A Single-Arm, Multicenter, Open-Label, Phase 2 Study of Nab®-Paclitaxel (Abraxane®) and Carboplatin Chemotherapy Plus Necitumumab (LY3012211) in the First-Line Treatment of Patients With Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Carcinoma, Non-Small Cell Lung Cancer (NSCLC)
Sponsor: Eli Lilly and Company

Protocol (b) I4X-MC-JFCP  
 
 
A Single-Arm, Multicenter, Open-Label, Phase 2 Study of nab®-Paclitaxel (Abraxane®) and 
Carboplatin Chemotherapy plus Necitumumab (LY3012211) in the First-Line Treatment of 
Patients with Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC) 
 
NCT02392507 
 
Approval Date: 25-Sep-2016 
 
 
 

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1.
Protocol I4X-MC-JFCP(b)
A Single-Arm, Multicenter, Open-Label, Phase 2 Study of
nab®-Paclitaxel (Abraxane®) and Carboplatin 
Chemotherapy plus Necitumumab (LY3012211) in the 
First-Line Treatment of Patients with Stage IV Squamous 
Non-Small Cell Lung Cancer (NSCLC)
EudraCT Number: 2016-002071-96
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 (LY3012211), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments are subject to United States Freedom of Information Act Exemption 4.
Necitumumab (LY3012211; IMC-11F8)
Single-arm Phase 2 study in patients with Stage IV squamous NSCLC.  Eligible patients 
will receive first-line treatment of chemotherapy plus necitumumab on a 3-week cycle as 
follows:  During the induction period, patients will receive a triplet regimen of Abraxane; 
hereafter referred to as nab-paclitaxel (100 mg/m
2 I.V. on Days 1, 8, and 15) and 
carboplatin (AUC 6 [mg·min/mL] I.V. on Day 1) plus necitumumab (800 mg absolute dose 
intravenously [I.V.] on Days 1 and 8) for a maximum of 4 cycles (or until there is 
radiographic documentation of progressive disease, toxicity requiring cessation, protocol 
noncompliance, or withdrawal of consent).  Only those patients with a disease response of 
complete response (CR), partial response (PR), or stable disease (SD) (radiographic 
evidence of response, not necessarily confirmed) after 4 cycles of induction regimen are 
eligible to then receive the maintenance (doublet) regimen of necitumumab (800 mg 
absolute dose on Days 1 and 8) plus nab-paclitaxel (100 mg/m
2 on Days 1 and 8) every 3 
weeks until disease progression occurs or other discontinuation criteria are met.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 06 January 2015
Amendment (a) Electronically Signed and Approved by Lilly on 07 June 2016 
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 25-Sep-2016 GMT

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2.
Synopsis
Study Rationale
Necitumumab (LY3012211; IMC-11F8; Portrazza®) 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.  Epidermal growth factor receptor activation leads to stimulation of tyrosine 
kinase-dependent signal transduction pathways that can contribute to neoplastic transformation 
and tumor growth.
Necitumumab has shown in vivo antitumor activity against a variety of human xenograft tumors, 
including non-small cell lung cancer (NSCLC). In clinical setting, the feasibility of 
administering necitumumab in combination with a standard platinum-based doublets in the first-
line treatment of advanced NSCLC has been demonstrated in 2 randomized Phase 3 trials. In the
Phase 3 SQUIRE study, which was performed in patients with first-line, Stage IV squamous 
disease, the combination of necitumumab plus gemcitabine and cisplatin showed a statistically 
significant advantage over the same chemotherapy alone in overall survival (OS), progression-
free survival (PFS), and disease control rate (DCR).  Necitumumab has recently been approved 
in the United States (US) and European Union (EU) for treatment of patients with metastatic 
squamous NSCLC in combination with gemcitabine and cisplatin.  
A randomized Phase 3 trial, Study BMS099, conducted with another EGFR-directed mAb, 
cetuximab, in combination with taxane and carboplatin (TC) as the chemotherapy backbone
demonstrated that the addition of cetuximab to TC regimen in patients with advanced NSCLC 
resulted in a statistically significant improvement in the best objective response rate (ORR; 
complete response [CR] + partial response [PR]), but not in PFS. The analysis of this study by 
histologic subtypes revealed major advantages in patients with squamous cell carcinoma for the 
cetuximab-containing regimen over the same chemotherapy alone in terms of PFS (HR=0.7).
Recently, paclitaxel protein-bound particles for injectable suspension (albumin-bound) 
(Abraxane), hereafter known as nab-paclitaxel, was approved in the United States (US) as first-
line therapy for locally advanced or metastatic NSCLC. The approval was based on a 
randomized Phase 3 study that demonstrated statistically significant advantages for this regimen 
over solvent-based paclitaxel plus carboplatin (sb-PC) in terms of ORR, as well as prolonged 
PFS and OS that met the prespecified non-inferiority statistical analysis. The subgroup analysis 
of this study by tumor histology showed in squamous NSCLC a statistically significant 
advantage for nab-paclitaxel plus carboplatin (nab-PC) regimen in terms of best ORR (41% 
versus [vs] 24%, p<.001), and trends of improved PFS and OS.
These preclinical data, the clinical efficacy of EGFR-directed mAbs in combination with taxanes 
and carboplatin, and the advantage of nab-PC over sb-PC in terms of safety and efficacy 
especially in squamous NSCLC together provide a strong rationale for the investigation of 
necitumumab in combination with nab-PC as first-line therapy in Stage IV squamous NSCLC.

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The present single-arm Phase 2 study is being conducted to evaluate ORR, PFS, OS, DCR, and 
safety and tolerability associated with the study treatment of nab-paclitaxel and carboplatin 
chemotherapy plus necitumumab as first-line therapy in patients with Stage IV squamous 
NSCLC.

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Clinical Protocol Synopsis:  Study I4X-MC-JFCP(b)
Name of Investigational Products:  Necitumumab (LY3012211; IMC-11F8), nab-paclitaxel, and carboplatin as
applicable on the region
Title of Study:  A Single-Arm, Multicenter, Open-Label, Phase 2 Study of nab®-Paclitaxel (Abraxane®) and 
Carboplatin Chemotherapy plus Necitumumab (LY3012211) in the First-Line Treatment of Patients with Stage IV 
Squamous Non-Small Cell Lung Cancer (NSCLC)
Number of Planned Patients:
Entered:  60
Enrolled:  50
Completed:  50 qualified patients
Phase of Development:  Phase 2
Length of Study:  Approximately 18 months
Planned first patient visit:  Apr 2015
Planned last patient visit:  Oct 2016
Objectives:  The primary objective of this study is to evaluate the best objective response rate (ORR; complete 
response [CR] + partial response [PR]) associated with a treatment regimen of nab-paclitaxel and carboplatin 
chemotherapy plus necitumumab as first-line therapy in patients with Stage IV squamous NSCLC.
The secondary objectives of the study are to:

evaluate progression-free survival (PFS),

evaluate overall survival (OS),

evaluate disease control rate (DCR),

evaluate the safety profile of necitumumab in combination with carboplatin and/or nab-paclitaxel
chemotherapy,

determine the pharmacokinetics (PK) of necitumumab, nab-paclitaxel, and carboplatin, and

determine the immunogenicity of necitumumab (anti-necitumumab antibodies)
The exploratory objectives of the study are to further evaluate the relationships between biomarkers related to the 
EGFR pathway, NSCLC etiology, and/or the mechanism of action of necitumumab and clinical outcomes.

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Study Design:  This is a single-arm Phase 2 study to investigate nab-paclitaxel and carboplatin chemotherapy in 
combination with necitumumab as first-line therapy in approximately 50 patients with Stage IV squamous NSCLC
(American Joint Committee on Cancer [AJCC] Staging Manual, 7th edition).  Prior to screening, patient tumor 
tissue must be available (a formalin-fixed, paraffin-embedded [FFPE] tissue block [preferred] or 15 freshly cut 
unstained slides [a minimum of 6 slides] is requested).  A treatment cycle is defined as 3 weeks.  The treatment 
schema is summarized in the following figure:
Abbreviations:  AUC = area under the concentration-time curve; CR = complete response; D = Day; DC = discontinuation; DCR = disease 
control rate; ECOG PS = Eastern Cooperative Oncology Group performance status; IG = immunogenicity (anti-necitumumab antibodies); 
I.V. = intravenous(ly); nab-paclitaxel = paclitaxel protein-bound particles for injectable suspension (albumin-bound); NSCLC = non-small cell 
lung cancer; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; 
PK = pharmacokinetic(s); PR = partial response; sq = squamous; SD = stable disease.
Note:  Figure includes Study Treatment Period only; it does not include the Continued Access Period.
Study therapy consists of an induction (triplet) regimen of nab-paclitaxel (100 mg/m2 I.V. on Days 1, 8, and 15) 
and carboplatin (area under the concentration-time curve [AUC] 6 [mg∙min/mL] intravenously [I.V.] on Day 1) 
plus necitumumab (800 mg absolute dose I.V. on Days 1 and 8) administered for a maximum of 4 cycles (or until
there is radiographic documentation of progressive disease [PD], toxicity requiring cessation, protocol 
noncompliance, or withdrawal of consent).  Only those patients with a disease response of CR, PR, or stable 
disease (SD) (radiographic evidence of response, not necessarily confirmed) after 4 cycles of induction regimen are 
eligible to then receive the maintenance (doublet) regimen of necitumumab (800 mg absolute dose on Days 1 and 
8) plus nab-paclitaxel (100 mg/m2 on Days 1 and 8) every 3 weeks until disease progression occurs or other 
discontinuation criteria are met.  No other chemotherapy is permitted until there is radiographic documentation of 
PD.

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If toxicity requires that necitumumab be modified by more than 2 dose reductions or delayed (held) for more than 6 
weeks following Day 1 of the most recent cycle, necitumumab is to be permanently discontinued.  nab-Paclitaxel 
and carboplatin are to be permanently discontinued in any of the following situations:  (1) third occurrence of 
neutropenic fever, >7-day delay of a cycle due to absolute neutrophil count (ANC) <1.5 × 103/µL, or ANC<0.5 × 
103/µL for >7 days; (2) second occurrence of platelet count <50 × 103/µL; or (3) third occurrence of Grade 3 or 4 
sensory neuropathy. Patients who discontinue study treatment for any reason other than PD will continue to 
undergo radiographic tumor assessments every 6 weeks (±3 days) until PD or overall study completion, whichever 
occurs first.
Patients will be followed for survival every 3 months (±7 days) until the patient’s death or overall study 
completion, whichever occurs first, where study completion is defined as the point when 70% of qualified patients 
experience a PFS event ( radiographically documented PD or death), or 6 months after completing enrollment, 
whichever occurs first, as determined by Lilly (the sponsor).
Baseline radiographic assessment of disease will be performed within 21 days prior to first dose of study therapy.  
Patients will undergo radiographic assessment (computed tomography [CT] or magnetic resonance imaging [MRI]) 
of disease status every 6 weeks (±3 days) after the first dose of study therapy, regardless of treatment delays, until 
there is radiographic documentation of PD as defined by the Response Evaluation Criteria in Solid Tumors, version 
1.1 (RECIST 1.1).
Adverse event (AE) information will be collected until at least 30 days after the decision is made to discontinue 
study treatment (and, in case of AEs that are serious, considered related to study treatment or study procedures, or 
that caused the patient to discontinue before completing the study, until the event has resolved or is explained). A 
short-term postdiscontinuation follow-up visit will occur at least 30 days (+ 0-7 days; ie, at least 30 days but no 
more than 37 days) after the decision to discontinue. After the Short-Term Follow-up visit, only new and ongoing 
serious adverse events (SAEs) deemed related to protocol procedures or study treatment will be collected.
Diagnosis and Main Criteria for Inclusion and Exclusions:
Key Inclusion Criteria

Histologically or cytologically confirmed squamous NSCLC

Stage IV disease at the time of study entry (AJCC Staging Manual, 7th edition)

Measurable disease at the time of study enrollment, as defined by RECIST 1.1

Tumor tissue (paraffin-embedded tissue block [preferred] or 15 freshly cut unstained slides [a minimum 
of 6 slides] is requested) available for analysis of EGFR protein expression by immunohistochemistry 
(IHC).
Key Exclusion Criteria

Nonsquamous NSCLC

Prior anticancer therapy with monoclonal antibodies, signal transduction inhibitors, or any therapies
targeting the EGFR, vascular endothelial growth factor (VEGF), or VEGF receptor

Previous chemotherapy for advanced NSCLC

Major surgery or received any investigational therapy in the 4 weeks prior to study entry

Systemic radiotherapy within 4 weeks prior to study entry, or focal radiotherapy within 2 weeks prior to 
study entry

Symptomatic central nervous system (CNS) malignancy or metastasis
Test Product, Dosage, and Mode of Administration:
Necitumumab drug product is a sterile, preservative-free, I.V. infusion supplied in 50-mL single-use vials 
containing 16 mg/mL (800 mg/50 mL) of product, and administered at a dose of 800 mg over 60 minutes on 
Days 1 and 8 of each 3-week cycle.

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Reference Therapy, Dose, and Mode of Administration:
nab-Paclitaxel will be administered at a dose of 100 mg/m2 I.V. over 30 minutes on Days 1, 8, and 15 of each 3-
week cycle during the induction period and on Days 1 and 8 of each 3-week cycle during the maintenance period.  
nab-Paclitaxel will be used and should be prepared and administered according to the manufacturer’s instructions.
Carboplatin will be administered immediately after the nab-paclitaxel infusion.  Carboplatin will be administered 
at AUC 6 (mg∙min/mL) I.V. over a minimum of 15 minutes (maximum of 60 minutes) on Day 1 of each 3-week 
cycle, for a maximum of 4 cycles (approximately 12 weeks).  Carboplatin will be used and should be prepared and 
administered according to the manufacturer’s instructions.
Planned Duration of Treatment:  A treatment cycle will be defined as 3 weeks, with radiographic evaluation of
tumor response every 6 weeks (±3 days). Patients will be treated according to the study design described above
until there is radiographic documentation of PD as assessed by the investigator, according to RECIST 1.1; toxicity 
requiring cessation; withdrawal of consent; or other discontinuation criteria are met.
Study Treatment Period:
    Induction regimen (triplet):  a maximum of 4 cycles (approximately 12 weeks), or until disease progression or 
unacceptable toxicity occurs
    Maintenance regimen (doublet):  n cycles following the induction period, until disease progression or 
unacceptable toxicity occurs
Short-Term Follow-up (postdiscontinuation):  at least 30 days (+ 0-7 days; ie, at least 30 days but no more than 37 
days)
Long-Term Follow-up (postdiscontinuation):  until the patient’s death or overall study completion, whichever 
occurs first

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Criteria for Evaluation:
Efficacy: For these definitions, the date of study enrollment is the date of first dose of study drug (necitumumab, 
nab-paclitaxel, and/or carboplatin).

Tumor response will be assessed by the investigator according to RECIST 1.1 every 6 weeks (±3 days),
with confirmatory assessment for patients with an objective assessment of PR or CR obtained at the next 
routine scheduled imaging time point (that is, after 6 weeks ±3 days).

PFS is defined as the time from the date of study enrollment to the date of first observation of objective 
(radiographically documented) PD or death from any cause, whichever comes first.

OS is defined as the time from the date of study enrollment to the date of death from any cause.

Disease control is defined as the best tumor response of PR, CR, or SD.
Safety: The safety of necitumumab in combination with carboplatin and/or nab-paclitaxel chemotherapy will be 
assessed by reported SAEs, AEs, vital signs measurements, electrocardiogram (ECG) results, and laboratory 
analyses. The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0 (v 4.0), will serve as the reference document for choosing appropriate terminology for, and grading the 
severity of, all AEs and other symptoms. This collection is in addition to the 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 (Lilly) or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA®).
Immunogenicity:  Antibodies against necitumumab, assessed for all patients at the following time points:

Prior to the administration of study treatment on Day 1 of Cycles 1, 3, and 4;

At the (30-day) Short-Term Follow-up; and

In the setting of any hypersensitivity/infusion-related reaction.
Pharmacokinetics:  Blood for determination of serum concentrations of necitumumab, plasma concentrations of 
paclitaxel, and plasma concentrations of total platinum from carboplatin, assessed for all patients at the following 
time points:

Prior to and following the administration of all (not each) study treatment on Day 1 of Cycles 1, 3, and 4;

At the (30-day) Short-Term Follow-up (PK for necitumumab only); and

In the setting of any hypersensitivity/ infusion-related reaction (PK for necitumumab only).
Translational Research:
(Tumor tissue submission for biomarkers) Collection of tumor tissue samples is mandatory for participation in this 
study.  Formalin-fixed, paraffin-embedded tissue derived from either the primary tumor or metastatic sites will be 
collected and stored at a secure central laboratory.  A FFPE tissue block (preferred) or 15 freshly cut unstained 
slides (a minimum of 6 slides) is requested and will be used for analysis of EGFR protein expression by IHC.  
Analysis may be performed on biomarker variants thought to play a role in the mechanism of action of 
necitumumab, the pathogenesis of NSCLC, cancer-related conditions, and/or the EGFR signaling pathway.
(Plasma samples for biomarkers) Analysis may be performed on biomarker variants thought to play a role in the 
mechanism of action of necitumumab, the pathogenesis of NSCLC, cancer-related conditions, and/or the EGFR 
signaling pathway.
(Whole blood for deoxyribonucleic acid [DNA] sample [pharmacogenetic analysis]) A one-time blood sample will 
be collected from all patients at Baseline (preferred) or later visits, for analysis that may be performed on genetic 
determinants that impact the mechanism of action of necitumumab and/or the etiology of NSCLC.

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Statistical Methods:
Efficacy:  The primary objective of this study is to estimate the ORR in qualified patients. The sample size of 50 
was selected to facilitate the estimation of the ORR with reasonable precision; no power calculation was 
performed.  With 50 qualified patients, the 95% confidence interval (CI) estimate of ORR will have a width no 
greater than 29 percentage points (that is, the ORR point estimate ±14.5%).  There are no planned formal tests of 
hypotheses about ORR.  However, the maximum width of the 95% CI (previously described) will permit the 
conclusion (with 95% confidence) that the true value of ORR does not differ from the estimated value of ORR by 
more than 14.5 percentage points.
Efficacy analyses for ORR and DCR will be performed for qualified patients, where a “qualified patient” is defined 
as an enrolled patient who has received any amount of study drug and has had a complete radiographic assessment 
at baseline.  A patient who is alive for at least 8 weeks after first dose and has had no postbaseline radiographic 
assessment will be disqualified.  Efficacy analyses for PFS and OS will be performed for all patients who have 
received any amount of study drug (necitumumab, nab-paclitaxel, and/or carboplatin).
The final analysis for all outcomes, primary and secondary, including the final analysis of OS, will be performed 
when 70% of qualified patients experience a PFS event ( radiographically documented PD or death), or 6 months 
after completing enrollment, whichever occurs first, as determined by Lilly (the sponsor).  This will provide an 
appropriate duration of observation from which to estimate ORR and median PFS.  Overall survival will be 
evaluated primarily in terms of the estimated 6-month survival.
For all time-to-event variables, such as median OS and PFS, the Kaplan-Meier method will be used to estimate 
related parameters (for example, medians, quartiles, 6-month event rates).  Exact 95% CIs will be calculated for 
ORR and DCR.
Safety:  Safety analyses will be performed for the Safety Population (all patients who have received any amount of 
study drug [necitumumab, nab-paclitaxel, and/or carboplatin]).
Overall exposure to study treatment, the numbers of patients completing each cycle, and the dose intensity will be 
summarized using descriptive statistics.  The number of patients with any dose adjustment will be presented for the 
entire Study Treatment Period.  The number of patients with dose reductions, dose delays, or dose omissions will 
also be summarized, as will the reasons for dose adjustments.
An overall summary of AEs will be provided for AEs deemed by the investigator to be at least possibly related to 
study treatment, and repeated for events regardless of causality.  The number of patients who experienced a 
treatment-emergent adverse event (TEAE), SAE, AE related to study treatment, died, or discontinued from the 
study treatment due to an AE will be summarized.  The NCI-CTCAE v 4.0 will be used to report AEs by NCI-
CTCAE terms. Laboratory and non-laboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grades, including the total for maximum Grade 3 and above. These summaries will be provided for events 
deemed by the investigator to be at least possibly related to study treatment, and repeated for events regardless of 
causality. Adverse events will be summarized by MedDRA System Organ Class (SOC), by decreasing frequency 
of Preferred Term within SOC.
Reasons for death will be summarized separately for on-therapy and within 30 days after last dose of study 
treatment.  Serious adverse events will be summarized by SOC and Preferred Term.  Hospitalizations and 
transfusions occurring during the Study Treatment Period or (30-day) Short-Term Follow-up will be summarized.
One safety interim analysis is planned when data are available from at least the first 10 qualified patients who have 
completed 2 cycles of study treatment or have died.  The interim analysis will be conducted to permit evaluation of 
safety data by the sponsor.

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Immunogenicity and Pharmacokinetics:  Serum concentrations of necitumumab, plasma concentrations of 
paclitaxel, and plasma concentrations of total platinum from carboplatin at each sampling time point will be 
summarized using descriptive statistics.  Immunogenicity (anti-necitumumab antibody) incidence will be tabulated, 
and correlation to necitumumab drug level, activity, and safety will be assessed, as appropriate.  Additional 
exploratory analyses will be performed if warranted by data, using validated PK software programs (for example, 
NONMEM) and if appropriate and approved by Global Pharmacokinetic management.  Interim analysis may be 
conducted to facilitate exploratory analyses of PK, safety, and immunogenicity through PK/pharmacodynamic 
modeling.  Interim data may also be pooled with final and interim data from other clinical studies of necitumumab 
to facilitate meta-analysis using non-linear mixed effects modeling.  Since the study is unblinded, study objectives 
will not be compromised by the interim access to data.

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3.
Table of Contents
A Single-Arm, Multicenter, Open-Label, Phase 2 Study of
nab®-Paclitaxel (Abraxane®) and Carboplatin Chemotherapy 
plus Necitumumab (LY3012211) in the First-Line Treatment of 
Patients with Stage IV Squamous Non-Small Cell Lung 
Cancer (NSCLC)
Section
Page
1.
Protocol I4X-MC-JFCP(b) A Single-Arm, Multicenter, Open-Label, 
Phase 2 Study of nab®-Paclitaxel (Abraxane®) and Carboplatin 
Chemotherapy plus Necitumumab (LY3012211) in the First-Line 
Treatment of Patients with Stage IV Squamous Non-Small Cell Lung 
Cancer (NSCLC).................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents..............................................................................................................11
4.
Abbreviations and Definitions...........................................................................................18
5.
Introduction ......................................................................................................................25
6.
Objectives.........................................................................................................................28
6.1.
Primary Objective ........................................................................................................28
6.2.
Secondary Objectives...................................................................................................28
6.3.
Exploratory Objectives.................................................................................................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.
Discontinuation............................................................................................................33
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................33
7.3.2.
Discontinuation of Study Treatment.....................................................................33
7.3.2.1.
Discontinuation of All Study Treatment..........................................................33
7.3.2.2.
Discontinuation of One or More Study Treatment 
Components ...................................................................................................34
7.3.3.
Discontinuation from the Study............................................................................34
7.3.4.
Patients Who Are Lost to Follow-up ....................................................................35
7.3.5.
Discontinuation of Study Sites .............................................................................35
7.3.6.
Discontinuation of the Study................................................................................35
8.
Investigational Plan...........................................................................................................36
8.1.
Summary of Study Design............................................................................................36

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8.1.1.
Study Completion and End of Trial......................................................................37
8.1.2.
Continued Access Period......................................................................................38
8.2.
Discussion of Design and Control ................................................................................39
9.
Treatment..........................................................................................................................40
9.1.
Treatments Administered .............................................................................................40
9.1.1.
Carboplatin Dosing ..............................................................................................41
9.1.2.
Premedication ......................................................................................................42
9.1.2.1.
Premedication for Necitumumab.....................................................................42
9.1.2.2.
Premedication for Nab-Paclitaxel and Carboplatin..........................................42
9.1.3.
Study Drugs .........................................................................................................42
9.1.3.1.
Necitumumab .................................................................................................42
9.1.3.2.
Nab-Paclitaxel................................................................................................43
9.1.3.3.
Carboplatin.....................................................................................................43
9.2.
Materials and Supplies .................................................................................................43
9.2.1.
Necitumumab Drug Product.................................................................................43
9.2.2.
Chemotherapy Agents..........................................................................................44
9.3.
Method of Assignment to Treatment ............................................................................44
9.4.
Selection and Timing of Doses.....................................................................................44
9.4.1.
Special Treatment Considerations ........................................................................45
9.4.1.1.
Treatment Requirements and Delays...............................................................45
9.4.1.2.
Treatment-Emergent Adverse Events and General Dose 
Modifications .................................................................................................46
9.4.1.2.1.
Necitumumab Dose Modifications............................................................46
9.4.1.2.1.1.
Skin Reactions ....................................................................................46
9.4.1.2.1.2.
Conjunctivitis......................................................................................48
9.4.1.2.1.3.
Electrolyte Abnormalities....................................................................48
9.4.1.2.1.4.
Pneumonia and Sepsis.........................................................................48
9.4.1.2.1.5.
Thromboembolic Events .....................................................................49
9.4.1.2.1.6.
Cardiorespiratory Disorders ................................................................49
9.4.1.2.2.
Dose Modifications for Infusion-Related Reactions ..................................50
9.4.1.2.3.
Chemotherapy Dose Modifications ...........................................................52
9.4.1.2.3.1.
Hematologic and Neurologic Toxicities ..............................................52
9.4.1.2.3.2.
Nonhematologic Toxicities .................................................................53
9.4.1.2.3.3.
Hepatic Impairment.............................................................................54
9.5.
Blinding .......................................................................................................................54
9.6.
Concomitant Therapy...................................................................................................54
9.6.1.
Supportive Care ...................................................................................................55
9.6.1.1.
Antidiarrheal Agents.......................................................................................55

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9.6.1.2.
Antiemetic Therapy........................................................................................55
9.6.1.3.
Analgesic Agents............................................................................................55
9.6.1.4.
Appetite Stimulants ........................................................................................55
9.6.1.5.
Colony-Stimulating Factors and Erythropoiesis-
Stimulating Agents .........................................................................................55
9.7.
Treatment Compliance .................................................................................................55
10.
Efficacy, Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements.....................................................................................56
10.1. Efficacy Measures........................................................................................................56
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................56
10.1.2.
Efficacy Assessments during Postdiscontinuation Follow-up................................56
10.1.3.
Definitions of Efficacy Measures .........................................................................57
10.1.3.1.
Primary Efficacy Measure ..............................................................................57
10.2. Safety Evaluations........................................................................................................58
10.2.1.
Adverse Events ....................................................................................................59
10.2.1.1.
Serious Adverse Events ..................................................................................60
10.2.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................61
10.2.2.
Other Safety Measures .........................................................................................62
10.2.2.1.
Electrocardiograms.........................................................................................62
10.2.3.
Safety Monitoring ................................................................................................62
10.2.4.
Complaint Handling.............................................................................................63
10.3. Sample Collection and Testing.....................................................................................63
10.3.1.
Samples for Standard Laboratory Testing.............................................................63
10.3.2.
Samples for Translational Research......................................................................64
10.3.2.1.
Tumor Tissue for Biomarkers .........................................................................64
10.3.2.2.
Plasma for Biomarkers ...................................................................................65
10.3.2.3.
Whole Blood for DNA Collection...................................................................65
10.3.3.
Samples for Immunogenicity Research.................................................................66
10.3.4.
Samples for Drug Concentration Measurements 
(Pharmacokinetics)...............................................................................................66
10.4. Appropriateness of Measurements................................................................................66
11.
Data Quality Assurance.....................................................................................................67
11.1. Data Capture System....................................................................................................67
12.
Sample Size and Statistical Methods .................................................................................68
12.1. Determination of Sample Size ......................................................................................68
12.2. Statistical and Analytical Plans.....................................................................................68
12.2.1.
General Considerations ........................................................................................68

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12.2.2.
Patient Disposition...............................................................................................68
12.2.3.
Patient Characteristics..........................................................................................69
12.2.4.
Concomitant Therapy...........................................................................................69
12.2.4.1.
Postdiscontinuation Therapy...........................................................................69
12.2.5.
Treatment Compliance .........................................................................................69
12.2.6.
Primary Outcome and Methodology.....................................................................69
12.2.7.
Analyses of Efficacy ............................................................................................69
12.2.8.
Pharmacokinetic and Immunogenicity Analyses...................................................70
12.2.9.
Safety Analyses....................................................................................................70
12.2.10. Interim Analyses..................................................................................................71
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................72
13.1. Informed Consent.........................................................................................................72
13.2. Ethical Review.............................................................................................................72
13.3. Regulatory Considerations ...........................................................................................72
13.3.1.
Investigator Information.......................................................................................73
13.3.2.
Protocol Signatures ..............................................................................................73
13.3.3.
Final Report Signature .........................................................................................73
14.
References ........................................................................................................................74

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List of Tables
Table
Page
Table JFCP.1.
Treatment Regimens and Dosing Schedule .............................................40
Table JFCP.2.
Criteria for Treatment.............................................................................45
Table JFCP.3.
Managing Skin Reactions .......................................................................47
Table JFCP.4.
NCI-CTCAE Infusion-Related Reactions ...............................................51
Table JFCP.5.
Dose Modifications for Hematologic and Neurologic Toxicities .............53
Table JFCP.6.
Dose Modifications for Nonhematologic Toxicities................................54
Table JFCP.7.
Definitions of Efficacy Measures per Patient ..........................................57
Table JFCP.8.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........59
Table JFCP.9.
Definitions of Key Efficacy Statistics .....................................................70

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List of Figures
Figure
Page
Figure JFCP.1.
Illustration of study design for Study I4X-MC-JFCP. .............................36
Figure JFCP.2.
Study Period and Continued Access Period diagram...............................38

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JFCP Study Schedule................................................................76
Attachment 2.
Protocol JFCP Clinical Laboratory Tests ................................................84
Attachment 3.
Protocol JFCP Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................85
Attachment 4.
Protocol JFCP ECOG Performance Status..............................................86
Attachment 5.
Protocol JFCP Creatinine Clearance Formula .........................................87
Attachment 6.
Protocol JFCP RECIST Criteria 1.1........................................................88
Attachment 7.
Protocol JFCP Pharmacokinetic, Immunogenicity, and 
Translational Research Sampling Schedule.............................................95
Attachment 8.
Protocol JFCP Necitumumab Dosing Scenarios for Chemotherapy 
Delays ....................................................................................................97
Attachment 9.
Protocol JFCP Protocol Amendment I4X-MC-JFCP(b) Summary
A Single-Arm, Multicenter, Open-Label, Phase 2 Study of nab®-
Paclitaxel (Abraxane®) and Carboplatin Chemotherapy plus 
Necitumumab (LY3012211) in the First-Line Treatment of 
Patients with Stage IV Squamous Non-Small Cell Lung Cancer 
(NSCLC)..............................................................................................100

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4.
Abbreviations and Definitions
Term
Definition
Abraxane®
trade name for paclitaxel protein-bound particles for injectable suspension (albumin-
bound) (nab-®paclitaxel); registered trademark of Celgene Corporation
AE
adverse event
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and risks involved in participating 
in a study required by some ethical review boards (ERBs) or institutional review boards 
(IRBs).
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
Att
Attachment
AUC
area under the concentration-time curve
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).
BMI
body mass index
BSA
body surface area
BUN
blood urea nitrogen
CK
creatine kinase
collection database
A computer database where clinical trial data are entered and validated.

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CRF/eCRF
case report form/electronic case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRP
clinical research physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician, or other medical officer.
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
Continued Access 
Period
The period between study completion and end of trial during which patients on study 
treatment who continue to experience clinical benefit and no undue risks may continue 
to receive study therapy until one of the criteria for discontinuation is met.
CR
complete response
CrCl
creatinine clearance
CSFs
colony-stimulating factors
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DC
discontinuation
DCR
disease control rate
DCSI
Development Core Safety Information (part of the Investigator’s Brochure)
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.

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enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical trial are protected.
ESAs
erythropoiesis-stimulating agents
EU
European Union
FFPE
formalin-fixed, paraffin-embedded (tumor tissue)
FSH
follicle-stimulating hormone
GCP
good clinical practice (also Good Clinical Practice, when referring to ICH E6 guideline)
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GnRH
gonadotropin-releasing hormone
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICP-MS
inductively coupled plasma–mass spectrometry
IDMC
independent data monitoring committee
IDMS
isotope dilution mass spectrometry
Ig
immunoglobulin
IG
immunogenicity (anti-drug antibodies)
IHC
immunohistochemistry
IMC-11F8
a code name for necitumumab

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informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
INR
International Normalized Ratio
INSPIRE
Study I4X-IE-JFCB or ImClone (IMCL) study CP11-0805
investigational 
product (IP)
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.  Investigational product (IP) includes a product 
with a marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from the 
authorized form,
2.
used for an unauthorized indication, or
3.
used to gain further information about the authorized form.
In this study, for US sites, the IPs are necitumumab (throughout the entire study) and 
nab-paclitaxel when administered as part of the maintenance regimen. In the United
States, nab-paclitaxel and carboplatin are considered as standard of care when 
administered as part of the induction regimen.
In this study, for sites outside the US, the IPs are necitumumab, nab-paclitaxel, and 
carboplatin throughout the entire study, when administered as part of both the induction
regimen and the maintenance regimen.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRR
infusion-related reaction
IUD
intrauterine contraceptive device
I.V.
intravenous(ly)
IWRS
interactive web response system
LC-MS/MS
liquid chromatography-tandem mass spectrometry
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LY3012211
a code name for necitumumab
mAb
monoclonal antibody
MCHC
mean cell hemoglobin concentration
MCV
mean cell volume

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MedDRA
Medical Dictionary for Regulatory Activities
mFOLFOX-6
modified FOLFOX-6; oxaliplatin + folinic acid + 5-fluorouracil
MRI
magnetic resonance imaging
nab-paclitaxel
paclitaxel protein-bound particles for injectable suspension (albumin-bound) (generic 
name for Abraxane)
nab-PC
nab-paclitaxel plus carboplatin
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
necitumumab
LY3012211 or IMC-11F8 (code names)
NOS
not otherwise specified
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
QTc
corrected QT interval
qualified patient
All enrolled patients who have received any amount of study drug and have had a 
complete radiographic assessment at baseline are qualified.  (Patients who are alive for 
at least 8 weeks after first dose and have had no postbaseline radiographic assessment
will be disqualified.)
RBC
erythrocyte (red blood cell)

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RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
statistical analysis plan
sb-PC
solvent-based paclitaxel plus carboplatin
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, blood 
draws).  For this type of screening, informed consent for these screening procedures
and/or tests shall be obtained.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SERM
selective estrogen receptor modulators
SOC
System Organ Class (of MedDRA)
SOPs
standard operating procedures
sq
squamous
SQUIRE
Study I4X-IE-JFCC or ImClone (IMCL) study CP11-0806
study completion
This study will be considered complete when 70% of qualified patients experience a 
PFS event (radiographically documented disease progression or death), or 6 months 
after completing enrollment, whichever occurs first, as determined by Lilly (the 
sponsor).  At this point in the study, the final analyses for all outcomes, primary and 
secondary, including the final analysis of OS, will be performed.
SUSARs
suspected unexpected serious adverse reactions
TC
taxane and carboplatin
TEAE
treatment-emergent adverse event
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened between the first dose of study treatment and 30 days after the last dose of 
study treatment or a related serious AE (SAE) reported beyond 30 days after the last 
dose of study treatment.
TPO
third-party organization
ULN
upper limit of normal

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US
United States
v
Version (of NCI-CTCAE)
VEGF
vascular endothelial growth factor
vs
versus
VTE
venous thromboembolic event
WBC
leukocyte (white blood cell)

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A Single Arm, Multicenter, Open-Label, Phase 2 Study of 
nab®-Paclitaxel (Abraxane®) and Carboplatin Chemotherapy 
plus Necitumumab (LY3012211) in the First-Line Treatment of 
Patients with Stage IV Squamous Non-Small Cell Lung 
Cancer (NSCLC)
5.
Introduction
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 preclinical 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.
Epidermal growth factor receptor is detectable in approximately 85% to 90% of patients with 
advanced, metastatic non-small cell lung cancer (NSCLC) (Fontanini et al. 1995; Pirker et al. 
2009) and development of EGFR-directed mAb, necitumumab, has been primarily focused on 
the treatment of this disease.
In a randomized Phase 3 study, the combination of necitumumab plus gemcitabine and cisplatin
chemotherapy as first-line therapy in patients with Stage IV squamous NSCLC demonstrated a
statistically significant advantage over the same chemotherapy alone in measures of overall 
survival (OS), progression-free survival (PFS), and disease control rate (DCR) (Thatcher et al. 
2014). The safety profile of the necitumumab plus gemcitabine and cisplatin triplet was 
acceptable.  When compared with the same chemotherapy alone, there was no increase in Grade 
3 or 4 toxicities, especially including hematologic toxicities associated with gemcitabine-
cisplatin, with the exception of skin toxicity and hypomagnesemia, which are primarily 
associated with necitumumab. Based on these data, necitumumab has recently been approved in 
the United States (US) and European Union (EU) for treatment of patients with metastatic 
squamous NSCLC in combination with gemcitabine and cisplatin.
The combination of carboplatin and paclitaxel protein-bound particles for injectable suspension 
(albumin-bound) (Abraxane; hereafter known as nab-paclitaxel) (nab-PC) was approved in the 
US as first-line therapy for locally advanced or metastatic NSCLC. The approval was based on a 
randomized Phase 3 study (Socinski et al. 2012) that demonstrated statistically significant 
advantages of the nab-PC regimen (100 mg/m2 nab-paclitaxel weekly plus carboplatin at area 
under the concentration-time curve [AUC] 6 [mg∙min/mL] once every 3 weeks) over solvent-
based paclitaxel plus carboplatin (sb-PC; 200 mg/m2 solvent-based paclitaxel plus carboplatin 
AUC 6 once every 3 weeks) in terms of objective response rate (ORR) (33% versus [vs] 25%; 
p<.005), as well as prolonged PFS (hazard ratio [HR]=0.90) and OS (HR=0.92) that met the 
prespecified non-inferiority statistical analysis. Median PFS was 6.3 vs 5.8 months and median 
OS was 12.1 vs 11.2 months in the nab-PC arm vs the sb-PC arm, respectively.

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The safety analysis revealed a statistically significant lower frequency of Grade 3 or 4 
neutropenia, sensory neuropathy, myalgia, and arthralgia for the nab-PC regimen.
The subgroup analysis of this study by tumor histology demonstrated a statistically significant 
advantage in squamous NSCLC for the nab-PC regimen in terms of best ORR (41% vs 24%, 
p<.001), as well as trends of improved PFS (HR=0.865) and OS (HR=0.89). Median PFS was 
5.6 and 5.7 months, and median OS was 10.7 and 9.5 months in nab-PC and sb-PC arms, 
respectively.
The impact of adding the EGFR-directed mAb cetuximab to the taxane and carboplatin (TC) 
doublet has been investigated as first-line therapy in the advanced, metastatic NSCLC setting in 
Study BMS099, a Phase 3 trial (Lynch et al. 2010). The addition of cetuximab resulted in a 
statistically significant improvement in ORR and not significant prolongation of PFS (HR=0.90) 
and OS (HR=0.89). The analysis of this study by histological subtypes revealed major 
advantages in patients with squamous cell carcinoma for the cetuximab-containing regimen over 
the same chemotherapy alone in terms of PFS (HR=0.7). The safety profile of cetuximab plus 
TC was acceptable and consistent with its individual components.
The recombinant human EGFR-directed mAb necitumumab and the chimeric EGFR mAb 
cetuximab have overlapping binding epitopes and compete with ligand binding to EGFR, thereby 
inhibiting receptor activation and downstream signaling (Li et al. 2008).
In preclinical studies in mice with lung cancer xenografts, necitumumab in combination with 
paclitaxel and cisplatin has demonstrated a significant improvement in tumor volume growth 
delay, compared with the same chemotherapy alone and with single-agent necitumumab
(Preclinical Research, Eli Lilly and Company, 2009).
In a Phase 2 necitumumab clinical trial (Study I4X-MC-JFCL [JFCL]) of necitumumab as first-
line therapy in Stage IV squamous NSCLC, the addition of necitumumab to paclitaxel-
carboplatin (N+PC) resulted in an increased ORR compared to chemotherapy alone (PC) (48.9% 
versus 40.0%), indicating an add-on treatment effect for this combination. For PFS the treatment 
effect (as measured by the stratified HR) was 1.0 (95% CI:  0.71, 1.42) (median PFS: 5.4 versus 
5.6 months).  For OS, the median OS was 13.2 months for the N+PC Arm versus 11.2 months 
for the chemotherapy alone arm (PC Arm). The OS HR for the treatment effect was 0.83 (95% 
CI: 0.55, 1.52).
In the N+PC Arm in Study JFCL, 10 patients (9.4%) had 11 AEs with an outcome of death
(where the primary cause of death may or may not be the AE). Seven of the 10 deaths occurred 
during the chemotherapy phase: acute respiratory failure, lung infection, septic shock, 
circulatory collapse, respiratory failure, pulmonary embolism, brain death, and cardiac arrest (in 
1 patient). The other 3 deaths were due to hypovolemic shock, cardiac failure congestive, and 
pneumonia. All AEs were assessed by the investigator as not related to any study drug, with the 
exception of lung infection (assessed as related to chemotherapy only), respiratory failure 
(assessed as related to all study drugs), and circulatory collapse (unknown). In the PC Arm, 3 
patients (5.5%) had 4 AEs with an outcome of death (all were assessed as not related to any 
study drugs) (one report each) of: death; sudden death; and pneumonia and sepsis (in 1 patient).  

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The OS analysis showed a higher rate of events for the necitumumab-containing arm during the 
first 4 months, with a later trend toward improved survival after 4 months.
The preclinical data, the clinical efficacy of EGFR-directed mAbs in combination with taxanes
and carboplatin, and the advantage of nab-PC over sb-PC in terms of safety and efficacy 
especially in squamous NSCLC together provide a strong rationale for the investigation of 
nab-PC in combination with necitumumab as first-line therapy in Stage IV squamous NSCLC.
More information about the known and expected benefits, risks and reasonably anticipated 
adverse events (AEs) of necitumumab may be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to necitumumab may be found in Section 7 
(Development Core Safety Information [DCSI]) of the IB.  Information on serious adverse 
events (SAEs) expected in the study population independent of drug exposure and that will be 
assessed by the sponsor (Lilly) in aggregate, periodically during the course of the study, may be 
found in Section 6 (Effects in Humans) of the IB.
More detailed information about the known and expected benefits and risks of nab-paclitaxel
may be found in the following:  Package Insert (Abraxane package insert, 2015) or Section 9.4.1.
More detailed information about the known and expected benefits and risks of carboplatin may 
be found in the following:  Package Insert (Carboplatin package insert, 2006 and 2015) or 
Section 9.4.1.

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6.
Objectives
6.1.
Primary Objective
The primary objective of this study is to evaluate the best objective response rate (ORR; 
complete response [CR] + partial response [PR]) associated with a treatment regimen of 
nab-paclitaxel and carboplatin chemotherapy plus necitumumab as first-line therapy in patients 
with Stage IV squamous NSCLC.
6.2.
Secondary Objectives
The secondary objectives of the study are to:

evaluate progression-free survival (PFS),

evaluate overall survival (OS),

evaluate disease control rate (DCR),

evaluate the safety profile of necitumumab in combination with carboplatin and/or 
nab-paclitaxel chemotherapy,

determine the pharmacokinetics (PK) of necitumumab, nab-paclitaxel, and 
carboplatin, and

determine the immunogenicity of necitumumab (anti-necitumumab antibodies)
6.3.
Exploratory Objectives
The exploratory objectives of the study are to further evaluate the relationships between 
biomarkers related to the EGFR pathway, NSCLC etiology, and/or the mechanism of action of 
necitumumab and clinical outcomes.

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7.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Patients may be considered for re-screening after discussion with the Lilly clinical 
research physician (CRP) or designee. Each time re-screening is performed, the individual must 
sign a new informed consent form (ICF) and will be assigned a new identification number.
Central laboratory testing is required for assessment of eligibility. Note that repeating laboratory
tests during the 21-day screening period (Baseline) does not constitute re-screening. Laboratory 
tests may not be repeated more than once in order to meet eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
have given written informed consent or assent prior to any study-specific 
procedures.  Written consent may also be given by a legal representative.
[2]
have histologically or cytologically confirmed squamous NSCLC.
[3]
have Stage IV disease at the time of study entry (American Joint Committee 
on Cancer [AJCC] Staging Manual, 7th edition [Edge et al. 2009]).
[4]
have measurable disease at the time of study enrollment as defined by 
Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) 
(Eisenhauer et al. 2009) (see Attachment 6).
[5]
have tumor tissue (primary tumor or metastatic site; a paraffin-embedded 
tissue block [preferred] or 15 freshly cut unstained slides [a minimum of 6 
slides] is requested) available for analysis of EGFR protein expression by 
immunohistochemistry (IHC).
[6]
are ≥18 years of age (or of an acceptable age according to local regulations, 
whichever is older).
[7]
have resolution to Grade ≤1 by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (v 4.0), of all 
clinically significant toxic effects of prior chemotherapy, surgery, 
radiotherapy, or hormonal therapy (with the exception of alopecia).
[8]
have an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 to 1 (see Attachment 4).
[9]
have an estimated life expectancy of at least 12 weeks.
[10] will be able to complete at least 2 cycles of treatment, in the judgment of the 
investigator.

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[11] have adequate hepatic function as defined by a total bilirubin ≤1.25 × the 
upper limit of normal (ULN), and aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) ≤5.0 × ULN in the presence of liver 
metastases or ≤2.5 × ULN in the absence of liver metastases.
[12] have adequate renal function as defined by serum creatinine ≤1.2 × ULN or 
calculated creatinine clearance (CrCl) ≥50 mL/min for patients with creatinine 
>1.2 x ULN.
[13] have adequate hematologic function as evidenced by white blood cell count 
≥3.0 × 103/µL, absolute neutrophil count (ANC) ≥1.5 × 103/µL, hemoglobin 
≥9.5 g/dL, and platelets ≥100 × 103/µL.
[14a]
are men who are either: (a) surgically sterile; or (b) agree to use a reliable 
method of birth control† and to not donate sperm during the study and for at 
least 6 months following last dose of study drug(s) or per country 
requirements, whichever is longer.
[14b]
are women who are either: (a) not of childbearing potential due to 
surgical sterilization (at least 6 weeks following surgical bilateral 
oophorectomy with or without hysterectomy or tubal ligation) confirmed by 
medical history or menopause*; or (b) of childbearing potential who have a 
negative serum pregnancy test within 14 days prior to first dose and agree to 
use a highly effective method of birth control† during the study and for 6 
months after the last dose of study drug(s) (oral hormonal contraception alone 
is not considered highly effective and must be used in combination with a 
barrier method).
*A “menopausal woman” is a woman meeting either of the following criteria:
1. spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications during the 
amenorrhea that induced the amenorrhea (for example, oral contraceptives, 
hormones, gonadotropin-releasing hormone [GnRH], antiestrogens, selective 
estrogen receptor modulators [SERMs], or chemotherapy)
2. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone 
(FSH) level >40 mIU/mL
†A highly effective method of birth control is defined as one that results in a 
low failure rate (that is, <1% per year) when used consistently and correctly, 
such as implants, injectables, combined oral contraceptives, some intrauterine 
contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner.  
For patients using a hormonal contraceptive method, information regarding 
the product under evaluation and its potential effect on the contraceptive 
should be addressed.
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:

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[15] are currently enrolled in a clinical trial involving an investigational product 
(IP) 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.
[16] have nonsquamous NSCLC (including adenocarcinoma, large cell, and not 
otherwise specified [NOS]).
[17] have received prior anticancer therapy with monoclonal antibodies, signal 
transduction inhibitors, or any therapies targeting the EGFR, vascular
endothelial growth factor (VEGF), or VEGF receptor.
[18] have received previous chemotherapy for advanced NSCLC.  Patients who 
have received adjuvant or neoadjuvant chemotherapy are eligible if the last 
administration of the prior regimens occurred at least 1 year prior to study 
entry.
[19] have undergone major surgery or received any investigational therapy in the 4 
weeks prior to study entry.
[20] have undergone systemic radiotherapy within 4 weeks prior to study entry, or 
focal radiotherapy within 2 weeks prior to study entry.
[21] have symptomatic central nervous system (CNS) malignancy or metastasis 
(screening not required). Patients with treated CNS metastases are eligible for 
this study if they are not currently receiving corticosteroids and/or 
anticonvulsants, and their disease is asymptomatic for at least 30 days prior to 
study entry.
[22] have a history of arterial or venous embolism within 6 months prior to study
entry.
[23] have current clinically relevant coronary artery disease (Canadian 
Cardiovascular Society Angina Grading Scale > class II‡) or congestive heart 
failure (New York Heart Association [NYHA] Congestive Heart Failure 
Classification class III or IV§).
[24] have experienced myocardial infarction within 6 months prior to study entry.
[25] have clinical evidence of concomitant infectious conditions, including early 
signs of ongoing or active infection, tuberculosis, or known infection with the 
human immunodeficiency virus (HIV).
[26] have a history of significant neurological or psychiatric disorders, including 
dementia, seizures, or bipolar disorder, potentially precluding protocol 
compliance.
[27] have any NCI-CTCAE v 4.0 Grade ≥2 peripheral neuropathy.
[28] have any other serious uncontrolled medical disorders or psychological 
conditions that would, in the opinion of the investigator, limit the patient’s 
ability to complete the study or sign an ICF.

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[29] 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.
[30] are pregnant or breastfeeding.
[31] have a known history of drug abuse.
[32] have a concurrent active malignancy.  Patients with a history of malignancy
are eligible provided the patient has been disease-free for ≥3 years, with the 
following exception:  Patients with adequately treated basal or squamous cell 
carcinoma of the skin, preinvasive carcinoma of the cervix, or any cancer that 
in the judgment of the investigator and Lilly CRP/designee may not affect the 
interpretation of results (for example, prostate, bladder) are eligible.
[33] are receiving concurrent treatment with other anticancer therapy, including 
other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemo-
embolization, targeted therapy, or an investigational agent.
[34] are unwilling or unable to participate in, or do not have tissue adequate for 
participation in the translational research portion of the study.
[35] have discontinued IP or nonapproved use of a drug or device from a clinical 
trial within 30 days before the first day of study treatment.
[36] have previously completed or discontinued from this study or any other study 
investigating necitumumab.  (This exclusion criterion does not apply to 
patients who are re-screened prior to enrollment.).
‡Canadian Cardiovascular Society Angina Grading Scale (Campeau 1976):
Class I – Ordinary physical activity does not cause angina, such as walking and climbing stairs. Angina with strenuous or rapid 
or prolonged exertion at work or recreation.
Class II – Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair climbing 
after meals, or in cold, or in wind, or under emotional stress, or only during the few hours after awakening. Walking more than 
two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions.
Class III – Marked limitation of ordinary physical activity. Walking one or two blocks on the level and climbing one flight of 
stairs in normal conditions and at normal pace.
Class IV – Inability to carry on any physical activity without discomfort, anginal syndrome may be present at rest.
§NYHA Congestive Heart Failure Classification (NYHA 1994):
Class I – Patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II – Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.
Class III – Patients with marked limitation of activity; they are comfortable only at rest.
Class IV – Patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and 
symptoms occur at rest.
7.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion [15] 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.

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Exclusion Criteria [16] to [36] help in maintaining specificity of the patient population for both
efficacy and safety analyses and/or to maintain patient safety.
7.3.
Discontinuation
The reason for discontinuation and the date of discontinuation will be collected for all patients.  
All enrolled patients who discontinue, regardless of whether or not they received study drug, will 
have procedures performed as shown in the Study Schedule (Attachment 1).
Patients who are discontinued from all study drugs will have follow-up procedures performed as 
shown in the Study Schedule (Attachment 1).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly (the sponsor) may continue to use previously 
collected medical research data prior to the withdrawal consistent with the original authorization.
7.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor CRP and the investigator to determine whether it is medically appropriate for the 
patient to continue in the study, with or without study treatment.  The investigator must obtain 
documented approval from the Lilly CRP to allow the inadvertently enrolled patient to continue 
in the study, with or without study treatment.
7.3.2. Discontinuation of Study Treatment
This section lists the reasons for permanent discontinuation of study treatment.
Section 7.3.2.1 lists reasons for permanent discontinuation of all study treatment.  Patients who 
are discontinued from all study treatment will be followed (for progressive disease [PD] and/or 
survival, as applicable) until study completion.
Section 7.3.2.2 lists reasons for permanent discontinuation of one or more study treatment 
components (that is, one or more study drugs that are part of the regimen being administered to 
the patient in this study).
For details regarding treatment delays and dose modifications, refer to Section 9.4.1.
7.3.2.1.
Discontinuation of All Study Treatment
Patients will be discontinued from all study treatment in the following circumstances:

Enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study.

The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication, discontinuation 
from study drug(s) occurs prior to introduction of the new agent.

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
The patient is significantly noncompliant with study procedures and/or treatment.

Radiographic documentation of disease progression.

A concurrent 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.
7.3.2.2.
Discontinuation of One or More Study Treatment Components
Patients will be discontinued from one or more of the study treatment components in the 
following circumstances (Note that patients who have been discontinued from one or more of the
study treatment components should continue to receive the remaining study treatment
component[s] that has [have] not been discontinued, according to this protocol):

The investigator decides that the patient should be discontinued from one or more of the 
study treatment components.

The patient or the patient’s designee (for example, parent, legal guardian, or caregiver) 
requests that the patient be discontinued from one or more study treatment components.
o
If the patient withdraws consent to treatment, he or she may still enter Short-Term
and/or Long-Term Follow-up if consent for follow-up is not also withdrawn.  It 
should be clarified with the patient and documented in the patient’s file whether 
follow-up information on tumor assessment and survival can be still obtained, and 
if so, to what extent.  Investigations scheduled for the Postdiscontinuation Follow-
up should be carried out to the extent possible.

Unacceptable AE/toxicity (for example, a persistent moderate toxicity that is intolerable 
to the patient).

Any study treatment-related event that is deemed life-threatening, regardless of grade, 
warrants discontinuation of that study treatment and/or discontinuation from all study 
treatment, if appropriate, in the opinion of the investigator.

Any event(s) that would require that necitumumab be modified by more than 2 dose 
reductions or delayed (held) for more than 6 weeks following Day 1 of the most recent 
cycle warrants permanent discontinuation of necitumumab.

nab-Paclitaxel and carboplatin are to be permanently discontinued in any of the following 
situations:  (1) third occurrence of neutropenic fever, >7-day delay of a cycle due to ANC 
<1.5 × 103/µL, or ANC<0.5 × 103/µL for more than 7 days; (2) second occurrence of 
platelet count <50 × 103/µL; or (3) third occurrence of Grade 3 or 4 sensory neuropathy
(Abraxane package insert, 2015).

A Grade 3 or 4 hypersensitivity/infusion-related reaction.
7.3.3. Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

The investigator decides that the patient should be discontinued from the study.

Screen failure or failure to meet enrollment criteria.

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).

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
The patient or the patient’s designee (for example, parent, legal guardian, or caregiver) 
requests that the patient be discontinued from the study.
Patients who are discontinued from study participation will not be followed for PD or survival.
7.3.4. Patients Who Are Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow.
Site personnel, or an independent third party, will attempt to collect the vital status (that is, alive 
or dead) for all patients who are lost to follow-up, including patients who do not receive study 
drug(s), within legal and ethical boundaries.  Site personnel, or an independent third party, may 
search public sources for vital status information. If the patient's vital status is determined, the 
vital status will be documented and the patient will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.
7.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.

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8.
Investigational Plan
8.1.
Summary of Study Design
Study I4X-MC-JFCP is a single-arm Phase 2 study to investigate nab-paclitaxel and carboplatin 
chemotherapy in combination with necitumumab as first-line therapy in patients with Stage IV 
squamous NSCLC.
Figure JFCP.1 illustrates the study design for the Study Treatment Period of Study I4X-MC-
JFCP.
Abbreviations:  AUC = area under the concentration-time curve; CR = complete 
response; D = Day; DC = discontinuation; DCR = disease control rate; ECOG PS = 
Eastern Cooperative Oncology Group performance status; IG = immunogenicity (anti-
necitumumab antibodies); I.V. = intravenous(ly); nab-paclitaxel = paclitaxel protein-
bound particles for injectable suspension (albumin-bound); NSCLC = non-small cell 
lung cancer; ORR = objective response rate; OS = overall survival; PD = progressive 
disease; PFS = progression-free survival; PK = pharmacokinetic(s); PR = partial 
response; sq = squamous; SD = stable disease.
Note:  Figure JFCP.1 includes the Study Treatment Period only; it does not include the 
Continued Access Period.
Figure JFCP.1.
Illustration of study design for Study I4X-MC-JFCP.
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the ICF is signed (study entry) and ends at the first study 
treatment (or at discontinuation, if no treatment is given).

Study Period:  begins at the first study treatment and ends at study completion. The 
Study Period does not include the Continued Access Period.
o
Study Treatment Period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue study 
treatment.  The date of this agreement is to be reported on the electronic case 
report form (eCRF) as the Date of Discontinuation from study treatment.  Note 
that for this study, the Study Treatment Period comprises the induction treatment 
(triplet) regimen and the maintenance treatment (doublet) regimen, as depicted in 
Figure JFCP.1.

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o
Postdiscontinuation Follow-up:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.
Short-Term Follow-up begins the day after the patient and the investigator agree 
that the patient will no longer continue study treatment and lasts at least 30 days
(+ 0-7 days; ie, at least 30 days but no more than 37 days).
Long-Term Follow-up begins the day after Short-Term Follow-up is completed 
and continues until the patient’s death or overall study completion.  Patients who 
discontinue study treatment for reasons other than PD will continue to undergo 
radiographic tumor assessments every 6 weeks (±3 days) until PD or overall study 
completion, whichever occurs first.  Patients will be followed for survival every 3 
months (±7 days) until the patient’s death or overall study completion, whichever 
occurs first.

Continued Access Period begins after study completion and ends at the end of trial.  
During the Continued Access Period, patients on study treatment who continue to 
experience clinical benefit and no undue risks may continue to receive study treatment 
until one of the criteria for discontinuation is met.  The Continued Access Period includes 
Continued Access Follow-up.
o
Continued Access Follow-up begins the day after the patient and the investigator 
agree that the patient will no longer continue treatment in the Continued Access 
Period and lasts at least 30 days (+ 0-7 days; ie, at least 30 days but no more than 
37 days).
8.1.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) when 70% of qualified patients experience a PFS event (radiographically 
documented PD or death), or 6 months after completing enrollment, whichever occurs first, as 
determined by Lilly.  At this point in the study, the final analyses for all outcomes, primary and 
secondary, including the final analysis of OS, will be performed.  Investigators will continue to 
follow the study schedule for all patients until notified by Lilly that study completion has 
occurred.  “End of trial” refers to the date of the last visit or last scheduled procedure for the last 
patient.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up.
Figure JFCP.2 illustrates the Study Period and the Continued Access Period.

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Abbreviation:  OS = overall survival.
Figure JFCP.2.
Study Period and Continued Access Period diagram.
8.1.2. Continued Access Period
The Continued Access Period will apply to this study only if at least one patient is still on study 
treatment when study completion occurs.
Patients receiving study treatment and experiencing ongoing clinical benefit and no undue risks 
may continue to receive study treatment in the Continued Access Period until one of the criteria 
for discontinuation is met (Section 7.3).  Lilly will notify investigators when the Continued 
Access Period begins.
Patients who are in Short-Term Follow-up when the Continued Access Period begins will 
continue in Short-Term Follow-up until the 30-day Short-Term Follow-up visit is completed.  
Long-Term Follow-up does not apply.
Patients who are in Long-Term Follow-up when the Continued Access Period begins will be 
discontinued from Long-Term Follow-up.
During the Continued Access Period, all AEs, SAEs, and exposure to study drug will be reported 
on the eCRF.  Serious adverse events will also be reported to Lilly Global Patient Safety (see 
End of 
Trial
Study 
Completion
Patients on 
Treatment
Patient on Study Treatment
Study Period
Continued 
Access Perioda
Patient on 
Study 
Treatment
a Lilly will notify sites when this begins and ends.  
Short-Term 
Follow-Up 
Long-Term 
Follow-Up
Patient 
Discontinues 
Study 
Treatment
Continued 
Access 
Period 
Follow-Up
Final Analysis 
of OS
Last visit/
scheduled 
procedure for 
last patient
Patient 
Discontinues 
Study 
Treatment

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Section 10.2.1).  In the event that an SAE occurs, Lilly may request additional information (such 
as local laboratory results, concomitant medications, and hospitalizations) in order to evaluate 
the reported SAE. Blood samples for PK and immunogenicity (anti-necitumumab antibody) 
analysis will be collected in the event of an infusion-related reaction during the Continued 
Access Follow-up.
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients and to confirm patient eligibility to continue on study treatment; however, the choice 
and timing of the tests will be at the investigator’s discretion.  Lilly will not routinely collect the 
results of these assessments.
8.2.
Discussion of Design and Control
This study is designed as a single-arm open-label trial to estimate a potential benefit of the 
induction (triplet) regimen (nab-paclitaxel and carboplatin plus necitumumab), as well as the 
maintenance (doublet) regimen of necitumumab plus nab-paclitaxel. During the induction 
regimen, all participants in this trial will receive nab-paclitaxel and carboplatin chemotherapy at 
the approved dose and schedule, plus necitumumab, which may increase the total antitumor 
activity.
The nab-paclitaxel regimen administered during induction will be 100 mg/m2 on Days 1, 8, and 
15 of each 3-week cycle, until progression. The nab-paclitaxel regimen administered during 
maintenance will be reduced to (100 mg/m2) Days 1 and 8 of each 3-week cycle to decrease 
potential toxicity and possibly optimize tolerability of treatment and drug exposure in patients.

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9.
Treatment
9.1.
Treatments Administered
Following necessary premedication (Section 9.1.2), patients will receive the treatment regimen in 
Table JFCP.1 (in the order shown in the table).  The treatment regimen comprises an induction 
(triplet) regimen and a maintenance (doublet) regimen.  First, the induction (triplet) regimen of 
nab-paclitaxel and carboplatin chemotherapy plus necitumumab is to be administered for a 
maximum of four 3-week cycles, or until there is radiographic documentation of PD, toxicity 
requiring cessation, protocol noncompliance, or withdrawal of consent.  Then, if there is 
radiographic evidence of a response (not necessarily confirmed) of CR, PR, or stable disease 
(SD) and the patient’s disease has not progressed or other discontinuation criteria have not been 
met, carboplatin is discontinued and the maintenance (doublet) regimen of necitumumab plus 
nab-paclitaxel is to be administered as 3-week cycles until there is radiographic documentation 
of PD, toxicity requiring cessation, protocol noncompliance, or withdrawal of consent.
No other chemotherapy is permitted until radiographic documentation of PD.
Table JFCP.1.
Treatment Regimens and Dosing Schedule
All treatments to be administered in the order shown in this table.
Induction (Triplet) Regimen - Up to four 3-week cycles of the following:
Drug
Dose
Time for Administration
Necitumumaba
800 mg absolute dose I.V. infusion
Administered over 60 minutes on Days 1 and 8 of 
each 3-week cycle.
nab-Paclitaxela,b
100 mg/m2 I.V. infusion
Administered over 30 minutes on Days 1, 8, and 15 of 
each 3-week cycle.
Carboplatina
AUC 6 (mg∙min/mL) I.V. infusionc
(Administered immediately after nab-paclitaxel.)  
Administered over a minimum of 15 minutes 
(maximum of 60 minutes) on Day 1 of each 3-week 
cycle, for a maximum of 4 cycles.
Maintenance (Doublet) Regimen – Every 3 weeks until disease progression occurs or other discontinuation
criteria are met:
Drug
Dose
Time for Administration
Necitumumaba
800 mg absolute dose I.V. infusion
Administered over 60 minutes on Days 1 and 8 of 
each 3-week cycle.
nab-Paclitaxela,b
100 mg/m2 I.V. infusion
Administered over 30 minutes on Days 1 and 8 of 
each 3-week cycle.
Abbreviations:  AUC = area under the concentration-time curve; I.V. = intravenous(ly); nab-paclitaxel = paclitaxel 
protein-bound particles for injectable suspension (albumin-bound).
a
Hypersensitivity/infusion-related reaction may occur during or following administration of necitumumab, nab-
paclitaxel, or carboplatin.  See Section 9.4.1.2.2 for a definition of Grade 3 and 4 hypersensitivity/infusion-
related reaction.
b
Source is Abraxane package insert, 2015.
c
Refer to Section 9.1.1 for additional information on carboplatin dosing.

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Refer to Section 9.4 for the selection and timing of doses.
Hypersensitivity/infusion-related reaction may occur during or following administration of
necitumumab, nab-paclitaxel (Abraxane package insert, 2015), or carboplatin (see
Section 9.4.1.2.2 for a definition of Grade 3 and 4 hypersensitivity/infusion-related reaction). As 
a routine precaution, patients treated with necitumumab should be observed closely for any 
potential adverse effects by the medical staff from the start of the infusion until at least 1 hour 
after the end of the infusion in an area with resuscitation equipment and other agents (for 
example, epinephrine or prednisolone equivalents) available.
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, infusions administered within 3 days before or after the planned
infusion time point will be considered acceptable.
In the event that infusions are administered before or after a planned time point in a given cycle,
the Day 1 infusion of the subsequent cycle should be administered 7 days (±3 days) after the
actual Day 15 administration of the previous cycle.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the site personnel,

verifying that instructions are followed properly,

maintaining accurate records of study drug dispensing and collection,

and returning all unused medication to Lilly or its designee at the end of the study.
Note:  In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
9.1.1. Carboplatin Dosing
At sites where serum creatinine is determined by a method standardized to the isotope dilution 
mass spectrometry (IDMS) reference material, the estimated glomerular filtration rate (GFR) 
used in the Calvert formula to calculate AUC-based dosing should not exceed 125 mL/min.  All 
US sites where the IDMS method is available should calculate carboplatin doses based upon 
serum creatinine values that were measured by the IDMS method.  At sites where the IDMS 
method is not available, for the estimated GFR used to calculate the Calvert formula, all sites 
will follow the dosing guidelines outlined below and cap the GFR at 125 mL/min.
The site is responsible to consult the local lab to determine what method of serum creatinine 
measurement is used by that laboratory.

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Calvert Formula
Total Dose (mg) = (target AUC) (GFR + 25)
Maximum carboplatin dose (mg) = target AUC 6 (mg•min/mL) (125 + 25) = 6 150 mL/min 
= 900 mg
9.1.2. Premedication
All premedication administered must be adequately documented in the eCRF.
9.1.2.1.
Premedication for 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).
As with all concomitant medications/procedures, any actions taken to ameliorate skin toxicity
with preemptive medications or procedures will be documented in the concomitant medication
module of the eCRF.
9.1.2.2.
Premedication for Nab-Paclitaxel and Carboplatin
No premedication is required prior to administration of nab-paclitaxel (Abraxane package insert, 
2015).  Patients who have experienced a severe hypersensitivity reaction to nab-paclitaxel should 
not be re-challenged with this drug.
An antiemetic (such as ondansetron 8 mg intravenously [I.V.], or equivalent) is recommended to 
be administered 30 to 120 minutes before dosing with carboplatin.
9.1.3. Study Drugs
In this study, for US sites, the IPs are necitumumab throughout the study, and nab-paclitaxel 
when administered as part of the maintenance regimen.  In the US, nab-paclitaxel and 
carboplatin are standard of care when administered as part of the induction regimen.
In this study, for sites outside the US, the IPs are necitumumab, nab-paclitaxel, and carboplatin 
throughout the study, when administered as part of both the induction regimen and the 
maintenance regimen.
Interactive web response system (IWRS) will be used for dispensing of IP.
9.1.3.1.
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 60 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 for detailed information.

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Add (or remove from AVIVA I.V. bag, which comes prefilled with 0.9% normal saline) a
sufficient quantity of sterile normal saline solution (0.9% weight/volume) to the container to
make the volume of saline in the I.V. container 200 mL.  Add 50 mL necitumumab to give a total 
volume of 250 mL. The container should be gently inverted to ensure adequate mixing. The 
infusion rate must never exceed 25 mg/minute.
The infusion set must be flushed postinfusion with sterile 0.9% normal saline equal to or
exceeding the infusion line hold-up to ensure delivery of the dose.
CAUTION: Hypersensitivity/infusion-related reactions may occur during or following
administration of necitumumab (see Section 9.4.1.2.2 for a definition of Grade 3 and 4
hypersensitivity/infusion-related reactions).
As a routine precaution, patients treated with necitumumab should be observed closely for any
potential adverse effects by the medical staff from the start of the infusion until at least 1 hour
after the end of the infusion in an area with resuscitation equipment and other agents (for
example, epinephrine or prednisolone equivalents) available. Premedication for carboplatin may 
be administered during this 1-hour observation period.
9.1.3.2.
Nab-Paclitaxel
nab-Paclitaxel will be used and should be prepared and administered according to the 
manufacturer’s instructions (Abraxane package insert, 2015).  (Refer to the local prescribing 
information for Abraxane for detailed instructions on the reconstitution, storage conditions, and 
I.V. administration of nab-paclitaxel.) nab-Paclitaxel will be administered at a dose of 100 
mg/m2 I.V. over 30 minutes on Days 1, 8 and 15 of each 3-week treatment cycle during the 
induction period and on Days 1 and 8 of each 3-week cycle during the maintenance period.
9.1.3.3.
Carboplatin
Carboplatin will be used and should be prepared and administered according to the 
manufacturer’s instructions. Carboplatin will be administered immediately after the nab-
paclitaxel infusion (during the induction period only; it is not to be administered during the 
maintenance period).  Carboplatin will be administered at AUC 6 (mg∙min/mL) I.V. over a 
minimum of 15 minutes (maximum of 60 minutes) on Day 1 of each 3-week treatment cycle, for 
a maximum of 4 cycles (approximately 12 weeks).
9.2.
Materials and Supplies
IPs will be provided by Lilly. Clinical trial materials will be labeled according to the country’s 
regulatory requirements.
9.2.1. Necitumumab Drug Product
Necitumumab drug product is a sterile, preservative-free, solution for I.V. infusion supplied in 
the following formulation:

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
Necitumumab drug substance at a final concentration of 16 mg/mL (800 mg/50 mL)
contained in single-use vials, in a formulation of 10mM sodium citrate, 40mM sodium 
chloride, 133mM glycine, 50mM mannitol, 0.01% polysorbate 80, pH 6.0.
All excipients used in the formulation of necitumumab drug product are of pharmacopeial grade. 
No animal-derived components are used in the manufacture of necitumumab drug product
excipients. Refer to the IB for detailed storage information.
9.2.2. Chemotherapy Agents
nab-Paclitaxel and carboplatin will be used in this study, and will be packaged, labeled, and 
stored according to manufacturer standards and according to the country’s regulatory 
requirements, if supplied by Lilly.
9.3.
Method of Assignment to Treatment
Not applicable. This is a single-arm open-label study.
9.4.
Selection and Timing of Doses
Local laboratory values will be used to determine the patient dose and/or dose adjustments.
A cycle is defined as an interval of 3 weeks (a delay of a cycle due to holidays, weekends, bad 
weather, or other unforeseen circumstances will be permitted up to 3 days and not counted as a 
protocol deviation).
Patients will receive up to 4 cycles of nab-paclitaxel and carboplatin chemotherapy plus
necitumumab as the induction (triplet) regimen.  Only those patients with a disease response of 
CR, PR, or SD (radiographic evidence of response, not necessarily confirmed) after 4 cycles of 
induction regimen are eligible to then receive the maintenance (doublet) regimen of 
necitumumab plus nab-paclitaxel every 3 weeks until disease progression occurs or other 
discontinuation criteria are met.
The actual dose of necitumumab administered will be an absolute dose of 800 mg.
The actual dose of nab-paclitaxel administered will be determined by calculating the patient's 
body surface area (BSA) at the beginning of each cycle.  If the patient’s weight does not 
fluctuate by more than 10% from the weight used to calculate the prior dose, the BSA will not 
need to be recalculated.  A 5% variance in the calculated total dose will be allowed for ease of 
dose administration.
The actual dose of carboplatin administered will be based on the calculations described in 
Section 9.1.1.
A patient may continue to receive the induction (triplet) regimen until he or she has received a 
maximum of 4 cycles or until he or she meets at least one of the specified reasons for 
discontinuation (as described in Section 7.3).  A patient may continue to receive the maintenance 
(doublet) regimen until he or she meets at least one of the specified reasons for discontinuation 
(as described in Section 7.3).

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Study treatment will be administered as described in Section 9.1.
9.4.1. Special Treatment Considerations
9.4.1.1.
Treatment Requirements and Delays
Prior to each administration of the study treatment regimen, hematology, liver function, and renal 
function must be adequate (see Table JFCP.2) and all other toxicities (except alopecia) must 
have resolved to Grade ≤2 or baseline, or, in the case of peripheral neuropathy, to Grade ≤1. 
Pretreatment laboratory data may not be older than 72 hours (Day 1 of each cycle) or 24 hours 
(Days 8 and 15 of each cycle during the induction period and Day 8 during the maintenance 
period).  Local laboratory results may be used to make this determination.
Table JFCP.2.
Criteria for Treatment
Analyte
Criteria
Neutrophils (ANC)
≥1.5 × 103/µL (Day 1 of a cycle) (Days 8 or 15:  ≥0.5 × 103/µL)a
Platelets
≥100 × 103/µL (Day 1 of a cycle) (Days 8 or 15:  ≥50 × 103/µL)a
Serum creatinine
≤1.2 × ULN or calculated CrCl ≥50 mL/minb
Bilirubin
≤1.25 × ULNa
AST
≤5 × ULN in the presence of liver metastasis; ≤2.5 × ULN in the absence of liver metastasisa
ALT
≤5 × ULN in the presence of liver metastasis; ≤2.5 × ULN in the absence of liver metastasis
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; CrCl = creatinine clearance; ULN = upper limit of normal.
a
Adapted from Abraxane package insert, 2015.
b
CrCl will be calculated according to Attachment 5.
If the criteria outlined in Table JFCP.2 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 necitumumab-related toxicity, administration of necitumumab will be at the 
reduced dose (refer to Section 9.4.1.2.1) or interrupted, but chemotherapy will continue 
according to the planned schedule.

In the case of chemotherapy-related toxicity or abnormal laboratory values, the start of 
the next cycle of chemotherapy will be delayed until recovery to the values stated in 
Table JFCP.2. However, necitumumab should be administered as planned. When 
chemotherapy-related toxicity has resolved, chemotherapy and necitumumab will resume 
on the regular schedule, such that a new cycle will not start until chemotherapy resumes
(see Attachment 8 for illustrative examples of dose delay management during both the 
induction and the maintenance regimens).

If administration of necitumumab is delayed (held) for more than 6 weeks after Day 1 of 
the most recent treatment cycle , treatment with necitumumab will be permanently 
discontinued. Refer to Table JFCP.5 for information on nab-paclitaxel and carboplatin 
dose reductions and permanent treatment discontinuation.  Note that chemotherapy dose 
modifications are permanent; once the dose of nab-paclitaxel or carboplatin has been 
reduced, it will remain reduced or be further reduced in subsequent cycles.  Note that 

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patients who have been discontinued from one or more of the study treatment
components should continue to receive the remaining study treatment component(s) that 
has (have) not been discontinued, according to this protocol.
9.4.1.2.
Treatment-Emergent Adverse Events and General Dose Modifications
Note that, as stated in Section 10.2.1 (Adverse Events), if a patient’s dosage is reduced or 
treatment is discontinued as a result of an AE, study site personnel must clearly report to Lilly or 
its designee via eCRF the circumstances and data leading to any such dosage reduction or 
discontinuation of treatment.
9.4.1.2.1. Necitumumab Dose Modifications
This section provides general dose modification guidelines for toxicity associated with
necitumumab treatment. Refer to Sections 9.4.1.2.2, 9.4.1.2.1.1, 9.4.1.2.1.2, 9.4.1.2.1.3, 
9.4.1.2.1.4, and 9.4.1.2.1.5 for specific information on the management of and/or necitumumab 
dose adjustments due to AEs of concern that may or may not be associated with necitumumab
treatment, which include hypersensitivity/infusion-related reactions, skin reactions, 
conjunctivitis, electrolyte abnormalities, pneumonia and sepsis, and thromboembolic events.
Apart from the necitumumab dose adjustment recommendations specific to 
hypersensitivity/infusion-related reactions and skin reactions (Sections 9.4.1.2.2 and 9.4.1.2.1.1, 
respectively), stepwise dose reductions to 600 mg and 400 mg necitumumab may be considered 
for non-life-threatening reversible Grade 3 and 4 toxicities after treatment interruption and 
resolution to Grade ≤2.  After a dose reduction, the dose of necitumumab may be re-escalated to 
the previous dose after a minimum of 2 administrations of the reduced dose.  In case of toxicities 
necessitating more than 2 dose reductions, treatment with necitumumab should be permanently 
discontinued.
9.4.1.2.1.1.
Skin Reactions
9.4.1.2.1.1.1.
Reactive Treatment
Recommendations for the management of skin reactions to EGFR inhibitors, based on the 
Canadian recommendations published by the BC Cancer Agency in 2009 (Melosky et al.), are 
detailed in Table JFCP.3.
Skin reactions were reported with necitumumab.  The onset of events occurred mainly during the 
first cycle of treatment.  Skin rash (any grade) should be treated, as per Table JFCP.3.  If a 
patient experiences a Grade 1 or 2 acne-like rash, necitumumab treatment should continue
without dose modification or delay.   Dose delays and or modifications for necitumumab are to be
considered in case of skin reactions of Grade 3 or that are considered intolerable.  If a patient 
experiences Grade 4 skin reactions, treatment with necitumumab should be permanently 
discontinued.

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Table JFCP.3.
Managing Skin Reactions
Grade of 
Reaction
Recommendations for Management
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% (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 (that is, after withholding 2 consecutive 
doses of necitumumab), or if reactions recur or become intolerable at 50% of the original dose,
necitumumab treatment should be permanently discontinued.
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.
Source:  Adapted from Melosky et al. 2009.
If necitumumab treatment is delayed or discontinued due to acneiform 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 after 1 to 2 weeks 
of symptomatic treatment, reactions that are severely symptomatic (for example, necrosis,
blistering, petechial, or purpuric lesions), reactions of NCI-CTCAE Grade ≥3, or reactions with
an uncharacteristic appearance.  Patients who develop skin toxicity should be monitored for early 
signs of infection and/or inflammation.

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As with all concomitant medications/procedures, any actions taken to ameliorate skin toxic ity
will be documented in the concomitant medication module of the eCRF.
9.4.1.2.1.1.2.
Preemptive Treatment
Refer to Section 9.1.2.1 (Premedication for Necitumumab) for information on preemptive 
treatment of skin reactions. As with all concomitant medications/procedures, any actions taken 
to ameliorate skin toxicity with preemptive medications or procedures will be documented in the 
concomitant medication module of the eCRF.
9.4.1.2.1.2.
Conjunctivitis
Conjunctivitis has been reported very commonly in patients receiving necitumumab. For 
patients with necitumumab-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.
9.4.1.2.1.3.
Electrolyte Abnormalities
Consistent with observations with other EGFR mAbs, 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 mAbs. Monitor patients for 
hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia prior to each 
administration of necitumumab and after completion of treatment of necitumumab, until within 
normal limits.  Prompt repletion is recommended, as appropriate.
9.4.1.2.1.4.
Pneumonia and Sepsis
Special attention should be given to patients with clinical evidence of concomitant infectious 
conditions including early signs of active infections.  Treatment of any infection should be 
initiated according to local standards.
In Study JFCL, a Phase 2 study to investigate carboplatin and solvent-based paclitaxel with or
without necitumumab in patients with squamous NSCLC (106 versus 55 patients, 2:1 
randomization), a total of 16 SAEs of pneumonia/sepsis in the necitumumab plus paclitaxel-
carboplatin arm (N+PC Arm) (13 [12.3%] pneumonia, and 3 [2.8%] of sepsis) versus 5 SAEs in 
the paclitaxel-carboplatin alone arm (PC Arm) (3 [5.5%] pneumonia, 2 [3.6%] sepsis]) were 
observed, including one fatal case in each arm. No clear pattern with regard to time after first 
administration of trial medication (range: 4-233 days) or laboratory values for 
leukocytes/neutrophils could be identified.
The early occurrence of a number of cases of pneumonia/sepsis may have indicated an issue 
regarding enrollment of inappropriate patients.  The sponsor had therefore provided clarification 
and reinforcement of the inclusion/exclusion criteria, requesting the investigator’s particular 
attention with regard to infections and conditions predisposing to infections ongoing at the time 
of enrollment in a protocol amendment.  During the further conduct of this trial, some additional 

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reports were received, notably of cases reporting pneumonia and septic complications with 
concurrent neutropenia.
The review of the data from the Phase 3 study of necitumumab in combination with gemcitabine
and cisplatin (Study JFCC; SQUIRE) did not show any evidence of an increased risk of serious 
lung infections or neutropenia associated with necitumumab in this combination.
9.4.1.2.1.5.
Thromboembolic Events
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.
Venous thromboembolic events (VTEs) and arterial thromboembolic events (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. 
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 
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).
9.4.1.2.1.6.
Cardiorespiratory Disorders
An increased frequency of cardiorespiratory arrest or sudden death was o bserved with 
necitumumab.  Cardiorespiratory arrest or sudden death was reported in the pivotal Study JFCC 
(SQUIRE) 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 (n=5), 
hypomagnesemia (n=4), and coronary artery disease (n=3).  Eleven of the 12 patients had an 
unwitnessed death.

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9.4.1.2.2. Dose Modifications for Infusion-Related Reactions
Hypersensitivity/infusion-related reactions (IRRs) 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 IRRs with 
resuscitation equipment readily available.
Furthermore, hypersensitivity/infusion-related reactions may occur during or following 
administration of nab-paclitaxel (Abraxane package insert, 2015) or carboplatin.
Hypersensitivity/infusion-related reactions are defined according to the NCI-CTCAE v 4.0
definition of allergic reaction / hypersensitivity, as follows:

Grade 1: transient flushing or rash, drug fever <38°C

Grade 2: rash, flushing, urticaria, dyspnea, drug fever ≥38°C

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)
Consistent with usual medical practice, selected parenteral medications and additional treatments 
may be utilized according to clinical symptoms and local standards at investigator discretion. 
Table JFCP.4 provides general treatment recommendations for hypersensitivity/infusion-related 
reactions to necitumumab.  For hypersensitivity/infusion-related reactions to the chemotherapy, 
refer to the respective package insert of carboplatin or Abraxane.
Note:  If a patient should have a hypersensitivity/infusion-related reaction to necitumumab, all 
attempts should be made to obtain an anti-necitumumab antibody (that is, immunogenicity) and 
PK blood sample as close to the onset of the event as possible, at the resolution of the event, and 
30 days following the event.  The procedure for sample collection and handling is described in a 
separate procedural manual.

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Table JFCP.4.
NCI-CTCAE Infusion-Related Reactions
Grade of 
Reaction
Recommendations for Management
First Occurrence
Second Occurrence
1

Decrease infusion rate by 50% for the 
duration of the infusion, and monitor patient 
for worsening of condition.a

For all subsequent infusions, premedicate 
with diphenhydramine hydrochloride 50 mg 
I.V. (or equivalent); additional 
premedication may be administered at the 
investigator’s discretion.

Decrease infusion rate by 50% for the duration 
of the infusion, and monitor patient for 
worsening of condition.a

Administer dexamethasone 10 mg I.V. (or
equivalent).

For all subsequent infusions, premedicate with
diphenhydramine hydrochloride 50 mg I.V. (or
equivalent), acetaminophen 650 mg orally (or
equivalent), and dexamethasone 10 mg I.V. (or
equivalent); additional premedication may be
administered at the investigator’s discretion.
2

Stop the infusion, and resume the infusion 
when the infusion reaction has resolved to 
≤Grade 1; decrease infusion rate by 50% 
when the infusion resumes.a

Monitor patient for worsening of condition.

If necessary, administer diphenhydramine
hydrochloride 50 mg I.V. (or equivalent),
acetaminophen 650 mg orally for fever, and
oxygen.

For all subsequent infusions, premedicate 
with diphenhydramine hydrochloride 50 mg 
I.V. (or equivalent); additional 
premedication may be administered at the 
investigator’s discretion.

Stop the infusion, and resume the infusion when
the infusion reaction has resolved to ≤Grade 1;
decrease infusion rate by 50% when the 
infusion resumes.a

Administer dexamethasone 10 mg I.V. (or
equivalent).

Monitor patient for worsening of condition.

If necessary, administer diphenhydramine
hydrochloride 50 mg I.V. (or equivalent),
acetaminophen 650 mg orally for fever, and
oxygen.

For all subsequent infusions, premedicate with
diphenhydramine hydrochloride 50 mg I.V. (or
equivalent), acetaminophen 650 mg orally (or
equivalent), and dexamethasone 10 mg I.V. (or
equivalent); additional premedication may be
administered at the investigator’s discretion.
3 or 4

Stop the infusion and disconnect the 
infusion tubing from the patient.

Administer diphenhydramine hydrochloride 
50 mg I.V. (or equivalent), dexamethasone 
10 mg I.V. (or equivalent), bronchodilators 
for bronchospasm, epinephrine, and other 
medications / treatments as medically 
indicated.

Hospital admission may be indicated.

Permanently discontinue necitumumab.
Not applicable
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; I.V. = intravenous(ly); NCI = 
National Cancer Institute.
a
Once the infusion rate has been reduced for a Grade 1 or 2 hypersensitivity/infusion-related reaction, it is
recommended that the lower infusion rate be utilized for all subsequent infusions. The infusion duration should
not exceed 2 hours.

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9.4.1.2.3. Chemotherapy Dose Modifications
nab-Paclitaxel and carboplatin may cause known hematologic and nonhematologic toxicities at 
the dose levels infused during this study; dose delays, dose reductions, or treatment 
discontinuation may be required (Abraxane package insert, 2015).
Refer to Table JFCP.2 for criteria pertaining to hematology, liver function, and renal function
that, if not met, may require a dose delay or dose reduction of study treatment.  In addition, 
Table JFCP.5 should be used to determine dose reductions and treatment discontinuation of
nab-paclitaxel and carboplatin (as applicable) in case of hematologic or neurologic toxicity. 
NOTE: Chemotherapy dose modifications are permanent; once the dose of nab-paclitaxel or 
carboplatin has been reduced, it will remain reduced or be further reduced in subsequent cycles.
nab-Paclitaxel and carboplatin (as applicable) are to be permanently discontinued in any of the 
following situations:  (1) third occurrence of neutropenic fever, >7-day delay of a cycle due to 
ANC <1.5 × 103/µL, or ANC<0.5 × 103/µL for >7 days; (2) second occurrence of platelet count 
<50 × 103/µL; or (3) third occurrence of Grade 3 or 4 sensory neuropathy (Abraxane package 
insert, 2015).  Note that patients who have been discontinued from one or more of the study 
therapy components should continue to receive the remaining study therapy component(s) that 
has (have) not been discontinued, according to this protocol.
9.4.1.2.3.1.
Hematologic and Neurologic Toxicities
General guidelines for dose modifications for hematologic and neurologic toxicities are 
presented in Table JFCP.5. Dose adjustments for hematologic toxicity at the start of a 
subsequent cycle should be based on nadir (worst) hematologic counts from the previous cycle of 
therapy; treatment may be delayed to allow sufficient time for recovery (to the levels defined in 
Table JFCP.2).
Do not administer nab-paclitaxel or carboplatin (as applicable) on Day 1 of a cycle until ANC 
≥1.5 × 103/µL and platelet count ≥100 × 103/µL (Abraxane package insert, 2015).  In patients 
who develop severe neutropenia or thrombocytopenia, withhold treatment until counts recover to 
ANC ≥1.5 × 103/µL and platelet count ≥100 × 103/µL on Day 1 or to ANC ≥0.5 × 103/µL and 
platelet count ≥50 × 103/µL on Days 8 or 15 of the cycle. Upon resumption of dosing,
permanently reduce nab-paclitaxel and carboplatin doses as outlined in Table JFCP.5.
Reduce the doses of nab-paclitaxel and carboplatin upon a first or second occurrence of Grade 3
or 4 peripheral neuropathy, as per Table JFCP.5.  Discontinue treatment with nab-paclitaxel and 
carboplatin upon a third occurrence of Grade 3 or 4 peripheral neuropathy.

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Table JFCP.5.
Dose Modifications for Hematologic and Neurologic Toxicities
Adverse Drug Reaction
Occurrence
Weekly 
Nab-Paclitaxel Dose
(mg/m2)
Every-3-Week 
Carboplatin Dose
(AUC mg∙min/mL)
Neutropenic fever (ANC <0.5 × 103/µL
with fever >38°C)
OR
Delay of next cycle by >7 days for 
ANC <1.5 × 103/µL
OR
ANC <0.5 × 103/µL for >7 days
First
75
4.5
Second
50
3
Third
Discontinue treatment
Discontinue treatment
Platelet count <50 × 103/µL
First
75
4.5
Second
Discontinue treatment
Discontinue treatment
Severe sensory neuropathy –
Grade 3 or 4
First
75
4.5
Second
50
3
Third
Discontinue treatment
Discontinue treatment
Abbreviations:  ANC = absolute neutrophil count; AUC = area under the concentration-time curve; nab-paclitaxel = 
paclitaxel protein-bound particles for injectable suspension (albumin-bound) (generic name for Abraxane).
Source:  Abraxane package insert, 2015.
9.4.1.2.3.2.
Nonhematologic Toxicities
For Grade 2 or 3 cutaneous toxicity, Grade 3 diarrhea, or Grade 3 mucositis, interrupt treatment 
until the toxicity improves to Grade ≤1, then restart treatment according to the guidelines in 
Table JFCP.6.  For Grade ≥3 peripheral neuropathy, withhold treatment until resolution to 
Grade ≤1.  Treatment may be resumed at the next lower dose level in subsequent cycles 
according to the guidelines in Table JFCP.6.  For any other Grade 3 or 4 non-hematologic 
toxicity, interrupt treatment until the toxicity improves to Grade ≤2, then restart treatment 
according to the guidelines in Table JFCP.6.

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Table JFCP.6.
Dose Modifications for Nonhematologic Toxicities
Adverse Drug Reaction
Occurrence
Weekly 
Nab-Paclitaxel Dose
(mg/m2)
Every-3-Week 
Carboplatin Dose
(AUC mg∙min/mL)
Grade 2 or 3 cutaneous toxicity
Grade 3 diarrhea
Grade 3 mucositis
Grade ≥3 peripheral neuropathy
Grade 3 or 4 nonhematologic toxicity
First
75
4.5
Second
50
3
Third
Discontinue treatment
Discontinue treatment
Grade 4 cutaneous toxicity, diarrhea, or 
mucositis
First
Discontinue treatment
Discontinue treatment
Abbreviations:  AUC = area under the concentration-time curve; nab-paclitaxel = paclitaxel protein-bound particles 
for injectable suspension (albumin-bound) (generic name for Abraxane).
Source:  Abraxane Summary of Product Characteristics, 2015.
9.4.1.2.3.3.
Hepatic Impairment
No dose adjustment is necessary for patients with mild hepatic impairment (Abraxane package 
insert, 2015). Patients with moderate and severe hepatic impairment treated with nab-paclitaxel
may be at increased risk of toxicities known to paclitaxel. Withhold nab-paclitaxel if the AST, 
ALT, and/or bilirubin criteria shown in Table JFCP.2 are not met.
9.5.
Blinding
This is an open-label study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured in the eCRF at each visit.  Concomitant medications and 
supportive care therapies must also be documented at the time of discontinuation and at the 
Short-Term Follow-up visit.
With the exceptions listed in the following subsections, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment.  Palliative radiation therapy is permitted for irradiating small areas of symptomatic
metastases that cannot be managed adequately.  Systemic radiotherapy is not allowed.  Any 
symptomatic deterioration or clinical disease progression requiring other forms of specific 
antitumor therapy, in the opinion of the investigator, will be cause for discontinuation of study 
therapy.
NOTE: The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4.  It is recommended 
that caution be exercised when administering nab-paclitaxel concomitantly with medicines 
known to inhibit (for example, ketoconazole and other imidazole antifungals, erythromycin, 
fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (for 

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example, rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either of these 
cytochrome P450 isoenzymes.
9.6.1. Supportive Care
Palliative and supportive care for other disease-related symptoms and for toxicity associated with
treatment will be offered to all patients on this trial. 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 (for example, blood cells, platelets, or fresh frozen plasma
transfusions) should be recorded on the eCRF. Refer to Section 9.4.1.2 for specific information 
on the management of necitumumab-related hypersensitivity/infusion-related reactions, skin 
reactions, conjunctivitis, hypomagnesemia, and serious thromboembolic events.  Guidelines 
regarding the use of other specific supportive care agents are presented in the following sections.
9.6.1.1.
Antidiarrheal Agents
In the event of Grade 3 or 4 diarrhea, supportive measures may include antidiarrheals
(loperamide), hydration, and octreotide. If diarrhea is severe (that is, 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 I.V. hydration and correction of electrolyte imbalance.
9.6.1.2.
Antiemetic Therapy
The use of antiemetic agents is permitted during this study.  Patients with severe nausea and /or
vomiting must be hospitalized for I.V. hydration and correction of electrolyte imbalance.
9.6.1.3.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.
9.6.1.4.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.
9.6.1.5.
Colony-Stimulating Factors and Erythropoiesis-Stimulating Agents
The use of colony-stimulating factors (CSFs) or erythropoiesis-stimulating agents (ESAs) are
permitted during study treatment, at the discretion of the investigator.
Because recommendations on the use of CSFs and ESAs are rapidly evolving, investigators 
should frequently refer to the local, national, or international standards (for example, European
Organisation for Research and Treatment of Cancer, European Society for Medical Oncology, 
National Comprehensive Cancer Network [NCCN], American Society of Clinical Oncology 
[ASCO], American Society of Hematology [ASH], and/or Centers for Medicare and Medicaid 
Services Web sites) for the latest guidelines.
9.7.
Treatment Compliance
The study medication will be administered only at the investigational sites by the authorized 
study personnel.  As a result, treatment compliance is ensured.

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10. Efficacy, Safety Evaluations, Sample Collection and 
Testing, and Appropriateness of Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.
Study procedures related to efficacy, safety, and sample collection and testing assessments and 
their timing are described in the following sections and shown in the Study Schedule 
(Attachment 1).
10.1. Efficacy Measures
Throughout this study, patients will be evaluated for response by the investigator, according to 
RECIST 1.1 (Eisenhauer et al. 2009).  The preferred methods of tumor measurement are 
computed tomography (CT; including spiral CT scans) and magnetic resonance imaging (MRI).  
Response assessments during the ongoing trial (and related treatment decisions) will be
performed by the treating investigator at the site in cooperation with the local radiologist(s).
10.1.1. Efficacy Assessments at Baseline and during Study Treatment
Within 21 days prior to the first dose of study drug, baseline tumor measurement(s) will be
performed on each patient.
Imaging studies required to investigate known disease should be repeated every 6 weeks (±3
days) following the first dose of study therapy, regardless of any treatment delays, until 
radiographic documentation of PD as defined by RECIST 1.1. Computed tomography of the 
chest and CT or MRI of the abdomen are required at each time point; CT or MRI of the brain 
must be performed if baseline assessment identified any lesion in this area or if clinically 
indicated, at the discretion of the treating physician. The method of assessment used at baseline 
must be used consistently for tumor assessment during the course of each patient’s evaluation 
during the study.
If an objective response of PR or CR is observed, confirmatory scans should be obtained at the 
next routine scheduled imaging time point (that is, 6 weeks [±3 days]). Thereafter, a responding 
patient will be followed every 6 weeks (±3 days) until radiographic documentation of PD.
During the Continued Access Period, efficacy assessments (frequency and type of assessments) 
will be at the discretion of the investigator, based on the standard of care.
10.1.2. Efficacy Assessments during Postdiscontinuation Follow-up
For patients who discontinue study treatment without objectively measured PD, the investigative 
sites will continue to monitor patients and evaluate tumor response every 6 weeks (±3 days), by 
the same method used at Baseline and throughout the study, until the patient has radiographic 
documentation of PD or until study completion, whichever occurs first. After the patient has 
objective PD, radiographic tests are no longer required and the patient will be followed up 
approximately every 3 months (±7 days) until the patient’s death or overall study completion, 
whichever occurs first (see Section 8.1.1).

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After radiographic documentation of PD, patients may receive additional anticancer therapy at
the discretion of the investigator. The additional treatments should be documented in the eCRF.
10.1.3. Definitions of Efficacy Measures
Definitions of efficacy measures per patient are provided in Table JFCP.7. Summary efficacy
statistics (rates, medians, etc) for study populations are defined in Section 12.2.1.  For these
definitions, the date of study enrollment is the date of first dose of study drug (necitumumab,
nab-paclitaxel, and/or carboplatin).
Table JFCP.7.
Definitions of Efficacy Measures per Patient
Endpoint
Definition
Best response
The best tumor response of CR or PR.
Progression-free 
survival
The time from the date of study enrollment to the date of first observation of objective 
(radiographically documented) PD or death from any cause, whichever comes first.  For 
patients not known to have died as of the data cut-off date and who do not have objective 
PD, PFS will be censored at the date of the last complete radiographic assessment.
Overall survival
The time from the date of study enrollment to the date of death from any cause.  For patients 
not known to have died as of the data cut-off date, OS will be censored at the last contact 
date (last contact for patients in Postdiscontinuation Follow-up = last known alive date in 
mortality status).
Disease control
Best tumor response of PR, CR, or SD.
Abbreviations:  CR = complete response; OS = overall survival; PD = progressive disease; PFS = progression-free
survival; PR = partial response; SD = stable disease.
10.1.3.1. Primary Efficacy Measure
The primary efficacy measure is response as defined by RECIST 1.1 (Eisenhauer et al. 2009)
provided in Attachment 6.  A responder is defined as any patient who exhibits a confirmed CR or 
PR.
Best response is determined from the sequence of responses assessed.
A second assessment must be performed 28 days after the first evidence of response, such that 
the next scheduled scan performed 6 weeks (±3 days) after the first evidence of response would 
qualify for response confirmation. Two objective status determinations of CR before
progression are required for a best response of CR.  Two determinations of PR or better before 
progression, but not qualifying for a CR, are required for a best response of PR.  A best response 
of SD is defined as disease that does not meet the criteria for CR, PR, or PD and has been 
evaluated at least one time, at least 6 weeks after the start of study treatment.
Best response will be derived to encompass all tumor assessments from baseline until the earliest 
of objective progression or start of new anticancer therapy.  Any responses observed after 
objective progression or the start of new anticancer therapy are excluded from the determination 
of best response.
The date of first documented objective disease progression must be recorded on the eCRF even if 
it occurs after the patient has started a new therapy. A brain lesion identified on a follow-up scan 

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is considered a new lesion and will indicate disease progression even though brain was not 
scanned at baseline.
The response rate (ORR) is estimated as the total number of confirmed CRs and PRs divided by 
the total number of qualified patients.
10.2. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment regimen or study procedures, 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).  
Table JFCP.8 presents a summary of AE and SAE reporting guidelines.  Table JFCP.8 also 
shows which database or system is used to store AE and SAE data.

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Table JFCP.8.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to Be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEsa
x
SAEs related to protocol procedures
x
x
Study Treatment Period
All AEs
x
All SAEs
x
x
Short-Term Postdiscontinuation 
Follow-up
All AEs
x
All SAEs
x
x
Long-Term Postdiscontinuation 
Follow-up
All SAEs related to protocol procedures 
or study drug(s)
x
x
Continued Access (treatment) Period
All AEs
x
All SAEs
x
x
Continued Access Follow-upa
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study drug(s) that the investigator 
becomes aware of
x
Abbreviations:  AE = adverse event; SAE = serious adverse event.
Note:  The investigator remains responsible for following, through an appropriate health care option, AEs that are 
serious, considered related to the study treatment or procedures, or that caused the patient to discontinue before 
completing the study.  The patient should be followed until the event is resolved or explained.
a
For patients who fail screening, only AEs related to protocol procedures are collected in the collection database.
10.2.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from electrocardiograms (ECGs), labs, and vital signs
measurements that result in a diagnosis should be reported to Lilly or its designee.
Cases of pregnancy that occur during maternal or paternal exposures to study treatment should 
be reported immediately (within 24 hours).  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 ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.

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In addition, all AEs occurring after the patient receives the first dose of study drug must be 
reported to Lilly or its designee via eCRF.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and/or study treatment via eCRF.
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to study medication or study procedure, the following 
terminologies are defined.

Probably related:  a direct cause-and-effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause-and-effect relationship between the study treatment and the 
AE has not been demonstrated at this time and is not probable, but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study 
treatment
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to IP/study procedure.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
The NCI-CTCAE v 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the NCI-CTCAE v 4.0 criteria, the investigator will be responsible 
for selecting the appropriate System Organ Class (SOC) and assessing severity grade based on 
the intensity of the event.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by Lilly or its designee to corresponding terminology within 
the Medical Dictionary for Regulatory Activities (MedDRA ®).
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.2.1.1. Serious Adverse Events
An SAE is any AE 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

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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event collection begins after the patient has signed informed consent and has 
received study drug.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving study drug, the event will not be reported as serious unless the investigator feels the 
event may have been caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If study site personnel contact Lilly or 
its designee by telephone regarding an SAE, study site personnel must also immediately provide 
official notification on study-specific SAE forms.  This 24-hour notification requirement refers 
to the initial SAE information and all follow-up SAE information.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events caused by disease progression, including death, should not be reported 
unless the investigator deems them to be possibly related to the study treatment.
The investigator does not need to actively monitor patients for AEs once the trial has ended, 
unless provided otherwise in the protocol; however, if an investigator becomes aware of an SAE 
occurring after the patient’s participation in the trial has ended, and the investigator believes that 
the SAE is related to a protocol procedure or study treatment, the investigator should report the 
SAE to the sponsor, and the SAE will be entered in the Lilly Safety System.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
10.2.1.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the DCSI in the IB and that the investigator identifies as related to the study treatment or study 
procedure.  United States 21 CFR 312.32 and European Union Clinical Trial Directive 
2001/20/EC and the associated detailed guidances or national regulatory requirements in 
participating countries require the reporting of SUSARs.  Lilly has procedures that will be 

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followed for the recording and expedited reporting of SUSARs that are consistent with global 
regulations and associated detailed guidances.
10.2.2. Other Safety Measures
10.2.2.1. Electrocardiograms
For each patient, 12-lead digital ECGs will be collected according to the Study Schedule 
(Attachment 1) as single ECGs (no overread).  Patients must be supine for approximately 5 to 10 
minutes before ECG collection and remain supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon as possible after the time of ECG collection, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT (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.
10.2.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP or 
designee will, as is appropriate, consult with the functionally independent Lilly Global Patient 
Safety therapeutic area physician or clinical scientist, and review:

trends in safety data

laboratory analytes

AEs, including monitoring of hypersensitivity/infusion-related reactions, skin reactions, 
conjunctivitis, hypomagnesemia, and thromboembolic events

If a patient experiences elevated alanine aminotransferase (ALT) >5 × ULN and elevated 
total bilirubin >2 × ULN, clinical and laboratory monitoring should be initiated by the 
investigator. For patients entering the study with ALT >3 × ULN, monitoring should be 
triggered at ALT >2 × baseline.

Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities. To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP regarding collection of specific
recommended clinical information and follow-up laboratory tests. See Attachment 3.

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Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by Lilly in aggregate periodically during the course of the trial may be found in 
the IB. In the NSCLC population, the occurrence of fatigue or weakness or asthenia, pain or 
chest pain, dyspnea, cough, nausea, anorexia or decreased appetite, disease progression, 
metastasis, hemoptysis, pleural effusion are reasonably anticipated due to the underlying 
malignancy.
10.2.4. Complaint Handling
Lilly collects product complaints on study drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and facilitate process and product improvements.
Complaints related to unblinded comparator drugs or concomitant drugs are reported directly to 
the manufacturers of those drugs/devices in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.3. Sample Collection and Testing
Samples collected for this study will be coded with the patient number.  The samples and any 
data generated from them can be linked back to the patient only by investigator site personnel.
Attachment 1 lists the schedules for general sample collections for this study (includes a separate 
schedule for the Continued Access Period).
Attachment 2 lists the specific clinical laboratory tests that will be performed for this study and 
whether these will be performed at a local and/or central laboratory.
Attachment 7 lists the schedules for sample collections for PK, immunogenicity, and 
translational research (tumor tissue, plasma for biomarker research, and whole blood for 
deoxyribonucleic acid [DNA] [pharmacogenetic] analysis).
A summary of the maximum number and volume of invasive samples, for all sampling, during
the study, will be provided in a separate procedural manual. Fewer invasive samplings may
actually occur, but this will not require a protocol amendment.
10.3.1. Samples for Standard Laboratory Testing
Standard laboratory tests, including chemistry, hematology, coagulation, and pregnancy testing 
(if applicable in women of childbearing potential), will be performed and analyzed centrally.  
The exception is urinalysis, which will be performed and analyzed locally. Attachment 2 lists 
the laboratory tests that will be performed for this study.

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Central laboratory results, except urinalysis which will be done locally as noted above, will be 
used to determine patient eligibility at baseline. Local laboratory results may be used for on-
study dosing decisions; if so, testing must also still be performed by the central laboratory. 
These central laboratory results will be used for subsequent safety analyses. In the event of 
minor discrepancies between local and central laboratory results, the investigator may use the 
local results for treatment decisions, and the central laboratory results will remain part of the 
safety database.
Blood and urine samples will be collected at the times specified in the Study Schedule
(Attachment 1).
Investigators must document their review of each laboratory safety report.
Based on laboratory safety values, unscheduled hepatic monitoring tests (see Attachment 3) may
be performed as part of patient follow-up, in consultation with the Lilly CRP.
Samples collected for specified laboratory tests will be destroyed within 60 days after 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.
10.3.2. Samples for Translational Research
Required samples for biomarker and pharmacogenetic research to be collected from all patients 
in this study are the following:

Tumor tissue for biomarkers (see Section 10.3.2.1)

Plasma for biomarkers (see Section 10.3.2.2)

Whole blood for DNA sample (pharmacogenetic analysis) (see Section 10.3.2.3)
Samples will be collected at the times specified in Attachment 7.
The translational research samples will be stored for up to a maximum 15 years after the last 
patient visit for the study at a facility selected by the sponsor or designee.  The duration allows 
the sponsor to respond to regulatory requests related to the study treatment.
Patients will not receive results of these investigations except where required by local law.  
Samples will be destroyed according to a process consistent with local regulation.
Supplies required for the collection and shipment of the patients’ stored samples will be supplied 
by the central laboratory vendor.  Sample handling and shipment to the central laboratory will 
occur per instructions provided to the study site.
10.3.2.1. Tumor Tissue for Biomarkers
Collection of tumor tissue samples (primary tumor or metastatic sites) is mandatory for 
participation in this study.  Patients must have tumor tissue (a paraffin-embedded tissue block 

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[preferred] or 15 freshly cut unstained slides [a minimum of 6 slides] is requested) available for 
analysis of EGFR protein expression by IHC.
Due diligence should be used to make sure that tumor specimen (not a normal adjacent or a 
tumor margin sample) is provided.  Pathology notes accompanying tissue may also be requested.  
The paraffin-embedded whole blocks will be sectioned.  After testing has been completed, the 
paraffin-embedded whole blocks will be returned to the site.  Whole blocks can be returned 
sooner, if requested by the sites.  Partial blocks and slides will not be returned.
Mutation profiling, copy number variability, gene expression, and/or IHC may be performed on 
these tissue samples to assess potential associations with biomarkers relevant to pathways 
associated with NSCLC, the mechanism of action of necitumumab, and cancer-related 
conditions, and may also be used for related research methods and clinical outcomes. Additional 
exploratory markers studied may include, but are not limited to, markers relevant to the EGFR 
pathway.
10.3.2.2. Plasma for Biomarkers
Potential pharmacodynamics and/or circulating markers may include, but are not limited to, 
markers relevant to EGFR pathway, NSCLC etiology, and/or the mechanism of action of 
necitumumab.
10.3.2.3. Whole Blood for DNA Collection
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.
Sampling for this analysis will be a one-time collection (refer to Attachment 7 for timing of the 
collection).  Samples will be stored and analysis may be performed on genetic variants/copy 
number variations that are thought to play a role in the EGFR pathway, NSCLC etiology, and/or 
the mechanism of action of necitumumab.
In the event of an unexpected AE or the observation of an unusual response, the 
pharmacogenetic biomarker samples may be genotyped and analysis may be performed to 
evaluate a genetic association with response to necitumumab.  These investigations may be 
limited to a focused candidate gene study or, if appropriate, genome-wide analysis may be 
performed to identify regions of the genome associated with the variability observed in drug 
response.  The pharmacogenetic biomarker will only be used for investigations related to disease, 
cancer-related conditions, and drug or class of drugs under study in the context of this clinical 
program.  They will not be used for broad exploratory unspecified disease or population genetic 
analysis.  Pharmacogenetic data will not be provided to the investigator or the patient except
where required by local law.

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10.3.3. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected at time points specified in 
Attachment 7 to determine antibody production against necitumumab.  The actual date and time 
of collection of each sample will be recorded.  Immunogenicity will be assessed by a validated 
assay designed to detect anti-drug antibodies in the presence of the necitumumab.  Antibodies 
may be further characterized and/or evaluated for their ability to neutralize the activity of 
necitumumab.
As noted in Attachment 1, 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). When any immunogenicity sample is drawn, a sample for drug concentration 
measurement (PK) should also be drawn (immunogenicity and PK samples to be collected from 
2 separate blood draws, within no more than 15 minutes’ time difference), to allow interpretation 
of immune response (see Section 10.3.4).
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to necitumumab.  
The duration allows the sponsor to respond to regulatory requests related to necitumumab.
10.3.4. Samples for Drug Concentration Measurements 
(Pharmacokinetics)
Pharmacokinetic samples (venous blood) will be collected as specified in the Pharmacokinetic,
Immunogenicity, and Translational Research Sampling Schedule (Attachment 7).  Blood samples 
will be collected to determine the serum concentrations of necitumumab using a validated 
enzyme-linked immunosorbent assay (ELISA) method at a laboratory approved by Lilly.
Blood samples will also be collected to determine the plasma concentrations of paclitaxel and 
total platinum from carboplatin.  The bioanalytical method to det ermine plasma concentrations 
of paclitaxel is a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.  The 
bioanalytical method to determine plasma concentrations of total platinum is an inductively 
coupled plasma–mass spectrometry (ICP-MS) method.
As noted in Attachment 1, samples will also be collected and necitumumab drug concentrations 
determined in the setting of an infusion-related/hypersensitivity reaction to necitumumab.  The 
actual date and time of collection of each sample will be recorded.
Bioanalytical samples collected to measure necitumumab, paclitaxel, and total platinum
concentrations will be retained for a maximum of 1 year following last patient visit for the study.
10.4. Appropriateness of Measurements
The measures used to assess safety and efficacy in this study are consistent with those used in
most conventional oncology trials.

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11. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the 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, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
Generic Laboratory System.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary objective of this study is to estimate the ORR in qualified patients. The sample size 
was selected to facilitate the estimation of the ORR with reasonable precision; no power 
calculation was performed.  With 50 qualified patients, the 95% confidence interval (CI)
estimate of ORR with a width no greater than 29 percentage points (that is, the ORR point 
estimate ±14.5%).
There are no planned formal tests of hypotheses about ORR.  However, the maximum width of 
the 95% CI (described in the previous paragraph) will permit the conclusion (with 95% 
confidence) that the true value of ORR does not differ from the estimated value of ORR by more 
than 14.5 percentage points.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
Efficacy analyses for ORR and DCR will be performed for qualified patients, where a “qualified 
patient” is defined as an enrolled patient who has received any amount of study drug and has had 
a complete radiographic assessment at baseline.  A patient who is alive for at least 8 weeks after 
first dose and has had no postbaseline radiographic assessment will be disqualified.  Efficacy 
analyses for PFS and OS will be performed for all patients who have received any amount of 
study drug (necitumumab, nab-paclitaxel, and/or carboplatin).
The final analysis for all outcomes, primary and secondary endpoints, will be performed when 
70% of qualified patients experience a PFS event (radiographically documented PD or death), or 
6 months after completing enrollment, whichever occurs first.  This will provide an appropriate 
duration of observation from which to estimate ORR and median PFS.  Overall survival will be 
evaluated primarily in terms of the estimated 6-month survival.
Safety analyses will be performed for the Safety Population (all patients who have received any 
amount of study drug [necitumumab, nab-paclitaxel, and/or carboplatin]).
Minor changes or clarifications to any statistical analyses described in this protocol may be
presented in the final statistical analysis plan (SAP) for this study.
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 enrolled in the study, treated, and qualified.  A summary of all 
important protocol deviations will be provided.

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12.2.3. Patient Characteristics
Patient demographics including age, sex, screening height and weight, and screening body mass 
index (BMI) will be reported using descriptive statistics.
Baseline disease characteristics and medical history will also be summarized.
12.2.4. Concomitant Therapy
Concomitant medications will be summarized for the safety population.
12.2.4.1. Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation anticancer therapies will 
be provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.
12.2.5. Treatment Compliance
The number of dose omissions, reductions, delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients.  Summarized data will be provided for the 
induction period (the first 4 cycles), the maintenance period (Cycles 5 and beyond), and for the 
combination of the induction and maintenance periods.
12.2.6. Primary Outcome and Methodology
Refer to Section 12.1 for details of the primary analysis.
12.2.7. Analyses of Efficacy
This section provides details of planned efficacy analyses besides those described in 
Section 12.1. For time-to-event variables, the Kaplan-Meier method will be used to estimate 
parameters (for example, medians, quartiles, 6-month event rates). Refer to the SAP for 
additional details.
Table JFCP.9 provides definitions of key efficacy statistics used for this study. Exact 95% CIs 
will be calculated for ORR and DCR.

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Table JFCP.9.
Definitions of Key Efficacy Statistics
Efficacy Statistic
Definition
Objective 
response rate 
(ORR)
The denominator of ORR includes all qualified patients.  The numerator includes those 
patients counted in the denominator with a best overall tumor response of CR or PR.
Median (OS, PFS)
Estimated using Kaplan-Meier method of estimation.
Disease control 
rate (DCR)
Using the same denominator as for ORR, the numerator of DCR includes those patients 
counted in the denominator with a best tumor response of SD, PR, or CR.
Abbreviations:  CR = complete response; DCR = disease control rate; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PR = partial response.
12.2.8. Pharmacokinetic and Immunogenicity Analyses
Serum concentrations of necitumumab and plasma concentrations of paclitaxel and total 
platinum from carboplatin at each sampling time point will be summarized using descriptive
statistics. Immunogenicity (anti-necitumumab antibody) incidence will be tabulated, and 
correlation to necitumumab drug level, activity, and safety will be assessed, as appropriate. 
Additional exploratory analyses will be performed if warranted by data, using validated PK 
software programs (for example, NONMEM) and if appropriate and approved by Global 
Pharmacokinetic management. The version of any software used for the analysis will be 
documented and the program will meet Lilly requirements for software validation.
Interim analysis may be conducted to facilitate exploratory analyses of PK, safety, and
immunogenicity through PK/pharmacodynamic modeling. Interim data may also be pooled with
final and interim data from other clinical studies of necitumumab to facilitate meta-analysis
using non-linear mixed effects modeling. Since the study is unblinded, study objectives will not
be compromised by the interim access to data.
12.2.9. Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.1.
Overall exposure to study treatment, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for the entire Study Treatment Period.  The number of patients with 
dose reductions, dose delays, or dose omissions will also be summarized, as will the reasons for 
dose adjustments.
An overall summary of AEs will be provided for AEs deemed by the investigator to be at least 
possibly related to study treatment or study procedure, and repeated for events regardless of 
causality.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened between the first dose of study treatment and 30 days after the last dose of study 
treatment or a related SAE reported beyond 30 days after the last dose of study treatment.  The 
number of patients who experienced a TEAE, SAE, AE related to study treatment, died, or 

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discontinued from study treatment due to an AE will be summarized.  Refer to the SAP for 
details.
Common Terminology Criteria for Adverse Events v 4.0 will be used to report AEs by CTCAE 
terms.
Laboratory and non-laboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grades, including the total for maximum Grade 3 and above.  These summaries will be 
provided for events deemed by the investigator to be at least possibly related to study treatment,
and repeated for events regardless of causality.
MedDRA, Version 17.0 (or higher) will be used when reporting AEs by MedDRA terms.  
Treatment-emergent adverse events will be summarized by SOC and by decreasing frequency of 
Preferred Term within SOC.
Reasons for death will be summarized separately for on-therapy and within 30 days after last 
dose of study treatment.  Serious adverse events will be summarized by SOC and Preferred 
Term.
Hospitalizations and transfusions occurring during the Study Treatment Period or (30-day)
Short-Term Follow-up will be summarized.
12.2.10.
Interim Analyses
One safety interim analysis is planned when data are available from at least the first 10 qualified 
patients who have completed 2 cycles of study treatment or have died. The interim analysis will 
be conducted to permit evaluation of safety data by Lilly.

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

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The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of Lilly 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 trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
The investigator chosen by Lilly or a designee will serve as the clinical study report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the clinical study report coordinating investigator.
The Lilly responsible medical officer and statistician will sign/approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.

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14. References
ABRAXANE for Injectable Suspension [package insert]. Summit, NJ: Celgene Corp; July 2015.
ABRAXANE Summary of Product Characteristics, 2015. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000778/WC500020435.pdf. Accessed on September 21, 2016.
Campeau L. Letter: Grading of angina pectoris. Circulation. 1976;54:522-523.
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging 
Manual: From the AJCC Cancer Staging Manual. 7th ed. NY: Springer; 2009.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
Fontanini G, Vignati S, Bigini D, et al. Epidermal growth factor receptor (EGFr) expression in 
non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal 
lymph nodes in the squamous subtype. Eur J Cancer. 1995;31A(2):178-183.
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.
Li S, Kussie P, Ferguson KM. Structural basis for EGF receptor inhibition by the therapeutic 
antibody IMC-11F8. Structure. 2008;16:216-227.
Lynch TJ, Patel T, Dreisbach L, et al. 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;28:911-917.
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;16:16-26.
[NYHA] The Criteria Committee of the New York Heart Association. Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston: Little, 
Brown & Co; 1994.
Carboplatin Injection [package insert]. Lake Forest, IL: Hospira, Inc.; August 2015.
Carboplatin Injection (Aqueous Solution), [package insert]. Corona, CA: Watson Laboratories
Inc.; September 2006.
Pirker R, Pereira JR, Szczesna A, et al; FLEX Study Team. Cetuximab plus chemotherapy in 
patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase 
III trial. Lancet. 2009;373:1525-1531.

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Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with 
carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients 
with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 
2012;30:2055-2062.
Thatcher N, Hirsch FR, Szczesna A, et al. A randomized, multicenter, open-label, phase III study 
of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) 
versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small 
cell lung cancer (sq-NSCLC) [abstract]. J Clin Oncol. 2014;32:5s. Abstract 8008 (2014 ASCO 
Annual Meeting).

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Attachment 1.
Protocol JFCP Study Schedule
Study Schedule, Protocol I4X-MC-JFCP
Perform procedures as indicated in the following schedules.

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Baseline Schedule, I4X-MC-JFCP 
 
 
 
Baseline 
 
 
 
Cycle 
BL 
 
 
 
Visit 
0
 
 
 
Relative day to Cycle 1, Day 1 
≤21
≤14 
 
Procedure 
Category 
Protocol 
Section or 
Attachment 
Procedure 
 
Comments 
Study Entry/ 
Enrollment 
13.1 
Informed consent form signed 
X 
 
ICF must be signed prior to performance of any protocol-specific 
tests/procedures. 
7.1, 7.2 
Inclusion/exclusion evaluation and IWRS enrollment 
X 
To be done once all the screening (Baseline) assessments are 
completed. 
Medical 
History 
10.2.1 
Initial history/preexisting conditions 
 
X 
 
 
Historical illnesses 
 
X 
 
Physical 
Examination 
 
Height 
 
X 
 
 
Weight 
 
X 
 
 
Blood pressure/pulse/body temperature/respiration rate 
 
X 
 
Att 4 
ECOG performance status 
 
X 
 
Efficacy 
Assessment 
10.1.1, Att 6 
Radiologic imaging (according to RECIST 1.1) and 
tumor measurement 
X 
 
 
Adverse 
Events 
10.2.1 
AE collection and CTCAE grading 
X 
 
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System. 
Concomitant 
Medications 
9.6 
Concomitant medication notation 
X 
 
 

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Baseline
Cycle
BL
Visit
0
Relative day to Cycle 1, Day 1
≤21
≤14
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Comments
Laboratory/
Diagnostic 
Tests
10.3.1, Att 2
Hematology (central)
X
10.3.1, Att 2
Chemistry (central)
X
10.3.1, Att 2
Coagulation (central)
X
10.3.1, Att 2
Pregnancy test (central)
X
10.3.1, Att 2
Urinalysis (local)
X
10.3.2, Att 7
Tumor tissue sample
Refer to Attachment 7.
10.3.2, Att 7
Plasma sample (biomarkers)
Refer to Attachment 7.
10.3.2, Att 7
Whole blood for DNA sample (pharmacogenetic 
analysis)
Refer to Attachment 7.
10.2.2.1
ECG (local)
X
Abbreviations:  AE = adverse event; Att = Attachment (in the protocol); BL = baseline; CTCAE = Common Terminology Criteria for Adverse Events; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ICF = informed consent form; IWRS = interactive 
web response system; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; SAE = serious adverse event.

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Treatment Period Schedule, I4X-MC-JFCP
Treatment Period
Comments
Induction (Triplet)
Regimen
Maintenance (Doublet)
Regimen
Cycle
(3-week cycle)
1-4
5-N
Visit
1-4
5-N
Relative day within a 
cycle
1
8
15
1
8
Except for the Cycle 1, Day 1 visit, allowable visit windows are ±3 
days, unless indicated otherwise.
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Physical 
Examination
Weight
X
X
Body surface area to be calculated at each cycle until nab-paclitaxel is 
discontinued.
Blood pressure/pulse/body 
temperature/respiration rate
X
X
Att 4
ECOG performance status
X
X
Efficacy 
Assessment
10.1.1, Att 6
Radiologic imaging 
(according to RECIST 1.1) 
and tumor measurement
X
X
To be performed every 6 weeks ±3 days after the first dose of study 
therapy, regardless of treatment delays, until there is radiographic 
documentation of PD as defined by RECIST 1.1.  The method of 
assessment used at baseline must be used consistently for tumor 
assessment during the course of each patient’s evaluation during the 
study.
Adverse 
Events
10.2.1
AE collection and CTCAE 
grading
X
X
X
X
X
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System.
Concomitant 
Medications
9.6
Concomitant medication 
notation
X
X
X
X
X
Study Drug
9.1, 9.1.2.1, 
9.1.3.1
Necitumumab
X
X
X
X
9.1, 9.1.2.2, 
9.1.3.2
nab-Paclitaxel
X
X
X
X
X
9.1, 9.1.1, 
9.1.2.2,
9.1.3.3
Carboplatin
X

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Treatment Period
Comments
Induction (Triplet)
Regimen
Maintenance (Doublet)
Regimen
Cycle
(3-week cycle)
1-4
5-N
Visit
1-4
5-N
Relative day within a 
cycle
1
8
15
1
8
Except for the Cycle 1, Day 1 visit, allowable visit windows are ±3 
days, unless indicated otherwise.
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Laboratory/
Diagnostic 
Tests
9.4.1.1, 
10.3.1, Att 2
Hematology (local and
central)
X
X
X
X
X
Local lab values to be used for dosing decisions, per Table JFCP.2.  
Pretreatment laboratory data may not be older than 72 hours (Day 1 of 
each cycle) or 24 hours (Days 8 and 15 of each cycle during the 
induction period and Day 8 of each cycle during the maintenance 
period).
Central lab values to be used for the eCRF/clinical database.
Hepatic monitoring tests ( per Attachment 3; performed by local lab 
and captured on the eCRF) to be done in the event of a treatment-
emergent hepatic abnormality.
9.4.1.1, 
10.3.1, Att 2
Chemistry (local and central)
X
X
X
X
X
Local lab values to be used for dosing decisions, per Table JFCP.2.  
Pretreatment laboratory data may not be older than 72 hours (Day 1 of 
each cycle) or 24 hours (Days 8 and 15 of each cycle during the 
induction period and Day 8 of each cycle during the maintenance 
period).
Central lab values to be used for the eCRF/clinical database.
Hepatic monitoring tests ( per Attachment 3; performed by local lab 
and captured on the eCRF) to be done in the event of a treatment-
emergent hepatic abnormality.
10.3.1, Att 2
Coagulation (central)
X*
X*
* Starting with Cycle 2, to be performed every second cycle (that is, 
Cycles 2, 4, etc).
10.3.1, Att 2
Pregnancy test (central)
X*
X*
* Starting with Cycle 2, to be performed every second cycle in women 
of childbearing potential (that is, Cycles 2, 4, etc).
10.3.1, Att 2
Urinalysis (local)
X*
X*
* Starting with Cycle 2, to be performed every second cycle (that is, 
Cycles 2, 4, etc).
10.3.4, Att 7
PK
Refer to Attachment 7.
If a patient experiences an IRR to necitumumab, blood samples for 
both immunogenicity and PK analysis should be drawn, with no more 
than 15 minutes’ time difference.  Samples will be taken at the 
following time points:  (1) as soon as possible after the onset of the 
IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
10.3.3, Att 7
Immunogenicity:  Anti-
necitumumab antibodies
10.3.2, Att 7
Plasma sample (biomarkers)
Refer to Attachment 7.
10.2.2.1
ECG (local)
X*
X*
* Starting with Cycle 2, to be performed every second cycle (that is, 
Cycles 2, 4, etc).
Abbreviations:  AE = adverse event; Att = Attachment (in the protocol); CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; IRR = infusion-related reaction; 
PD = progressive disease; PK = pharmacokinetic(s); RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; SAE = serious adverse event.

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Postdiscontinuation Follow-up Schedule, I4X-MC-JFCP
Postdiscontinuation Follow-up
Cycle
Short-Term Follow-up
Long-Term Follow-up
Visit
801
802-8XX
Relative day within a cycle
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Comments
Physical 
Examination
Weight
X
Blood pressure/pulse/body 
temperature/respiration rate
X
Att 4
ECOG performance status
X
Efficacy
Assessment
10.1.1, Att 6
Radiologic imaging (according to 
RECIST 1.1) and tumor 
measurement
X
X
Patients who discontinue study treatment for any reason other than 
PD will continue to undergo radiographic tumor assessments every 6 
weeks (±3 days) until PD or overall study completion, whichever 
occurs first.  The method of assessment used at baseline must be used 
consistently for tumor assessment during the course of each patient’s 
evaluation during the study.
After the patient has objective disease progression, radiologic tests 
are no longer required and the patient will be followed for survival 
every 3 months (±7 days) until the patient’s death or overall study 
completion, whichever occurs first.
Survival 
Information
7.3.2, 8.1.1
Collection of survival information
X
X
Collection of survival data every 3 months (±7 days) until the 
patient’s death or overall study completion, whichever occurs 
first. Whenever possible, survival follow-up is conducted in 
person. If an in-person visit is not possible, the site may confirm 
survival by contacting the patient directly via telephone.
Adverse 
Events
10.2.1
AE collection and CTCAE grading
X
X
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System.  During 
Postdiscontinuation Long-Term Follow-up, only SAEs that are 
related to protocol procedures or study treatment will be collected.
Concomitant 
Medications
9.6
Concomitant medication notation
X
Laboratory/
Diagnostic 
Tests
10.3.1, Att 2
Hematology (central)
X
10.3.1, Att 2
Chemistry (central)
X
10.3.1, Att 2
Coagulation (central)
X
10.3.1, Att 2
Pregnancy test (central)
X
10.3.1, Att 2
Urinalysis (local)
X
10.3.4, Att 7
PK
Refer to Attachment 7.
10.3.3, Att 7
Immunogenicity:  Anti-
necitumumab antibodies
10.3.2, Att 7
Plasma sample (biomarkers)
10.2.2.1
ECG (local)
X

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Postdiscontinuation Follow-up Schedule, I4X-MC-JFCP (concluded)
Abbreviations:  AE = adverse event; Attachment (in the protocol); CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; PD = progressive disease; PK = pharmacokinetic(s); RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors, version 1.1; SAEs = serious adverse events.
Note:  No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.
Short-Term Follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment and lasts at least
30 days (+ 0-7 days; ie, at least 30 days but no more than 37 days).
Long-Term Follow-up begins the day after Short-Term Follow-up is completed and continues until the patient’s death or overall study completion.  Patients 
who discontinue study treatment for reasons other than PD will continue to undergo radiographic tumor assessments every 6 weeks (±3 days) until PD or 
overall study completion, whichever occurs first.  Patients will be followed for survival every 3 months (±7 days) until the patient’s death or overall study 
completion, whichever occurs first.

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Continued Access Schedule, I4X-MC-JFCP
Continued Access Period
Treatment Period
Continued Access 
Follow-up
Cycle
X-Y
Follow-up
Visit
501-5XX
901
Relative day within 
a cycle
1
8
Procedure 
Category
Protocol 
Section or 
Attachment
Procedure
Comments
Physical 
Examination
Weight
X
Body surface area to be calculated at each cycle until nab-paclitaxel
is discontinued.
Adverse 
Events
10.2.1
AE collection and CTCAE grading
X
X
X
Data on SAEs that occur before the end of trial will be stored in the 
collection database and the Lilly Safety System.
Laboratory/
Diagnostic 
Tests
10.3.4, Att 7
PK
Refer to Attachment 7.
If a patient experiences an IRR to necitumumab, blood samples for 
both immunogenicity and PK analysis should be drawn, with no more 
than 15 minutes’ time difference.  Samples will be taken at the 
following time points:  (1) as soon as possible after the onset of the 
IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
10.3.3, Att 7
Immunogenicity:  Anti-necitumumab 
antibodies
Study Drug
9.1, 9.1.2.1, 
9.1.3.1
Necitumumab
X
X
At the time of study completion, it is expected that no patients will be 
on the induction (triplet) regimen.  Patients who are on the 
maintenance (doublet) regimen may continue to receive that regimen 
during the Continued Access (treatment) Period.
9.1, 9.1.2.2, 
9.1.3.2
nab-Paclitaxel
X
X
Not 
applicable
Carboplatin
Abbreviations: AE = adverse event; Attachment (in the protocol); CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related 
reaction; PK = pharmacokinetics; SAE = serious adverse event.
Note:  No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.
Continued Access Period begins after study completion and ends at the end of trial.  During the Continued Access Period, patients on study treatment who 
continue to experience clinical benefit and no undue risks may continue to receive study treatment until one of the criteria for discontinuation is met.  The 
Continued Access Period includes Continued Access Follow-up.  During the Continued Access Period, required evaluations are shown in the table.  
Investigators will perform any other standard procedures and tests needed to treat and evaluate patients and to confirm patient eligibility to continue on 
treatment; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly will not routinely collect the results of these assessments.
Continued Access Follow-up begins the day after the patient and the investigator agree that the patient will no longer continue treatment in the Continued 
Access Period and lasts at least 30 days (+ 0-7 days; ie, at least 30 days but no more than 37 days).
Note:  Efficacy assessments will be done at the investigator’s discretion based on the standard of care.

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Attachment 2.
Protocol JFCP Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya,b:
Clinical Chemistrya,b:
Hemoglobin
Serum concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Magnesium
Mean cell volume (MCV)
Potassium
Mean cell hemoglobin concentration (MCHC)
Phosphate
Leukocytes (WBC)
Total bilirubin
Neutrophils, segmented and bands
Direct bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes
Alanine aminotransferase (ALT)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatininec
Uric acid
Calcium
Glucose, nonfasting
Urinalysisa:
Albumin
Color
Cholesterol
Specific gravity
Creatine kinase (CK)
pH
Protein
Pregnancy Test (WOCBP only, serum required)b
Glucose
Ketones
Coagulation Testsb:
Blood
INR and PT
Urine leukocyte esterase
PTT
Fibrin D dimer
Protein C activity (baseline only)
Protein S activity (baseline only)
Abbreviations:  AE = adverse event; CRF = case report form; IDMS = isotope dilution mass spectrometry; 
INR = International Normalized Ratio; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red 
blood cells; US = United States; WBC = white blood cells; WOCBP = women of childbearing potential.
a
Assayed by local laboratory.  Local laboratory results will not be collected on the CRF, except in the case of an 
AE.
b
Assayed by Lilly-designated (central) laboratory.
c
IDMS for US sites.

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Attachment 3.
Protocol JFCP Hepatic Monitoring Tests 
for Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly clinical research physician
(CRP).
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time (PT)
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Anti-nuclear antibodya
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase GGT
Anti-smooth muscle antibodya
Creatine kinase (or creatine phosphokinase) (CK [or 
CPK])
Abbreviations:  CRF = case report form; Ig = immunoglobulin; INR = International Normalized Ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by local laboratory (can be performed centrally, if needed or per discretion of the investigator).
b
Note:  Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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

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

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

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

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

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

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

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Table 2 is to be used when patients have nonmeasurable disease only.
Table 2.
Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations:  CR = complete response; PD = progressive disease ; NE = inevaluable.
a
non-CR/non-PD is preferred over SD for nontarget disease. 
Frequency of Tumor Re-Evaluation
A baseline tumor evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6-8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur; assessment of 
nontargets is not required.
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required.  But, elimination of the requirement may 
increase the importance of central review to protect against bias, in particular of studies which 
are not blinded.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from first dose.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 

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progression is observed (taking as reference for PD the smallest measurements recorded on 
study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
PD).
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.

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Attachment 7.
Protocol JFCP Pharmacokinetic, 
Immunogenicity, and Translational Research Sampling
Schedule
It is essential that the exact infusion start and stop times (actual clock readings) as well as 
infusion parameters (such as type of infusion pump, flow rate settings) are recorded.  The exact 
time of collection of each venous blood sample will be based on the clock used to record 
infusion times.  It is essential that the PK blood samples not be drawn from the same I.V. site as 
the drug infusion.
In addition, if a patient experiences an infusion-related reaction (IRR), blood samples for both 
immunogenicity (anti-necitumumab antibody) and PK analysis should be drawn, with no more 
than 15 minutes’ time difference. Samples will be taken at the following time points:  (1) as 
soon as possible after the onset of the IRR, (2) at the resolution of the IRR, and (3) 30 days after 
the IRR.
Collection of tumor tissue samples (primary tumor or metastatic sites) is mandatory for 
participation in this study.  Patients must have tumor tissue (a paraffin-embedded tissue block 
[preferred] or 15 freshly cut unstained slides [a minimum of 6 slides] is requested) available for 
analysis of EGFR protein expression by IHC.

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Pharmacokinetic, Immunogenicity, and Translational Research Sampling Schedule
Baseline
Study Treatment Period (3-wk cycles)
Post-DC 
Follow-up
Cycle 1
Cycle 3
Cycle 4
Day 1
Day 1
Day 1
Sample for:
Protocol Section
≤14 days
Pre-inf
Post-inf
Pre-inf
Post-inf
Pre-inf
Post-inf
Short-Term 
Follow-upa
Necitumumab PKb
10.3.4
Xc
Xd
Xc
Xd
Xc
Xd
Xe
nab-Paclitaxel PK
Carboplatin PK
Immunogenicityb
10.3.3
Xc
Xc
Xc
X
Tumor tissue submission
10.3.2.1
X
Plasma sample for biomarkers
10.3.2.2
X
X
Xf
Whole blood sample for DNA analysisg
10.3.2.3
X
Abbreviations:  DC = discontinuation; DNA = deoxyribonucleic acid; EDTA = ethylenediaminetetraacetic acid; inf = infusion; IRR = infusion-related reaction; 
PGx = pharmacogenetic; PK = pharmacokinetic(s).
Note:  It is essential that the draw dates and draw times are accurately recorded.
Note:  For all samples collected prior to an infusion, it is recommended that samples be collected after it is confirmed that the patient is qualified to receive the 
infusion at that time point.
a
Short-Term Follow-up begins the day after the patient and the investigator agree that the patient will no longer continue study treatment (during the Study 
Treatment Period) and lasts at least 30 days (+ 0-7 days; ie, at least 30 days but no more than 37 days).
b
If a patient experiences an infusion-related reaction (IRR), separate blood samples for immunogenicity (anti-necitumumab antibody) and PK analysis should 
be drawn, within no more than 15 minutes’ time difference.  Samples will be taken at the following time points:  (1) as soon as possible after the onset of the 
IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.
c
At Cycle 1, Day 1:  At any time prior to the necitumumab infusion.  For all other time points:  Within 4 hours prior to the beginning of the necitumumab 
infusion.  The exact time of collection of each blood sample should be recorded.  The sample taken at this time point will include serum for necitumumab PK 
assessment and blood for nab-paclitaxel and carboplatin PK assessments.  Refer to the laboratory manual for details regarding the required number of blood 
collection tubes for any given time point.
d
A postinfusion sample is to be drawn within 15 minutes after the last infusion for that study day is completed.  The exact time of collection of each blood 
sample should be recorded.  The sample taken at this time point will include serum for necitumumab PK assessment and blood for nab-paclitaxel and 
carboplatin PK assessments.  Refer to the laboratory manual for details regarding the required number of blood collection tubes for any given time point.
e
PK for necitumumab only.
f
When applicable, EDTA plasma should be collected as near as possible to the time of disease progression, during the Study Treatment Period.  If, for any 
reason, the post-progression sample cannot be collected at the time of progression, it should be collected at (or by) the (30-day) Short-Term Follow-up visit.  
The post-progression sample should be collected before the initiation of any new anticancer therapy.
g
Collected at Baseline (preferred) or at later visits.

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Attachment 8.
Protocol JFCP Necitumumab Dosing 
Scenarios for Chemotherapy Delays
Induction Regimen (Cycles 1-4)
Cycle
Day
Administer 
Necitumumab?
Administer nab-
Paclitaxel?/Carboplatin?
Planned – No Delays
1
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
2
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
3
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
Chemotherapy Delay of 1 Week after Cycle 1 (Preventing Start of Cycle 2)
1
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
22
Yes
Delay of nab-paclitaxel 
and/or carboplatin
2
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
3
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
Chemotherapy Delay of 2 Weeks after Cycle 1 (Preventing Start of Cycle 2)
1
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
22
Yes
Delay of nab-paclitaxel 
and/or carboplatin
29
Yes
2
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
3
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No

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Induction Regimen (Cycles 1-4)
Cycle
Day
Administer 
Necitumumab?
Administer nab-
Paclitaxel?/Carboplatin?
Chemotherapy Delay of 3 Weeks after Cycle 1 (Preventing Start of Cycle 2)
1
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
22
Yes
Delay of nab-paclitaxel 
and/or carboplatin
29
Yes
36
No
2
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
3
1
Yes
Yes/Yes
8
Yes
Yes/No
15
No
Yes/No
Maintenance Regimen (Cycles 5-n)
Cycle
Day
Administer 
Necitumumab?
Administer nab-Paclitaxel?
Planned – No Delays
1
1
Yes
Yes
8
Yes
Yes
2
1
Yes
Yes
8
Yes
Yes
3
1
Yes
Yes
8
Yes
Yes
Chemotherapy Delay of 1 Week after Cycle 1 (Preventing Start of Cycle 2)
1
1
Yes
Yes
8
Yes
Yes
15
No
Delay
2
1
Yes
Yes
8
Yes
Yes
3
1
Yes
Yes
8
Yes
Yes

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Maintenance Regimen (Cycles 5-n)
Cycle
Day
Administer 
Necitumumab?
Administer nab-Paclitaxel?
Chemotherapy Delay of 2 Weeks after Cycle 1 (Preventing Start of Cycle 2)
1
1
Yes
Yes
8
Yes
Yes
15
No
Delay
22
Yes
2
1
Yes
Yes
8
Yes
Yes
3
1
Yes
Yes
8
Yes
Yes
Chemotherapy Delay of 3 Weeks after Cycle 1 (Preventing Start of Cycle 2)
1
1
Yes
Yes
8
Yes
Yes
15
(Not applicable)
(Not applicable)
22
Yes
Delay
29
Yes
36
No
2
1
Yes
Yes
8
Yes
Yes
3
1
Yes
Yes
8
Yes
Yes

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Attachment 9.
Protocol JFCP Protocol Amendment I4X-
MC-JFCP(b) Summary
A Single-Arm, Multicenter, Open-Label, Phase 2 Study of 
nab®-Paclitaxel (Abraxane®) and Carboplatin 
Chemotherapy plus Necitumumab (LY3012211) in the 
First-Line Treatment of Patients with Stage IV Squamous 
Non-Small Cell Lung Cancer (NSCLC)
Overview
Protocol I4X-MC-JFCP, A Single-Arm, Multicenter, Open-Label, Phase 2 Study of nab®-
Paclitaxel (Abraxane®) and Carboplatin Chemotherapy plus Necitumumab (LY3012211) in the 
First-Line Treatment of Patients with Stage IV Squamous Non-Small Cell Lung Cancer 
(NSCLC), has been amended.  The new protocol is indicated by Amendment (b) and will be used 
to conduct the study in place of any preceding version of the protocol.
The following additions were made as requested by the German competent authority, Paul-
Ehrlich Institute:

detailed information on the SAEs of pneumonia/sepsis occurring in Study JFCL 
in Section 9.4.1.2.1.4, 

the number of AEs with outcome death occurring in Study JFCL in Section 5,

dose modification guidelines for nonhematologic toxicities according to the 
Abraxane Summary of Product Characteristics in Section 9.4.1.2.3.2
(Nonhematologic Toxicities), and

guidance regarding hospitalization of patients with severe nausea and vomiting in 
Section 9.6.1.2 (Antiemetic Therapy).
Additionally, a deletion of the example non-life-threatening reversible Grade 3 and 4 toxicities in 
Section 9.4.1.2.1 was made, as fatigue and anorexia are not adverse drug reactions of 
necitumumab.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
5.
Introduction
…
In preclinical studies in mice with lung cancer xenografts, necitumumab in combination with 
paclitaxel and cisplatin has demonstrated a significant improvement in tumor volume growth 
delay, compared with the same chemotherapy alone and with single-agent necitumumab
(Preclinical Research, Eli Lilly and Company, 2009).
In a Phase 2 necitumumab clinical trial (Study I4X-MC-JFCL [JFCL]) of necitumumab as first-
line therapy in Stage IV squamous NSCLC, the addition of necitumumab to paclitaxel-
carboplatin (N+PC) resulted in an increased ORR compared to chemotherapy alone (PC) (48.9% 
versus 40.0%), indicating an add-on treatment effect for this combination. For PFS the treatment 
effect (as measured by the stratified HR) was 1.0 (95% CI:  0.71, 1.42) (median PFS:  5.4 versus 
5.6 months).  For OS, the median OS was 13.2 months for the N+PC Arm versus 11.2 months 
for the chemotherapy alone arm (PC Arm). The OS HR for the treatment effect was 0.83 (95% 
CI:  0.55, 1.52).
In the N+PC Arm, 10 patients (9.4%) had 11 AEs with an outcome of death (where the primary 
cause of death may or may not be the AE).  Seven of the 10 deaths occurred during the 
chemotherapy phase:  acute respiratory failure, lung infection, septic shock, circulatory collapse, 
respiratory failure, pulmonary embolism, brain death, and cardiac arrest (in 1 patient).  The other 
3 deaths were due to hypovolemic shock, cardiac failure congestive, and pneumonia.  All AEs 
were assessed by the investigator as not related to any study drug, with the exception of lung 
infection (assessed as related to chemotherapy only), respiratory failure (assessed as related to all 
study drugs), and circulatory collapse (unknown). In the PC Arm, 3 patients (5.5%) had 4 AEs 
with an outcome of death (all were assessed as not related to any study drugs) (one report each) 
of: death; sudden death; and pneumonia and sepsis (in 1 patient).
The OS analysis showed a higher rate of events for the necitumumab-containing arm during the 
first 4 months, with a later trend toward improved survival after 4 months.
The These preclinical data, the clinical efficacy of EGFR-directed mAbs in combination with 
taxanes and carboplatin, and the advantage of nab-PC over sb-PC in terms of safety and efficacy 
especially in squamous NSCLC together provide a strong rationale for the investigation of 
nab-PC in combination with necitumumab as first-line therapy in Stage IV squamous NSCLC.
More information about the known and expected benefits, risks and reasonably anticipated 
adverse events (AEs) of necitumumab may be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to necitumumab may be found in Section 7 
(Development Core Safety Information [DCSI]) of the IB.  Information on serious adverse 
events (SAEs) expected in the study population independent of drug exposure and that will be 

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assessed by the sponsor (Lilly) in aggregate, periodically during the course of the study, may be 
found in Section 6 (Effects in Humans) of the IB.
More detailed information about the known and expected benefits and risks of nab-paclitaxel 
may be found in the following:  Package Insert (Abraxane package insert, 2015) or Section 9.4.1.
More detailed information about the known and expected benefits and risks of carboplatin may 
be found in the following:  Package Insert (Carboplatin package insert, 2006 and 2015) or 
Section 9.4.1.
9.4.1.2.1.
Necitumumab Dose Modifications
In tThis section are provides general dose modification guidelines for toxicity associated with
necitumumab treatment. Refer to Sections 9.4.1.2.2, 9.4.1.2.1.1, 9.4.1.2.1.2, 9.4.1.2.1.3, 
9.4.1.2.1.4, and 9.4.1.2.1.5 for specific information on the management of and/or necitumumab 
dose adjustments due to AEs of concern that may or may not be associated with necitumumab
treatment, which include hypersensitivity/infusion-related reactions, skin reactions, 
conjunctivitis, electrolyte abnormalities, pneumonia and sepsis, and thromboembolic events.
Apart from the necitumumab dose adjustment recommendations specific to 
hypersensitivity/infusion-related reactions and skin reactions (Sections 9.4.1.2.2 and 9.4.1.2.1.1, 
respectively), stepwise dose reductions to 600 mg and 400 mg necitumumab may be considered 
for non-life-threatening reversible Grade 3 and 4 toxicities (for example, fatigue, anorexia, and 
fever) after treatment interruption and resolution to Grade ≤2.  After a dose reduction, the dose of 
necitumumab may be re-escalated to the previous dose after a minimum of 2 administrations of 
the reduced dose.  In case of toxicities necessitating more than 2 dose reductions, treatment with 
necitumumab should be permanently discontinued.
9.4.1.2.1.4.
Pneumonia and Sepsis   
During the conduct of Study JFCL (Phase 2 study to investigate carboplatin and solvent-based 
paclitaxel [not the albumin-bound formulation] with or without necitumumab in patients with 
squamous NSCLC), following the non-blinded review of SAE cases that included reports related 
to pneumonia and sepsis, an imbalance in the number of SAEs, including fatal cases, for the 
necitumumab group compared with the paclitaxel-carboplatin group was found. 
Special attention should be given to patients with clinical evidence of concimtant infectious 
conditions including early signs of active infections.  Treatment of any infection should be 
initiated according to local standards.
In Study JFCL, a Phase 2 study to investigate carboplatin and solvent-based paclitaxel with or
without necitumumab in patients with squamous NSCLC (106 versus 55 patients, 2:1 
randomization), a total of 16 SAEs of pneumonia/sepsis in the necitumumab plus paclitaxel-
carboplatin arm (N+PC Arm) (13 [12.3%] pneumonia, and 3 [2.8%] of sepsis) versus 5 SAEs in 
the paclitaxel-carboplatin alone arm (PC Arm) (3 [5.5%] pneumonia, 2 [3.6%] sepsis]) were 

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observed, including one fatal case in each arm.  No clear pattern with regard to time after first 
administration of trial medication (range: 4-233 days) or laboratory values for 
leukocytes/neutrophils could be identified.
The early occurrence of a number of cases of pneumonia/sepsis may have indicated an issue 
regarding the enrollment of the inappropriate patients.  The sponsor had therefore provided 
clarification and reinforcement of the inclusion/exclusion criteria, requesting the investigator’s 
particular attention with regard to infections and conditions predisposing to infections ongoing at 
the time of enrollment in a protocol amendment.  During the further conduct of this trial, only
single some additional reports were received, notably of cases reporting pneumonia and septic 
complications with concurrent neutropenia.
The review of the data from the Phase 3 study of necitumumab in combination with gemcitabine 
and cisplatin (Study JFCC; SQUIRE) did not show any evidence of an increased risk of serious 
lung infections or neutropenia associated with necitumumab in this combination.
Special attention should be given to early signs of pulmonary infection.  Treatment of any 
infection should be initiated according to local standards.
9.4.1.2.3.
Chemotherapy Dose Modifications
…
Refer to Table JFCP.2 for criteria pertaining to hematology, liver function, and renal function 
that, if not met, may require a dose delay or dose reduction of study treatment.  In addition, 
Table JFCP.5 should be used to determine dose reductions and treatment discontinuation of
nab-paclitaxel and carboplatin (as applicable) in case of hematological or neurologic toxicity. 
NOTE: Chemotherapy dose modifications are permanent; once the dose of nab-paclitaxel or 
carboplatin has been reduced, it will remain reduced or be further reduced in subsequent cycles.
…
9.4.1.2.3.1.
Hematological and Neurologic Toxicities
9.4.1.2.3.2.
Nonhematologic Toxicities
For Grade 2 or 3 cutaneous toxicity, Grade 3 diarrhea, or Grade 3 mucositis, interrupt treatment 
until the toxicity improves to Grade ≤1, then restart treatment according to the guidelines in 
Table JFCP.6.  For Grade ≥3 peripheral neuropathy, withhold treatment until resolution to Grade 
≤1.  Treatment may be resumed at the next lower dose level in subsequent cycles according to 
the guidelines in Table JFCP.6.  For any other Grade 3 or 4 non-hematologic toxicity, interrupt 
treatment until the toxicity improves to Grade ≤2, then restart treatment according to the 
guidelines in Table JFCP.6.

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Table JFCP.6.
Dose Modifications for Nonhematologic Toxicities
Adverse Drug Reaction
Occurrence
Weekly 
Nab-Paclitaxel Dose
(mg/m2)
Every-3-Week 
Carboplatin Dose
(AUC mg∙min/mL)
Grade 2 or 3 cutaneous toxicity
Grade 3 diarrhea
Grade 3 mucositis
Grade ≥3 peripheral neuropathy
Grade 3 or 4 nonhematologic toxicity
First
75
4.5
Second
50
3
Third
Discontinue treatment
Discontinue treatment
Grade 4 cutaneous toxicity, diarrhea, or 
mucositis
First
Discontinue treatment
Discontinue treatment
Abbreviations:  AUC = area under the concentration-time curve; nab-paclitaxel = paclitaxel protein-bound particles 
for injectable suspension (albumin-bound) (generic name for Abraxane).
Source:  Abraxane Summary of Product Characteristics, 2015.
9.6.1.2.
Antiemetic Therapy
The use of antiemetic agents is permitted during this study.  Patients with severe nausea and/or
vomiting must be hospitalized for I.V. hydration and correction of electrolyte imbalance.
14.
References
ABRAXANE Summary of Product Characteristics, 2015. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000778/WC500020435.pdf. Accessed on September 21, 2016.

Leo Document ID = 9e7e9a96-e4a1-462d-9201-b25d0a7b7cbe
Approver: 
Approval Date & Time: 23-Sep-2016 12:38:51 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 25-Sep-2016 23:55:04 GMT
Signature meaning: Approved
PPD
PPD