response of PR or CR
Safety:  
Phase 1b: DLTs, SAEs, adverse events (AEs), vital sign measurements, laboratory analyses, electrocardiograms 
(ECGs)
Phase 2: SAEs, AEs, vital sign measurements, laboratory analyses, ECGs
Health Outcomes:  
All patients will undergo periodic evaluation of Health Outcomes, using:
(1) the LCSS; patient symptom scale only; and (2) the EQ-5D questionnaire.  
Bioanalytical:  
Blood concentration of necitumumab, gemcitabine, its deaminated metabolite 2',2'-difluorodeoxyuridine (dFdU),
and total and free platinum from cisplatin 
Pharmacokinetics: 
Pharmacokinetics parameters, including, but not limited to, maximum concentration (Cmax), area under the 
concentration-time curve (AUC), half-life (t1/2), clearance (CL), and volume of distribution (V) of necitumumab in 
combination with gemcitabine and cisplatin, will be estimated using noncompartmental methods of analysis.  Also 
AUC, Cmax, CL, t1/2, and V of gemcitabine combination with necitumumab and cisplatin will be analyzed, and 
AUC and Cmax of cisplatin combination with necitumumab and gemcitabine will be analyzed in the same manner.  
An exploratory population PK analysis may be performed if warranted by data and other validated PK software 
programs (for example, NONMEM) may be used.
Immunogenicity: 
Serum for analysis of antibodies against necitumumab (immunogenicity)
Translational Research:
A tumor tissue block or minimum of 5 tumor tissue slides will be collected for the assessment of EGFR protein 
expression (IHC), HER2 and HER3 protein expression (IHC), KRAS and EGFR mutation status.  Blood samples 
will be collected for the assessment of FCγR polymorphisms.  Additional biomarkers related to the necitumumab, 
gemcitabine and cisplatin mechanism of action may also be assessed.
Statistical Methods: 
The primary efficacy analyses will be conducted on the patients who are randomized and receive at least one dose 
of study treatment in Phase 2 part.  The sample size of 180 patients (137 events) for the primary efficacy evaluation 
set has 68% power for a log-rank test at 0.2 one-sided alpha under the following assumptions:

HR = 0.8 (median OS: 13.75 months vs. 11 months)

Study period of 38 months (Enrollment: 23 months, Follow-Up: 15 months)

Allocation 1:1
Since a dropout rate of 5% is considered, 190 patients is planned to be enrolled for Phase 2 part.
The final analysis will be performed when at least 137 events (deaths) are observed.
Efficacy: The primary efficacy analyses will be conducted on the full analysis set (FAS), defined as all patients 
who are randomized and receive at least one dose of study treatments, and patients will be grouped according to 
treatment received.
For the primary endpoint, OS, the Kaplan-Meier (KM) method will be used to generate KM curves, the medians, 

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quartiles and percentages of patients event-free every 3-month interval for each arm in FAS. The HR of Arm A to 
Arm B and its 95% confidence interval (CI) will be estimated using a stratified Cox regression model by the 
variables used for randomization (ECOG PS and gender), and a stratified log-rank test will be performed.
For ORR, a 95% CI of each arm will be calculated using an exact method, and the difference of ORR between two 
arms and its 95% CI will be estimated in FAS. The ORR will be compared between the test arm and the control 
arm using Fisher exact test.  
As for TTF and PFS, the same analysis as ones for OS will be performed.
In Phase 1b part, the ORR and CI will be calculated on the patients who are enrolled and treated separately.
Safety:  The safety analyses will be conducted on the Safety Population, defined as all treated patients in Phase 1b 
part and Phase 2 part.  
In Phase 1b part, DLT will be summarized by cohort in the patients who are evaluable for DLT assessments and be 
listed by patient.
For Phase 1b part, Phase 2 part and treated patients with necitumumab (Phase 1b Arm A in Phase 2 part), the 
following will be summarized and listed; TEAEs, AEs leading to dose adjustments for any study therapy, 
laboratory measures and vital signs.  
Health Outcomes: Health Outcomes (LCSS and EQ-5D) data will be separately summarized by treatment and time 
points using descriptive statistics and graphic displays.
Bioanalytical:  The result from PK assay and biomarker measurement will be summarized as descriptive statistics.
Pharmacokinetic:  Blood concentrations of necitumumab, gemcitabine, dFdU, and total and free platinum from
cisplatin at each sampling time point will be graphically summarized as time courses.   
PK parameters including CL and V may be estimated by population PK analysis.  
Immunogenicity: Incidence of anti-necitumumab antibodies will be tabulated. 
Pharmacokinetic/Pharmacodynamic:  Relationship with necitumumab drug level, efficacy, and safety will be 
assessed as appropriate.   
Translational Research:  Translational research analyses will be performed to analyze relevant biomarkers and to 
correlate them to clinical outcome.
Interim Analysis:
In Phase 1b part, the interim analysis will be performed after completing DLT evaluation period in Phase 1b part, 
and patient characteristics, laboratory values, DLTs, and AEs occurring in Cycle 1 might be summarized by cohort.
Additionally, even after the above interim analysis, the Sponsor might analyze the data for scientific disclosures.
During Phase 2 part, approximately 6 interim analyses will be performed to monitor the safety data of this study.  
The first interim analysis for safety monitoring will be performed after 50 patients in Phase 2 part have receives at 
least two cycles or 6 months after enrollment of the first patient in Phase 2 part, which is earlier.  After the first 
interim analysis, analyses will then be conducted every 6 months until all patients have discontinued all therapy (or 
until the study completion or the study has been terminated).  The independent data monitoring committee (IDMC)
members will review safety data at each interim analysis to determine whether there are sufficient safety concerns 
to justify the termination of study treatment and/or enrollment.
In addition, the Sponsor might consider the interim analysis for regulatory communication purposes. One of 
possible communications is a discussion of complete clinical data package with Pharmaceutical and Medical 
Devices Agency (PMDA), considering the results in the global Phase 3 which will be available during this study.  

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3.
Table of Contents
An Open-label, Multicenter, Phase 1b/2 Study to Evaluate 
Necitumumab in Combination with Gemcitabine and 
Cisplatin in the First-Line Treatment of Patients with 
Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer 
(NSCLC)
Section
Page
1.
Protocol I4X-JE-JFCM(e) An Open-label, Multicenter, Phase 1b/2 
Study to Evaluate Necitumumab in Combination with Gemcitabine 
and Cisplatin in the First-Line Treatment of Patients with Advanced 
(Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC) ............................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................8
4.
Abbreviations and Definitions...........................................................................................15
5.
Introduction ......................................................................................................................20
5.1.
General Introduction to Necitumumab..........................................................................20
5.2.
Clinical Studies of Necitumumab .................................................................................21
5.3.
Study Rationale............................................................................................................23
5.4.
Rationale for Selection of Dose....................................................................................25
6.
Objectives.........................................................................................................................28
6.1.
Primary Objective ........................................................................................................28
6.2.
Secondary Objectives...................................................................................................28
6.3.
Exploratory Objective ..................................................................................................28
7.
Study Population...............................................................................................................29
7.1.
Inclusion Criteria..........................................................................................................29
7.2.
Exclusion Criteria ........................................................................................................30
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................32
7.3.
Discontinuations ..........................................................................................................32
7.3.1.
Discontinuation of Patients...................................................................................32
7.3.2.
Discontinuation of Study Sites .............................................................................33
7.3.3.
Discontinuation of the Study................................................................................33
8.
Investigational Plan...........................................................................................................34
8.1.
Summary of Study Design............................................................................................34
8.1.1.
Phase 1b Part........................................................................................................36
8.1.2.
Phase 2 Part .........................................................................................................38
8.1.3.
Baseline and Study Treatment Period assessments ...............................................39

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8.1.4.
Post-discontinuation Follow-Up Period Assessments ...........................................40
8.1.4.1.
30-Day Safety Follow-Up Period....................................................................40
8.1.4.2.
Long-term Follow-Up Period..........................................................................40
8.1.5.
Study Completion ................................................................................................41
8.1.6.
Study Extension ...................................................................................................41
8.1.7.
End of Study........................................................................................................41
8.1.8.
Committees..........................................................................................................41
8.2.
Discussion of Design and Control ................................................................................42
9.
Treatment..........................................................................................................................44
9.1.
Treatments Administered .............................................................................................44
9.1.1.
Premedication ......................................................................................................45
9.1.1.1.
Premedication for Cisplatin and Gemcitabine .................................................45
9.1.2.
Investigational Product.........................................................................................45
9.1.2.1.
Necitumumab .................................................................................................45
9.1.2.2.
Gemcitabine ...................................................................................................45
9.1.3.
Cisplatin...............................................................................................................45
9.2.
Materials and Supplies .................................................................................................46
9.3.
Method of Assignment to Treatment ............................................................................46
9.4.
Selection and Timing of Doses.....................................................................................46
9.4.1.
Special Treatment Considerations ........................................................................47
9.4.1.1.
Dose-Limiting Toxicity Determination (Phase 1b part)...................................47
9.4.1.2.
Treatment Requirements and Delays...............................................................48
9.4.1.3.
Dose Modification..........................................................................................51
9.4.1.3.1.
Necitumumab ...........................................................................................51
9.4.1.3.2.
Gemcitabine and Cisplatin .......................................................................51
9.4.1.3.2.1.
Hematological Toxicity.......................................................................52
9.4.1.3.2.2.
Nonhematological Toxicity.................................................................52
9.5.
Continued Access to Study Drug..................................................................................53
9.6.
Blinding .......................................................................................................................53
9.7.
Concomitant Therapy...................................................................................................53
9.7.1.
Supportive Care ...................................................................................................54
9.7.1.1.
Infusion-Related Reactions.............................................................................54
9.7.1.2.
Skin Reactions................................................................................................55
9.7.1.2.1.
Reactive Treatment...................................................................................55
9.7.1.2.2.
Pre-emptive Treatment..............................................................................57
9.7.1.3.
Conjunctivitis .................................................................................................57
9.7.1.4.
Electrolyte Abnormalities ...............................................................................57
9.7.1.5.
Interstitial Lung Disease .................................................................................58

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9.7.1.6.
Thromboembolic Events.................................................................................58
9.7.1.7.
Cardiorespiratory Disorders............................................................................58
9.7.1.8.
Disseminated Intravascular Coagulation (DIC)...............................................59
9.7.1.9.
Others.............................................................................................................59
9.7.1.9.1.
Antidiarrheal Agents.................................................................................59
9.7.1.9.2.
Granulocyte-Colony Stimulating Factors ..................................................59
9.7.1.9.3.
Transfusion of Blood Products..................................................................59
9.8.
Treatment Compliance .................................................................................................59
10.
Efficacy, Health Outcome, Safety Evaluations, Sample Collection 
and Testing, and Appropriateness of Measurements..........................................................60
10.1. Efficacy Measures........................................................................................................60
10.1.1.
Efficacy Assessments at Baseline and during Study .............................................60
10.1.2.
Efficacy Assessments during the Post-discontinuation Period
(only Phase 2 part) ...............................................................................................60
10.2. Health Outcome Measures............................................................................................61
10.2.1.
Patient-Reported Outcomes (only Phase 2 part)....................................................61
10.2.1.1.
Lung Cancer Symptom Scale (LCSS).............................................................61
10.2.1.2.
EQ-5D............................................................................................................61
10.3. Safety Evaluations........................................................................................................62
10.3.1.
Adverse Events ....................................................................................................62
10.3.1.1.
Serious Adverse Events ..................................................................................63
10.3.1.2.
Adverse Event and Serious Adverse Event Reporting .....................................64
10.3.1.2.1.
Prior to Administration of Study Treatment(s) ..........................................64
10.3.1.2.2.
On Study...................................................................................................64
10.3.1.2.3.
Follow-Up Visit........................................................................................64
10.3.2.
Other Safety Measures .........................................................................................65
10.3.2.1.
Collection of Electrocardiograms....................................................................65
10.3.2.2.
Skin Reactions................................................................................................66
10.3.3.
Safety Monitoring ................................................................................................66
10.3.4.
Complaint Handling.............................................................................................66
10.4. Sample Collection and Testing.....................................................................................66
10.4.1.
Samples for Standard Laboratory Testing.............................................................66
10.4.2.
Pharmacogenetic Samples....................................................................................67
10.4.3.
Nonpharmacogenetic/Biomarker Stored Samples.................................................67
10.4.4.
Immunogenicity Samples .....................................................................................68
10.4.5.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................68
10.5. Appropriateness of Measurements................................................................................68

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11.
Data Quality Assurance.....................................................................................................69
11.1. Data Capture System....................................................................................................69
12.
Sample Size and Statistical Methods .................................................................................70
12.1. Determination of Sample Size ......................................................................................70
12.2. Statistical and Analytical Plans.....................................................................................70
12.2.1.
General Considerations ........................................................................................70
12.2.2.
Patient Disposition...............................................................................................71
12.2.3.
Patient Characteristics..........................................................................................71
12.2.4.
Concomitant Therapy...........................................................................................71
12.2.4.1.
Post-discontinuation Therapy..........................................................................71
12.2.5.
Efficacy Analyses ................................................................................................71
12.2.5.1.
Primary Endpoint ...........................................................................................71
12.2.5.2.
Secondary Endpoints ......................................................................................72
12.2.6.
Pharmacokinetic Analyses....................................................................................73
12.2.7.
Biomarker Analyses.............................................................................................73
12.2.8.
Pharmacokinetic/Pharmacodynamic Analyses......................................................73
12.2.9.
Health Outcome Analyses ....................................................................................74
12.2.9.1.
Lung Cancer Symptom Scale (LCSS).............................................................74
12.2.9.2.
EQ-5D:  Health State Utilities.........................................................................74
12.2.10. Safety Analyses....................................................................................................74
12.2.10.1. Extent of Exposure .........................................................................................74
12.2.10.2. Adverse Events...............................................................................................75
12.2.10.3. Immunogenicity..............................................................................................75
12.2.11. Subgroup Analyses ..............................................................................................75
12.2.12. Interim Analyses..................................................................................................75
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................77
13.1. Informed Consent.........................................................................................................77
13.2. Ethical Review.............................................................................................................77
13.3. Regulatory Considerations ...........................................................................................77
13.3.1.
Investigator Information.......................................................................................78
13.3.2.
Protocol Signatures ..............................................................................................78
13.3.3.
Final Report Signature .........................................................................................78
14.
References ........................................................................................................................79

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List of Tables
Table
Page
Table JFCM.1.
Summary of Clinical Studies .........................................................................21
Table JFCM.2.
Treatment Regimens (3-week Cycle) .............................................................44
Table JFCM.3.
Criteria for Treatment with Necitumumab (on Day 1)....................................48
Table JFCM.4.
Criteria for Treatment with Gemcitabine-Cisplatin (on Day 1).......................48
Table JFCM.5.
Criteria for Treatment with Necitumumab (on Day 8, or Day15 if 
delayed).........................................................................................................49
Table JFCM.6.
Criteria for Treatment with Gemcitabine (on Day 8)......................................49
Table JFCM.7.
Criteria for Treatment with Necitumumab......................................................50
Table JFCM.8.
Criteria for Treatment with Cisplatin-Gemcitabine (on Day 1) and 
Gemcitabine (on Day 8).................................................................................50
Table JFCM.9.
Dose Reductions for Gemcitabine and Cisplatin ............................................52
Table JFCM.10. Dose Reductions for Hematologic Toxicity....................................................52
Table JFCM.11. Dose Reductions for Nonhematologic Toxicity..............................................53
Table JFCM.12. Infusion-Related Reactions – Management Recommendations.......................55
Table JFCM.13. Skin Reactions – Management Recommendations .........................................56
Table JFCM.14. Adverse Event, Serious Adverse Event, and Preexisting Condition 
Reporting Guidelines for Study JFCM...........................................................64

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List of Figures
Figure
Page
Figure JFCM.1. Illustration of study design for Protocol I4X-JE-JFCM. .................................34
Figure JFCM.2. Illustration of study schedule in Phase 1b and Phase 2 part (Arm A)..............35
Figure JFCM.3. Illustration of study schedule in Phase 2 part (Arm B) ...................................35
Figure JFCM.4. The scheme of dose escalation in Phase 1b part .............................................37
Figure JFCM.5. Illustration of study design in Phase 2 part.....................................................38

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JFCM Study Schedule .....................................................................81
Attachment 2.
Protocol JFCM Schedule for Pharmacokinetic and Immunogenicity 
Sampling .......................................................................................................88
Attachment 3.
Protocol JFCM Clinical Laboratory Tests ......................................................90
Attachment 4.
Protocol JFCM ECOG Performance Status....................................................91
Attachment 5.
Protocol JFCM Necitumumab, Gemcitabine, and Cisplatin Dosing 
Scenarios for Chemotherapy Delays ..............................................................92
Attachment 6.
Protocol JFCM Amendment (e) Summary [An Open-label, Multicenter, 
Phase 1b/2 Study to Evaluate Necitumumab in Combination with 
Gemcitabine and Cisplatin in the First-Line Treatment of Patients with 
Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer 
(NSCLC)]......................................................................................................95

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4.
Abbreviations and Definitions
Term
Definition
adverse event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
AIDS
Acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASBI
average symptom burden index
AST
aspartate aminotransferase
AUC0-tlast
Area Under the (plasma) Concentration versus time curve from time zero to time, where is 
the last time point with a measurable concentration
AUC0-
Area Under the (plasma) Concentration versus time curve from zero to infinity
audit
A systematic and independent examination of the trial-related activities and documents to 
determine whether the evaluated trial-related activities were conducted, and the data were 
recorded, analyzed, and accurately reported according to the protocol, applicable standard 
operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory 
requirement(s).
clinical research 
physician 
(CRP)/clinical 
research scientist 
(CRS)
Individual responsible for the medical conduct of the study.  Responsibilities of the CRP 
may be performed by a physician, clinical research scientist, global safety physician, or 
other medical officer.
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
clearance
Cmax
maximum observed (plasma/serum) drug concentration
Ctrough
minimum observed (plasma/serum) drug concentration during a dosing interval
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.

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compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
CR
complete response
CRC
colorectal cancer
CrCL
creatinine clearance
CT
computed tomography
CTCAE
common Terminology Criteria for Adverse Events
CXR
chest X-ray
DCSI
Development Core Safety Information
dFdU
2',2'-difluorodeoxyuridine
DIC
disseminated intravascular coagulation
DLT
dose-limiting toxicity
DNA
Deoxyribo Nucleic Acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
electronic case 
report form (eCRF)
Sometimes referred to as clinical report form:  A printed or electronic form for recording 
study participants’ data during a clinical study, as required by the protocol.
end of study (trial)
End of study (trial) is the date of the last visit or last scheduled procedure shown in the 
Study Schedule for the last active patient in the study.  
enroll/randomize
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are those 
who have been assigned to a treatment.
Phase 1b part:  Enroll
Phase 2 part:  Randomize
enter
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients entered 
into a trial are those who sign the Informed Consent Form directly or through their legally 
acceptable representatives.
ESEC
Efficacy and Safety Evaluation Committee
ethical review 
board (ERB)
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical trial are protected.

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EQ-5D
EuroQol
FAS
full analysis set
FCγR
fragment C gamma receptor
FISH
fluorescence in situ hybridization
GCP
good clinical practice
HBs
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IHC
immunohistochemistry
ILD
interstitial lung disease
ILDC
Interstitial Lung Disease Committee
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.
IRRC
Independent Radiography Review Committee
ITT
intent-to-treat
I.V.
Intravenous
IWRS
interactive web-response system
legal 
representative
An individual, judicial, or other body authorized under applicable law to consent on behalf 
of a prospective patient to the patient’s participation in the clinical study.
KM
Kaplan-Meier

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LCSS
Lung Cancer Symptom Scale
Mab
monoclonal antibody
mCRC
metastatic colorectal cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MST
median survival time
NCI
National Cancer Institute
NYHA
New York Heart Association
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational product 
is targeted.
PD
progressive disease
per protocol set 
(PPS)
The set of data generated by the subset of patients who sufficiently complied with the 
protocol to ensure that these data would be likely to exhibit the effects of treatment, 
according to the underlying scientific model.
PFS
progression-free survival
PK
pharmacokinetic
PMDA
Pharmaceutical and Medical Devices Agency
PR
partial response
PRO
patient-reported outcomes
PS
performance status
QOL
quality of life
QTc 
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
Statistical Analysis Plan

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screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical trial.  In this study, screening 
involves invasive or diagnostic procedures and/or tests (for example, diagnostic 
psychological tests, x-rays, blood draws, etc).  For this type of screening, informed consent 
for these screening procedures and/or tests shall be obtained; this consent may be separate 
from obtaining consent for the study.
SD
stable disease
t1/2
half-life
TPO
third-party organization
treatment-
emergent adverse 
event (TEAE)
Any untoward medical occurrence that either occurs or worsens at any time after treatment 
baseline and that does not necessarily have to have a causal relationship with this treatment.
TTF
time to treatment failure
TW
Time to Worsening
ULN
upper limits of normal
V
volume of distribution
VAS
visual analog scale
WBC
white blood cell

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An Open-label, Multicenter, Phase 1b/2 Study to Evaluate 
Necitumumab in Combination with Gemcitabine and 
Cisplatin in the First-Line Treatment of Patients with 
Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer 
(NSCLC)
5.
Introduction
5.1.
General Introduction to Necitumumab
Necitumumab (LY3012211; IMC-11F8) is a recombinant human monoclonal antibody (Mab) of 
the immunoglobulin G, subclass 1 that blocks the ligand binding site of the epidermal growth 
factor receptor (EGFR).  In nonclinical studies, it has proven to be similar in antitumor activity to 
the chimeric mouse/human anti-EGFR Mab cetuximab, which has been approved in various 
regions of the world for the treatment of squamous cell carcinoma of the head and neck and 
KRAS wild-type metastatic colorectal cancer (mCRC).
The EGFR is a member of the human EGFR family of tyrosine kinases.  The EGFR activation 
leads to stimulation of tyrosine kinase-dependent signal transduction pathways that can 
contribute to neoplastic transformation and tumor growth.  Inhibition of the EGFR pathway in 
cells can result in disruption of cell cycle progression and mitosis, and blocks the inhibitory 
effect on apoptosis.  Decreased angiogenesis may also occur as a result of EGFR inhibition 
through effects on angiogenic factor production.
Epidermal growth factor receptor is expressed in a variety of tumors, including colorectal, head 
and neck, pancreatic, lung, breast, non-small cell lung cancer (NSCLC), and renal cell carcinoma 
(Salomon et al. 1995).  Expression of EGFR has been correlated with malignant progression, 
induction of angiogenesis, and inhibition of apoptosis.  It has furthermore been associated with 
chemoresistance and radioresistance.  Inhibition of EGFR function has proven to be an effective 
means of inhibiting tumor cell growth and proliferation (Ennis et al. 1991).  Inhibiting EGFR 
function through the inhibition of ligand binding to EGFR-positive tumor cells is one mechanism 
for achieving inhibition of tumor growth (Kawamoto et al. 1984; Klohs et al. 1997; Prewett et al. 
1998).
Necitumumab, which blocks ligand binding to EGFR, has shown in vivo antitumor activity 
against a variety of human xenograft tumors.  Nonclinical pharmacology studies have 
demonstrated the ability of necitumumab to offer additive to synergistic antitumor effects to 
those of irinotecan and oxaliplatin in colorectal cancer (CRC) models, with similar effects on 
cisplatin-based chemotherapy in NSCLC models.  This demonstrated capability to inhibit tumor 
growth as a single agent, and the ability to significantly complement the antitumor effects of 
cytotoxic therapy, support the development of necitumumab for the treatment of cancer.
Please see the most current necitumumab Investigator’s Brochure (IB) for additional information.

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5.2.
Clinical Studies of Necitumumab
Necitumumab (at doses ranging from 100 to 1000 mg) has been administered to patients enrolled 
in a total of 5 studies (Phase 1 to 3), including:

2 completed Phase 1 studies in non-Japanese patients and Japanese patients 
(necitumumab monotherapy in advanced solid tumors);

1 completed Phase 2 study (necitumumab in combination with modified 
FOLFOX-6 in locally advanced CRC or mCRC); and

2 ongoing Phase 3 studies (necitumumab plus pemetrexed-cisplatin or 
gemcitabine-cisplatin in nonsquamous or squamous NSCLC, respectively).
Table JFCM.1 summarizes design information for all 5 studies (including enrollment information, 
current through 12 July 2012 for ongoing studies).
Table JFCM.1.
Summary of Clinical Studies
Study No.
Study Title
Design
Treatment Regimen
Patients
Enrolled a
CP11-0401
Phase 1 Study of the Fully Human 
Anti-Epidermal Growth Factor 
Receptor (EGFR) Monoclonal 
Antibody IMC-11F8 in Patients With 
Solid Tumors Who Have Failed 
Standard Therapy
Phase 1, 
single-agent, 
dose-escalation 
study
Necitumumab at 100 mg every 
week (Arm A) and every 2 weeks 
(Arm B), with escalation in 
subsequent cohorts to 200, 400, 
600, 800, and 1000 mg.
60
Study Complete 
[Kuenen et al. 
2010]
CP11-0907
A Phase 1 Study of IMC-11F8 in 
Patients with Advanced Solid 
Tumors
Phase 1, 
single-agent, 
dose-escalation 
study in Japanese 
patients
Patients receive necitumumab at 
doses of 600 mg (Days 1 and 8 of 
a 3-week cycle), 800 mg (every 
2 weeks), or 800 mg (Days 1 and 
8 of a 3-week cycle).
15
Study Complete
CP11-0602
Open-Label, Multicenter, Phase 2 
Study Evaluating the Efficacy and 
Safety of IMC-11F8 in Combination 
with 5-FU/FA and Oxaliplatin 
(Modified FOLFOX-6) in Patients 
with Treatment-Naïve, Locally 
Advanced or Metastatic Colorectal 
Cancer
Phase 2, 
single-arm study
All patients receive necitumumab 
at 800 mg plus mFOLFOX-6 
chemotherapy every 2 weeks.
44
Study Complete
(continued)

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Summary of Clinical Studies (concluded)
Study No.
Study Title
Design
Treatment Regimen
Patients
Enrolled a
CP11-0805
A Randomized, Multicenter, 
Open-Label Phase 3 Study of 
Pemetrexed-Cisplatin Chemotherapy 
Plus Necitumumab (IMC-11F8) 
Versus Pemetrexed-Cisplatin 
Chemotherapy Alone in the 
First-Line Treatment of Patients With 
Stage IV Nonsquamous Non-Small 
Cell Lung Cancer (NSCLC)
Phase 3, 
randomized, 
open-label study
Arm A

pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 (Day 1 of 
every 3 week cycle)

necitumumab 800 mg (Days 1 
and 8 of every 3-week cycle)
Arm B

pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 (Day 1 of 
every 3 week cycle)
647
Ongoing
Enrollment 
Stopped b
CP11-0806
A Randomized, Multicenter, 
Open-Label, Phase 3 Study of 
Gemcitabine-Cisplatin 
Chemotherapy Plus Necitumumab 
(IMC-11F8) Versus Gemcitabine-
Cisplatin Chemotherapy Alone in the 
First-Line Treatment of Patients With 
Stage IV Squamous Non-Small Cell 
Lung Cancer (NSCLC)
Phase 3, 
randomized, 
open-label study
Arm A

gemcitabine 1250 mg/m2
(Days 1 and 8 of every 3 week 
cycle)

cisplatin 75 mg/m2 (Day 1 of 
every 3 week cycle)

necitumumab 800 mg (Days 1 
and 8 of every 3-week cycle)
Arm B

gemcitabine 1250 mg/m2
(Days 1 and 8 of every 3 week 
cycle)

cisplatin 75 mg/m2 (Day 1 of 
every 3 week cycle)
1094
Ongoing
Enrollment 
Complete
a
As of 07 July 2012.
b
Enrollment stopped on 02 February 2011 per Independent Data Monitoring Committee (IDMC) recommendation; see also the 
Development Core Safety Information (DCSI) in the investigator’s brochure for necitumumab.
As of 28 June 2012, the final analysis for Japanese Phase 1 study (CP11-0907) has been finished 
and the final study report has not been completed.  In Study CP11-0907, no Dose-Limiting 
Toxicity (DLT) was observed.  Most common adverse events (AEs) possibly related to 
necitumumab by the investigator were dry skin and headache (10 patients each; 66.7%), pruritus 
and rash (8 patients each; 53.3%), stomatitis and anorexia (7 patients each; 46.7%), nausea and 
pyrexia (6 patients each; 40.0%), and acne (5 patients; 33.3%).  One patient in Cohort 2 
(necitumumab 800 mg every 2 weeks) experienced two AEs of Grade 3 (dry skin and rash) 
related to necitumumab, and all other necitumumab related adverse events were of Grade 2.  A 
serious adverse event (SAE) related to necitumumab was observed in one patient at Cohort 1 
(necitumumab 600 mg on Days 1 and 8 of a 3-week cycle) with oropharyngeal discomfort 
(Grade 2).
More information about the known and expected benefits, risks and reasonably anticipated AEs 
may be found in the IB.  Information on AEs expected to be related to the study drug may be 
found in Section 7 (Development Core Safety Information:  DCSI) of the IB.  Information on 
SAEs expected in the study population independent of drug exposure and that will be assessed 

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by the Sponsor in aggregate periodically during the course of the study may be found in Section 
6 (Effects in Humans) of the IB.
The Sponsor and investigators will perform this study in compliance with the protocol, good 
clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, and 
applicable regulatory requirements.
5.3.
Study Rationale
The common chemotherapy regimens for advanced, metastatic NSCLC are based on cisplatin or 
carboplatin in combination with either taxane (docetaxel or paclitaxel), gemcitabine, vinorelbine, 
or pemetrexed.
The EGFR is overexpressed in 40% to 80% of NSCLC tumors, where it plays an important role 
in tumorgenesis.  In FLEX, a recent Phase 3 study of cetuximab plus cisplatin-vinorelbine versus 
cisplatin–vinorelbine alone in the treatment of NSCLC, approximately 85% of 1688 patients 
screened for entry were positive for EGFR expression (Pirker et al. 2009).  
The feasibility of administering EGFR-directed Mabs in combination with a standard 
platinum-based doublet in the first-line treatment of advanced NSCLC has been demonstrated in 
several randomized trials.  Two randomized Phase 3 trials were conducted with cetuximab in 
combination with either vinorelbine-cisplatin (FLEX; Pirker et al. 2009) or carboplatin-taxane 
(BMS-099; Lynch et al. 2010) as the chemotherapy backbone.  The addition of cetuximab to 
both regimens resulted in a statistically significant improvement in the best overall response rate 
(complete response [CR] partial response [PR]) in both studies, and in a significant 
prolongation of survival with statistical significance in FLEX.  However in both studies, 
progression-free survival (PFS) was not different for both treatment arms (hazard ratio [HR] 0.94 
[FLEX], HR 0.90 [BMS-099]).
The analyses of both studies by histologic subtypes showed, that for cetuximab-containing 
regimens, a more pronounced trend in improvement of overall survival (OS) in squamous cell 
carcinoma (HR 0.80 [FLEX], HR 0.87 [BMS-099]) than in adenocarcinoma (HR 0.94 [FLEX], 
HR 0.89 [BMS-099]) when compared to chemotherapy alone only.  In BMS-099, patients with 
squamous cell carcinoma had a favorable PFS (HR 0.7) and OS (HR 0.87) when treated with 
cetuximab-containing regimen compared to chemotherapy alone.
A positive impact of cetuximab on efficacy parameters was reported in 1 randomized Phase 2 
study comparing cetuximab in combination with gemcitabine–cisplatin/carboplatin versus the 
same chemotherapy alone (Butts et al. 2007).  The best overall response rate (ORR) was 28% 
and 18% in the cetuximab-containing arm and the control arm, respectively.  Median PFS time 
was 5.1 versus 4.2 months, and OS time was 12 versus 9.3 months, both for the cetuximab 
containing-arm versus control, respectively.
Tumor histology has not been consistently associated with clinical outcome for first-line therapy 
in advanced/metastatic NSCLC, but has recently emerged as a potential predictive factor.  In a 
randomized Phase 3 study by Scagliotti et al. (2008) evaluating pemetrexed-cisplatin versus 
gemcitabine-cisplatin as first-line treatment in 1725 patients with advanced NSCLC, the OS 

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associated with these 2 regimens was similar (10.3 months for each arm; HR 0.94).  However 
there were significant differences in OS between the regimens when the patient population was 
retrospectively analyzed by disease histology.  In patients with nonsquamous histology, OS with 
pemetrexed-cisplatin was significantly greater than gemcitabine-cisplatin (11.8 versus 
10.4 months, respectively; HR 0.81; 95% confidence interval [CI] 0.70 to 0.94; p=0.005).  
Conversely, the OS among patients with squamous cell histology was 10.8 months for 
gemcitabine-cisplatin versus 9.4 months for pemetrexed-cisplatin (HR 1.23; 95% CI 1.00 to
1.51; p=0.05).  Furthermore, in the squamous histological subgroup gemcitabine-cisplatin 
showed significant advantages over pemetrexed-cisplatin in PFS (HR 1.36, p=0.002) and best 
ORR (31% versus 23%).
Because of these data and due to the promising add-on effect of EGFR-directed Mabs on the 
efficacy of gemcitabine-platinum-based chemotherapy, the combination of necitumumab plus 
gemcitabine-cisplatin chemotherapy versus the same chemotherapy alone is being investigated in 
a randomized Phase 3 trial as first-line therapy in 1094 patients with Stage IV squamous NSCLC 
(Study CP11-0806).  This study has recently completed patient enrollment.
A post-hoc analysis of the FLEX trial showed evidence that the EGFR expression measured by a 
semi-quantitative immunohistochemistry score (IHC H-score) may be predictive for the efficacy 
of EGFR-directed Mabs in combination with platinum-based chemotherapy as first-line therapy 
in NSCLC (Pirker et al. 2012).  
The H-score for the FLEX study was based on a scale ranging from 0 to 300.  The H-score of 
200 was the cutoff selected to distinguish between low and high H-scores.  The cutoff value of 
200 was determined by using response data to select an outcome-based discrimination threshold 
for EGFR expression to distinguish between low versus high EGFR-expressing patients.
The clinical outcome analyses of the FLEX study on the basis of EGFR-expression level based 
on 1121 patients with EGFR detectable tumor tissue represented 99.6% of the intent-to-treat 
(ITT) population.  The efficacy analysis of the FLEX study revealed no positive impact of 
cetuximab on cisplatin-vinorelbine in terms of all efficacy parameters (OS, PFS, and ORR) in 
patients with tumor tissue and an EGFR-IHC H-score <200.  A positive impact was 
demonstrated for patients with an EGFR-IHC H-score of >200 in terms of response rate (increase 
16%) and OS (HR 0.73), but the advantage in PFS (HR 0.86) was limited in comparison to the 
chemotherapy-alone arm.
The subgroup analysis of the FLEX study by tumor histology and EGFR IHC H-score showed, 
in patients with an H-score <200 for both treatment groups, a similar OS in adenocarcinoma and 
squamous cell carcinoma.  In patients with an H-score of >200 a clinically meaningful risk 
reduction for death was demonstrated in both adenocarcinoma (HR 0.74) as well as squamous 
cell carcinoma (HR 0.62) for the cetuximab-containing arm versus the chemotherapy-alone arm.  
Further, important efficacy data such as PFS and best ORR were not shown for both histological 
subtypes.
The lack of these data and the selection of an EGFR IHC H-score cut-off value (>200) on the 
basis of the response rate independent from the histological subtypes raised questions in terms of 

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the predictive value of this test for the efficacy of EGFR-directed Mabs in combination with 
different platinum-based chemotherapy regimens, especially in specific histological subtypes of 
NSCLC.
The Japan Phase 1b/2 study, Study I4X-JE-JFCM (JFCM), is being conducted to evaluate the 
efficacy of necitumumab in combination with gemcitabine-cisplatin chemotherapy in terms of 
OS in Japanese patient with advanced squamous NSCLC.  The result will be confirmed 
consistent efficacy trend with global Phase 3 study.
5.4.
Rationale for Selection of Dose
In this study, the combination of gemcitabine-cisplatin chemotherapy with or without 
necitumumab will be administered at the same dose schedule as used in the ongoing Phase 3 
study (CP11-0806, gemcitabine-cisplatin with or without necitumumab in first-line treatment of 
Stage IV squamous NSCLC).
Gemcitabine and Cisplatin
The combination of necitumumab plus gemcitabine-cisplatin chemotherapy versus the same 
chemotherapy alone is being investigated in a randomized Phase 3 study as first-line therapy in 
1094 patients with Stage IV squamous NSCLC (Study CP11-0806).  This study has recently 
completed patient enrollment.  The dose selection of Study CP11-0806 for cisplatin in 
combination with gemcitabine is based on the regimen that had been used in a previous Phase 3 
study comparing cisplatin (75 mg/m2)-gemcitabine (1250 mg/m2) with pemetrexed 
(500 mg/m2)-cisplatin (75 mg/m2) as first-line therapy in 1725 patients with advanced or 
metastatic NSCLC.  The results of the study demonstrated superior efficacy for 
cisplatin-gemcitabine in patients with squamous histology, in comparison to 
pemetrexed-cisplatin (Scagliotti et al. 2008).  In the study, the major treatment-related Grade 3 
and 4 AEs for cisplatin and gemcitabine in a total of 830 patients were neutropenia (20.7%), 
thrombocytopenia (12.7%), anemia (9.9%), and vomiting (6.1%).  
Japan Phase 1/2 study demonstrates that the combination of CDDP and gemcitabine 1250 mg/m2
every three weeks is tolerable for Japanese patients with NSCLC (Kusaba et al. 2002).  In this 
study, gemcitabine 1000 mg/m2 (approved dose in Japan) will be administered to confirm the 
safety of necitumumab in combination with gemcitabine-cisplatin before the administration of 
necitumumab and cisplatin (75 mg/m2)-gemcitabine (1250 mg/m2).  
Based on results of DLT assessment at the Phase 1b part in this study, the recommended dose for 
the Phase 2 part was determined as necitumumab 800 mg ( Days 1 and 8 of each 3-week cycle) 
in combination with  cisplatin 75 mg/m2 (Day 1) and gemcitabine 1250 mg/m2 (Days 1 and 8).
Necitumumab
Safety data from Study CP11-0401 demonstrated that the maximum tolerated dose of 
necitumumab is 800 mg once weekly or once every 2 weeks (Kuenen et al. 2010).  The most 
common drug-related AEs were typical for this class of agents, and consisted of skin reactions, 
headache, nausea/vomiting, and fatigue (mostly of Grades 1 and 2).  In addition, the results in 

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Study CP11-0907 showed a tolerability of the dose in Japanese patients with advanced solid 
tumors and could support to apply the doses to further clinical study for Japanese patients.
Nonclinical tumor xenograft models suggested that antitumor activity requires a minimum 
trough level of necitumumab above 40 μg/mL.  Exploratory simulation using clinical 
pharmacokinetics (PK) data from Study CP11-0401 was conducted to predict trough levels of 
necitumumab following doses of 600 or 800 mg on Days 1 and 8 of a 3-week cycle, a dosing 
regimen that is consistent with the standard chemotherapy used in NSCLC.  The simulation 
results suggested that only 800 mg (Days 1 and 8 of a 21-day cycle) would maintain geometric 
mean trough levels greater than 40 μg/mL throughout the treatment cycle, including on both 
Day 8 (prior to second infusion:  126 μg/mL) and Day 22 (prior to infusion on Day 1 of Cycle 2:  
66 μg/mL).
For treatment regimens based on a 3-week cycle duration, the recommended dose regimen for 
necitumumab is 800 mg administered on Days 1 and 8 of a 3-week (21 day) cycle.  This dose 
regimen is based on PK simulations, which predicted approximate necitumumab minimum 
observed drug concentrations (Ctrough) ranging from 52 to 108 μg/mL and 70 to 112 μg/mL 
following 600 and 800 mg on Days 1 and 8, respectively of a 3-week day cycle.  Therefore, 
doses of 600 mg or above on Days 1 and 8 of a 3-week cycle would attain the target minimum 
trough levels of necitumumab associated with antitumor activity in preclinical tumor xenograft 
models (40 μg/ml); thus, a dose of 800 mg on Days 1 and 8 would provide a suitable margin 
above target Ctrough concentrations.
Based on PK data from Study CP11-0401, an exploratory graphical analysis was conducted to 
assess correlation between clearance and body weight.  No apparent correlation was observed 
between clearance and body weight, which suggested that necitumumab clearance is independent 
of patient body weight.  Therefore, a flat dose (that is, no dose adjustment based on body weight) 
of 800 mg necitumumab given on Days 1 and 8 of a 3-week cycle is recommended for this study.  
This dose regimen is expected to be safe and attain targeted efficacious exposure within the 
entire study duration.
Necitumumab, Gemcitabine, and Cisplatin
It is considered based on the mechanism of action that the safety profiles of 
gemcitabine-cisplatin and necitumumab showed at the selected dose schedules no or only 
marginal overlapping side effects.  Therefore, it is expected that necitumumab can be safely 
administered at the recommended dose with the full dose of gemcitabine and cisplatin.  This 
assumption is confirmed by repeated Independent Data Monitoring Committee (IDMC) safety 
assessments in the ongoing Phase 3 study (CP11-0806), which revealed no safety concerns 
associated with the combination of necitumumab with gemcitabine-cisplatin versus the same 
chemotherapy alone.  The Study CP11-0806 completed subject enrollment without any study 
modification under close safety monitoring by IDMC.  EGFR-directed Mabs have been 
associated with an add-on effect to the efficacy of gemcitabine-cisplatin (Butts et al. 2007).  At a 
pooled data analysis in Study CP11-0806, as of 18 December 2011, the most frequent Grade 3 
AEs regardless causality were neutropenia (159 patients; 16.2%), anemia (85 patients; 8.7%), 

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thrombocytopenia (53 patients; 5.4%), leukopenia (43 patients; 4.4%), asthenia (38 patients; 
3.9%), dyspnea (29 patients; 3.0%), and hypomagnesemia (29 patients; 3.0%).  Grade 4 events 
affecting >1% of the total treated population included neutropenia (56 patients; 5.7%), 
thrombocytopenia (29 patients; 3.0%), pulmonary embolism (14 patients; 1.4%), and pneumonia 
(10 patients; 1.0 %).  The IDMC has been recommending to continue the study for 
approximately 500 patients treated with necitumumab in combination with gemcitabine and 
cisplatin.  
Based on these data, the benefit-risk balance for the selected combination regimen is regarded as 
favorable.

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6.
Objectives
6.1.
Primary Objective
The study is divided into two parts: 
Phase 1b part:  to investigate the tolerability of necitumumab as measured by DLT, in 
combination with gemcitabine-cisplatin chemotherapy as first line treatment in patients with 
Stage IV squamous NSCLC and to determine the recommended dose for the subsequent Phase 2 
study.
Phase 2 part:  to evaluate the efficacy of necitumumab in combination with 
gemcitabine-cisplatin chemotherapy in terms of OS in patients with Stage IV squamous NSCLC 
in a first-line setting.
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:
Phase 1b part

to investigate the safety profile as assessed by clinically significant events of 
necitumumab in combination with gemcitabine-cisplatin chemotherapy 

to investigate the anti-tumor effect  

to assess PK of necitumumab, gemcitabine and cisplatin  

to determine the immunogenicity of necitumumab
Phase 2 part

to investigate the safety profile as assessed by clinically significant events of 
necitumumab in combination with gemcitabine-cisplatin chemotherapy 

to investigate PFS 

to investigate ORR 

to investigate time to treatment failure (TTF) 

to assess PK of necitumumab in combination with gemcitabine-cisplatin 

to assess Quality of life (QOL; Patient-reported outcomes:  PROs) using Lung Cancer 
Symptom Scale (LCSS) and EuroQol (EQ-5D)

to assess the relationship between EGFR protein expression (as measured by 
immunohistochemistry [IHC]) and each of several efficacy measures:  OS, PFS, and 
ORR

to determine the immunogenicity of necitumumab 
6.3.
Exploratory Objective
Phase 1b/2 part:  to explore biomarkers including HER2 and HER3 protein expression (IHC), 
KRAS and EGFR mutation status, fragment C gamma receptor (FCγR) polymorphisms, and/or 
additional biomarkers of interest related to the necitumumab, gemcitabine and cisplatin 
mechanism of action.

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7.
Study Population
7.1.
Inclusion Criteria
The criteria for enrollment must be followed explicitly. Patients are eligible to be included in the 
study only if they meet all of the following criteria at the time of enrollment (Phase 1b) or 
randomization (Phase 2):
[1]
Patient has histologically confirmed squamous NSCLC.
[2]
Patient has Stage IV NSCLC disease (based on the American Joint Committee 
on Cancer [AJCC], Seventh Edition [Edge et al. 2009]).
[3]
Patients have measurable or nonmeasurable disease documented by computed 
tomography (CT) scan or magnetic resonance imaging (MRI) as defined by 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
(Eisenhauer et al. 2009).
[4]
Patient has the Eastern Cooperative Oncology Group (ECOG) a performance 
status (PS) of 0 or 1 (Attachment 4).  
[5]
The patient had not received prior anticancer therapy for NSCLC (eg, surgery, 
chest radiotherapy, systematic chemotherapy, and targeted therapy).
[6]
Patient has resolution to Grade 1 by the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, of all 
clinically significant toxic effects of prior therapy for other than NSCLC.
[7]
Patient has adequate organ function, defined as:  

Total bilirubin 1.5 x the upper limit of normal value (ULN), 

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
2.5 x ULN 

Serum creatinine 1.2 x ULN or calculated creatinine clearance (CrCL) 
>50 mL/min (per the Cockcroft Gault formula or equivalent and/or 
24-hour urine collection).  
Cockcroft-Gault formula filtration rate
CrCL =
(mL/min) 
(140 – agea) (wta)    0.85 (if woman), or 1.0 (if male)
72 serum creatinine (mg/dL)
a
age in years, weight (wt) in kilograms.

Absolute neutrophil count (ANC) 1.5 x 103/µL 

Hemoglobin 10.0 g/dL

Platelets 100 x 103/µL.
[8]
At least 20 years of age
[9]
Patient has a life expectancy of 12 weeks

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[10] A formalin-fixed, paraffin-embedded tumor tissue block or a minimum of 
5 unstained slides of tumor sample (archived or recent) must be made 
available prior to randomization for the evaluation of EGFR protein 
expression (IHC).
[11] If women, the patient is surgically sterile, postmenopausal, or compliant with 
a highly effective contraceptive method (failure rate <1%) during and for 
6 months after the treatment period (oral hormonal contraception alone is not 
considered highly effective and must be used in combination with a barrier 
method).  
If men, the patient is surgically sterile or compliant with a highly effective 
contraceptive regimen during and for 6 months after the treatment period.
[12] Patient has provided signed informed consent and is amenable to compliance 
with protocol schedules and testing.
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria at the time of 
enrollment (Phase 1b) or randomization (Phase 2):
[13] The patient is currently enrolled in, or discontinued within the last 30 days
from, a clinical trial involving an investigational product or non-approved use 
of a drug or device, or concurrently enrolled in any other type of medical 
research judged not to be scientifically or medically compatible with this 
study.
[14] Patient has undergone major surgery within 28 days or subcutaneous venous 
access device placement within 7 days prior to enrollment (Phase 1b) or 
randomization (Phase 2).  Furthermore, any patient with postoperative 
bleeding complications or wound complications from a surgical procedure 
performed in the last 2 months will be excluded.  
[15] Patient has undergone any prior radiation therapy, except for stereotactic 
irradiation and palliative radiation treatment at least 14 days have elapsed 
from last radiation treatment prior to enrollment (Phase 1b) or randomization
(Phase 2). Prior radiation therapy is allowed to less than 25% of bone marrow.  
[16] The patient has brain metastases that are symptomatic or require surgery, 
medication and radiotherapy except for stereotactic irradiation.  
Patients who have undergone previous stereotactic irradiation for brain 
metastases, who are now non-symptomatic and no longer require treatment 
with steroids or anticonvulsants at least 14 days prior to enrollment (Phase 1b) 
or randomization (Phase 2), are eligible.  
[17] Patient has superior vena cava syndrome.  
[18] Patient has clinically relevant coronary artery disease or uncontrolled 
congestive heart failure (New York Heart Association [NYHA] III or IV) or 
cardiac arrhythmia poorly controlled by medications.  

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[19] Patient has uncontrolled hypertension defined as systolic blood pressure 
150 mmHg or diastolic blood pressure 90 mmHg despite standard medical 
management.  
[20] Patient has diabetes requiring insulin.  
[21] Patient has an angina or has experienced myocardial infarction within 
6 months prior to enrollment (Phase 1b) or randomization (Phase 2).  
[22] Acquired immunodeficiency syndrome (AIDS)-related illness, or have 
evidence of or test positive test results for human immunodeficiency virus 
(HIV).
[23] Have evidence of or test positive test results for hepatitis B, or hepatitis C 
virus antibodies (HCVb)
-
positive for hepatitis B surface antigen (HBsAg), or
-
positive for anti-hepatitis B core antibody and positive for hepatitis B 
deoxyribonucleic acid (HBV DNA), or
-
positive for anti-hepatitis B surface antibody (HBsAB) and positive for 
hepatitis B deoxyribonucleic acid (HBV DNA) 
[24] Previous or concurrent malignancy except for basal or squamous cell skin 
cancer (non-melanoma) and/or preinvasive carcinoma of the cervix, mucosal 
gastrointestinal or uterine carcinoma, or other solid tumors treated curatively 
(ie, curative resection of tumors) and without evidence of recurrence for at 
least 3 years prior to enrollment (Phase 1b) or randomization (Phase 2)
[25] Have a known allergy / history of hypersensitivity reaction to any of the 
treatment components, including any ingredient used in the formulation of 
necitumumab, or any other contraindication to one of the administered 
treatments 
[26] Have significant third-space fluid retention (for example, ascites or pleural 
effusion) requiring drainage.  
[27] Have history of interstitial pneumonia, or patient who showed clinically 
significant diffuse shadows (interstitial pneumonia or pulmonary fibrosis) as 
opacity on chest X-ray (CXR) or CT.
[28] Have an ongoing or active infection (requiring systemic treatment), including 
active tuberculosis.  
[29] Have a history of significant neurological or psychiatric disorders, including 
dementia, seizures, or bipolar disorder, potentially precluding protocol 
compliance.  
[30] Have a peripheral neuropathy Grade 2 (NCI-CTCAE version 4.0).  

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[31] Are pregnant (confirmed within 7 days prior to enrollment [Phase 1b] or 
randomization [Phase 2]), or breastfeeding. If women who stop breastfeeding 
enter the study, the women must stop breastfeeding during and for at least 
30 days after the treatment period.
[32] Have known history of drug abuse.  
[33] Are assessed as inadequate for the study by the investigator or sub investigator.
7.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion [13] eliminates drugs that cannot be mapped to a standard drug dictionary, or 
for which little data are known to analyze the potential relationship of AEs or drug interactions.  
Exclusion Criteria [14] to [33] help in maintaining specificity of the patient population for both 
efficacy and safety analyses and/or to maintain patient safety.
7.3.
Discontinuations
7.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the Sponsor must be 
notified.  If the Sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the Sponsor CRP and the investigator to determine whether the patient may continue in the 
study, with or without investigational product.  Inadvertently enrolled patients may be 
maintained in the study and on investigational product when the Lilly CRP agrees with the 
investigator that it is medically appropriate for that patient.  The patient may not continue in the 
study with or without investigational product if the Lilly CRP does not agree with the 
investigator’s determination it is medically appropriate for the patient to continue.  The 
investigator must obtain documented approval from the Lilly CRP to allow the inadvertently 
enrolled patient to continue in the study with or without investigational product.
Patients will be discontinued from the study treatment in the following circumstances.

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
The investigator/physician decides that the patient should be withdrawn from the 
study or 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.

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
Patient Decision 
o
The patient or patient’s designee (for example, parents or legal guardian) requests 
to be withdrawn from the study or study treatment.

Sponsor Decision
o
The Sponsor stops the study or stops the patient’s participation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP

The patient is significantly noncompliant with study procedures and/or treatment

An unacceptable adverse event/toxicity (eg, a persistent moderate toxicity that is 
intolerable to the patient)

A Grade 3 to 4 infusion-related reaction

Any therapy-related event that is deemed life-threatening, regardless of grade

Any event that 1) requires a given study therapy to be modified by more than two dose 
reductions in all study treatments (necitumumab, gemcitabine, and cisplatin), or 2) 
requires all study treatments to be discontinued for more than 6 weeks following Day 1 of 
the most recent cycle, would warrant discontinuation of all treatments (The 
discontinuation criteria for each treatment are shown in Section 9.4.1.2).

Radiographic documentation of progressive disease (PD)

An intercurrent illness or change in the patient’s condition that renders the patient 
unsuitable for further treatment in the opinion of the investigator

The patient becomes pregnant during treatment.
The reason and date for discontinuation will be collected for all patients.  All enrolled (Phase 1b) 
or randomized (Phase 2) patients who discontinue regardless of whether they received study 
treatment or not, will have procedures performed as shown in the Study Schedule (Attachment 
1).
Follow-up evaluations should be performed as described in Protocol Attachment 1.  All patients 
will be followed for survival at regularly scheduled intervals (every 90 days), for as long as the 
patient remains alive until study completion.
7.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if the Sponsor, the investigator, or the ethical 
review board (ERB) of the study site judges it necessary for medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.
7.3.3. Discontinuation of the Study
The study will be discontinued if the Sponsor judges it necessary for medical, safety, regulatory, 
ethical, or other reasons consistent with applicable laws, regulations, and GCP.

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8.
Investigational Plan
8.1.
Summary of Study Design
Study JFCM is an open-label, multicenter, Phase 1b/2 study in patients with Stage IV squamous 
NSCLC.
The study is divided into two parts:  the Phase 1b part and the Phase 2 part (Figure JFCM.1).  
Abbreviations:  n = numbers of patient, PD = progressive disease
Figure JFCM.1.
Illustration of study design for Protocol I4X-JE-JFCM.
•Necitumumab 800 mg
•Gemcitabine 1000 mg/m2
•Cisplatin 75 mg/m2
Cohort 1 (n = 3 to 9)
•Necitumumab 800 mg
•Gemcitabine 1250 mg/m2
•Cisplatin 75 mg/m2
Cohort 2 (n=6 to 9)
•Necitumumab 800 mg
•Gemcitabine 1000 or 1250 mg/m2
•Cisplatin 75 mg/m2
Gemcitabine and cisplatin continue for a maximum of four cycles.  
Necitumumab continues until PD or toxicity.
1:1
R
A
N
D
O
M
I
Z
E
•Gemcitabine 1000 or 1250 mg/m2
•Cisplatin 75 mg/m2
Gemcitabine and cisplatin continue for a maximum of four cycles.
Phase 1b Part
Phase 2 Part
Arm A (n = 90) 
Arm B (n = 90) 
1250 mg/m2
1250 mg/m2

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Abbreviations:  IC = informed consent, D = Day
Figure JFCM.2.
Illustration of study schedule in Phase 1b and Phase 2 part (Arm A)
Abbreviations:  IC = informed consent, D = Day
Figure JFCM.3.
Illustration of study schedule in Phase 2 part (Arm B)
Screening may occur up to 21 days prior to the enrollment (Phase 1b) or randomization (Phase 2) 
for each patient.  Following enrollment (Phase 1b) or randomization (Phase 2), the first dose of 
study medication should be administered within 7 days.  Patients may admit to the study site 
during Cycle 1 as appropriate.  A treatment cycle will be defined as 3 weeks.  Patients will be 
treated until there is radiographic PD, toxicity requiring cessation, withdrawal of consent, or until 
Screening
Cycles 2 to 4
21 days
Cycle 1
21 days
Dose
(D1)
21 days
Dose
(D8)
Nacitumumab
(800 mg)
Gemcitabine
(1000 or 1250 mg/m2)
Cisplatin
(75 mg/m2)
Dose
(D1)
Dose
(D8)
Dose
(D1)
Dose
(D8)
Dose
(D1)
Combination Therapy
Cycles 5 to n
21 days
Dose
(D1)
Dose
(D8)
Maintenance Therapy
Dose
(D1)
Dose
(D8)
Dose
(D1)
Enroll (Ph1b)/ 
Randomize (Ph2)
IC
(Ph1b: 1000 or 1250 mg/m2)
(Ph2:  1250 mg/m2)
Screening
Cycles 2 to 4
21 days
Cycle 1
21 days
21 days
Gemcitabine
(1000 or 1250 mg/m2)
Cisplatin
(75 mg/m2)
Dose
(D1)
Dose
(D8)
Dose
(D1)
Combination Therapy
Dose
(D1)
Dose
(D8)
Dose
(D1)
Randomize
IC
(1250 mg/m2)

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other withdrawal criteria are met.  The overviews of study schedule are shown in Figure JFCM.2
and Figure JFCM.3.
Terms used to describe the study periods are defined below:

Baseline:  from the time of screening to first study treatment (or discontinuation, if no 
treatment is given)

Study Treatment Period:  time from treatment start to discontinuation from study 
treatment

Post-discontinuation Follow-Up:  begins the day after the patient and the investigator 
agree that the patient will no longer continue study treatment  For the patient who 
completed all treatments of Cycle 4 in Arm B of Phase 2 part, post-discontinuation 
follow-up begins the day after the Cycle 4 completion.
o
30-Day Safety Follow-Up Period:  begins one day after the decision to 
discontinue study treatment and lasts approximately 30 days.  For the patient who 
completed all treatments of Cycle 4 in Arm B of Phase 2 part 30-day safety 
follow-up period begins one day after Cycle 4 completion and lasts approximately 
30 days.
o
Long-term Follow-Up Period:  begins one day after the 30-day safety follow-up 
period is completed and continues until death to collect additional data (for 
example, survival data).

Study Completion:  defined as the point at which a sufficient number of OS events 
(deaths) have been observed for final analysis, and the clinical trial database has been 
locked for final analysis of all endpoints.

Study Extension:  time following study completion and prior to the end of trial as 
defined in Section 8.1.6.

End of Trial:  Defined as the point at which a sufficient number of OS events (deaths) 
have been observed for final analysis, and the last patient has discontinued study 
treatment and completed the 30-day safety follow-up visit.
8.1.1. Phase 1b Part
The Phase 1b part is single arm, dose-escalation to determine the recommended dose for Phase 2 
part.  
Following necessary premedication, all patients will receive study therapy, consisting of :  

Necitumumab, administered intravenously (I.V.) over 50 minutes at an absolute dose 
of 800 mg on Days 1 and 8.  

Gemcitabine, administered I.V. over approximately 30 minutes at a dose of 1000 or 
1250 mg/m2 for a maximum of 4 cycles on Days 1 and 8.  

Cisplatin, administered I.V. over approximately 120 minutes at a dose of 75 mg/m2 on 
Day 1 for a maximum of 4 cycles.
Patients will receive necitumumab, followed by gemcitabine.  Cisplatin will be administered to 
patients at least 30 minutes following the end of the gemcitabine infusion.  

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At least 9 patients will be enrolled to Phase 1b part (3 patients in Cohort 1 and 6 patients in 
Cohort 2) (Figure JFCM.4).  A DLT-evaluable patient is considered to be one who has received 
at least one dose of gemcitabine and cisplatin and two doses of necitumumab and completed 
safety monitoring for DLT evaluation period (21 days in Cycle 1) (see Section 9.4.1.1).  Any 
patient who is discontinued from the study before completing safety monitoring for DLT 
evaluation period will be deemed non-evaluable for assessment the tolerability of a dose level 
unless the patient experience a DLT before withdrawal or it can be documented that the patient 
doesn’t experience a DLT during DLT evaluation period (21 days in Cycle 1).  Additional 
patients may be enrolled as replacements for non-DLT evaluable patients.  
Abbreviations:  DLT = Dose limited-toxicity; ESEC = Efficacy and Safety Evaluation Committee; Ph2 = Phase 2; 
pts = patient
Figure JFCM.4.
The scheme of dose escalation in Phase 1b part
Cohort 1 will be started at a dose level of necitumumab 800 mg, Gemcitabine 1000 mg/m2, and 
Cisplatin 75 mg/m2 , and 3 subjects will be enrolled in Cohort 1.  If none of 3 DLT evaluable 
patients in Cohort 1 develops DLT, Cohort 2 will be started at a dose level of necitumumab 
800 mg, Gemcitabine 1250 mg/m2, and Cisplatin 75 mg/m2.  If 1 of the first 3 DLT evaluable 
patients develops DLT at Cohort 1, 3 more patients will be added.  If 2 DLT evaluable patients 
develop DLT at Cohort 1, the enrollment will be continued up to total 9 patients for Cohort 1, or 
until 3 patients develop DLTs, whichever occurs first.  
If the number of DLT evaluable patients with DLT is none out of 3, 1 out of 6, or 2 out of 9 in 
Cohort 1, Cohort 2 will be started after consultation with the Efficacy and Safety Evaluation 
Committee (ESEC).  If 3 patients or more develop DLTs in Cohort 1, the Sponsor will consult 
the ESEC to decide whether study should be discontinued or not.
Cohort 2 will be started at a dose level of necitumumab 800 mg, Gemcitabine 1250 mg/m2, and 
Cisplatin 75 mg/m2, and 6 patients will be enrolled in Cohort 2.  If 1 of the first 6 DLT 
•Necitumumab 800 mg
•Gemcitabine 1000 mg/m2
•Cisplatin 75 mg/m2
Cohort 1: 3 pts
0 DLT/3 pts
1 DLT/6 pts
Decision of 
Recommended Dose 
(Move to Ph2 part)
1 DLT /6 pts
•Necitumumab 800 mg
•Gemcitabine 1250 mg/m2
•Cisplatin 75 mg/m2
Cohort 2: 6 pts
Add 3 pts
Decision through 
discussion with ESEC
Add 3 pts 
Add up to 9 pts in total
2 DLTs/9 pts
Decision through 
discussion with ESEC
1 DLT
2 DLTs
3 DLTs
3 DLTs
2 DLTs
2 DLTs/9 pts

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evaluable patients develops DLT in Cohort 2, the Phase 2 part will be started with the dose level 
of Cohort 2 after consultation with the ESEC.  
If 2 of the first 6 DLT evaluable patients develop DLT in the Cohort 2, 3 more patients will be 
added.  If none of the additional 3 DLT evaluable patients develops DLT, the Phase 2 part will 
be started with the dose level of Cohort 2 after consultation with the ESEC.
If 3 DLT evaluable patients or more develop DLTs in Cohort 2, the Phase 2 part may be started 
with the dose level of Cohort 1 after consultation with the ESEC.  Further patients’ enrollment in 
Cohort 1 may be considered to investigate safety and tolerability of the do se level concretely.  
Patients in whom DLT occurs in Cycle 1 may still continue study treatment according to the 
criteria for starting the next cycle (Section 9.4.1.2) or dose modification (Section 9.4.1.3) if the 
patients are benefiting from study treatment in the opinion of the investigator.  
Gemcitabine-cisplatin plus necitumumab may continue for a maximum of 4 cycles; patients with 
at least stable disease may continue to receive necitumumab until disease progression, the 
development of unacceptable toxicity or withdrawal of consent by the patient, or 
Sponsor/investigator decision.
8.1.2. Phase 2 Part
The Phase 2 part is randomized study to evaluate efficacy and safety of necitumumab in 
combination with gemcitabine-cisplatin (Figure JFCM.5).  
Abbreviations:  n = numbers of patient, CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, OS = overall survival, PS = performance status
Figure JFCM.5.
Illustration of study design in Phase 2 part
In the Phase 2 part, 180 patients with Stage IV squamous NSCLC will be randomized on a 1:1 
basis to receive:  
CR
PR
SD
•Necitumumab 800 mg
•Gemcitabine 1000 or 1250 mg/m2
•Cisplatin 75 mg/m2
Gemcitabine and cisplatin continue for a maximum of four cycles.  
Necitumumab continues until PD or toxicity.
1:1
OS 
analysis
R
A
N
D
O
M
I
Z
E
*
S
T
U
D
Y
C
O
M
P
L
E
T
I
O
N
•Gemcitabine 1000 or 1250 mg/m2
•Cisplatin 75 mg/m2
Gemcitabine and cisplatin continue for a maximum of four cycles.
Only Follow-up
Necitumumab
800 mg
PD
Arm A (n = 90) 
Arm B (n = 90) 
(n = 180) 
Necitumumab
800 mg
Combination Therapy
Maintenance Therapy
Extension Phase
*Stratification factors
- ECOG PS (0 vs.1)
- Gender (female vs.male)
CR
PR
SD
PD
1250 mg/m2
1250 mg/m2

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(1)
necitumumab plus gemcitabine-cisplatin chemotherapy (Arm A); or 
(2)
gemcitabine-cisplatin chemotherapy alone (Arm B)  
Randomization will be stratified by ECOG PS (0 vs. 1) and gender (female vs. male).  
Following necessary premedication, all patients will receive study therapy, consisting of:
Arm A

Necitumumab, administered I.V. over 50 minutes at an absolute dose of 800 mg on Days 1 
and 8 

Gemcitabine, administered I.V. over approximately 30 minutes at a dose of 1250 mg/m2
(based on the outcome of the Phase 1b part) on Days 1 and 8 for a maximum of 4 cycles; 
and 

Cisplatin, administered I.V. over approximately 120 minutes at a dose of 75 mg/m2 on 
Day 1 for a maximum of 4 cycles.  
Arm B

Gemcitabine, administered I.V. over approximately 30 minutes at a dose of 1250 mg/m2
(based on the outcome of the Phase 1b part) on Days 1 and 8 for a maximum of 4 cycles; 
and 

Cisplatin, administered I.V. over approximately 120 minutes at a dose of 75 mg/m2 on 
Day 1 for a maximum of 4 cycles.  
In Arm A, patients will receive necitumumab, followed by gemcitabine.  In both arms, cisplatin 
will be administered to patients at least 30 minutes following the end of the gemcitabine infusion.
Gemcitabine and cisplatin continue for a maximum of 4 cycles.  In Arm A, necitumumab 
continue exceeding 4 cycles, until disease progression, the development of unacceptable toxicity, 
protocol noncompliance or withdrawal of consent by the patient, or Sponsor/investigator 
decision.  In Arm B, no maintenance therapy is permitted after 4 cycles of gemcitabine-cisplatin 
until disease progression.  
8.1.3. Baseline and Study Treatment Period assessments
The Study Schedule (Attachment 1) describes the timing of baseline and study treatment period 
assessments.
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.  
At baseline (within 21 days prior to dosing unless otherwise specified in Attachment 1) and 
during the study treatment period, medical and physical examinations, tumor measurements of 
palpable or visible lesions, ECOG PS evaluation, electrocardiogram (ECG) assessment, and 
serum chemistry, hematology, urinalysis, and coagulation laboratory tests will be completed. 
Blood samples for PK, biomarker, immunogenicity, and other evaluations, and tumor tissue for 
exploratory analyses, will be collected.

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Baseline radiographic assessment of disease will be performed within 21 days prior to 
enrollment (Phase 1b part) or randomization (Phase 2 part); first treatment will be administered 
within 7 days following enrollment (Phase 1b) or randomization (Phase 2).
Patients will undergo radiographic assessment of disease status (CT or MRI) every 6 weeks 
(7 to 3 business days), as calculated from the first dose of study therapy, regardless of 
treatment delays, until there is radiographic documentation of PD, per efficacy measurement 
criteria described in Section 10.1.  Tumor responses will be confirmed for patients with objective 
assessment of PR or CR at the next routine scheduled imaging time point (no less than 4 weeks 
after the initial response is noted).  Imaging methods used at baseline should be consistently used 
during study.
All enrolled patients will be assessed for toxicity at each visit.
Criteria for starting the next cycle are defined in Section 9.4.1.2.  Dose reductions of 
investigational product and/or gemcitabine-cisplatin chemotherapy will be made in the event of 
specific treatment related AEs, as described in Section 9.4.1.3.  Administration of one or more 
components of therapy (gemcitabine or cisplatin, and necitumumab in Arm A) may be delayed 
due to toxicity for a maximum of 6 weeks from the first dose of the previous cycle.  If toxicity 
occurs necessitating a delay to administration of any given component of longer than 6 weeks, 
that component must be permanently discontinued; other components of therapy may be 
continued without interruption or modification if appropriate in the opinion of the investigator.   
Supportive care guidelines are detailed in Section 9.7.1.
8.1.4. Post-discontinuation Follow-Up Period Assessments
Post-discontinuation follow-up period begins one day after the patient and the investigator agree 
that the patient will no longer continue study treatment, and continues until the study completion.  
For the patient who completed all treatments of Cycle 4 in Arm B of Phase 2 part, Post -
discontinuation follow-up begins the day after the Cycle 4 completion and continues until the 
study completion.  Follow-up assessments will be conducted as shown in the Study Schedule 
(Attachment 1).
8.1.4.1.
30-Day Safety Follow-Up Period
All patients should be followed and AEs reported for a minimum of 30 days from the date of the 
decision to discontinue therapy (as described in Section 10.3).  
A 30-day safety follow-up visit will be completed at least 30 days (0 to 7 days) after the 
decision is made to discontinue therapy.
8.1.4.2.
Long-term Follow-Up Period
Following discontinuation of all study treatment, patients will be followed for survival every 
90 days, until death or until study completion as defined in Section 8.1.5.
Patients who discontinue study treatment for any reason other than PD will continue to undergo 
radiographic tumor assessments every 6 weeks (7 to 3 business days) until PD, except when 
not feasible in the opinion of the investigator.  Assessment will continue until radiographic 

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documentation of PD, as long as the patient is alive or until study completion as def ined in 
Section 8.1.5.
Other follow-up assessments will be conducted as shown in the Study Schedule (Attachment 1).
8.1.5. Study Completion
This study will be considered complete on the date which 137 OS events (deaths) have been 
observed for the final analysis (approximately 15 months after the last patient starts study 
treatment).  
8.1.6. Study Extension
Following study completion, if there are patients that have not experienced disease progression 
and are still receiving study therapy, the study will enter an extension period during which 
patients may continue to receive study therapy until there is radiographic documentation of PD, 
intolerable toxicity, withdrawal of consent, or until new anticancer treatment is initiated. Sites 
will be notified when the extension phase will begin.  
During the study extension phase, the following information will be collected according to
Attachment 1:

AE assessment (including SAEs), until at least 30 days after the decision is 
made to discontinue study treatment;

Administration information of study treatment; 

Reason for study therapy discontinuation (disposition); and

Blood sampling for immunogenicity analysis in the event of an 
infusion-related reaction and at the 30-day Safety Follow-up visit.
During the extension phase, routine safety and efficacy monitoring, including an assessment 
schedule similar to that outlined in this protocol with radiographic evaluation of disease at least 
every 6 weeks, should be continued as necessary to confirm patient eligibility to continue in the 
study.  The Sponsor will collect only data shown in Protocol Attachment 1 for the extension 
phase.
8.1.7. End of Study
The end of trial is the date when:

A sufficient number of OS events (deaths) have been observed for final analysis (for 
details please see the statistical analysis plan [SAP] for this study); and

The last patient has discontinued study treatment and completed the 30-day safety 
follow-up visit.
8.1.8. Committees
The following committees will be established to evaluate or patients’ safety or efficacy of the 
study treatments.  In addition, examination results such as image data and tissue samples may be 

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submitted to the committees to evaluate the results.  For detailed information, refer to the 
handling procedures provided for this study.
Interstitial Lung Disease Committee (ILDC)
Interstitial Lung Disease Committee will be established.  For the interstitial lung disease (ILD) 
and suspected ILD cases being diagnosed after starting the study treatments (on Day 1 in Cycle 
1), external specialists will evaluate its related examination results such as image data and tissue 
samples. The assessments by the ILDC are independent from assessments by investigators and 
will not be collected in the clinical trial database.  The assessments by the ILDC will be provided 
to the Sponsor and used for safety monitoring.  Assessments by the ILDC will not be made 
available to investigators in principle. 
Efficacy and Safety Evaluation Committee (ESEC)
Efficacy and Safety Evaluation Committee will be established as an independent organization for 
Phase 1b part. The Sponsor will consult with ESEC about DLT evaluation and cohort transition.
Independent Data Monitoring Committee (IDMC)
Independent Data Monitoring Committee will be established prior to the inclusion of the first 
patient in the study of Phase 2 part, and will perform the evaluation for safety.
Independent Radiography Review Committee (IRRC)
Independent Response Review Committee may review the CT scans and MRI data for tumor 
assessments independently if necessary (eg, inquiries from regulatory authorities).  
8.2.
Discussion of Design and Control
In this study, the efficacy of necitumumab in combination with gemcitabine -cisplatin 
chemotherapy in terms of OS in patient with advanced squamous NSCLC in Phase 2 part after 
confirming the tolerability of necitumumab in combination with gemcitabine -cisplatin 
chemotherapy in Phase 1b part.  
Phase 1b part
In Study CP11-0907, the dose of 800 mg of necitumumab monotherapy which is the global 
recommended dose in Study CP11-0806 was tolerable for Japanese patients with solid tumors.  
The tolerability of necitumumab in combination with gemcitabine-cisplatin was not investigated 
in Japan.  Therefore, Phase 1b part is planned to confirm the tolerability of necitumumab 
(800 mg) in combination with gemcitabine-cisplatin before Phase 2 part.  The design of Phase 1b 
part is based on the Guidelines for Clinical Evaluation Methods of Antimalignant Tumor Drugs 
(Pharmaceutical and Food Safety Bureau. 2005).
The part is single arm, open-label, dose-escalation to determine the recommended dose of 
gemcitabine for Phase 2 part.  In the first cohort of Phase 1b part, necitumumab 800 mg, 
gemcitabine 1000 mg/m2 and cisplatin 75 mg/m2 are to be examined.  After confirming the 
tolerability of necitumumab 800 mg, gemcitabine 1000 mg/m2, and cisplatin 75 mg/m2, 

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necitumumab 800 mg, gemcitabine 1250 mg/m2, and cisplatin 75 mg/m2 which are the 
recommended doses in Study CP11-0806 are to be investigated in the second cohort.  
Based on results of DLT assessment at the Phase 1b part in this study, the recommended dose for 
the Phase 2 part was determined as necitumumab 800 mg ( Days 1 and 8 of each 3-week cycle) 
in combination with  cisplatin 75 mg/m 2 (Day 1) and gemcitabine 1250 mg/m2 (Days 1 and 8).
Phase 2 part
The Phase 2 part is open-label, randomized study to evaluate efficacy and safety of necitumumab
in combination with gemcitabine-cisplatin.  
The part will be conducted open-label, since following the first treatment session, the expected 
occurrence of acneform rash (common with EGFR inhibitors) in the necitumumab plus 
chemotherapy arm (Arm A) relative to the chemotherapy-only arm (Arm B) would unblind most 
patients and investigators to treatment assignment.
A randomized, controlled design is being used in this part.  Randomization minimizes systematic 
bias in the selection and assignment of patients to study therapy and provides justification for 
inferential statistical methods to be used on data from this part.  Using an appropriate concurrent 
control arm enables direct statistical estimation of benefits and harms due to study therapy and 
minimizes bias in the assessment and interpretation of observed treatment effects.

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9.
Treatment
9.1.
Treatments Administered
Following necessary premedication (Section 9.1.1), patients will receive the treatment regimens 
in the order shown in Table JFCM.2.
Table JFCM.2.
Treatment Regimens (3-week Cycle)
Abbreviations:  I.V. = intravenous.
Gemcitabine:  Administration in each 3-week cycle for a maximum of 4 cycles.
Cisplatin:  
Administration in each 3-week cycle for a maximum of 4 cycles, at least 30 minutes following the 
end of the gemcitabine infusion.
NOTE:  The duration of each infusion will be based on standard procedure (eg, package insert) in 
standard therapeutic practice.
It is recognized that in the course of clinical cancer care, it is not always possible to schedule 
therapeutic infusions at precise intervals (because of holidays, travel difficulties, or other 
circumstances).  Accordingly, for Day 1 of every cycle, infusions administered within 5 days 
after the planned infusion time point will be considered acceptable.  Deviations beyond this 
window are strongly discouraged.
Drug
Dose
Day
Infusion duration
Phase 1b
Cohort 1
Necitumumab
800 mg absolute dose I.V. infusion
Days 1 and 8
over 50 minutes
Gemcitabine
1000 mg/m2 I.V. infusion
Days 1 and 8
over 30 minutes
Cisplatin
75 mg/m2 I.V. infusion
Day 1
over 120 minutes
Cohort 2
Necitumumab
800 mg absolute dose I.V. infusion
Days 1 and 8
over 50 minutes
Gemcitabine
1250 mg/m2 I.V. infusion
Days 1 and 8
over 30 minutes
Cisplatin
75 mg/m2 I.V. infusion
Day 1
over 120 minutes
Phase 2
Arm A
Necitumumab
800 mg absolute dose I.V. infusion
Days 1 and 8
over 50 minutes
Gemcitabine
1250 mg/m2 I.V. infusion
Days 1 and 8
over 30 minutes
Cisplatin
75 mg/m2 I.V. infusion
Day 1
over 120 minutes
Arm B
Gemcitabine
1250 mg/m2 I.V. infusion
Days 1 and 8
over 30 minutes
Cisplatin
75 mg/m2 I.V. infusion
Day 1
over 120 minutes

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The investigator or his/her designee is responsible for the following:

explaining the correct use of the drug(s) and planned duration of each individual’s 
treatment to the patient, site personnel, and legal representative,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensing and collection, and

returning all unused medication to the Sponsor or its designee at the end of the study.
9.1.1. Premedication
All premedication administered must be adequately documented in the electronic case report 
form (eCRF).
9.1.1.1.
Premedication for Cisplatin and Gemcitabine
Premedication for cisplatin will be recommended in accordance with the package insert.
Gemcitabine will be administered on Days 1 and 8 for 30 minutes. Cisplatin will be
administered on Day 1 for 120 minutes.  Prophylactic antiemetics will be routinely administered. 
Drugs will be administered intravenously as follows. On Days 1, patients will be given I.V.
hydration of normal saline. A 5-HT3 receptor antagonist (eg, 3 mg), steroides (eg, 16 mg of 
dexamethasone) and a neurokinin 1 (NK1) receptor antagonist (eg, aprepitant) will be given.  
9.1.2. Investigational Product
9.1.2.1.
Necitumumab
Patients will receive necitumumab at an absolute dose of 800 mg on Days 1 and 8 of each 
3-week cycle, administered as an I.V. infusion over 50 minutes.
Aseptic technique is to be used when preparing and handling necitumumab.  Different drug 
product lots must not be mixed in a single infusion.  Necitumumab is compatible with commonly 
used infusion containers.  Refer to the IB or procedure for detailed information.  Necitumumab 
administration which is different from that outlined in the IB but described in the Investigational 
Product Handling Procedures is acceptable.
9.1.2.2.
Gemcitabine
Gemcitabine will be supplied by the Sponsor, and should be prepared and administered 
according to the manufacturer’s instructions.  In the Phase 1b part, gemcitabine will be 
administered at a dose of 1000 or 1250 mg/m2 (I.V.) over 30 minutes on Days 1 and 8 of each 3-
week treatment cycle, for a maximum of 4 cycles.  In the Phase 2 part, gemcitabine will be 
administered at a dose of 1250 mg/m2 (I.V.) over 30 minutes on Days 1 and 8 of each 3-week 
treatment cycle, for a maximum of 4 cycles.
9.1.3. Cisplatin
A commercial preparation of cisplatin will be used and should be prepared and administered 
according to the manufacturer’s instructions.  Cisplatin will be administered beginning at least 
30 minutes after the completion of the gemcitabine infusion on Day 1 of each 3-week treatment 

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cycle, at a dose of 75 mg/m2 (I.V.) administered over 120 minutes.  Cisplatin will be 
administered for a maximum of 4 cycles.
9.2.
Materials and Supplies
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
Necitumumab is a sterile, preservative-free solution for infusion of necitumumab formulated in 
an aqueous solution at a concentration of 16 mg/mL (800 mg/50 mL vial).  The buffer contains 
10 mM citrate, 40 mM sodium chloride, 133 mM glycine, 50 mM mannitol, 0.01% polysorbate 
80.  The drug product must be stored under refrigeration at 2ºC to 8ºC with protection from light.  
Gemcitabine is a lyophilized powder, I.V. infusion supplied in sterile vials containing 1 g as the 
hydrochloride salt (expressed as the free base), mannitol, and sodium acetate of product.  The 
drug product must be stored at controlled room temperature.
Cisplatin of a commercial product will be used and should be stored in accordance with the 
package insert.  
9.3.
Method of Assignment to Treatment
Phase 1b part:
Patients who meet all criteria for enrollment will be assigned to receive necitumumab 800 mg, 
gemcitabine 1000 or 1250 mg/m2, and Cisplatin 75 mg/m2 in this part.  Upon confirmation of 
eligibility, the Sponsor will assign the treatment cohort (dose level) for each patient.  
Phase 2 part:
Patients who meet all criteria for enrollment will be randomly assigned to receive either Arm A 
or Arm B within 7 days prior to administration of first treatment.
Upon completion of all screening evaluations to confirm a patient’s eligibility, the sites will 
register the patient by the interactive web-response system (IWRS).  The IWRS registration 
consists of assigning the patient a unique study identification number and randomizing the 
patient to 1 of the 2 treatment arms on a 1:1 basis (Arm A : Arm B).
Once the patient is registered through the IWRS, he/she is considered to be randomized in the 
study.  The IWRS will assign patients to treatment arms according to a stratified method of 
randomization (that is, independent randomization within each of 4 strata, or cells), defined b y 
all 4 combinations of the following 2 prognostic factors:

ECOG PS at baseline (0 vs. 1); and

gender (females vs. males).
9.4.
Selection and Timing of Doses
The first treatment will be administered within 7 days of enrollment (Phase 1b) or randomization 
(Phase 2).  Study treatment will be administered as described in Section 9.1.

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9.4.1. Special Treatment Considerations
9.4.1.1.
Dose-Limiting Toxicity Determination (Phase 1b part)
In Phase 1b part, DLT assessment will be performed.  A DLT is defined as one of the following 
events, graded according to the NCI-CTCAE version 4.0, when the event occurs within 21 days 
from Day 1 in the Cycle 1 and is considered to be definitely or probably related to necitumumab
and/or gemcitabine-cisplatin chemotherapy.  DLT evaluation period is defined as 21 days from 
Day 1 of Cycle 1 even if next cycle treatment will be delayed due to AEs.  Full supportive care 
may be allowed during the Cycle 1.
Advice will be obtained from the ESEC if needed, .

Grade 4 neutropenia lasting 7 days 

Grade 3 febrile neutropenia except for transient febrile neutropenia (Grade 3 
neutropenia associated with fever 38.0ºC for 24 hours)

Grade 3 thrombocytopenia requiring platelet substitution 

Grade 4 thrombocytopenia (<25,000 /mm3)
If investigator consider the first data of Grade 4 thrombocytopenia (<25,000 /mm3) 
would be uncertain, DLT could be judged by re-examination data.  Re-examination 
should be done before supportive care and separate from first determination.  When the 
result of reexamination does not match the DLT criteria, it would not be considered 
DLTs 

Grade 3 nonhematologic toxicity, with except ions as follows:  

The following toxicities will not be considered DLTs if they are transient
(7 days) with full supportive therapy

Grade 3 arthralgia or myalgia 

Grade 3 asthenia or fatigue 

Grade 3 diarrhea, constipation, or anorexia 

Grade 3 nausea or vomiting

The following toxicities will not be considered DLTs:  

Grade 3 skin toxicity

Grade 3 or 4 hypersensitivity 

Grade 3 injection-site reaction 

Grade 3 elevation of transaminases lasting 7 days 

Grade 3 elevation of serum-bilirubin lasting 7 days 

Transient Grade 3 elevation or decrease of electrolytes

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
Any toxicity leading to the omission of Day 8 or 15 of necitumumab (for those patients 
for whom necitumumab is delayed from Days 8 to 15) during the Cycle 1.
If a Grade 3 or 4 infusion-related reaction (hypersensitivity) occurs, due to either 
gemcitabine-cisplatin or necitumumab, this event will not be considered a DLT; the patient will 
not receive any further study therapy and will be replaced in the study by a new patient.  Upon 
the occurrence of Grade 3 or 4 infusion-related reactions in two or more patients, enrollment will 
be suspended and the Sponsor will determine whether or not patient enrollment should be 
continued after consultation with the ESEC.
Dose-Limiting Toxicity will be decided after review of preliminary safety data by the 
investigator and the Sponsor.
9.4.1.2.
Treatment Requirements and Delays
Cycle 1
Pretreatment local laboratory data on Day 1 in Cycle 1 may not be older than 7 days.  The results 
at the screening test can be utilized to confirm the criteria for treatment on Day 1 if they are 
obtained within 7 days before the first dose of study treatment.  The first cycle should be started 
within 7 days after the randomization.  The criteria for administration of study treatment at the 
planned schedule are shown in Table JFCM.3 and Table JFCM.4.
Table JFCM.3.
Criteria for Treatment with Necitumumab (on Day 1)
Conjunctivitis
Grade 2
Hypomagnemia 
Grade 2
Skin Toxicity
Grade 2 (please refer to Section 9.7.1.2)
Other a
Grade 2 (for infusion-related reactions, please refer to Section 9.7.1.1)
a:  At least possibly related to necitumumab
Table JFCM.4.
Criteria for Treatment with Gemcitabine-Cisplatin (on Day 1)
Hemoglobin
10.0 g/dL
Neutrophils
1.5 x 109/L
Platelets
100 x 109/L
Serum creatinine a
1.2 x ULN or creatinine clearance >50 mL/min
Bilirubin
1.5 x ULN
AST
2.5 x ULN
ALT
2.5 x ULN
Other b
Grade 2, except skin toxicity
Abbreviation:  ALT = alanine aminotransferase; AST = aspartate aminotransferase
a:  Urine samples up to 24 hours will be used if both blood and urine samples for creatinine clearance are collected.
b:  At least possibly related to gemcitabine.

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On Day 8, pretreatment local laboratory data may be checked on the day of administration (Table 
JFCM.5 and Table JFCM.6).
Table JFCM.5.
Criteria for Treatment with Necitumumab (on Day 8, or Day15 if 
delayed)
Conjunctivitis
Grade 2
Hypomagnemia 
Grade 2
Skin Toxicity
Grade 2 (please refer to Section 9.7.1.2)
Other a
Grade 2 (for infusion-related reactions, please refer to Section 9.7.1.1)
Note:  If necitumumab treatment is delayed from Day 8 to Day 15, these criteria should be met at the time of 
necitumumab treatment on Day 15.
a:  At least possibly related to necitumumab
Table JFCM.6.
Criteria for Treatment with Gemcitabine (on Day 8)
Neutrophils
1.5 x 109/L
Platelets
100 x 109/L
Serum creatinine a
1.2 x ULN or creatinine clearance >50 mL/min
Bilirubin
1.5 x ULN
AST
2.5 x ULN
ALT
2.5 x ULN
Other b
Grade 2, except skin toxicity
Abbreviation:  ALT = alanine aminotransferase; AST = aspartate aminotransferase
a:  Urine samples up to 24 hours will be used if both blood and urine samples for creatinine clearance are collected.
b:  At least possibly related to gemcitabine.
If the criteria outlined in both Table JFCM.5 and Table JFCM.6 are not met at the time of a 
planned treatment, the following general rules for the management of treatment delays apply:

In the case of toxicity that does not meet the criteria described in Table JFCM.5, 
administration of necitumumab will be interrupted, but gemcitabine will continue 
according to the planned schedule. Specifically, in case of necitumumab-related 
toxicities on Day 8, gemcitabine will be administered according to the planned schedu le 
and necitumumab administration will be delayed for 1 week and administered on Day 15.  
If patient does not meet the criteria described in Table JFCM.5 on Day 15, the infusion of 
necitumumab will be skipped.

If on Day 8, the criteria described in Table JFCM.6 are not met, gemcitabine 
administration should be skipped for this cycle.
Continuation of Therapy (Cycle 2 and Beyond) 
Pretreatment laboratory data required for treatment on Day 1 in Cycle 2 and all following cycles 
may not be older than 3 days.  Treatment on Day 8 may be administered within a ±3 day window.  

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Pretreatment laboratory data required for treatment on Day 8 must be collected on Day 5 or later, 
but 3 days or less prior to treatment.   
The criteria for administration of study treatment at the planned schedule are shown in Table 
JFCM.7 and Table JFCM.8.
Table JFCM.7.
Criteria for Treatment with Necitumumab
Conjunctivitis
Grade 2
Hypomagnemia 
Grade 2
Skin Toxicity
Grade 2 (please refer to Section 9.7.1.2)
Other a
Grade 2 (for infusion-related reactions, please refer to Section 9.7.1.1)
a:  At least possibly related to necitumumab
Table JFCM.8.
Criteria for Treatment with Cisplatin-Gemcitabine (on Day 1) and 
Gemcitabine (on Day 8)
Neutrophils
1.5 x 109/L
Platelets
100 x 109/L
Serum creatinine a
1.2 x ULN or creatinine clearance >50 mL/min
Bilirubin
1.5 x ULN
AST
2.5 x ULN
ALT
2.5 x ULN
Other b
Grade 2, except skin toxicity
Abbreviation:  ALT = alanine aminotransferase; AST = aspartate aminotransferase
a:  Urine samples up to 24 hours will be used if both blood and urine samples for creatinine clearance are collected.
b:  At least possibly related to cisplatin-gemcitabine
If the criteria outlined in Table JFCM.7 and Table JFCM.8 are not met at the time of a planned 
treatment, the following general rules for the management of treatment delays apply:

In the case where a patient meets the criteria (Table JFCM.7 and Table JFCM.8), the 
administration of gemcitabine, cisplatin, and necitumumab will occur on Day 1.

In the case of toxicity such that the patient does not meet the criteria in Table JFCM.7, 
administration of necitumumab will be interrupted, but gemcitabine will continue 
according to the planned schedule. In that case, necitumumab administration will be 
delayed for 1 week and administered on Day 15.  If patient does not meet the criteria 
described in Table JFCM.7 on Day 15, the infusion of necitumumab will be skipped.

If on Day 8 of any cycle, the criteria described in Table JFCM.8 are not met, gemcitabine 
administration should be skipped for this cycle.

If administration of a given each treatment is delayed for more than 6 weeks after Day 1
of the most recent treatment cycle, this patient will discontinue of the administration of 
study treatment. If gemcitabine, cisplatin, or necitumumab is discontinued due to toxicity, 
the remaining agents should be continued according to this study protocol.

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When gemcitabine-cisplatin-related toxicity has resolved, gemcitabine-cisplatin and 
necitumumab will resume on the regular schedule (please see Attachment 5 for illustrative 
examples of dose delay management).
9.4.1.3.
Dose Modification
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report the circumstances and data leading to any such dosage reduction, 
discontinuation of treatment.
9.4.1.3.1. Necitumumab
The following are general dose modification guidelines for toxicit y associated with necitumumab.  
The following sections contain specific information on the management of necitumumab related 
infusion-related reactions, skin reactions, conjunctivitis, hypomagnesemia, disseminated 
intravascular coagulation (DIC), and thromboembolic events.
Dose modifications are permitted for necitumumab following reversible Grade 3 or 4 
necitumumab related AEs (ie, fatigue, anorexia, or fever) that require delay of necitumumab
treatmment for up to 6 weeks following Day 1 of the most recent treatment cycle (Section 9.7.1.1
and 9.7.1.2 for infusion-related reactions and skin reactions, respectively). In this setting, 
necitumumab may be re-administered at a reduced dose (600 mg).  A second dose reduction (to 
400 mg) is permitted for this level of event (Grade 3 or 4) based on the investigator consideration.  
Events that necessitate more than two dose reductions warrant discontinuation of necitumumab.  
The dose of necitumumab may be re-escalated to the pre-reduction dose, provided that at least 
3 weeks have elapsed following the first administration of the reduced dose, if appropriate in the 
opinion of the investigator or subinvestigator and they consult the Sponsor.
Patients who enter the study with symptoms or laboratory values equivalent t o NCI-CTCAE 
version 4.0 Grade 1 or 2 AEs should not have dose reductions related to the persistence or mild 
worsening (eg, from Grade 1 to 2) of those symptoms or laboratory values. Investigators may 
reduce the dosage of necitumumab when Grade 3 necitumumab related AEs occur during the 
treatment cycle.
For Phase 1b, dose modifications for necitumumab are not permitted during the Cycle 1.  If a 
patient experiences skin reaction, the necitumumab treatment may be modified according to 
Section 9.7.1.2.
9.4.1.3.2. Gemcitabine and Cisplatin
Gemcitabine and cisplatin may cause known hematologic and nonhematologic toxicities at the 
dose levels infused during this study; dose interruptions or reductions may be required.  In such 
cases, the dose levels outlined in Table JFCM.9 should be used in the determination of 
gemcitabine and cisplatin doses.  Investigators may reduce the dosage of gemcitabine and 
cisplatin when Grade 3 gemcitabine and cisplatin related AEs occur during the treatment cycle.
For Phase 1b, the dose modifications gemcitabine on Day 8 are permitted also during the Cycle 1.  

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NOTE:  Chemotherapy dose modifications are permanent; once the dose of any agent has been 
reduced, it will remain reduced or be further reduced in subsequent cycles. Any patient with two 
prior dose reductions to one agent who experiences a toxicity that would cause a third dose 
reduction (or a reduction below the dose level associated with a second dose reduction; see the 
Table JFCM.9) must be discontinued from that agent. Therapy must also be discontinued if 
toxicity would necessitate a dose delay of more than 6 weeks following Day 1 of the most recent 
treatment cycle.
Table JFCM.9.
Dose Reductions for Gemcitabine and Cisplatin
Dose Level
Gemcitabine
Cisplatin
Starting Dose
1000 mg/m2
1250 mg/m2
75 mg/m2
First Dose Reduction
75% / 750 mg/m2
75% / 950 mg/m2
75% / 56 mg/m2
Second Dose Reduction
50% / 500 mg/m2
50% / 625 mg/m2
50% / 38 mg/m2
The gemcitabine and cisplatin dose levels are not linked and may be adjusted independently as 
summarized in Table JFCM.10 and Table JFCM.11.
9.4.1.3.2.1.
Hematological Toxicity
Dose modification criteria that are the recommendation for hematologic toxicities are 
summarized in the Table JFCM.10.  Dose adjustments for hematologic toxicity at the start of a 
subsequent cycle should be based on nadir hematologic counts from the previous cycle of 
therapy.
Table JFCM.10.
Dose Reductions for Hematologic Toxicity
Drug-Related Toxicity During Previous Cycle
Gemcitabine Dose
Cisplatin Dose
ANC
Grade 4 (> 7 days)
Reduce one dose level
Reduce one dose level
Platelets
Grade 3
(requiring platelet 
substitution)
Reduce one dose level
Reduce one dose level
Grade 4
Reduce one dose level
Reduce one dose level
Abbreviations:  ANC = absolute neutrophil count
9.4.1.3.2.2.
Nonhematological Toxicity
In any case where serum creatinine is >1.2 x ULN or calculated creatinine clearance is 
<50 mL/min, treatment of both gemcitabine and cisplatin must be delayed until recovery (Table 
JFCM.4, Table JFCM.6, and Table JFCM.8); after recovery dose adjustment is recommended.  
Additional guidelines for chemotherapy dose modification related to nonhematologic toxicity are 
summarized in Table JFCM.11.  For nonhematologic toxicity not specifically covered in Table 
JFCM.11, dose reduction may be warranted for events if clinically appropriate in the opinion of
the investigator or subinvestigator and based on worst toxicity in the previous cycle.

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Table JFCM.11.
Dose Reductions for Nonhematologic Toxicity
Drug-Related Toxicity During Previous Cycle
Gemcitabine Dose
Cisplatin Dose
Mucositis/Stomatitis
Grade 3
Reduce one dose level
-
Neurotoxicity
Grade 0 to 1
-
-
Grade 2
-
Reduce two dose levels a
Grade 3 to 4
Discontinue
Discontinue
Ototoxicity
Grade 2 to 4
-
Consider discontinuation
All Other 
Grade 3 b
Reduce one dose level c
Reduce one dose level c
a: Reduction of two dose levels is recommended.  
b: Excluding Grade 3 nausea/vomiting, and Grade 3 paronychia, for which no dose reduction is necessary.  
c: If clinically appropriate in the opinion of the investigator; discontinuation of one or more agents may also be 
warranted in some cases.
9.5.
Continued Access to Study Drug
Necitumumab may be made available after study completion to patients who are still receiving 
and benefitting from study treatment (see Section 8.1.6).
9.6.
Blinding
This is an open-label study.
9.7.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the eCRF.  Concomitant medications and 
supportive care therapies must be documented at the time of discontinuation and also at the 
30-day follow-up visit.
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
concurrent chemotherapy, surgery for cancer, biologic response modifiers, or other 
investigational agents will be permitted while patients are on study treatment.  
If any major surgery required full anesthesia should be required during the study treatment 
period, the patient should discontinue study treatment.  However, a minor surgery performed 
with local anesthesia may be permitted.  The time of study treatment interruption before minor 
surgery should be at least 7 days following the last dose of study treatment.  Patients may resume 
all study treatment no less than 7 days following minor surgery, provided there has been 
adequate recovery in the opinion of the investigator.  Following minor surgery that may affect 
the evaluable lesion, radiological evaluation of disease is required prior to resumption of study 
treatment.
Patients undergoing surgery before PD should be followed-up by imaging every 6 weeks until 
radiographically documented PD.

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9.7.1. Supportive Care
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to all patients on this study.  Supportive care measures may include but 
are not limited to antidiarrheal agents, antiemetic agents, opiate and nonopiate analgesic agents, 
appetite stimulants, and granulocyte and erythroid growth factors.  Details of interventions, 
procedures, or blood products (eg, blood cells, platelets, or fresh frozen plasma transfusions) 
should be recorded on the eCRF.  Please see Section 9.4.1.3 for specific information on the 
management of necitumumab-related infusion reactions, skin reactions, conjunctivitis, and 
hypomagnesemia.  Guidelines regarding the use of other specific supportive care agents are 
presented below.
9.7.1.1.
Infusion-Related Reactions
Hypersensitivity/infusion-related reactions are defined according to the NCI-CTCAE version 4.0 
definition of allergic reaction/hypersensitivity, as follows:

Grade 1: transient flushing or rash, drug fever <38.0ºC

Grade 2: rash, flushing, urticaria, dyspnea, drug fever 38.0ºC

Grade 3: symptomatic bronchospasm, requiring parenteral medication(s), with or 
without urticaria; allergy-related edema/angioedema, hypotension

Grade 4: anaphylaxis (a life-threatening event characterized by the rapid onset 
[often within minutes] of airway obstruction [bronchospasm, stridor, 
hoarseness], urticaria, and/or hypotension)
Hypersensitivity/infusion-related reactions were reported with necitumumab.  The onset of 
events usually occurred after the first or second administration of necitumumab.  Monitor 
patients during and following the infusion for signs of hypersensitivity and inf usion-related 
reactions with resuscitation equipment readily available.  For mild or moderate (Grade 1 or 2) 
infusion-related reactions, adjust dose per Table JFCM.12.  Immediately and permanently 
discontinue necitumumab for severe (Grade 3 or 4) infusion-related reactions.
Consistent with usual medical practice, selected parenteral medications may be utilized for as 
detailed below (Table JFCM.12).  Additional treatments, chosen according to clinical symptoms 
and local standards, may be utilized at investigator discretion.

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Table JFCM.12.
Infusion-Related Reactions – Management Recommendations
Grade of 
Reaction
Management Recommendations
1

Slow the infusion rate by 50%.

Monitor the patient for worsening of condition.
2

Stop the infusion.

Administer diphenhydramine hydrochloride 50 mg oral (PO) or equivalent,  acetaminophen 650 mg orally 
for fever, and oxygen.

Resume the infusion at 50% of the prior rate once the infusion-related reaction has resolved or decreased to 
Grade 1; the total infusion duration should not exceed 2 hours.

Monitor for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg PO (or equivalent)
For a second Grade 1 or 2 infusion-related reaction, administer dexamethasone 10 mg I.V. (or equivalent); then, 
for subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg PO (or equivalent), 
acetaminophen 650 mg orally or I.V., and dexamethasone 10 mg I.V. (or equivalent).
3

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg PO (or equivalent), dexamethasone 10 mg I.V. (or 
equivalent), bronchodilators for bronchospasm, and other medications/treatment as medically indicated.

Patients who have a Grade 3 infusion-related reaction will not receive further treatment with necitumumab, 
but will continue to be followed on the protocol.
4

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg PO (or equivalent), dexamethasone 10 mg I.V. (or 
equivalent), and other medications/treatment as indicated.

Give epinephrine or bronchodilators as indicated.

Hospital admission for observation may be indicated.

Patients who have a Grade 4 infusion-related reaction will not receive further treatment with necitumumab, 
but will continue to be followed on the protocol.
Abbreviations:  I.V. = intravenously; PO = oral.
If a patient should have a hypersensitivity/infusion-related reaction to necitumumab, all attempts 
should be made to obtain an anti-necitumumab antibody blood sample as close to the onset of the 
event as possible, at the resolution of the event, and 30 days following the event.  In addition, 
these same samples may be assessed for levels of necitumumab and for biomarkers to provide 
information on the nature of the infusion-related reaction.  The procedure for sample collection 
and handling is described in a separate procedural manual.
9.7.1.2.
Skin Reactions
9.7.1.2.1. Reactive Treatment
Skin reactions were reported with necitumumab.  The onset of events occurred mainly during the 
first cycle of treatment.
Based on emerging data from cetuximab, there appears to be a correlation between acneform 
rash and various efficacy outcomes.  Therefore, if a patient experiences a Grade 1 or 2 acne-like 
rash, necitumumab treatment should continue without dose modification or delay.  If a patient 
experiences acute or chronic Grade 3 rash acneiform (ie, rash associated with pain, disfigurement, 

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ulceration, or desquamation), pruritus, desquamation, dry skin, cheilitis, or hand -foot reaction, 
necitumumab treatment will be delayed for a maximum of 6 weeks following Day 1 of the most 
recent treatment cycle, until there is improvement to Grade 2. At this time, necitumumab may 
be re-administered (as described in Table JFCM.13). Patients who experience Grade 3 skin 
induration / fibrosis or any Grade 4 skin toxicity will be immediately and permanently 
discontinued from necitumumab.
Prior to necitumumab infusion, consider premedication for possible skin reactions.  Preemptive 
treatment with skin moisturizers, topical steroids, doxycycline, or sunscreen may be administered 
as clinically appropriate to patients receiving necitumumab (Lacouture et al. 2011).  For 
additional information regarding preemptive management of skin toxicity, see Canadian 
recommendations (Melosky et al. 2009).
Table JFCM.13.
Skin Reactions – Management Recommendations
Grade of 
Reaction
Management Recommendations
1

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.
2

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

If clinically appropriate in the opinion of the investigator, administer oral minocycline or 
doxycycline 100 mg twice daily (or equivalent), for a minimum of 4 weeks and continuing for as 
long as rash is symptomatic.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.
3

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

Administer oral minocycline or doxycycline 100 mg twice daily (or equivalent), for a minimum of 
4 weeks and continuing for as long as rash is symptomatic.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.

Necitumumab administration will be temporarily withheld until symptoms resolve to Grade ≤ 2, 
but not for longer than a maximum of 6 weeks following Day 1 of the most recent treatment cycle.

Following improvement to Grade ≤2, necitumumab may be readministered, with a dose reduction 
of 50% of the original dose (400 mg).  This dose may be increased to 75% of the original dose 
(600 mg) after a minimum of one treatment cycle (3 weeks), if symptoms do not recur.  If 
symptoms do not recur for another treatment cycle, the dose may be re-escalated to the full 
recommended dose (800 mg).

If reactions do not resolve to Grade ≤2 after 6 weeks following Day 1, or if reactions recur or 
become intolerable at 50% of the original dose, necitumumab treatment should be permanently 
discontinued.

Patients who experience Grade 3 skin induration / fibrosis will be immediately discontinued from 
necitumumab.

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Grade of 
Reaction
Management Recommendations
4

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

Administer oral minocycline or doxycycline 100 mg twice daily (or equivalent), for a minimum of 
4 weeks and continuing for as long as rash is symptomatic.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.

Necitumumab administration must be immediately and permanently discontinued.
If necitumumab therapy is delayed or discontinued due to acneform rash, chemotherapy may be 
administered without interruption in the absence of disease progression.
A dermatology referral may be indicated for skin reactions that do not improve following 
1 to 2 weeks of treatment, reactions that are severely symptomatic (for example, necrosis, 
blistering, petechial, or purpuric lesions), reactions of NCI-CTCAE version 4.0 Grade 3, or 
reactions with an uncharacteristic appearance.
As with all concomitant medications and procedures, any actions taken to ameliorate skin 
toxicity will be documented in the concomitant medication module of the eCRF.
9.7.1.2.2. Pre-emptive Treatment
Recent findings have suggested that pre-emptive treatment may reduce the severity and treatment 
impact of EGFR-inhibitor-related skin toxicity.  Please note; pre-emptive treatment for skin 
toxicity on only Phase 1b part may not be administered prior to the beginning of the second 
treatment cycle.  
9.7.1.3.
Conjunctivitis
Conjunctivitis has been reported very commonly in patients receiving necitumumab.
For patients with treatment-related conjunctivitis <Grade 3, the investigator is advised to initiate 
symptomatic treatment and follow-up observation of the event.  If the severity increases to 
Grade 3, or symptoms persists for >10 days after symptomatic treatment, the investigator is 
advised to refer the patient to an ophthalmologist for further evaluation and treatment.
Serious cases of keratitis and ulcerative keratitis have been reported as uncommon or rare side 
effects for other anti-EGFR antibodies and are to be considered a class effect. If the diagnosis is 
confirmed, anti-EGFR treatment should be interrupted or discontinued, with benefits and risks of 
continuation of treatment to be carefully considered.
9.7.1.4.
Electrolyte Abnormalities
Consistent with observations with other EGFR-targeting antibodies (as with panitumumab and 
cetuximab), hypomagnesemia has been very commonly reported in patients treated with 
necitumumab in combination with cisplatin-based regimens.  Hypomagnesemia is considered a 
class effect for EGFR-targeting antibodies. Monitor patients for hypomagnesemia, 
hypocalcemia, hypokalemia, and hypophosphatemia prior to each administration of 

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necitumumab and after completion of the treatment of necitumumab, until within normal limits.  
Prompt repletion is recommended, as appropriate.  Hypomagnesemia is reversible following 
discontinuation of EGFR antibody therapy.  Treatment of any hypomagnesemia should be as 
clinically indicated according to local standards, and necitumumab therapy should be continued 
unless the investigator has any related safety concern.
9.7.1.5.
Interstitial Lung Disease
Cases of interstitial lung disease (ILD), including cases with fatal outcome, have been reported 
as an uncommon side effect for other anti-EGFR antibodies, mainly in the Japanese population. 
ILD may represent a class effect of such kind of drugs. If ILD is diagnosed, anti-EGFR antibody 
therapy is to be permanently discontinued and the patient should be treated appropriately.
9.7.1.6.
Thromboembolic Events
Venous thromboembolic events and ATEs were observed with necitumumab in combination 
with gemcitabine and cisplatin.  The relative risk of VTEs or ATEs was approximately 3-fold 
higher in patients with a reported history of VTEs or ATEs.
Discontinuation of necitumumab in patients who experience a VTE or ATE should be considered 
after a thorough benefit-risk assessment for the individual patient. 
Treatment of any thromboembolic events occurring under necitumumab treatment should be as 
clinically indicated according to local standards, and the continuation of necitumumab therapy in 
these cases should be decided by the investigator after thorough risk-benefit assessment for the 
individual patient.
Necitumumab in Combination with Pemetrexed and Cisplatin 
Administration of necitumumab in combination with pemetrexed and cisp latin is not 
recommended.  Patients experienced an increased rate of serious thromboembolic events 
(including fatal events) in the necitumumab plus pemetrexed and cisplatin arm as compared to 
the pemetrexed and cisplatin arm.  The addition of necitumumab did not improve the efficacy 
outcome over pemetrexed and cisplatin alone in advanced nonsquamous NSCLC. 
Necitumumab in Combination with other agents
No safety signal with regard to thromboembolic events, including fatal events, has been 
identified for necitumumab in completed clinical trials when administered as monotherapy or in 
combination with modified FOLFOX-6 chemotherapy (mFOLFOX-6; oxaliplatin + folinic acid 
+ 5-fluorouracil).
9.7.1.7.
Cardiorespiratory Disorders
An increased frequency of cardiorespiratory arrest or sudden death was observed with 
necitumumab.  Cardiorespiratory arrest or sudden death was reported in the pivotal Study JFCC 
(SQUIRE, CP11-0806) in 2.8% (15/538) of patients treated with necitumumab plus gemcitabine 
and cisplatin compared to 0.6% (3/541) of patients treated with chemotherapy alone.  Twelve of 
the 15 patients died within 30 days of the last dose of necitumumab and had comorbid 
conditions, including history of chronic obstructive pulmonary disease (n=7), hypertension 

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(n=5), hypomagnesemia (n=4), and coronary artery disease (n=3).  Eleven of the 12 patients had 
an unwitnessed death.
9.7.1.8.
Disseminated Intravascular Coagulation (DIC)
In a preclinical study, a single case of DIC with fatal outcome was observed in a monkey 
exposed to 18 administrations of the highest dose (60 mg/kg) of necitumumab.  Although the 
DIC may have been due to an underlying septicemia, a causal relationship of the event to 
necitumumab cannot be ruled out.  Clinical safety data obtained to date do not indicate that 
necitumumab is associated with an increased risk of a disseminated intravascular coagulation.  
Nevertheless, the investigator should pay special attention to any clinical signs indicative of 
hemorrhage or coagulopathy, in addition to the monitoring of coagulation and hematological 
laboratory parameters as specified in the protocol.
9.7.1.9.
Others
9.7.1.9.1. Antidiarrheal Agents
In the event of Grade 3 or 4 diarrhea, supportive measures may include antidiarrheals 
(loperamide), hydration etc.  If diarrhea is severe (ie, requires I.V. hydration) and associated with 
fever or severe (Grade 3 or 4) neutropenia, broad-spectrum antibiotics may be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting must be 
hospitalized for intravenous hydration and correction of electrolyte imbalance.
9.7.1.9.2. Granulocyte-Colony Stimulating Factors
The use of granulocyte colony stimulating factors is permitted during the study at the discretion 
of the investigator.  Prophylaxis administration will not be performed during the DLT assessment 
period.  The treatment for granulocyte colony stimulating factors will be recommended in 
accordance with the package insert.
9.7.1.9.3. Transfusion of Blood Products
Transfusions of red blood cells, platelets, or other blood products are permitted at the 
investigator’s discretion.  Prophylaxis administration will not be performed during the DLT 
assessment period.
9.8.
Treatment Compliance
The study medication will be administered only at the investigational sites by the authorized 
study personnel.  As a result, treatment compliance is ensured.

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10. Efficacy, Health Outcome, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of 
Measurements
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
study schedule (Attachment 1).
10.1. Efficacy Measures
10.1.1. Efficacy Assessments at Baseline and during Study
Patients may be enrolled on study with measurable or non-measurable disease based on the 
RECIST, version 1.1.  Disease assessment will be undertaken at baseline (within 21 days prior to 
enrollment [Phase 1b] or randomization [Phase 2]) and then every 6 weeks (7 to 3 business 
days) as calculated from the first dose of study therapy until discontinued from the study (Phase 
1b) or radiographically documented PD (Phase 2).  The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion at baseline and 
during the study.  
Assessment for response will be performed with confirmatory assessment for patients with an 
objective response of PR or CR obtained at the next routine scheduled imaging timepoint (no 
less than 4 weeks after the initial response is noted).  Two objective status determinations of CR 
before progression are required for a best overall response of CR.  Two determinations of PR or 
better before progression are required for PR.  In the case of stable disease (SD), follow-up 
measurements must have met the SD criteria at least once after the enrollment (Phase 1b) and 
randomization (Phase 2) at a minimum interval of 6 weeks. In cases where confirmation of 
response is not feasible, it should be noted in any study outcome report that the responses are not 
confirmed
All evaluated imaging data including CT scan and MRI will be collected and stored centrally; if 
necessary (eg, inquiries from regulatory authorities), independent review of all or representative 
sample of scans may be considered.
10.1.2. Efficacy Assessments during the Post-discontinuation Period
(only Phase 2 part)
For patients who discontinue study treatment for any reason other than radiographically 
documented PD (for example, symptomatic deterioration) in Phase 2 part, radiographic 
assessments should continue as scheduled every 6 weeks (7 to 3 business days), following the 
first dose of study therapy until objective radiographic evidence of PD.  Follow-up will continue 
as long as the patient is alive, or until study completion.  After the patient has objective disease 
progression, radiologic tests are no longer required and the patient will be followed for s urvival 
approximately every 90 days (14 days) until death or study completion.
After radiographic documentation of PD, patients may receive additional anticancer therapy at 
the discretion of the investigator.  The additional treatments should be documented on the eCRF.

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10.2. Health Outcome Measures
10.2.1. Patient-Reported Outcomes (only Phase 2 part)
All patients for whom there is a validated translation in which the patient is fluent will undergo 
assessment for symptoms and QOL using the LCSS and the EuroQol (EQ-5D).  It is 
recommended that the instruments is administered together and in sequence order, with the 
LCSS presented first, followed by presentation of the EQ-5D. 
Patients will complete the instruments at baseline (within 14 days prior to randomization), prior 
to the first infusion of Cycles 2 to 4, and in Arm A, every 2-cycle interval thereafter (ie, Cycle 6, 
Cycle 8, Cycle 10 and so on).  Chemotherapy in Arm B will not continue beyond Cycle 4.  The 
instruments will be completed every 6 weeks after discontinuation of the study treatment in Arm 
A until PD (ie, concurrent with radiological evaluation), and every 6 weeks after discontinuation 
of chemotherapy in Arm B until PD (ie, concurrent with radiological evaluation).  The 
instruments should be completed at the beginning of the visit, before any extensive contact and 
consultation with the clinician/study investigator; such encounters may thereafter bias patient 
responses.  The LCSS and the EQ-5D will be completed by all patients using the validated 
translated version of Japanese.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect PRO 
measures (for example, a rating scale), a daily dosing schedule, or an event diary.  
10.2.1.1. Lung Cancer Symptom Scale (LCSS)
Disease-related symptoms and quality of life will be assessed with the self-administered LCSS 
(Hollen et al. 1994).  The LCSS is a validated and reliable instrument to assess lung 
cancer-specific symptoms and their impact on QOL.  Each of the 9 symptom or summary items 
is assessed on a 100-mm visual analogue scale (VAS), with 0 representing no symptoms or better 
QOL.
10.2.1.2. EQ-5D
The EQ-5D is a standardized instrument that measures health status and is applicable to a wide 
range of health conditions and treatments (EuroQol Group 1990).
The EQ-5D consists of 2 parts.  The first part includes 5 descriptive questions relating to 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, on which the patient 
is required to rate his/her health.  Each attribute has 3 levels:  no problems, some problems, and 
extreme problems, thus defining 243 possible health states.  Weights for Japan will be used in 
analysis.
The second part of the EQ-5D is a VAS that allows patients to rate their present health condition.  
Possible scores range from 0 (worst imaginable health state) to 100 (best imaginable health 
state).

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10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that caused the patient to discontinue before completing the study.  The 
patient should be followed until the event is resolved or explained.  Frequency of follow -up 
evaluation is left to the discretion of the investigator.  
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).
10.3.1. Adverse Events
The Sponsor has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent.  A clinical study AE is any untoward medical 
event associated with the use of a drug in humans, whether or not it is considered related to that 
drug.  
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from ECGs, laboratories, vital sign measurements that result 
in a diagnosis should be reported to Sponsor or its designee.
Cases of pregnancy that occur during maternal or paternal exposures to study drug  should be 
reported.  Data on fetal outcome and breast-feeding are collected for regulatory reporting and 
drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the informed consent form (ICF) is signed, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs and any change in the preexisting 
condition(s).  All AEs related to protocol procedures are reported to the Sponsor or designee.
In addition, all AEs occurring after the patient receives the first dose of study treatment until 
30 days after the decision is made to discontinue study treatment must be reported to the Sponsor 
or its designee via eCRF.
Investigators will be instructed to report to the Sponsor or its designee their assessment of the 
potential relatedness of each AE to protocol procedure, study treatment, and/or drug delivery 
system via eCRF.
The investigator should evaluate for AEs at each visit and will instruct to call their physician to 
report any AEs between visits.

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The NCI-CTCAE version 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and ot her symptoms.  For AEs without 
matching terminology within the NCI-CTCAE version 4.0 criteria, the investigator will be 
responsible for selecting the appropriate system organ class and assessing severity grade based 
on the intensity of the event.  Note that both CTCAE term (actual or coded) and severity grade 
must be selected and collected on the eCRF.  This collection is in addition to verbatim text used 
to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the Sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionar y.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to the Sponsor or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
Serious adverse event collection begins after the patient has signed informed consent and has 
received study treatment.  If a patient experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will NOT be collected unless the investigator feels 
the event may have been caused by a protocol procedure.
Study site personnel must alert the Sponsor or its designee of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method.  Alerts are to be 
immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.  
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study treatment(s). Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious adverse drug events when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
Previously planned (prior to signing the ICF) surgeries should not be reported as SAEs unless the 
underlying medical condition has worsened during the course of the study.  
Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in 
the patient’s medical history at the time of study enrollment should not be considered SAEs.  

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Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs.  However, if the preexisting condition worsened during the course of the 
study, it should be reported as an SAE.
Serious adverse events occurring after a patient has taken the last dose of study treatment will be 
collected in the pharmacovigilance system and clinical data collection database for 30 days after 
discontinuation from study treatment, regardless of the i nvestigator’s opinion of causation.  
If an investigator becomes aware of an SAE occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
treatment(s), the investigator should report the SAE to the Sponsor, and the SAE will be entered 
in the Lilly Safety System.
10.3.1.2. Adverse Event and Serious Adverse Event Reporting
Table JFCM.14 describes AE and SAE collection with regard to the type of events to be 
collected in each study period.
Table JFCM.14.
Adverse Event, Serious Adverse Event, and Preexisting Condition 
Reporting Guidelines for Study JFCM
Treatment Period
Types of Information Collected/Reported
Baseline (pretreatment)
Preexisting conditions.
Procedure-related AEs/SAEs
Study treatment period (on therapy)
All AEs/SAEs 
Extension period
All AEs/SAEs
30-day safety follow-up visit 
All AEs/SAEs 
Subsequent post-discontinuation 
follow-up visits, if necessary 
SAEs are required to be reported only if the investigator feels 
the events were related to either study treatment, or a protocol 
procedure.
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1.2.1.Prior to Administration of Study Treatment(s)
Adverse event and SAE collection begins after the patient has signed the ICF and has received 
study treatment.  If a patient experiences an AE or SAE after signing informed consent, but prior 
to receiving study treatment, the event will NOT be collected unless the investigator believes the 
event may have been caused by a protocol procedure.
10.3.1.2.2.On Study
All AEs and SAEs, regardless of relatedness to study treatment(s), or protocol procedures, 
occurring while the patient is receiving study treatment must be reported to the Sponsor or its 
designee.  A patient is considered to be receiving study treatment from the time he/she receives 
the first dose of study treatment to when he/she receives the last dose of study treatment.
10.3.1.2.3.Follow-Up Visit
All SAEs, regardless of relatedness to study treatment(s) or protocol procedures, occurring 
during the follow-up visit (Visit 801) must be reported to the Sponsor or its designee.  The 

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follow-up periods begins on the day after the patient and the investigator agree to discontinue the 
patient from the treatment portion of the trial and lasts approximately 30 days.   For the patient 
who completed all treatments of Cycle 4 in Arm B of Phase 2 part, the follow-up periods begins 
on the day after the Cycle 4 completion.  After the 30-day follow-up, only new and ongoing 
SAEs deemed related to study treatment will be collected.
10.3.2. Other Safety Measures
10.3.2.1. Collection of Electrocardiograms 
For each patient, 12-lead digital ECGs will be collected as ECGs according to the Study 
Schedule (Attachment 1). Electrocardiograms may be obtained at additional times, when 
deemed clinically necessary.  Collection of more ECGs than expected at a particular time point is 
allowed when needed to ensure high quality records.
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.
Phase 1b part
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by the 
Sponsor.  The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory if necessary (eg, inquiries from 
regulatory authorities).  The machine-read ECG intervals and heart rate may be used for data 
analysis and report writing purposes unless an overread of the ECGs is conducted prior to 
completion of the final study report (in which case the overread data would be used).
Phase 2 part
Electrocardiograms will be collected locally as single ECGs in Phase 2 part.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.
The investigator (or qualified designee) must document his/her review of the ECG printed at the 
time of evaluation.

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10.3.2.2. Skin Reactions
Skin reactions are the events known as the toxicity of anti-EGFR monoclonal antibody, such as 
cetuximab or panitumumab.  Skin reaction will be monitored under treatment in the study.  The 
purpose of monitoring skin reactions is to enable detection of safety signals as early as possible.  
Once skin reactions are reported as events, additional information will be collected at the time of 
toxicity assesments/AEs as shown in the Study Schedule (see Attachment 1).  This aggregative 
assessment will result in a compilation of the characteristics of skin reactions, including 
frequency, duration, severity, locations, causalities and outcome, etc.
10.3.3. Safety Monitoring
The Sponsor’s clinical research physician (CRP) or clinical research scientist (CRS) will monitor 
safety data throughout the course of the study.
Sponsor or designee will review SAEs within time frames mandated by company procedures.  
The Sponsor’s CRP, CRS, or designee, will, as is appropriate, consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical scientist, and review 
trends and laboratory analytes.  
10.3.4. Complaint Handling
The Sponsor collects product complaints on study treatments and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Complaints related to unblinded comparator drugs or concomitant drugs/drug delivery systems
are reported directly to the manufacturers of those drugs/devices in accordance with the package 
insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to the Sponsor or its 
designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 and Attachment 2 list the schedule for sample collections in this study.
10.4.1. Samples for Standard Laboratory Testing
Blood and urine samples will be collected at the times specified in the study schedule 
(Attachment 1).  Standard laboratory tests, including hematology, coagulation, and urinalysis 
panels, will be performed and analyzed by a local laboratory.  Chemistry will be performed and 

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analyzed centrally.  Central chemistry laboratory results will be used to determine patient 
eligibility at baseline. Local chemistry lab results may be used for assessment of safety and 
on-study dosing decisions; if so, chemistry testing scheduled on Attachment 1 must also still be 
performed by the central laboratory.  These central chemistry laboratory res ults will be used for 
subsequent safety analyses.  In the event of minor discrepancies between local and central 
laboratory results, the investigator may use the local results for treatment decisions, and the 
central laboratory results will remain part of the safety database.  A serum or urine pregnancy 
test will be performed locally.  Attachment 3 lists the specific tests that will be performed for this 
study.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Pharmacogenetic Samples
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, a blood sample 
will be collected for pharmacogenetic analysis.  It is a one-time collection, as noted in the Study 
Schedule (Attachment 1).
Samples will only be used for investigations related to disease and drug or class of drugs under 
study in the context of this clinical program.  They will not be used for broad exploratory 
unspecified disease or population genetic analysis.  
The samples will be identified by the patient number (coded) and stored for up to a maximum 
15 years after the last patient visit for the study at a facility selected by the Sponsor.  The 
samples and any data generated from them can only be linked back to the patient by investigator 
site personnel.  The duration allows the Sponsor to respond to regulatory requests related to the 
study treatment.
10.4.3. Nonpharmacogenetic/Biomarker Stored Samples
Collection of samples for nonpharmacogenetic biomarker research is a required part of this 
study.  A formalin-fixed, paraffin-embedded tumor tissue block or a minimum of 5 unstained 
slides of tumor sample (archived or recent) must be made available at baseline for evaluation of 
EGFR protein expression (IHC) and other biomarker assessments.
Samples may be used for research into the EGFR pathway, pathways associated with disease 
state, mechanism of action of necitumumab, gemcitabine, and cisplatin, research methods and/or 
validating diagnostic tools or assay(s) related to NSCLC and the EGFR-pathway.  

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The samples will be identified by the patient number (coded) and stored for up to a maximum of 
15 years after the last patient visit for the study at facility selected by the Sponsor.  
10.4.4. Immunogenicity Samples
Samples for immunogenicity testing will be collected at time points indicated in Study Schedule 
(Attachment 2).  Blood samples will be used to determine antibody production against 
necitumumab.  The actual date of each sampling will be recorded.  Immunogenicity will be 
assessed by a validated assay designed to detect anti-drug antibodies in the presence of 
necitumumab.  Antibodies may be further characterized and/or evaluated for their ability to 
neutralize the activity of necitumumab.
A sample for evaluation of antibodies against necitumumab will also be collected in the setting 
of an infusion-related/hypersensitivity reaction to necitumumab (as close to the onset of the 
event as possible, at the resolution of the event, and 30 days following the event).
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the Sponsor to enable further analysis of immune responses to necitumumab.  
The duration allows the Sponsor to respond to regulatory requests related to the study treatment.
10.4.5. Samples for Drug Concentration Measurements 
Pharmacokinetics
At the visits and times specified in the Study Schedule (Attachment 2).  Blood samples will be 
used to determine the serum concentrations of necitumumab and the plasma concentrations of
gemcitabine, its deaminated metabolite 2',2'-difluorodeoxyuridine (dFdU) and total and free 
platinum from cisplatin and will be assessed by a validated assay.  Determination of 
necitumumab drug concentrations will also be performed in the setting of an infusion-related 
reaction.  The actual date and time (24-hour clock time) of each sampling will be recorded.
A maximum of 5 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and Sponsor.  Instructions for the collection and 
handling of blood samples will be provided by the Sponsor.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
10.5. Appropriateness of Measurements
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology studies.

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11. Data Quality Assurance
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following:

provide instructional material to the study sites, as appropriate

sponsor a start-up training session to instruct the investigators and study coordinators.  
This session will give instruction on the protocol, the completion of the eCRFs, and study 
procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, the Sponsor or its representatives may periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by the Sponsor or 
its representatives, and/or regulatory agencies at any time.  Investigators will be given notice 
before an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the Sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the Sponsor-provided electronic data capture system.
Electronic case report form data will be encoded and stored in a clinical trial database.  Data 
managed by a central vendor, such as laboratory test data or ECG data in Phase 1b part, will be 
stored electronically in the central vendor’s database system.  Data will subsequently be 
transferred from the central vendor to the Lilly generic labs system.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper to collect PRO 
measures (for example, a rating scale).
Data from complaint forms submitted to the Sponsor or designee will be encoded and stored in 
the global product complaint management system.

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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
The study is divided into two parts:  the Phase 1b part and the Phase 2 part.  
The Phase 1b part is designed based on a conventional 33 cohort design to investigate the 
tolerability of necitumumab, in combination with gemcitabine-cisplatin chemotherapy.  At least 
9 patients will be enrolled (3 patients in Cohort 1 and 6 patients in Cohort 2).
The purpose of Phase 2 part is to evaluate the efficacy of necitumumab in combination with 
gemcitabine-cisplatin chemotherapy in terms of OS.  The sample size for Phase 2 part was 
calculated to be 180 patients based on OS.  In Phase 2 part, 180 patients (up to 190 patients) will 
be randomized 1:1 to Arm A or B.  It is assumed that the expected median survival time (MST) 
of Arm A and Arm B are 13.75 and 11 months (HR = 0.8), respectively, which is the similar 
assumption to one in Study CP11-0806. When the enrollment period is 23 months and the 
follow-up period is 15 months, the sample size of 180 patients (137 events) has 68% power for a 
log-rank test at 0.2 one-sided alpha.  Additionally, the probabilities of obtaining estimated HR 
<0.9 or of the longer MST in necitumumab arm than one of control arm were calculated at 76%
and 85% respectively, in 180 patients.  The final analysis will be performed when at least 
137 OS events (deaths) are observed.
Since a dropout rate of 5% is considered, 190 patients is planned to be enrolled for Phase 2 part.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
The primary efficacy analyses will be conducted on the full analysis set (FAS).  This population 
is defined as all patients who are randomized and receive at least one dose of study treatments in 
Phase 2 part.  Patients will be grouped according to treatment received.  
If there are significant numbers of patients with major protocol violations, the Per Protocol Set 
(PPS) analysis will be performed for the primary and secondary efficacy endpoints.  Results will 
serve as supportive for FAS analysis.
The safety analyses will be conducted on the Safety Population, defined as all treated patients in 
Phase 1b part and Phase 2 part, and patients will be grouped as follows; Phase 1b part, Arm A 
and Arm B in Phase 2 part, and treated patients with necitumumab (Phase 1b part Arm A in 
Phase 2 part).  
Pharmacogenomic analyses will be based on the subset of patients from the above populations 
from whom a valid assay result (according to laboratory guideline) has been obtained.  
Missing data will generally not be imputed, except for partial dates concerning pivotal efficacy 
or safety parameters.  Baseline is defined as the last measurement for a variable prior to the 

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initial dose of any investigational product.  A complete description of data handling rules and 
planned statistical analyses is detailed in a separate SAP.
The statistical tests will be performed but p values will be shown just for reference.  All CIs will 
be given at a 2-sided 95% level, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  
A summary of all important protocol violations will be provided.
12.2.3. Patient Characteristics
Patient demographics including age, gender, race, screening height and weight, screening 
smoking status will be summarized.  
Baseline disease characteristics will be summarized for histologic subtype, disease stage, TNM 
classification, ECOG PS prior to Cycle 1.
Categorical data will be summarized as frequency and its corresponding percentage.  For 
continuous data, the number of patients (n), mean, standard deviation, median (as appropriate), 
minimum, and maximum will be provided for each of the parameters.
12.2.4. Concomitant Therapy 
Concomitant medications will be summarized for the safety population.  
12.2.4.1. Post-discontinuation Therapy
The numbers and percentages of patients reporting post-discontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.  
12.2.5. Efficacy Analyses
12.2.5.1. Primary Endpoint
The primary efficacy endpoint for the Phase 2 part of this study is OS.  The OS is defined as the 
time from the date of randomization to the date of death from any cause.  Patients who are alive 
at the time of study completion or are lost to follow-up will be censored at the time they were 
last known to be alive.  

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The Kaplan-Meier (KM) method will be used to generate KM curves, the medians, quartiles and 
percentages of patients event-free every 3-month interval for each arm.  The HR of Arm A to 
Arm B and the CI will be estimated using a stratified Cox regression model by the variables used 
for randomization (ECOG PS and gender), and a stratified log-rank test will be performed.
The HR will be also estimated using the unstratified Cox regression model and an unstratified 
log-rank test will be performed.
12.2.5.2. Secondary Endpoints
The secondary efficacy endpoints in this study will include PFS, ORR, TTF, and Health 
outcomes.  As for Health Outcomes, the detailed is described in Section 12.2.9.
The PFS is defined as the time from the date of randomization until the date of radiographically 
documented PD or death due to any cause, whichever is earlier. Patients who die without a 
reported progression will be considered to have progressed on the day of their death.  Patients 
who did not progress or are lost to follow-up will be censored at the day of their last radiographic 
tumor assessment.  If no baseline or post-baseline radiologic assessment is available, the patient 
will be censored at the date of randomization.  If death or PD occurs after two or more 
consecutive missing radiographic visits, censoring will occur at the date of the last radiographic 
visit prior to the missed visits.  The use of a new anticancer therapy prior to the occurrence of PD 
will result in censoring at the date of last radiographic assessment prior to initiation of new 
therapy.
The TTF is defined as the time from the date of randomization until the date of the first 
observation of radiographically documented PD, death due to any cause, discontinuation of 
treatment for any reason, or initiation of new anticancer therapy.  
For PFS, sensitivity analyses will be conducted by including or excluding symptomatic/clinical 
deterioration as progression outcome or considering different censoring rules to control for 
missing data, patients lost to follow-up, and other censoring conditions.
The ORR is defined as the proportion of treated patients achieving a best response of PR or CR.  
The ORR in the patients with measurable lesions may be calculated, if deemed necessary.  
Phase 1b part
The ORR and CI will be calculated on the patients.
Phase 2 part
As for PFS and TTF, the same analysis as ones for OS will be performed in FAS.
For PFS, sensitivity analyses will be conducted by including or excluding symptomatic/clinical 
deterioration as progression outcome or considering different censoring rules to control for 
missing data, patients lost to follow-up, and other censoring conditions.  For ORR, a CI of each 
arm will be calculated based on binominal distribution, and the difference of ORR between two 
arms and the CI will be estimated in FAS.  The ORR will be compared between the test arm and 
the control arm using Fisher exact test.  

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12.2.6. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of the 
study treatment and have had samples collected.  
Phase 1b part
Pharmacokinetic parameter estimates for necitumumab, gemcitabine, and cisplatin, if appropriate,
will be calculated by standard noncompartmental methods of analysis.
The primary parameters for analysis will be maximum concentration (Cmax) and area under the 
concentration-time curve (AUC0-tlast and/or AUC0-).  Other noncompartmental parameters, 
such as time of half-life (t1/2), clearance (CL), and/or volume of distribution (V) may be 
reported.  Also Ctrough of necitumumab will be analyzed.  Additional exploratory analyses will 
be performed if warranted by data and other validated PK software programs (for example, 
NONMEM) may be used if appropriate and approved by Global PK management.  The version 
of any software used for the analysis will be documented and the program will meet the Sponsor 
requirements of software validation.
Phase 2 part
The PK parameters of necitumumab including Cmax and Ctrough will be summarized as 
descriptive statistics.  An exploratory population PK analysis may be performed if warranted by 
data and other validated PK software programs (for example, NONMEM) may be used if 
appropriate and approved by Global PK management.  The version of any software used for the 
analysis will be documented and the program will meet the Sponsor requirements of software 
validation.
12.2.7. Biomarker Analyses
Descriptive statistics for biomarkers will be summarized in Phase 1b and Phase 2 part.
In Phase 2 part, for OS and PFS, survival curves of each arm will be estimated using KM method 
by EGFR protein expression level (IHC), EGFR and KRAS mutation status, and EGFR gene 
copy number (fluorescence in situ hybridization [FISH]) in tumor tissue, and FCγR 
polymorphisms in white blood cell (WBC).  The ORR will also be summarized by biomarker 
characteristics.
The other exploratory biomarkers, if they are identified, will be analyzed in the same manner.
12.2.8. Pharmacokinetic/Pharmacodynamic Analyses
In addition to a standard noncompartmental assessment, and provided that the data allows, the 
relationship between necitumumab PK and Pharmacodynamics may also be investigated with 
exploratory manner.  Serum data from all patients will be pooled for analyses to determine the 
compartmental PK parameters and between- and within-patient variability.
A population PK model will then be used to develop a PK/Pharmacodynamics model where 
relevant efficacy Pharmacodynamics data will be analyzed.  Additional PK/ Pharmacodynamics 

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models may be developed using other Pharmacodynamics measures, if/when warranted.  
Additional exploratory analyses will be performed if warranted by the data.
12.2.9. Health Outcome Analyses 
For each instrument, percentage compliance will be calculated as the number of completed 
assessments divided by the number of expected assessments (that is, patients still on study).  
Percentage compliance will be summarized by treatment arm for each assessment period.
12.2.9.1. Lung Cancer Symptom Scale (LCSS)
The average symptom burden index (ASBI) is defined as the mean of six symptom-specific lung 
cancer questions, and the total score is defined as the mean of all 9 questions.  
For each index, worsening is defined as a 15-mm increase from the corresponding baseline 
scores.  
Descriptive statistics for the nine LCSS items will be calculated.  Frequency distributions, and 
measures of central tendency and variability (for example, means, medians, and standard 
deviations) will be calculated for individual LCSS items, ASBI, and total score.  
The ASBI, the total score, and each of 9 individual items will be analyzed using a mixed effects 
analysis of variance model to estimate treatment effect as well as time-by-treatment interaction 
effect.  Analysis of each of the ASBI and total score will be conducted using Time to Worsening 
(TW) as measured from the date of randomization to the first date of a clinically meaningful 
worsening/change.  For each patient who is not known to have had a worsening, or who is lost to 
follow-up, TW will be censored at the date of the patient’s last LCSS assessment.  The KM 
curves of TW for the index will be estimated using KM method and the HR and the CI will be 
estimated using an unstratified Cox regression model.
12.2.9.2. EQ-5D:  Health State Utilities
The index score is calculated from a set of item weights to derive a score on a theoretical scale of 
0 to 1, with 1 representing the best health status and zero representing death based on item 
weights for the Japanese population (Ikeda et al. 2002).  
Descriptive statistics for the index and VAS will be calculated.  Frequency distributions, 
including measures of central tendency and variability (for example, means, medians, and 
standard deviations) will be calculated for individual items and for the index score.  The index 
scores and VAS may be analyzed using a mixed effects analysis of variance model to estimate 
treatment effect as well as time-by-treatment interaction effect.
12.2.10.
Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.1.  
12.2.10.1.
Extent of Exposure
Dosing data will be summarized by treatment group to include duration of treatment (weeks), 
number of patients treated by cycle, number of cycles of treatment per patient received, 

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cumulative dose, dose intensity and relative dose intensity, and number (%) of patients with dose 
modifications (reduced or delayed).
12.2.10.2.
Adverse Events
Treatment emergent AE is defined as any untoward medical occurrence that either occurs or 
worsens at any time after treatment baseline and that does not necessarily have to have a causal 
relationship with this treatment.  
In Phase 1b part, DLT will be summarized by cohort in the patients who are evaluable for DLT 
assessments and be listed by patient.
Safety analyses will include listings or summaries of the following for both of Phase 1b part and 
Phase 2 part.

Treatment-emergent adverse events (TEAEs), including seriousness, severity, 
and possible relationship to study treatment

AEs leading to dose adjustments for any study therapy

Laboratory measures

Vital signs
12.2.10.3.
Immunogenicity
Pre- and post-treatment samples for analysis of antibodies against necitumumab
(immunogenicity) will be assayed using validated assays.  
Incidence of anti-necitumumab antibodies will be tabulated.
12.2.11.
Subgroup Analyses
Subgroup analysis will be performed for OS, PFS, and ORR for the following subgroups:  age 
(65 vs. >65 years; and 70 vs. >70 years); gender (male vs. female); ECOG PS (0 vs. 1).  
12.2.12.
Interim Analyses
In Phase 1b part, the interim analysis will be performed after completing DLT evaluation period, 
and patient characteristics, clinical laboratory values, DLTs, and AEs occurring in Cycle 1 might 
be summarized by cohort. Additionally, even after the above interim analysis, the Sponsor might
analyze the data for scientific disclosures.
During Phase 2 part, approximately 6 interim analyses will be performed to monitor the safety 
data of this study.  The first interim analysis for safety monitoring will be per formed after 
50 patients in Phase 2 part have receives at least two cycles or 6 months after enrollment of the 
first patient in Phase 2 part, which is earlier.  After the first interim analysis, analyses will then 
be conducted every 6 months until all patients have discontinued all therapy (or until the study 
completion or been terminated).  There will be no pre-specified rules for stopping the study due 
to safety concerns.  The IDMC members will review safety data at each interim analysis to 
determine whether there are sufficient safety concerns to justify the termination of study 
treatment and/or enrollment.

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Only the IDMC is authorized to evaluate unblinded interim safety analyses.  Study sites will 
receive information about interim results ONLY if they need to know for the safety of their 
patients.
In addition, the Sponsor might consider the interim analysis for regulatory communication 
purposes. One of possible communications is a discussion of complete clinical data package 
with Pharmaceutical and Medical Devices Agency (PMDA), considering the results in the global 
Phase 3 study (Study CP11-0806) which will be available during this study.  In this case, the 
safety and efficacy data collected at the time will be analyzed.  

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13. Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study 
treatment.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
The Sponsor or its representatives must approve all ICFs before they are submitted to the ERB 
and are used at investigative sites(s).  All ICFs must be compliant with the ICH guideline on 
GCP.  
Documentation of ERB approval of the protocol and the ICF must be provided to the Sponsor
before the study may begin at the investigative site(s).  
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling and updates during the course of the study

ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:
1)
consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 
2)
the ICH GCP Guideline [E6]

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

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14. References
Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, 
Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA. 
Randomized phase II study of gemcitabine plus cisplatin or carboplatin, with or without 
cetuximab, as first-line therapy for patients with advanced or metastatic non-small-cell lung 
cancer. J Clin Oncol. 2007;25(36):5777-5784.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging 
Handbook: From the AJCC Cancer Staging Manual. 7th ed. NY: Springer; 2009.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
Ennis BW, Lippman ME, Dickson RB. The EGF receptor system as a target for antitumor 
therapy. Cancer Invest. 1991;9:553-562.
Hollen PJ, Gralla RJ, Kris MG, Cox C. Quality of life during clinical trials: conceptual model for 
the Lung Cancer Symptom Scale (LCSS). Support Care Cancer. 1994;2(4):213-222. 
Ikeda S, Ikegami N. Preference-based measure (focus on EQ-5D). Handbook of QOL evaluation
[in Japanese]. Tokyo: Igaku-Shoin; 2002:45–49
Kawamoto T, Mendelsohn J, Le A, Sato GH, Lazar CS, Gill GN.  Relation of epidermal growth 
factor receptor concentration to growth of human epidermoid carcinoma A431 cells. J Biol 
Chem. 1984;259:7761-7766.
Klohs WD, Fry DW, Kraker AJ. Inhibitors of tyrosine kinase. Curr Opin Oncol. 1997;9:562-568.
Kuenen B, Witteveen PO, Ruijter R, Giaccone G, Dontabhaktuni A, Fox F, et al. A Phase I 
Pharmacologic Study of Necitumumab (IMC-11F8), a Fully Human IgG1 Monoclonal 
Antibody Directed Against EGFR in Patients With Advanced Solid Malignancies. Clin Cancer 
Res. 2010;16(6):1915-1923.
Kusaba H, Tamura T, Shimoyama T, Hotta K, Inoue A, Nokihara H, et al. Phase I/II study of 3-
week cycle cisplatin-gemcitabine in advanced non-small cell lung cancer. Jpn J Clin Oncol. 
2002; 32(2):43-47.
Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, 
Murphy BA; MASCC Skin Toxicity Study Group. Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care 
Cancer. 2011:19(8);1079-1095.
Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, 
Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D. Cetuximab and first-line 
taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the 
randomized multicenter phase III trial BMS099. J Clin Oncol. 2010;28(6):911-917.
Melosky B, Burkes R, Rayson D, Alcindor T, Shear N, Lacouture M. Management of skin rash 
during EGFR targeted monoclonal antibody treatment for gastrointestinal malignancies: 
Canadian recommendations. Curr Oncol. 2009;16 (1):16-26.

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Mitchell EP, LaCouture M, Shearer H, Inannotti N, Piperdi B, Pillai MV, et al. Updated results 
of STEPP, a Phase 2, open-label study of pre-emptive versus reactive skin toxicity treatment in 
metastatic colorectal cancer (mCRC) patients receiving panitumumab FOLFIRI or 
irinotecan-only chemotherapy as second-line treatment. 10th World Congress on GI Cancer, 
Barcelona, Spain; 25-28 June 2008 [Abstract O-021].
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: 
The remarkable universality of half a standard deviation. Medical Care. 2003;41:582-593.
Pharmaceutical and Food Safety Bureau. Guidelines for clinical evaluation methods of 
antimalignant tumor drugs. Notification No. 1101001 of the Evaluation and Licensing 
Division. Tokyo. 2005. 
Pirker R, Pereira JR, Szczesna A, von Pawal J, Krzakowski M, Ramlau R, Vynnychenko I, 
Park K, Vu C-T, Granul V, Roh J-K, Bajetta E, O’Byrne K, de Marinis F, Eberhardt W, 
Goddemeier T, Emig M, Gatzemeier U. Cetuximab plus chemotherapy in patients with 
advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. 
Lancet. 2009; 373:1525-1531.
Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, de Marinis F, 
Eberhardt WE, Paz-Ares L, Störkel S, Schumacher KM, von Heydebreck A, Celik I, 
O'Byrne KJ. EGFR expression as a predictor of survival for first-line chemotherapy plus 
cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the 
phase 3 FLEX study. Lancet Oncol. 2012;13(1):33-42.
Prewett M, Rothman M, Waksal H, Feldman M, Bander NH, Hicklin DJ. Mouse-human 
chimeric anti-epidermal growth factor receptor antibody C225 inhibits the growth of human 
renal cell carcinoma xenografts in nude mice. Clin Cancer Res. 1998;4:2957-2966.
Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and 
their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183-232.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III 
study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in 
chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 
2008;26(21):3543-3551.
The EuroQol Group. A new facility for the measurement of health-related quality of life. Health 
Policy. 1990; 16(3): 199-208.

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Attachment 1.Protocol JFCM Study Schedule

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Study Schedule:  Study I4X-JE-JFCM
Cycle
Baseline Period
(21 days prior to 
enrollment or 
randomization)
Treatment Period
(21-day cycles)
Post-discontinuation
Follow-Up Period
(Visit 801 to 8XX)
Baseline a
Combination Therapy
Maintenance 
Therapy
(if applied)
Summary 
Visit b
(0 to +7d)
30 day Safety
Follow-Up c
(0 to +7d)
Long-Term 
Follow-Up Every 
90 days
(±14d)
1
2
3
4
5 to X
Relative day within cycle
≤21
≤14
≤7
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Procedures
Clinical Evaluations
Informed Consent d
X
In-/exclusion Criteria Review
X
Demography
X
Medical History (including 
smoking history)
X e
HBsAg, HCVAb f, ζ
X
ECG (Phase 1b) 
X
X
X
X
X
X
X
ECG (Phase 2) f, g
X
X
X
ECOG PS
X
Xh
Xh
Xh
Xh
Xh
X
X
Concomitant Medication q
X
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
X
X
Physical Exam, Height & 
Weight i
X
Xh
Xh
Xh
Xh
Xh
X
X
BSA j
X
X
X
X
X
Vital Signs k
X
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
X
X
Toxicity Assessments/AEs q
Xe
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xm
Xm
Xn
QOL Assessments (LCSS, 
EQ-5D)
Xo
Xo
Xo
Xo
Xo
Xo
Laboratory Evaluations
Hematology Profile f, p, q
X
Xr
X
X
X
X
X
X
X
X
X
X
X
Coagulation Profile f, p, s
X
Xr
X
X
Chemistry Profile p, q
X
Xr
X
X
X
X
X
X
X
X
X
X
X
Urinalysis f, p, s, t
Xr
Xr
X
X
Pregnancy Test f
Xu
Xu
Efficacy Assessments
Survival Information
Xv
Imaging f/Tumor Assessments
w
Xx
Xy
Contrast CT or MRI of the 
brain
Xz
Xz

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Study Schedule:  Study I4X-JE-JFCM (continued)
Cycle
Baseline Period
(21 days prior to 
randomization)
Treatment Period
(21-day cycles)
Post-discontinuation Follow-Up Period
Baseline a
Combination Therapy
Maintenance 
Therapy
(if applied)
Summary
Visit b
(0 to +7d)
30 day Safety
Follow-Up c
(0 to +7d)
Long-term 
Follow-Up 
Every 90 days
(±14d)
1
2
3
4
5 to X
Relative day within cycle
≤21
≤14
≤7
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Procedures
Additional and Exploratory Analyses
Whole blood samples for DNA 
and FCR 
X
Tissue Sample Confirmation 
X
Immunogenicity
See Protocol Attachment for Sampling Schedule
Pharmacokinetic Sample
Treatment Administration 
Necitumumab
X
X
X
X
X
X
X
X
X
X
Administer Gemcitabine 
X
X 
X
X 
X
X 
X
X 
Administer Cisplatin , 
X
X
X
X

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Study Schedule:  Study I4X-JE-JFCM (continued)
Abbreviations:  AE = adverse event; BSA = body surface area; CT = computed tomography; d = day; ECG = electrocardiogram; ECOG PS = Eastern 
Cooperative Oncology Group performance status; EQ-5D = European Quality of Life – 5 dimensions; LCSS = Lung Cancer Symptom Scale; MRI = magnetic 
resonance imaging.
a
Examination conducted before informed consent date will be accepted to use as screening data, if informed consent include such a notice and the patient 
consents to it.
b
The summary visit is used when the decision is made to stop treatment and is completed up to 7 days after the decision to discontinue study treatment. For the 
patient who completed all treatments of Cycle 4 in Arm B of Phase 2 part or who discontinued necitumumab treatment before maintenance therapy but 
completed chemotherapy (gemcitabine and cisplatin) of Cycle 4 in Arm A of Phase 2 part, the summary visit is completed up to 7 days after the Cycle 4 
completion (Cycle 4 Day 21 [+7 days]).
c
The 30-day safety follow-up period begins on the day after the decision to discontinue study treatment and lasts approximately 30 days.  For the patient who 
completed all treatments of Cycle 4 in Arm B of Phase 2 part, the 30-day safety follow-up period begins on the day after the Cycle 4 completion and lasts 
approximately 30 days (Cycle 4 Day 51 [+7 days]).  The 30-day safety follow-up visit occurs at or near the end of the 30-day safety follow-up period (7 
days).
d
Obtain informed consent prior to any study-related procedures or evaluations.
e
Any preexisting and pretreatment toxicity should be documented and recorded as part of the pretreatment medical history.
f
Performed locally.
g
ECGs will be collected at baseline, prior to the first infusion of Cycle 3, and at the summary visit. A time window of -3 days is permitted for the Day 1 of 
Cycle 3 assessments.
h
Before the treatment
i
Height measurements to be performed at baseline only.  A time window of -7 days is permitted for the physical exam on Day 1.
j
For BSA calculation height from screening visit to be used at each subsequent cycle.
kTemperature, Pulse rate, Respiratory rate, and Systolic/Diastolic Blood pressure
l
To be obtained at every treatment visit, immediately prior to and at the completion of each infusion of necitumumab, and before and at the completion of 
chemotherapy (gemcitabine and cisplatin) administration.  
m All AEs/SAEs will be followed for up to 30 days after the decision is made to discontinue study treatment.
n
After the 30-day safety follow-up, only new and ongoing SAEs deemed related to study treatment will be collected.

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Study Schedule:  Study I4X-JE-JFCM (continued)
o
Health Outcomes will be evaluated prior to the first infusion of every cycle thereafter until PD.  Self-reported health outcome assessments (LCSS and EQ-5D) 
will be performed pretreatment (within 14 days of randomization), prior to the first infusion of Cycles 2 to 4, and every 2-cycle interval thereafter (ie, Cycle 6, 
Cycle 8, Cycle 10 and so on). Chemotherapy in Arm B will not continue beyond Cycle 4.  The instruments will be completed every 6 weeks after 
discontinuation of the study treatment in Arm A until PD (ie, concurrent with radiological evaluation), and every 6 weeks after discontinuation of 
chemotherapy in Arm B until PD (ie, concurrent with radiological evaluation).  At every scheduled timepoint, the LCSS should be administered prior to the 
EQ-5D. The first assessment must be done in investigator sites to ensure that patients understand how to complete the questionnaires.  Following the 
pretreatment assessment, patients may complete the health outcomes assessments up to 3 days prior to the scheduled assessment time and may complete them 
at home if patients can contact site personnel with any questions. 
p
Hematology, chemistry and coagulation profiles to be collected within 3 days prior to treatment on Day 1 in each cycle.  Hematology and chemistry profiles 
will also be collected within 3 days prior to treatment on Day 8 in each cycle. The laboratory data required for treatment on Day 8 must be collected on Day 5 
or later, but 3 days or less prior to treatment (e.g., if treatment scheduled on Day 8 is administered on Day 5, pretreatment laboratory data must be collected on 
Day 5 only).  If the patient has gemcitabine and/or cisplatin-related toxicities, perform hematology and/or chemistry tests weekly based on toxicity. In this 
case, local chemistry laboratory results may be used for safety assessment; if so, the chemistry tests must also be performed by the central laboratory.  If 
results of the laboratory tests obtained on planned Day 1 of the next cycle require a delay in the start of the subsequent cycle, any repeat laboratory tests 
should be obtained as clinically indicated. Central chemistry laboratory results will be used to determine patient eligibility at baseline.  Local chemistry 
laboratory results may be used for safety assessment and dosing decisions; if so, the tests scheduled on the study protocol must also be performed by the 
central laboratory, regardless of delayed or omitted the study treatment.    
qIf necitumumab and/or chemotherapy are delayed or omitted, all procedures (including concomitant medication, toxicity assessments/AEs, hematology and 
chemistry tests) planned on Day 8 must be performed on Day 8, and the same procedures will also be conducted before the next administration of 
necitumumab on Day15.  Regardless of delayed or omitted the study treatment, the chemistry test which scheduled on the study protocol must be performed 
by central laboratory.
r
For the Cycle 1, it might be acceptable to use the test results of the safety laboratory values obtained during screening if these tests have been performed 
within 7 days of Day 1 and are deemed still clinically valid by the treating investigator.  Urinalysis and BSA calculation do not have to be performed again for 
the Cycle 1.
s
Urinalysis and coagulation profiles to be collected within 3 days prior to treatment on Day 1 in Cycle 1, and every 2 cycles thereafter (ie, Cycle 3, Cycle 5, 
Cycle 7 and so on).
t
Routine dipstick measurements within 14 days prior to treatment on Day 1 and at the time of 30-day Safety Follow-Up.
u Pregnancy test for women of childbearing potential.  Patients are not considered to be of childbearing potential if:  (a) they are surgically sterile (hysterectomy, 
bilateral tubal ligation or bilateral oophorectomy), (b) they are postmenopausal.  Pregnancy testing will occur during screening and 30-day safety follow-up 
periods.
v
This follow-up might be a phone-call to the patient, her/his family, or local doctor.  Collection of survival data and subsequent antitumor therapies.  In Phase 
1b part, survival information is not necessary after 30 day safety follow-up period.

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w Disease assessment will be performed as scheduled every 6 weeks (-7 to 3 business days) from the first dose of study therapy.  The method used at baseline 
must be used consistently for tumor assessment.
Study Schedule:  Study I4X-JE-JFCM (complete)
x
For baseline imaging, besides a CT scan or MRI of chest and upper abdomen including both adrenal glands, a contrast CT scan or MRI of the brain is required
within 21 days prior to randomization.
y
Imaging studies and tumor assessments should be performed as scheduled every 6 weeks (7 to 3 business days) following first dose of study therapy until 
discontinued from the study (Phase 1b) or radiographically documented PD (Phase 2), even if therapy is delayed, except when not feasible in the opinion of 
the investigator due to patient’s clinical status.  Patients with pathological bone lesions at baseline should undergo respective assessments as well.  In Phase 1b 
part, tumor assessment is not necessary after 30-day safety follow-up period.
z
A contrast CT or MRI of the brain will be performed at baseline within 21 days prior to randomization for all patients.  If the patient had brain metastases at 
baseline or if clinically indicated, a contrast CT or MRI of the brain will be performed thereafter every 6 weeks (7 to 3 business days) weeks despite any 
treatment delays.
Phase 1b/2 parts

For treatment guidelines, refer to Section 9.1.
A time window of ±3 days is permitted for the Day 8 assessments, but the assessments should be done prior to treatment. Infusions administered within 3 
days before or after the planned infusion timepoint is considered acceptable; however, infusions administered within 3 days after the planned infusion 
timepoint is preferable. 
Subsequent doses of cisplatin and gemcitabine must be recalculated if there is a 10% change (increase or decrease) in body weight from the last dose 
calculation; subsequent doses may be recalculated if there is a <10% change (increase or decrease) in body weight from the last dose calculation.  For patients 
undergoing repeated palliative drainage procedures to remove pleural or peritoneal fluid, dry weight will be defined as weight obtained after the drainage 
procedure and before fluid reaccumulation. In such circumstances, dry weight will be used for dose calculation, if obtained within 30 days prior to dose.  If 
no recent dry weight is available, actual weight will be used.  

The administration of cisplatin will be based on standard procedure (eg, package insert) in standard therapeutic practice.
ζ
The test conducted before the informed consent date will be accepted for use as screening data if the test result was not positive and is still deemed clinically 
valid by the investigator.

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Data Collected by the Sponsor for the Extension Phase Only
Procedure a
Treatment Period
(21-day cycles)
Summary 
Visitb
30 day Safety 
Follow-Upc
Toxicity Assessments/AEs
X
X
X
Immunogenicity
Xd
X
Pharmacokinetics sample (necitumumab)
Xd
X
Administer Study Therapy
X
Reason for study therapy discontinuation
X
a
During the extension phase, routine safety and efficacy monitoring, including radiographic evaluation of disease and laboratory testing, such as pregnancy 
testing, should be continued as necessary to confirm patient eligibility to continue in the study.  The Sponsor will collect only data shown in this table for the 
extension phase.
b
The summary visit is used when the decision is made to stop treatment and is completed up to 7 days after the decision is made to discontinue treatment.
c
The 30-day safety follow-up period begins on the day after the patient and the investigator agree to discontinue the patient from the treatment portion of the 
study and lasts approximately 30 days.  The 30-day safety follow-up visit occurs at or near the end of the 30-day safety follow-up period (+7 days).
d
In the event of an infusion-related reaction, a blood sample will be collected for analysis as close to the onset of the reaction as possible, at the resolution of 
the event, and 30 days following the event.

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Attachment 2.Protocol JFCM Schedule for Pharmacokinetic 
and Immunogenicity Sampling
Schedule for Pharmacokinetic and Immunogenicity Sampling, 
Protocol I4X-JE-JFCM (Phase 1b)
Pharmacokinetic sample
Immunogenicity
Necitumumab
(Nec)
Gemcitabine
（Gem）
Cisplatin
（Cis）
Cycle 1
Day 1
Pre-inf of Nec
X
X
X
X
Post-inf of Nec d
X
30 min Post-inf of Nec
X
(Post-inf of Gem) c, d
1 h Post-inf of Nec
X
X
(30 min Post-inf of Gem) c
1h 30 min Post-inf of Nec
X
(1 h Post-inf of Gem) c
2h 30 min Post-inf of Nec
X
(2 h Post-inf of Gem) c
3 h Post-inf of Nec
X
X
(Post-inf of Cis) c, d
6 h Post-inf of Nec
X
X
(3 h Post-inf of Cis) c
Day 2
24 h Post-inf of Nec
X
X
(21 h Post-inf of Cis) c
Day 5
96 h Post-inf of Nec
X
X
(93 h Post-inf of Cis) c
Day 8
Pre-inf of Nec day 8 a
X
X
(165 h Post-inf of Cis) c
Post-inf of Nec day 8 a, d
X
Day 15
167 h Post-inf of Nec day 8 a
X
(Pre-inf of Nec day 15) a
(X) 
(Post-inf of Nec day 15) a,d
(X) 
Cycle 2
Day 1
Pre-inf of Nec
X
X
Day 8
Pre-inf of Nec
X
Cycle 3
Day 1
Pre-inf of Nec day 1
X
X
Post-inf of Nec day 1 d
X
1 h Post-inf of Nec day 1
X
3 h Post-inf of Nec day 1
X
(6 h Post-inf of Nec day 1) b
(X)
(Day 2)
(24 h Post-inf of Nec day 1) b
(X)
(Day 5)
(96 h Post-inf of Nec day 1) b
(X)
Day 8
Pre-inf of Nec day 8 a
X
Post-inf of Nec day 8 a, d
X
(Day 15)
(167 h Post-inf of Nec day 8) a, b
(X)
(Pre-inf of Nec day 15) a
(X) 
(Post-inf of Nec day 15) a, d
(X) 

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Pharmacokinetic sample
Immunogenicity
Necitumumab
(Nec)
Gemcitabine
（Gem）
Cisplatin
（Cis）
Cycle 4
Day 1
Pre-inf of Nec
X
X
Day 8
Pre-inf of Nec
X
Visit 801
30 days after the decision to discontinue study 
treatment
X
X
Note:  It is essential that the draw dates and draw times are accurately recorded.
Blood samples for PK evaluation will be collected based on the starting and completion of Necitumumab administration.  
Abbreviations:  Nec=Necitumumab, Gem=Gemcitabine, Cis=Cisplatin, h = hour, post-inf = post-infusion, pre-inf = pre-infusion.
a
If treatment for necitumumab will be postpone from Days 8 to 15, sample collection will be skipped and collected on Day 15.
b
Optional
c
Post-inf times are PK sample collection time points starting on completion of Gemcitabine or Cisplatin administration.  If 
time points starting on completion of each study drug administration  were different, bood samples will be collected at time 
points starting on the administration of Gemcitabine or Cisplatin rather than that of Necitumumab.
d
“Post-infusion” blood samples for necitumumab, gemcitabine, and cisplatin will be taken immediately prior to or taken  
immediately after the end of infusion to ensure an accurate Cmax.
Schedule for Pharmacokinetic and Immunogenicity Sampling, 
Protocol I4X-JE-JFCM (Arm A in Phase 2)
Pharmacokinetic sample for Necitumumab 
(Nec)
Immunogenicity
Cycle 1
Day 1
Pre-inf of Nec
X
X
Post-inf of Nec b
X
Cycle 2
Day 1
Pre-inf of Nec c
X
Cycle 3
Day 1
Pre-inf of Nec c
X
X
Post-inf of Nec b
X
Cycle 4
Day 1
Pre-inf of Nec c
X
Cycles 5 to X
Day 1
Pre-inf of Nec
X a
X a
Visit 801
30 days after the decision to discontinue study treatment d
X
X
Note:  It is essential that the draw dates and draw times are accurately recorded.
Blood samples for PK evaluation will be collected based on the starting and completion of Necitumumab administration.
Abbreviations:  Nec=Necitumumab, h = hour, post-inf = post-infusion, pre-inf = pre-infusion.
a
After 5 cycle:  pharmacokinetics and immunogenicity will be examined every 2 cycles
b
“Post-infusion” blood samples for necitumumab will be taken immediately prior to or taken  immediately after the end of 
infusion to ensure an accurate Cmax.
c
If only necitumumab is discontinued before Cycle 4 (chemotherapy continues for a maximum of 4 cycles), a PK sample will 
be taken at Day 1 of the first cycle after the decision to discontinue necitumumab (i.e. the first cycle when only chemotherapy 
is administered).  If this is Cycle 3 Day 1, an immunogenicity sample will also be taken.  Collection of PK and/or 
immunogenicity samples at Day 1 of the subsequent cycle is not required.
d
If only necitumumab is discontinued before Cycle 4 (chemotherapy continues for a maximum of 4 cycles), this PK and 
immunogenicity sampling will be taken at the nearest planned visit to 30 days after the decision to discontinue necitumumab.

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Attachment 3.Protocol JFCM Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology a
Clinical Chemistry b
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Magnesium
Erythrocyte count (RBC)
Potassium
Mean cell volume (MCV)
Total bilirubin
Mean cell hemoglobin concentration (MCHC)
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils
Alanine aminotransferase/serum glutamic 
pyruvic transaminase (ALT/SGPT)
Lymphocytes
Aspartate aminotransferase/ Serum glutamic 
oxaloacetic transaminase (AST/SGOT)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose, nonfasting
Urinalysis a
Albumin
Glucose
Cholesterol
Protein
Creatine kinase (CK)
Ketones
Inorganic phosphorus (IP)a, d
Blood
Specific gravity
Pregnancy Test (Urine/Serum)a, c
pH
Urine leukocyte esterase
Coagulation Profile a
Prothrombin Time (PT)
Partial Thromboplastin Time (PTT)
International Normalized Ratio (INR)
Abbreviations:  RBC = red blood cells; WBC = white blood cells; 
a
Assayed by investigator-designated (local) laboratory.
b
Assayed by Sponsor-designated (central) laboratory.
c
Whichever is selected should be followed throughout.
d
The assay result will be monitored by investigators to assess safety and be captured as an adverse event in the 
eCRF, if necessary.  It is not necessary to record the actual assay result in the eCRF because it will not be used in 
the safety analysis.

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Attachment 4.Protocol JFCM ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to 
carry out any work activities.  Up and about more than 
50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours
4
Completely disabled.  Cannot carry on any selfcare.  
Totally confined to bed or chair
5
Dead.
Source:  Oken et al. 1982.
References:
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol.
1982;5:649-655.

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Attachment 5.Protocol JFCM Necitumumab, Gemcitabine, 
and Cisplatin Dosing Scenarios for Chemotherapy Delays
Cycle
Day
Necitumumab
Gemcitabine
Cisplatin
No treatment delay
1
1
X
X
X
8
X
(X)
15
2
1(22)
X
X
X
Necitumumab schedule change
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
X
2
1(22)
X
X
X
Necitumumab schedule change and skip
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
No administration due to 
treatment criteria is not met
2
1(22)
X
X
X
Treatment delay for Cycle 2 (1 week):
1
1
X
X
X
8
X
(X)
15
22
No administration due to treatment criteria is not met
2
1(29)
X
X
X
Treatment delay for Cycle 2 (1 week):  Necitumumab schedule change
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
X
22
No administration due to treatment criteria is not met
2
1(29)
X
X
X
Treatment delay for Cycle 2 (1 week):  Necitumumab schedule change and skip
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
No administration due to 
treatment criteria is not met
22
No administration due to treatment criteria is not met
2
1(29)
X
X
X

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Cycle
Day
Necitumumab
Gemcitabine
Cisplatin
Treatment delay for Cycle 2 (2 weeks):
1
1
X
X
X
8
X
(X)
15
22
No administration due to treatment criteria is not met
29
No administration due to treatment criteria is not met
2
1(36)
X
X
X
Treatment delay for Cycle 2 (2 weeks):  Necitumumab schedule change
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
X
22
No administration due to treatment criteria is not met
29
No administration due to treatment criteria is not met
2
1(36)
X
X
X
Treatment delay for Cycle 2 (2 weeks):  Necitumumab schedule change and skip
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
No administration due to 
treatment criteria is not met
22
No administration due to treatment criteria is not met
29
No administration due to treatment criteria is not met
2
1(36)
X
X
X
Treatment delay for Cycle 2 (3 weeks):
1
1
X
X
X
8
X
(X)
15
22
No administration due to treatment criteria is not met
29
No administration due to treatment criteria is not met
36
No administration due to treatment criteria is not met
2
1(43)
X
X
X
Treatment delay for Cycle 2 (3 weeks):  Necitumumab schedule change
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
X
22
No administration due to treatment criteria is not met
29
No administration due to treatment criteria is not met
36
No administration due to treatment criteria is not met
2
1(43)
X
X
X

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Cycle
Day
Necitumumab
Gemcitabine
Cisplatin
Treatment delay for Cycle 2 (3 weeks):  Necitumumab schedule change and skip
1
1
X
X
X
8
No administration due to 
treatment criteria is not met
(X)
15
No administration due to 
treatment criteria is not met
22
No administration due to treatment criteria is not met
29
No administration due to treatment criteria is not met
36
No administration due to treatment criteria is not met
2
1(43)
X
X
X

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Attachment 6.Protocol JFCM Amendment (e) Summary [An 
Open-label, Multicenter, Phase 1b/2 Study to Evaluate 
Necitumumab in Combination with Gemcitabine and 
Cisplatin in the First-Line Treatment of Patients with 
Advanced (Stage IV) Squamous Non-Small Cell Lung 
Cancer (NSCLC)]
Overview
Protocol I4X-JE-JFCM [An Open-label, Multicenter, Phase 1b/2 Study to Evaluate 
Necitumumab in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of 
Patients with Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC)] has been 
amended.  The amended protocol is indicated by the revised study alias, Protocol 14X-JE-JFCM
(e) and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The following changes related to patient safety were made to maintain consistency with
the latest updated IB (approved 30-Mar-2016).
o
Section 9.7.1.1 Infusion-Related Reactions was updated.
o
Section 9.7.1.2.1 Reactive Treatment was updated.
o
Section 9.7.1.3 Conjunctivitis was updated.
o
Section 9.7.1.4 Hypomagnesemia was changed to Electrolyte Abnormalities and 
updated.
o
Section 9.7.1.6 Thromboembolic Events was updated and divided into two 
sections “Section 9.7.1.6 Thromboembolic Events” and “Section 9.7.1.7 
Cardiorespiratory Disorders”.
o
Section 14:  Added references.
o
Attachement 3:  Added “inorganic phosphorus” to monitor patients for 
hypophosphatemia as described in Section 9.7.1.4.

Other changes are as follows:
o
Section 8.1.8:  Added the text to clarify the position of the ILDC in this study.
o
Section 10.2.1 and Attachment 1:  Added the text to clarify the data collection 
after discontinuation of the study treatment in Arm A.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1.
Protocol I4X-JE-JFCM(e)
An Open-label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in 
Combination with Gemcitabine and Cisplatin in the First-Line Treatment of 
Patients with Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer 
(NSCLC)
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
Necitumumab (IMC-11F8; LY3012211), unless such persons are bound by a confidentiality 
agreement with Eli Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is and its associated attachments are subject to United 
States Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its 
subsidiaries.
8.1.8. Committees
Interstitial Lung Disease Committee (ILDC)
Interstitial Lung Disease Committee will be established.  For the interstitial lung disease (ILD) 
and suspected ILD cases being diagnosed after starting the study treatments (on Day 1 in Cycle 
1), external specialists will evaluate its related examination results such as image data and tissue 
samples.  The assessments by the ILDC are independent from assessments by investigators and 
will not be collected in the clinical trial database.  The assessments by the ILDC will be provided 
to the Sponsor and used for safety monitoring.  Assessments by the ILDC will not be made 
available to investigators in principle.
9.7.1.1.
Infusion-Related Reactions
Hypersensitivity/infusion-related reactions are defined according to the NCI-CTCAE version 4.0 
definition of allergic reaction/hypersensitivity, as follows:

Grade 1: transient flushing or rash, drug fever <38.0ºC

Grade 2: rash, flushing, urticaria, dyspnea, drug fever 38.0ºC

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
Grade 3: symptomatic bronchospasm, requiring parenteral medication(s), with or 
without urticaria; allergy-related edema/angioedema, hypotension

Grade 4: anaphylaxis (a life-threatening event characterized by the rapid onset 
[often within minutes] of airway obstruction [bronchospasm, stridor, 
hoarseness], urticaria, and/or hypotension)
Hypersensitivity/infusion-related reactions were reported with necitumumab.  The onset of 
events usually occurred after the first or second administration of necitumumab.  Monitor 
patients during and following the infusion for signs of hypersensitivity and infusion-related 
reactions with resuscitation equipment readily available.  For mild or moderate (Grade 1 or 2) 
infusion-related reactions, adjust dose per Table JFCM.12.  Immediately and permanently 
discontinue necitumumab for severe (Grade 3 or 4) infusion-related reactons.
Consistent with usual medical practice, selected parenteral medications may be utilized for as 
detailed below (Table JFCM.12).  Additional treatments, chosen according to clinical symptoms 
and local standards, may be utilized at investigator discretion.
9.7.1.2.1.
Reactive Treatment
Skin reactions were reported with necitumumab.  The onset of events occurred mainly during the 
first cycle of treatment.
Based on emerging data from cetuximab, there appears to be a correlation between acneform 
rash and various efficacy outcomes.  Therefore, if a patient experiences a Grade 1 or 2 acne-like 
rash, necitumumab treatment should continue without dose modification or delay.  If a patient 
experiences acute or chronic Grade 3 rash acneiform (ie, rash associated with pain, disfigurement, 
ulceration, or desquamation), pruritus, desquamation, dry skin, cheilitis, or hand-foot reaction, 
necitumumab treatment will be delayed for a maximum of 6 weeks following Day 1 of the most 
recent treatment cycle, until there is improvement to Grade 2. At this time, necitumumab may 
be re-administered (as described in Table JFCM.13). Patients who experience Grade 3 skin 
induration / fibrosis or any Grade 4 skin toxicity will be immediately and permanently 
discontinued from necitumumab.
At the June 2008 World GI Congress in Barcelona, Spain, Mitchell et al presented results of a 
study comparing pre-emptive versus reactive treatment of skin toxicity among patients receiving 
panitumumab, another monoclonal antibody directed against the EGFR.  In this study, 
pre-emptive treatment reduced the incidence of skin toxicity Grade 2 by more than 50% over 
reactive treatment, and resulted in fewer dose delays.  As a recommendation, on the basis of 
these data, pre-emptive treatment with skin moisturizers, topical steroids, doxycycline, or 
sunscreen may be administered as clinically appropriate to patients receiving necitumumab.Prior 
to necitumumab infusion, consider premedication for possible skin reactions.  Preemptive 
treatment with skin moisturizers, topical steroids, doxycycline, or sunscreen may be administered 
as clinically appropriate to patients receiving necitumumab (Lacouture et al. 2011).  For 
additional information regarding preemptive management of skin toxicity, see Canadian 
recommendations (Melosky et al. 2009).

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9.7.1.3.
Conjunctivitis
Conjunctivitis has been reported very commonly in patients receiving necitumumab.
For patients with treatment-related conjunctivitis <Grade 3, the investigator is advised to initiate 
symptomatic treatment and follow-up observation of the event.  If the severity increases to 
Grade 3, or symptoms persists for >10 days after symptomatic treatment, the investigator is 
advised to refer the patient to an ophthalmologist for further evaluation and treatment.
Serious cases of keratitis and ulcerative keratitis have been reported as uncommon or rare side 
effects for other anti-EGFR antibodies and are to be considered a class effect. If the diagnosis is 
confirmed, anti-EGFR treatment should be interrupted or discontinued, with benefits and risks of 
continuation of treatment to be carefully considered.
9.7.1.4.
Electrolyte AbnormalitiesHypomagnesemia
Consistent with observations with other EGFR-targeting antibodies (as with panitumumab and 
cetuximab), hypomagnesemia has been very commonly reported in patients treated with 
necitumumab in combination with cisplatin-based regimens.  Hypomagnesemia is considered a 
class effect for EGFR-targeting antibodies. Monitor patients for hypomagnesemia, 
hypocalcemia, hypokalemia, and hypophosphatemia prior to each administration of 
necitumumab and after completion of the treatment of necitumumab, until within normal limits.  
Prompt repletion is recommended, as appropriate.Hypomagnesemia has been reported with 
necitumumab therapy and is considered to be a class effect with EGFR-targeting antibodies (as 
with panitumumab and cetuximab).  Hypomagnesemia is reversible following discontinuation of 
EGFR antibody therapy.  Treatment of any hypomagnesemia should be as clinically indicated 
according to local standards, and necitumumab therapy should be continued unless the 
investigator has any related safety concern.
9.7.1.6.
Thromboembolic Events
Venous thromboembolic events and ATEs were observed with necitumumab in combination 
with gemcitabine and cisplatin.  The relative risk of VTEs or ATEs was approximately 3-fold 
higher in patients with a reported history of VTEs or ATEs.
Discontinuation of necitumumab in patients who experience a VTE or ATE should be considered 
after a thorough benefit-risk assessment for the individual patient. 
Treatment of any thromboembolic events occurring under necitumumab treatment should be as 
clinically indicated according to local standards, and the continuation of necitumumab therapy in 
these cases should be decided by the investigator after thorough risk-benefit assessment for the 
individual patient.
Necitumumab in Combination with Pemetrexed and Cisplatin 
Administration of necitumumab in combination with pemetrexed and cisplatin is not 
recommended.  Patients experienced an increased rate of serious thromboembolic events 
(including fatal events) in the necitumumab plus pemetrexed and cisplatin arm as compared to 

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the pemetrexed and cisplatin arm.  The addition of necitumumab did not improve the efficacy 
outcome over pemetrexed and cisplatin alone in advanced nonsquamous NSCLC. 
Necitumumab in Combination with other agents
No safety signal with regard to thromboembolic events, including fatal events, has been 
identified for necitumumab in completed clinical trials when administered as monotherapy or in 
combination with modified FOLFOX-6 chemotherapy (mFOLFOX-6; oxaliplatin + folinic acid 
+ 5-fluorouracil).
In an ongoing Study (CP11-0805) for the combination of necitumumab with pemetrexed and 
cisplatin in nonsquamous NSCLC, an increased rate of serious thromboembolic events, including 
fatal events, as compared to the treatment with pemetrexed and cisplatin alone has been observed.  
These cases included cases of arterial thromboembolism (for example, cerebrovascular ischemia, 
intestinal ischemia, or leg ischemia), venous thromboembolism (for example, pulmonary 
embolism) and cases where thromboembolism was not proven, but could not be excluded (for 
example, cases of sudden death with limited information); the latter cases mainly contributed to 
the excess of fatal events.
The majority of fatal cases occurred within the first two cycles of therapy, leading to the IDMC 
recommendation to stop enrollment and to stop treatment in patients who have not yet completed 
Cycle 2 of treatment.  No other strategies on how to prevent serious thromboembolic events in 
this study could be identified from a thorough review of the data.  Further analysis is ongoing.
For the combination of necitumumab with gemcitabine and cisplatin in another ongoing study, in 
squamous NSCLC (CP11-0806) a higher rate of serious venous thromboembolic events (mainly 
deep vein thrombosis and pulmonary embolism) as compared to the treatment with gemcitabine 
and cisplatin alone has been observed; this imbalance however, did not pertain to fatal cases.  
Further analysis is ongoing.
No safety signal with regard to thromboembolic events, including fatal thromboembolic events, 
has been identified for necitumumab when administered as monotherapy or in combination with 
modified FOLFOX-6 chemotherapy (5-fluorouracil, folinic acid, and oxaliplatin).Treatment of 
any thromboembolic events should be as clinically indicated according to local standards, and 
the continuation of necitumumab therapy in these cases should be decided by the investigator 
after thorough risk-benefit assessment for the individual patient.
In cases of sudden death, investigators are requested to record on the SAE report form as much 
information as possible regarding the symptoms and signs immediately preceding death and any 
postmortem results so that an accurate cause of death may be established (specifically so that 
thromboembolism may be confirmed or denied).
9.7.1.7.
Cardiorespiratory Disorders
An increased frequency of cardiorespiratory arrest or sudden death was observed with 
necitumumab.  Cardiorespiratory arrest or sudden death was reported in the pivotal Study JFCC 
(SQUIRE, CP11-0806) in 2.8% (15/538) of patients treated with necitumumab plus gemcitabine 
and cisplatin compared to 0.6% (3/541) of patients treated with chemotherapy alone.  Twelve of 

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the 15 patients died within 30 days of the last dose of necitumumab and had comorbid 
conditions, including history of chronic obstructive pulmonary disease (n=7), hypertension 
(n=5), hypomagnesemia (n=4), and coronary artery disease (n=3).  Eleven of the 12 patients had 
an unwitnessed death.
10.2.1.
Patient-Reported Outcomes (only Phase 2 part)
All patients for whom there is a validated translation in which the patient is fluent will undergo 
assessment for symptoms and QOL using the LCSS and the EuroQol (EQ-5D).  It is 
recommended that the instruments is administered together and in sequence order, with the 
LCSS presented first, followed by presentation of the EQ-5D. 
Patients will complete the instruments at baseline (within 14 days prior to randomization), prior 
to the first infusion of Cycles 2 to 4, and in Arm A, every 2 2-cycles interval thereafter (ie, Cycle 
6, Cycle 8, Cycle 10 and so on).  Chemotherapy in Arm B will not continue beyond Cycle 4.  
The instruments will be completed every 6 weeks after discontinuation of the study treatment in 
Arm A until PD (ie, concurrent with radiological evaluation), in Arm A and every 6 weeks after 
discontinuation of chemotherapy in Arm B until PD (ie, concurrent with radiological evaluation
after discontinuation of chemotherapy).  The instruments should be completed at the beginning 
of the visit, before any extensive contact and consultation with the clinician/study investigator; 
such encounters may thereafter bias patient responses.  The LCSS and the EQ-5D will be 
completed by all patients using the validated translated version of Japanese.
14.
References
Kusaba H, Tamura T, Shimoyama T, Hotta K, Inoue A, Nokihara H, et al. Phase I/II study of 3-
week cycle cisplatin-gemcitabine in advanced non-small cell lung cancer. Jpn J Clin Oncol. 
2002; 32(2):43-47.
Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, 
Murphy BA; MASCC Skin Toxicity Study Group. Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care 
Cancer. 2011:19(8);1079-1095.
Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, 
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randomized multicenter phase III trial BMS099. J Clin Oncol. 2010;28(6):911-917.
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during EGFR targeted monoclonal antibody treatment for gastrointestinal malignancies: 
Canadian recommendations. Curr Oncol. 2009;16 (1):16-26.

I4X-JE-JFCM(e) Clinical Protocol
Page 101
LY3012211 and LY188011
Mitchell EP, LaCouture M, Shearer H, Inannotti N, Piperdi B, Pillai MV, et al. Updated results 
of STEPP, a Phase 2, open-label study of pre-emptive versus reactive skin toxicity treatment in 
metastatic colorectal cancer (mCRC) patients receiving panitumumab FOLFIRI or 
irinotecan-only chemotherapy as second-line treatment. 10th World Congress on GI Cancer, 
Barcelona, Spain; 25-28 June 2008 [Abstract O-021].
Attachment 1.
Protocol JFCM Study Schedule
o
Health Outcomes will be evaluated prior to the first infusion of every cycle thereafter until PD.  Self-reported 
health outcome assessments (LCSS and EQ-5D) will be performed pretreatment (within 14 days of 
randomization), prior to the first infusion of Cycles 2 to 4, and every 2-cycle interval thereafter (ie, Cycle 6, 
Cycle 8, Cycle 10 and so on). Chemotherapy in Arm B will not continue beyond Cycle 4.  The instruments will 
be completed every 6 weeks after discontinuation of the study treatment in Arm A until PD (ie, concurrent with 
radiological evaluation),in Arm A and every 6 weeks after discontinuation of chemotherapy in Arm B until PD
(ie, concurrent with radiological evaluation after discontinuation of chemotherapy).  At every scheduled 
timepoint, the LCSS should be administered prior to the EQ-5D. The first assessment must be done in 
investigator sites to ensure that patients understand how to complete the questionnaires.  Following the 
pretreatment assessment, patients may complete the health outcomes assessments up to 3 days prior to the 
scheduled assessment time and may complete them at home if patients can contact site personnel with any 
questions. 
Attachment 3.
Protocol JFCM Clinical Laboratory Tests
Clinical Laboratory Tests
Clinical Chemistry b
Serum Concentrations of:
Inorganic phosphorus (IP)a, d
d
The assay result will be monitored by investigators to assess safety and be captured as an adverse event in the 
eCRF, if necessary.  It is not necessary to record the actual assay result in the eCRF because it will not be used in 
the safety analysis.

Leo Document ID = a215722d-f5f4-4364-bb0f-0771fc94348b
Approver: 
Approval Date & Time: 10-Jun-2016 18:30:44 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 12-Jun-2016 21:59:08 GMT
Signature meaning: Approved
PPD
PPD