A Single-Arm, Multicenter, Phase 1b Study With an Expansion Cohort to Evaluate Safety and Efficacy of Necitumumab in Combination With Abemaciclib in Treatment of Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung, Neoplasm Metastasis
Sponsor: Eli Lilly and Company

I4X-MC-JFCU(b) 
A Single-Arm, Multicenter, Phase 1b Study with an Expansion Cohort to Evaluate Safety and 
Efficacy of Necitumumab in Combination with Abemaciclib in Treatment of Patients with Stage 
IV Non-Small Cell Lung 
Cancer (NSCLC) 
 
NCT02411591  
 
Approval Date: 12-May-2016 
 
 
 

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1.
Protocol I4X-MC-JFCU(b)
A Single-Arm, Multicenter, Phase 1b Study with an 
Expansion Cohort to Evaluate Safety and Efficacy of 
Necitumumab in Combination with Abemaciclib in 
Treatment of Patients with Stage IV Non-Small Cell Lung 
Cancer (NSCLC)
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
necitumumab (LY3012211) or abemaciclib (LY2835219), 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), Abemaciclib (LY2835219)
This is a single-arm Phase 1b study with an expansion cohort in patients with Stage IV non-small cell lung 
cancer (NSCLC). The study consists of 2 parts (Part A and Part B). Part A is a single-arm, open-label, 
dose-escalation study to determine the recommended dose of abemaciclib in combination with 
necitumumab for Part B (expansion cohort).  Part B is an open-label study to evaluate the efficacy and 
safety of necitumumab in combination with abemaciclib.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 11 December 2014.
Amendment (a) Electronically Signed and Approved by Lilly on 10 June 2015.
Amendment (b) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 12-May-2016 GMT

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2.
Synopsis
Study Rationale
Necitumumab (IMC-11F8; LY 3012211; Portrazza®) is a recombinant human monoclonal 
antibody (mAb) of the immunoglobulin G, subclass 1 (IgG1) that blocks the ligand-binding site 
of the epidermal growth factor receptor (EGFR). EGFR is detectable in approximately 85% of 
patients with advanced, metastatic non-small cell lung cancer (NSCLC). Necitumumab has 
shown signals of antitumor activity in 2 Phase 1 trials when administered as monotherapy in
heavily pretreated patients including but not limited to patients with NSCLC. Portrazza has 
recently been approved in the United States (US) and European Union (EU) for the treatment of 
adult patients with metastatic squamous NSCLC in combination with gemcitabine and cisplatin.  
The cetuximab FLEX Phase 3 trial has demonstrated a statistically significant improvement in
survival for the combination of an EGFR mAb in combination with chemotherapy in the first-
line treatment of patients with advanced metastatic NSCLC.
Abemaciclib, a selective and potent small molecule inhibitor of CDK4/6, prevents cell cycle 
progression through the G1 restriction point, thus arresting tumor growth. Abemaciclib has 
shown single-agent antitumor activity in a Phase 1 trial in heavily pretreated patients with 
NSCLC.
Necitumumab and abemaciclib inhibit tumor progression by different, independent modes of 
action (cell surface and cell nucleus, respectively), where necitumumab blocks the 
ligand-binding site of the EGFR and abemaciclib blocks DNA synthesis by prohibiting cell cycle 
progression from G1- to S-phase.
A xenograft tumor cell-line model has shown an add-on effect of necitumumab to abemaciclib
where the combination was more effective when compared to the activity of either drug alone.
The individual toxicity profile from clinical trials with each of the compounds (that is, 
necitumumab and abemaciclib) suggests that no or only marginal overlapping toxicity is 
expected.  The most common Grade 3 adverse events (AEs; > 5% of patients) for single-agent 
abemaciclib were leukopenia and neutropenia.  For necitumumab single agent, the most frequent 
AEs reported were skin reactions (in terms of rash) and hypomagnesemia.
Different mode of actions, preclinical data, and the clinical efficacy of necitumumab as well as 
other EGFR mAbs and abemaciclib in NSCLC provide a rationale for the investigation of 
necitumumab in combination with abemaciclib in patients with Stage IV NSCLC.
The purpose of this Phase 1b study with an expansion cohort is to explore the safety and 
preliminary efficacy of necitumumab plus abemaciclib in patients with Stage IV NSCLC who 
have received no more than 2 lines of chemotherapy of which at least one must be 
platinum-based.

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Clinical Protocol Synopsis:  Study I4X-MC-JFCU
Name of Investigational Product:  Necitumumab (LY3012211) and Abemaciclib (LY2835219)
Title of Study:  A Single-Arm, Multicenter, Phase 1b Study with an Expansion Cohort to Evaluate Safety and 
Efficacy of Necitumumab in Combination with Abemaciclib in Treatment of Patients with Stage IV Non-Small 
Cell Lung Cancer (NSCLC)
Number of Planned Patients:
Part A
   Enrolled: 3 to 18
Part B (Expansion Cohort)
   Enrolled: 50
Phase of Development:  1b
Length of Study:  approximately 21 months
Planned first patient visit:  08 Sep 2015
Planned last patient visit:  19 Jun 2017
Planned interim analyses:  first 15 evaluable patients in Part B portion of the study who have completed 2 cycles of 
study treatment (or otherwise discontinued study treatment) will be analyzed for safety. Interim analyses for 
efficacy may be performed as needed to aid in the planning of future trials.  Patients with squamous and 
nonsquamous NSCLC who received the recommended abemaciclib dose for Part B in Part A will be taken into 
account for the interim analyses.
Objectives:
The primary objectives of the study are:
Part A: to determine the dose-limiting toxicity (DLT) of abemaciclib at doses up to 200 mg when combined with 
necitumumab 800 mg, in patients with Stage IV NSCLC as measured by the number of patients with a DLT in 
Cycle 1.
Part B: to evaluate the efficacy of necitumumab in combination with abemaciclib in terms of progression-free 
survival (PFS) rate at 3 months in patients with Stage IV NSCLC.
The secondary objectives of the study are:
Part A:

to investigate the safety profile as assessed by clinical and laboratory significant events of necitumumab in 
combination with abemaciclib

to determine the objective response rate (ORR)

to determine the pharmacokinetics (PK) of necitumumab and abemaciclib

to determine the immunogenicity of necitumumab
Part B: to demonstrate the safety, efficacy, and feasibility of necitumumab in combination with abemaciclib at the 
recommended dose by:

determining PFS

determining the ORR and disease control rate (DCR)

estimating overall survival (OS)

investigating the safety profile as assessed by clinical and laboratory significant events of necitumumab in 
combination with abemaciclib

determining the PK of necitumumab and abemaciclib

determining the immunogenicity of necitumumab
The exploratory objective is to further evaluate as follows:
Parts A and B:  to correlate biomarkers with clinical outcomes, including, but not limited to, KRAS mutation 
assessment, EGFR protein expression, and/or other biomarkers associated with the disease pathobiology, the cell
cycle, EGFR pathway, and/or the mechanism of action of the therapeutic molecules.

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Study Design: This is a single-arm, multicenter Phase 1b study with an expansion cohort to investigate 
necitumumab in combination with abemaciclib in approximately 70 patients with Stage IV NSCLC (American 
Joint Committee on Cancer Staging Manual, 7th edition).  The study consists of 2 parts:

Part A:  Dose-escalation part with increasing doses of abemaciclib (100 mg, 150 mg, or 200 mg every 
12 hours [Q12H] on Days 1 to 21) to determine a recommended dose range for abemaciclib that may be 
safely administered in combination with a fixed regimen of necitumumab 800 mg Days 1 and 8 every 
21 days in patients with Stage IV NSCLC.

Part B (expansion cohort):  Dose confirmation of abemaciclib in combination with a fixed regimen of 
necitumumab 800 mg on Days 1 and 8 every 21 days and exploration of clinical antitumor activity.
Approximately 50 patients will be enrolled in Part B: approximately 25 patients with squamous histology and
approximately 25 patients with nonsquamous histology.
Patients will be treated until progressive disease, toxicity requiring cessation, protocol noncompliance, or 
withdrawal of consent.  Patients who are on study therapy at study completion may continue to receive study 
therapy in the extension phase until they meet the discontinuation criteria. Study completion is expected to be
approximately 5 months after the last patient has been enrolled.
Diagnosis and Main Criteria for Inclusion and Exclusions:
Key inclusion/exclusion criteria at the time of enrollment
•
The patient has Stage IV NSCLC.
Part A: NSCLC Stage IV (any type)
Part B: NSCLC Stage IV (squamous and nonsquamous)
•
The patient must have progressed after platinum-based chemotherapy AND have received a maximum of 
1 other prior chemotherapy for advanced and/or metastatic disease OR must be judged by the physician as 
ineligible for further standard second-line chemotherapy. Prior treatment with EGFR-tyrosine kinase 
inhibitor and anaplastic lymphoma kinase (ALK) inhibitors is mandatory in patients whose tumor has an 
EGFR activating mutations or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant
therapies are permitted with the exception of CDK4/6-targeting agents or necitumumab.
•
Measurable disease at the time of study entry as defined by Response Evaluation Criteria In Solid Tumors
version 1.1 (RECIST 1.1).
•
The patient has tumor tissue available for biomarker analyses.
•
The patient has resolution to Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤1 of all 
clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy (with the exception of 
alopecia).
•
Eastern Cooperative Oncology Group performance status score of 0-1.
•
The patient has no brain metastases that are symptomatic.
Test Product, Dosage, and Mode of Administration:

Necitumumab is a sterile, preservative-free, intravenous infusion supplied in 50-mL vials containing 
16 mg/mL (800 mg/50 mL) of product, and administered at a dose of 800 mg on Days 1 and 8 of each 21-day
cycle.

Abemaciclib is administered orally as capsules (supplied for clinical trial use in strength of 50 mg/capsule) 
every 12 hours.  In Part A, abemaciclib will be administered at increasing doses of 100, 150, or 200 mg Q12H 
on Days 1 to 21.  In Part B, abemaciclib will be administered at a fixed dose determined in Part A of the study
Q12H on Days 1 to 21.
Reference Therapy, Dose, and Mode of Administration:
Not Applicable

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Planned Duration of Treatment:
Baseline period:  21 days
Treatment period: 21 days treatment cycle.
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  begins the day after short-term follow-up is completed and continues 
until the patient’s death or overall study completion
Study Completion: approximately 5 months after the last patient qualified for Part B of the study has enrolled
Study Extension:  Patients who are on study therapy at study completion may continue to receive study therapy in 
the extension phase until they meet the discontinuation criteria.
Criteria for Evaluation:
Progression-Free Survival (PFS) is defined as the time from the date of enrollment until the date of 
radiographically documented progressive disease (PD) or death due to any cause, whichever is earlier.
Overall Survival (OS) is defined as the time from the date of study enrollment to the date of death from any 
cause.
Objective Response Rate (ORR) is defined as the proportion of patients achieving a best overall response of 
partial response (PR) or complete response (CR).
Disease Control Rate (DCR) is defined as the proportion of patients achieving a best overall response of stable 
disease (SD), PR, or CR.
Safety:
Part A: DLTs, serious adverse events (SAEs), AEs, vital sign measurements, laboratory analyses, and 
electrocardiograms (ECGs)
Part B: SAEs, AEs, vital sign measurements, laboratory analyses, and ECGs
Pharmacokinetics:
Pharmacokinetics parameters, including, but not limited to, maximum concentration, area under the concentration-
time curve, and terminal half-life for abemaciclib (Part A only). Descriptive summary of exposure for abemaciclib 
in Part B, as well as for necitumumab in both Part A and Part B.
Bioanalytical:
Serum concentrations of necitumumab will be measured using a validated enzyme-linked immunosorbent assay
bioanalytical method.  Plasma concentrations of abemaciclib and metabolites will be measured using a validated 
liquid chromatography–tandem mass spectrometry method.
Immunogenicity:
Serum for analysis of antibodies against necitumumab (immunogenicity)
Translational Research:
A tumor tissue block or tumor tissue slides will be collected to correlate biomarker results with clinical outcomes, 
including, but not limited to, KRAS mutation assessment, EGFR protein expression, and/or other biomarkers 
associated with the disease pathobiology and therapeutic molecules.
Blood samples (EDTA-anticoagulated plasma) will be collected for exploratory biomarker analyses.

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Statistical Methods:
Efficacy:  The primary Part B outcome variable in this study will be the 3-month PFS rate, as estimated by the 
Kaplan Meier method. The Part B statistical null hypothesis states that the true 3-month PFS rate is 50%, whereas 
the research hypothesis states that the true 3-month PFS rate is 65%.  Assuming the Part B portion of the study
continues to a full enrollment of 50 evaluable patients, the null hypothesis will be rejected at the final analysis only 
if at least 60% of evaluable patients experience PFS ≥ 3 months.  If the research hypothesis is true, there is an 81% 
chance of reaching full Part B enrollment and rejecting the null hypothesis.  If the null hypothesis is true, then there 
is a 10% chance of reaching full Part B enrollment and rejecting the null hypothesis.  Therefore, the Part B portion 
of this study has a one-sided alpha level of 0.10, with statistical power of 81%.
Safety:  Safety analyses will be performed for all patients enrolled in the study who receive any amount of study
drug (necitumumab or abemaciclib).  Numbers and rates of AEs will be reported by National Cancer Institute 
CTCAE terms. Laboratory and nonlaboratory 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 
regardless of study drug causality, and repeated for events deemed by the investigator to be possibly related to 
study medication. Adverse events will be summarized by Medical Dictionary for Regulatory Activities™) System 
Organ Class (SOC), by decreasing frequency of Preferred Term within SOC. Other safety parameters will be 
summarized as appropriate.
A safety interim analysis will be performed after the first 15 evaluable patients in the Part B portion of the trial 
have completed 2 cycles of study treatment (or otherwise discontinued study treatment).  Patients with squamous 
and nonsquamous NSCLC who received the recommended abemaciclib dose for Part B in Part A will be taken into 
account for the interim analyses.  The safety interim analysis will be conducted to permit evaluation of safety data 
by the sponsor.
Interim analyses for efficacy may be performed as needed to aid in the planning of future trials.  There is no plan to 
stop the study for positive efficacy.  The type-1 error for final primary analysis will not be affected and hence is 
not adjusted.
Immunogenicity: Incidence of anti-necitumumab antibodies will be tabulated.
Pharmacokinetics:  Pharmacokinetic parameters of abemaciclib and necitumumab in Part A will be calculated 
using noncompartmental analysis (NCA) methodology as applied in Phoenix WinNonlin (version as validated by 
PK/pharmacodynamic standard operating procedures at the time of analysis). Summary level data for Part B will 
be presented as graphics and table listings. Additional analysis of data through mixed-effects modeling through 
NONMEM or similar software may be applied.
Translational research:  Translational research will be performed to analyze relevant biomarkers and to correlate 
them with clinical outcome.

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3.
Table of Contents
A Single-Arm, Multicenter, Phase 1b Study with an 
Expansion Cohort to Evaluate Safety and Efficacy of 
Necitumumab in Combination with Abemaciclib in Treatment 
of Patients with Stage IV Non-Small Cell Lung Cancer 
(NSCLC)
Section
Page
1.
Protocol I4X-MC-JFCU(b) A Single-Arm, Multicenter, Phase 1b 
Study with an Expansion Cohort to Evaluate Safety and Efficacy of 
Necitumumab in Combination with Abemaciclib in Treatment of 
Patients with Stage IV Non-Small Cell Lung Cancer (NSCLC)...........................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................14
5.
Introduction ......................................................................................................................19
5.1.
Non-Small Cell Lung Cancer .......................................................................................19
5.2.
Necitumumab...............................................................................................................20
5.3.
Abemaciclib.................................................................................................................22
5.4.
Study Rationale............................................................................................................23
6.
Objectives.........................................................................................................................25
6.1.
Primary Objective ........................................................................................................25
6.2.
Secondary Objectives...................................................................................................25
6.3.
Exploratory Objectives.................................................................................................25
7.
Study Population...............................................................................................................26
7.1.
Inclusion Criteria..........................................................................................................26
7.2.
Exclusion Criteria ........................................................................................................28
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................29
7.3.
Discontinuation............................................................................................................30
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................30
7.3.2.
Discontinuation From Study Therapy...................................................................30
7.3.3.
Discontinuation from the Study............................................................................31
7.3.4.
Patients who are Lost to Follow-Up .....................................................................31
7.3.5.
Discontinuation of Study Sites .............................................................................31
7.3.6.
Discontinuation of the Study................................................................................31
8.
Investigational Plan...........................................................................................................32
8.1.
Summary of Study Design............................................................................................32

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8.1.1.
Study Completion and End of Trial......................................................................35
8.1.2.
Continued Access Period......................................................................................36
8.2.
Discussion of Design and Control ................................................................................37
9.
Treatment..........................................................................................................................38
9.1.
Treatments Administered .............................................................................................38
9.2.
Materials and Supplies .................................................................................................39
9.3.
Method of Assignment to Treatment ............................................................................40
9.3.1.
Selection and Timing of Doses.............................................................................40
9.3.2.
Special Treatment Considerations ........................................................................40
9.3.2.1.
Dose-Limiting Toxicity (Part A).....................................................................40
9.3.2.2.
Dose Adjustments and Delays ........................................................................41
9.3.2.2.1.
Abemaciclib..............................................................................................41
9.3.2.2.1.1.
Guidance for Monitoring of Renal Function in 
Patients on Abemaciclib......................................................................42
9.3.2.2.2.
Necitumumab ...........................................................................................42
9.3.2.2.3.
Necitumumab Dose Modifications............................................................43
9.3.2.2.3.1.
Treatment Guidelines and Dose Modifications for 
Specific Adverse Events of Necitumumab...........................................44
9.4.
Blinding .......................................................................................................................49
9.5.
Concomitant Therapy...................................................................................................49
9.5.1.
Supportive Care ...................................................................................................50
9.5.2.
Colony-Stimulating Factors and Erythropoiesis-Stimulating 
Agents..................................................................................................................50
9.5.3.
Therapy for Diarrhea............................................................................................50
9.5.4.
Antiemetic Therapy..............................................................................................51
9.5.4.1.
Analgesic Agents............................................................................................51
9.5.5.
Bisphosphonates and RANK-L Targeted Agents..................................................51
9.5.6.
Therapy for Febrile Neutropenia ..........................................................................51
9.6.
Treatment Compliance .................................................................................................51
10.
Efficacy, Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements.....................................................................................53
10.1. Efficacy Measures........................................................................................................53
10.1.1.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................53
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................54
10.1.3.
Primary Efficacy Measure (Part B only)...............................................................54
10.1.4.
Secondary Efficacy Measures...............................................................................54

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10.1.5.
Disease Control Rate (DCR):  The proportion of patients 
achieving a best overall response of SD, PR, or CR.  
Resource Utilization.............................................................................................55
10.2. Safety Evaluations........................................................................................................55
10.2.1.
Adverse Events ....................................................................................................56
10.2.1.1.
Serious Adverse Events ..................................................................................57
10.2.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................58
10.2.2.
Other Safety Measures .........................................................................................59
10.2.2.1.
Electrocardiograms.........................................................................................59
10.2.3.
Safety Monitoring ................................................................................................59
10.2.4.
Complaint Handling.............................................................................................60
10.3. Sample Collection and Testing.....................................................................................60
10.3.1.
Samples for Study Qualification and Health Monitoring.......................................60
10.3.2.
Samples for Pharmacogenetics and Translational Research ..................................61
10.3.2.1.
Samples for Pharmacogenetic Evaluation .......................................................61
10.3.2.2.
Archived Tumor Tissue Collection .................................................................62
10.3.2.3.
Plasma Sample Collection ..............................................................................63
10.3.3.
Samples for Immunogenicity Research.................................................................63
10.3.4.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................63
10.4. Appropriateness of Measurements................................................................................64
11.
Data Quality Assurance.....................................................................................................65
11.1. Data Capture System....................................................................................................65
12.
Sample Size and Statistical Methods .................................................................................66
12.1. Determination of Sample Size ......................................................................................66
12.2. Statistical and Analytical Plans.....................................................................................66
12.2.1.
General Considerations ........................................................................................66
12.2.2.
Patient Disposition...............................................................................................66
12.2.3.
Patient Characteristics..........................................................................................67
12.2.4.
Concomitant Therapy...........................................................................................67
12.2.4.1.
Postdiscontinuation Therapy...........................................................................67
12.2.5.
Treatment Compliance .........................................................................................67
12.2.6.
Primary Outcome and Methodology.....................................................................67
12.2.6.1.
Analyses of Efficacy.......................................................................................67
12.2.7.
Pharmacokinetic and Immunogenicity Analyses...................................................68
12.2.8.
Translational Research Analyses..........................................................................69
12.2.9.
Safety Analyses....................................................................................................69
12.2.10. Interim Analyses..................................................................................................70

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13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................71
13.1. Informed Consent.........................................................................................................71
13.2. Ethical Review.............................................................................................................71
13.3. Regulatory Considerations ...........................................................................................71
13.3.1.
Investigator Information.......................................................................................72
13.3.2.
Protocol Signatures ..............................................................................................72
13.3.3.
Final Report Signature .........................................................................................72
14.
References ........................................................................................................................73

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List of Tables
Table
Page
Table JFCU.9.1.
Treatment Regimens/Dosing Schedule ...................................................38
Table JFCU.9.2.
Dose Adjustments of Abemaciclib..........................................................42
Table JFCU.9.3.
NCI-CTCAE 4.0 Infusion-Related Reactions..........................................45
Table JFCU.9.4.
Managing Skin Reactions .......................................................................47
Table JFCU.10.1.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........56
Table JFCU.12.1.
Definitions of Key Efficacy Statistics .....................................................68

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List of Figures
Figure
Page
Figure JFCU.8.1.
Illustration of study design......................................................................33
Figure JFCU.8.2.
Study period and continued access diagram. ...........................................36

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JFCU Study Schedule...............................................................75
Attachment 2.
Protocol JFCU Clinical Laboratory Tests................................................84
Attachment 3.
Protocol JFCU Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................85
Attachment 4.
Protocol JFCU ECOG Performance Status .............................................86
Attachment 5.
Protocol JFCU Creatinine Clearance Formula.........................................87
Attachment 6.
Protocol JFCU RECIST Criteria 1.1 .......................................................88
Attachment 7.
Protocol JFCU Pharmacokinetic, Immunogenicity, and Blood-
Based Markers Sampling  Schedule........................................................95
Attachment 8.
Protocol JFCU Inducers and Strong Inhibitors of CYP3A4 or 
Substrates of CYP2B..............................................................................99
Attachment 9.
Protocol JFCU Amendment (b) Summary.............................................100

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4.
Abbreviations and Definitions
Term
Definition
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
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
assent
Agreement from an individual who is not legally capable of providing consent, but who 
can understand the circumstances and risks involved in participating in a study 
AST
aspartate aminotransferase
ATE
arterial thromboembolic event
AUC
area under the 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).
CDK
cyclin dependent kinases
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.
companion diagnostic
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product
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 treatment until one of the criteria for discontinuation is met. 

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CR
complete response
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.
CrCl
creatinine clearance
CSF
colony-stimulating factor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been 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
FFPE
formaldehyde fixed-paraffin embedded
FSH
follicle-stimulating hormone
GC
gemcitabine/cisplatin

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GC+N
gemcitabine/cisplatin plus necitumumab
GCP
good clinical practice
H0
null hypothesis
Ha
alternative hypothesis
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
Ig
immunoglobulin
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical trial data, that is conducted before the final 
reporting database is created/locked.
investigational 
product (IP)
[hereon referred to as 
study treatment]
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.  Investigational product (IP) includes a product 
with a marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from the 
authorized form,
2.
used for an unauthorized indication, or 
3.
used to gain further information about the authorized form.
In this study, the IPs are necitumumab (LY3012211; IMC-11F8) and abemaciclib 
(LY2835219).
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.
I.V.
intravenous(ly)
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
mAb
monoclonal antibody

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MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PC
pemetrexed - cisplatin
PC+N
necitumumab plus pemetrexed - cisplatin
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PI
package insert
PK
pharmacokinetic(s)
PR
partial response
PT
Preferred Term
Q12H
every 12 hours
Rb
retinoblastoma
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

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screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical 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
SmPC
Summary of Product Characteristics
SOC
System Organ Class
Study completion
This study will be considered complete 5 months after the last patient in Part B of the 
study has been enrolled.  
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
TKI
tyrosine kinase inhibitor
ULN
upper limits of normal
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event

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A Single-Arm Multicenter, Phase 1b Study with an Expansion 
Cohort to Evaluate Safety and Efficacy of Necitumumab in 
Combination with Abemaciclib in Advanced Treatment of 
Patients with Stage IV Non-Small Cell Lung Cancer (NSCLC)
5.
Introduction
5.1.
Non-Small Cell Lung Cancer
Lung cancer is the most common cancer worldwide, with an estimated 1.6 million new cases per 
year, and the leading cause of cancer-related mortality with an estimated 1.4 million cancer-
related deaths per year (Bray et al. 2012; Bunn 2012).
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers.  
Patients with localized disease have a 5-year survival rate of approximately 55%; however, 
5-year survival drops significantly for patients with regional (26.1%) or distant (3.9%) disease at 
diagnosis (Howlader et al. 2013).
Current standard first-line chemotherapy for patients with advanced or metastatic NSCLC and a 
good performance status consists of a platinum-based doublet, using either cisplatin or 
carboplatin in combination with pemetrexed (only for nonsquamous NSCLC), taxanes, 
vinorelbine, or gemcitabine. The combination of a platinum-doublet with the anti-vascular 
endothelial growth factor (VEGF) antibody bevacizumab is a treatment option for nonsquamous 
patients only. Induction chemotherapy maybe followed by maintenance therapy, administered 
either as switch- or continuation maintenance. Second-line treatment options after failure of 
first-line chemotherapy with or without maintenance treatment consists of monotherapy with 
either docetaxel, erlotinib, or pemetrexed depending on type of prior treatment. Lately, an anti-
vascular endothelial growth factor receptor 2 (VEGFR2) antibody, ramucirumab, in combination 
with docetaxel was approved in the US and EU for the second-line treatment of metastatic 
NSCLC, including squamous and nonsquamous histologies (Cyramza Summary of Product 
Characteristics [SmPC]/US package insert [USPI]).  Recently, monoclonal antibodies (mAbs) 
directed against programmed death-1 (PD-1) T-cell co-receptor, nivolumab and pembrolizumab, 
have been approved in the US for the treatment of patients with metastatic NSCLC with 
progression on or after platinum-based chemotherapy, whereby pembrolizumab was approved 
for the treatment of those NSCLC patients whose tumors express PD-L1 as determined by an 
FDA-approved test (Opdivo USPI, Keytruda USPI). In the EU nivolumab is available for the 
treatment of adult patients with locally advanced or metastatic NSCLC after prior chemotherapy
(Opdivo SmPC). For patients with tumors harboring epidermal growth factor receptor (EGFR)-
tyrosine kinase inhibitor (TKI)-activating mutations, monotherapy with an EGFR TKI is used 
upfront, followed by osimertinib (Tagrisso PI) in patients with EGFR T790M mutation-positive 
cancer or a platinum-based doublet as second-line, or as second- or third-line treatment if not 
used previously. For patients with anaplastic lymphoma kinase (ALK)-gene arrangement, 
treatment should include monotherapy with an ALK inhibitor (Heigener et al. 2014).

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Despite the advancement of systemic treatments for patients with advanced or metastatic 
NSCLC, the available therapeutic options remain limited and the prognosis of the patients is 
poor, resulting in a continued medical need for new treatment options.
5.2.
Necitumumab
Necitumumab (LY3012211) is a recombinant human mAb of the immunoglobulin (Ig) G1 class, 
which targets EGFR.  Necitumumab demonstrates a high affinity to its target and blocks ligand-
induced receptor phosphorylation and downstream signaling. In vitro studies further 
demonstrate that necitumumab inhibits EGFR-dependent tumor cell proliferation, and can exert 
cytotoxic effect in tumor cells through antibody-dependent cell cytotoxicity.
EGFR is expressed in a variety of tumors, including colorectal, head and neck, breast, and 
NSCLC (Salomon et al 1995).  In patients with advanced and metastatic NSCLC, EGFR is 
detectable in approximately 85% to 90% of patients (Fontanini et al 1995; Pirker et al 2009).  
Pharmacologic inhibition of EGFR signaling through competitive inhibition of ligand binding 
has been shown to play a role in the treatment of several cancers, leading to registration of 
necitumumab in squamous NSCLC and 2 other anti-EGFR mAbs in a number of other 
indications (Necitumumab/Portrazza SmPC, Cetuximab/Erbitux SmPC, Panitumumab/Vectibix 
SmPC). Moreover, another randomized Phase 3 trial, conducted with cetuximab, showed
evidence that the addition of an EGFR mAb to a platinum-based doublet can significantly 
increase survival in patients with advanced NSCLC (Pirker et al. 2009).
The necitumumab Phase 1 program included 2 single-agent dose-escalation Phase 1 trials in 
Western (I4X-IE-JFCE [JFCE]) and Japanese (I4X-IE-JFCA [JFCA]) patients with advanced 
solid tumors or for whom no standard therapy was available.
Study JFCE included 60 patients and investigated necitumumab intravenous (I.V.) once a week 
(Arm A, n=29) or once every 2 weeks (Arm B, n=31) at sequential absolute dose levels from 
100 mg to 1000 mg. No dose-limiting toxicities (DLTs) were observed in Arm A, which 
included 9 patients treated at 1000 mg.  Grade 3 headache was the major DLT, occurring in 2 of 
9 patients in the 1000-mg dose cohort of Arm B. Because of the timely relationship to the first 
dose of necitumumab, these were considered to be dose-related and the dose level of 800 mg was 
defined as the maximum tolerated dose (MTD) for both schedules. Grade ≥3 adverse events 
(AEs) considered at least possibly related to necitumumab affected 10.3% (n = 3) of patients in 
Arm A and 22.6% (n = 7) of patients in Arm B. Overall, the most common related Grade ≥3 
AEs were fatigue (4 patients; 2 patients each in Arm A and Arm B); headache (2 patients in Arm 
B), and acne (2 patients, 1 patient each in Arm A and Arm B); others included anemia, diarrhea, 
nausea, vomiting, hypokalemia, and decreased blood magnesium (1 patient each, all in Arm B). 
No Grade 5 necitumumab-related AEs were observed in this study.
In Study JFCA, 15 patients were enrolled and treated (Cohort 1: 600 mg necitumumab on Days 1 
and 8 of a 3-week cycle, n = 3; Cohort 2: 800 mg every 2 weeks, n = 6; and Cohort 3: 800 mg on 
Days 1 and 8 of a 3-week cycle, n = 6). No DLTs were observed in this study during the first 6-
week cycle for any cohort.  The most common treatment-emergent AEs (TEAEs) regardless of 
grade or relationship to study therapy were headache (n = 11; 73.3%), dry skin (n = 10; 66.7%), 

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pruritus (n = 9; 60.0%), and rash (n = 8; 53.3%). One patient in Cohort 2 experienced 2 related 
Grade 3 TEAEs of dry skin and rash; all other related events observed in the study were Grade 
≤2.
Signals of antitumor activity of necitumumab monotherapy were observed in both studies with 
heavily pretreated patients.  For Study JFCE, in total 2 partial response (PR) and 16 stable 
disease (SD; 1 PR, 8 SD for each treatment arm) were observed (disease control rate [DCR]
Arm A 31%, Arm B 29%). For Study JFCA, SD was seen within all cohorts in a total of 
10 patients (DCR 66.7%), including 1 patient with squamous NSCLC and 1 patient with 
nonsquamous NCLC.
Based on both Phase 1 trials, the recommended necitumumab dosing schedule is 800 mg once 
every week, once every 2 weeks, or on Days 1 and 8 of a 3-week cycle.
The pivotal, randomized Phase 3 trial SQUIRE (I4X-IE-JFCC) compared gemcitabine/cisplatin 
plus necitumumab (GC+N) versus gemcitabine/cisplatin (GC) as first-line therapy in 1093 
patients with Stage IV squamous NSCLC (Thatcher et al. 2015).  The study met its primary 
objective, demonstrating a statistically significant improvement in overall survival (OS) in the 
GC+N Arm compared with the GC Arm (hazard ratio [HR] = 0.84; p=0.012). This was 
supported by a statistically significant improvement in progression-free survival (PFS;
HR = 0.85; p=0.02). Several prespecified subgroup analyses for OS and PFS showed a 
consistent treatment effect in favor of GC+N. Post-progression anticancer therapy was similar 
(47% vs. 45%). The safety data obtained in SQUIRE overall were consistent with the safety 
profile expected for an anti-EGFR mAb, with skin reactions (any grade: 79% vs. 12%, including 
Grade ≥3:  8.2% vs. 0.6%) and hypomagnesemia (any grade: 31% vs. 16%, including 
Grade ≥39.3% vs. 1.1%) being the most frequently reported events (pooled terms) occurring at 
higher rates for patients receiving necitumumab. The Grade ≥3 TEAEs with highest incidence 
for which incidence was higher in the necitumumab arm than in the control arm were 
hypomagnesemia (8.7% vs. 1.1%), rash (3.7% vs. 0.2%), pulmonary embolism (3.5% vs. 1.8%), 
hypokalemia (3.0% vs. 1.5%), and vomiting (2.8% vs. 0.9%).
In another randomized Phase 3 trial, INSPIRE (I4X-IE-JFCB [JFCB]), 947 patients were 
planned to be randomly assigned to necitumumab plus pemetrexed - cisplatin (PC+N) versus 
pemetrexed - cisplatin (PC) as first-line therapy for Stage IV nonsquamous NSCLC (Paz-Ares et 
al. 2013).  Enrollment was halted, following an independent data monitoring committee (IDMC)
recommendation, after 633 patients because of safety concerns related to thromboembolism as 
well as the overall number of deaths from all causes that were unbalanced against the 
experimental group; the trial continued for patients that had been enrolled. Based on the final 
analysis, PC+N did not improve the efficacy outcome over PC alone in advanced nonsquamous
NSCLC (OS HR 1.01, p=0.96; PFS HR 0.96, p=0.66). The addition of necitumumab resulted in 
a higher frequency of Grade ≥3 TEAEs. Grade ≥3 TEAEs occurring more frequently in the 
necitumumab arm included skin or subcutaneous disorders (14.1 vs. 0.3%), thromboembolic 
events (9.5 vs. 6.4%), hypomagnesaemia (7.6 vs. 2.2%), asthenia (6.9 vs. 1.9%), vomiting (6.6 
vs. 3.2%), dyspnea (5.3 vs. 2.6%), and diarrhea (4.3 vs. 2.2%). The frequency of study drug 
related deaths was 4.9% and 2.9% for PC+N and PC, respectively.

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Based on these data, the combination of necitumumab plus pemetrexed-cisplatin is not being 
considered for further development. Of note, no safety signal with regard to thromboembolic or 
potential thromboembolic events, including fatal events, has been identified for necitumumab in 
completed clinical trials when administered as monotherapy or in combination with mFOLFOX6 
chemotherapy.
The randomized Phase 2 trial, I4X-MC-JFCL (JFCL), compared paclitaxel-carboplatin plus 
necitumumab versus paclitaxel-carboplatin in the first-line treatment of patients with Stage IV 
squamous NSCLC. The overall efficacy and safety results were generally consistent with those 
of SQUIRE. Study I4X-JE-JFCM is a Phase 1b/2 study in Japanese patients with Stage IV 
squamous NSCLC that compares necitumumab plus gemcitabine-cisplatin versus gemcitabine-
cisplatin alone. The trial is monitored by an IDMC and continues as planned.
For more details regarding the necitumumab development program, reference is made to the 
Investigator Brochure (IB).
5.3.
Abemaciclib
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
regulation of cell division (Sherr 1996; Ortega et al. 2002).  The CDK4/6 – cyclin D1 complex 
regulates the G1 restriction point through phosphorylation and inactivation of the retinoblastoma 
(Rb) tumor suppressor protein.  Except for tumors with functional loss of Rb, which functions 
downstream of the CDK4/6 – cyclin D1 complex, most cancers are potentially sensitive to 
pharmacologic inhibition of CDK4/6.
Abemaciclib (LY2835219) represents a selective small molecule inhibitor of CDK4/6.  It 
demonstrates antitumor activity in multiple mouse models of human cancer, physical and 
pharmacokinetic (PK) properties suitable for drug development, and an acceptable toxicity 
profile in nonclinical species. This compound inhibits tumor growth in multiple human 
xenograft models including, but not limited to, the following tumor types:  1) colorectal cancer, 
2) glioblastoma multiforme, 3) acute myeloid leukemia, 4) NSCLC, and 5) mantle cell 
lymphoma. Recent studies with abemaciclib in murine models bearing human xenografts 
provide support for the relationship for lung adenocarcinomas in xenograft models, which all 
express an activated KRAS oncogene. Models that expressed an activated KRAS oncogene were 
observed to be the most sensitive to growth inhibition. Models that expressed a wild-type KRAS
gene were observed to be among the least sensitive of the lung adenocarcinoma models to 
growth inhibition by abemaciclib.
In a Phase 1 study (I3Y-MC-JPBA [JPBA]), 57 patients with advanced NSCLC who progressed 
or relapsed after standard treatments were treated with abemaciclib at doses between 50 mg and 
225 mg every 24 hours, or at doses between 75 and 275 mg every 12 hours (Q12H) (Goldman et 
al. 2014).  The patients enrolled received a median of 4 prior regimens, and the MTD was 
established at 200 mg Q12H.  The most common Grade 3 AEs (greater than 5% incidence) were 
leukopenia (14%) and neutropenia (9%). No patients in the lung cancer cohort experienced 
Grade 4 AEs. Less than 2% of patients discontinued due to AEs in this study cohort. Disease 
control rate (complete response [CR], PR, or SD) was 49 % for patients on abemaciclib, 

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including 2 PR and 26 patients with SD. Six patients had squamous cell NSCLC.  The response 
assessment for these 6 patients was 1 PR, 2 SD, 1 PD, and 2 were inevaluable.
Study I3Y-MC-JPBJ (JPBJ) is an ongoing Phase 1b study in patients with previously treated 
NSCLC Stage IV. Patients are divided into 4 treatment arms based on prior therapy or histology
and receive abemaciclib in combination with either pemetrexed, gemcitabine, ramucirumab, or 
PI3K/mTOR dual inhibitor. The primary objective of this study is to evaluate the safety and 
tolerability of abemaciclib combinations.
5.4.
Study Rationale
The purpose of this study is to explore the efficacy and safety of necitumumab plus abemaciclib 
in patients with Stage IV NSCLC who have received no more than 2 lines of chemotherapy of 
which at least one must be platinum-based.
Necitumumab (LY3012211) is a recombinant human mAb of IgG1 class, which targets EGFR. 
Necitumumab demonstrates a high affinity to its target and blocks ligand-induced receptor 
phosphorylation and downstream signaling. EGFR is detectable in approximately 85% to 90% 
of patients with NSCLC (Fontanini et al 1995; Pirker et al 2009).  Pharmacologic inhibition of 
EGFR signaling through competitive inhibition of ligand binding has been shown to play a role 
in the treatment of several cancers, and EGFR mAbs are approved in various tumor indications 
(Erbitux PI/SmPC, Vectibix PI/SmPC). Portrazza has recently been approved in the United 
States (US) and European Union (EU) for the treatment of adult patients with metastatic 
squamous NSCLC in combination with gemcitabine and cisplatin (Portrazza USPI and SmPC).  
The necitumumab SQUIRE trial showed statistically significant improvements in OS and PFS,
with an overall favorable benefit-risk profile. In addition, a recent meta-analysis investigating 
the addition of an EGFR mAb to platinum-based first-line therapy demonstrated a significantly 
improved OS and PFS in patients with advanced NSCLC (Pujol et al. 2014).
Abemaciclib, a selective and potent small molecule inhibitor of CDK4/6, prevents cell cycle 
progression through the G1 restriction point, thus arresting tumor growth. The data in NSCLC 
studies (JPBA and JPBJ) show activity for abemaciclib in both KRAS mutant and KRAS
wild-type tumors. Some of the longest survivors on abemaciclib have been patients with 
squamous histology and KRAS wild-type tumors. Preliminary data suggest that more KRAS
mutant patients have responded; however, the numbers are small and do not in any way preclude 
treatment of KRAS wild-type patients, especially in this setting (combination with necitumumab).
Necitumumab and abemaciclib inhibit tumor progression by different, independent modes of 
action (cell surface and cell nucleus), where necitumumab blocks the ligand-binding site of the 
EGFR and abemaciclib blocks DNA synthesis by prohibiting cell cycle progression from G1- to 
S-phase.  Both agents have shown activity signals when administered as monotherapy in heavily 
pretreated patients, including patients with NSCLC. In a 549 xenograft model of NSCLC, the 
addition of necitumumab to abemaciclib improved the antitumor efficacy compared to either 
monotherapy (Eli Lilly, data on file).

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The individual toxicity profile from clinical trials with each of the compounds (that is, 
necitumumab and abemaciclib) suggests that no or only marginal overlapping toxicity is 
expected.  The most common Grade ≥3 AEs (>5% of patients) for single-agent abemaciclib were 
leukopenia and neutropenia.  For necitumumab single agent, the most frequent AEs reported 
were skin reactions in terms of rash and hypomagnesemia.
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of necitumumab and abemaciclib may be found in the IBs and Portrazza SmPC.  Information on 
AEs expected to be related to the study drugs may be found in Section 7 (Development Core 
Safety Information) of the IB.  Information on serious adverse events (SAEs) expected in the 
study population independent of drug exposure and that will be assessed by the sponsor in 
aggregate, periodically during the course of the study, may be found in Section 6 (Effects in 
Humans) of the IB.

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6.
Objectives
6.1.
Primary Objective
This study is divided into 2 parts:
Part A: to determine the dose-limiting toxicity (DLT) of abemaciclib at doses up to 200 mg 
when combined with necitumumab 800 mg, in patients with Stage IV NSCLC as measured by 
the number of patients with a DLT in Cycle 1
Part B: to evaluate the efficacy of necitumumab in combination with abemaciclib in terms of 
PFS rate at 3 months in patients with Stage IV NSCLC
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:
Part A:

to investigate the safety profile as assessed by clinical and laboratory significant events of 
necitumumab in combination with abemaciclib

to determine the objective response rate (ORR)

to determine pharmacokinetics (PK) of necitumumab and abemaciclib

to determine the immunogenicity of necitumumab
Part B:
To demonstrate the safety, efficacy, and feasibility of necitumumab in combination with
abemaciclib at the recommended dose by

determining PFS

determining ORR and disease control rate (DCR)

estimating OS

investigating the safety profile as assessed by clinical and laboratory significant events

determining PK of necitumumab and abemaciclib

determining the immunogenicity of necitumumab
6.3.
Exploratory Objectives

to correlate biomarkers with clinical outcomes, including, but not limited to KRAS
mutation assessment, EGFR protein expression, and/or other biomarkers associated with 
the disease pathobiology, the cell cycle, EGFR pathway, and/or the mechanism of action
of the therapeutic molecules.

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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. Individuals may be re-screened once. At the time of re-screening, 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 screening period does not constitute rescreening.  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]
Histologically or cytologically confirmed NSCLC

Part A: NSCLC Stage IV (any type)

Part B: NSCLC Stage IV (squamous and nonsquamous)
[2]
Stage IV disease at the time of study entry (American Joint Committee on Cancer 
[AJCC] Staging Manual, 7th Edition [Edge et al. 2009])
[3]
Measurable disease at the time of study entry as defined by Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Eisenhauer et al. 2009)
[4]
The patient must have progressed after platinum-based chemotherapy AND have 
received a maximum of 1 other prior chemotherapy for advanced and/or 
metastatic disease OR must be judged by the physician as ineligible for further 
standard second-line chemotherapy. Prior treatment with EGFR-TKI and ALK 
inhibitors is mandatory in patients whose tumor has EGFR-activating mutations 
or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant therapies 
are permitted with the exception of CDK4/6-targeting agents or necitumumab.
[5]
The patient has tumor tissue available for biomarker analyses. The sample can be 
either 12 serially paraffin-embedded unstained tissue slides or a 
paraffin-embedded tissue block (see Section 10.3.2.2 for further details).
[6]
The patient has given written informed consent prior to any study specific 
procedures.  Written consent may also be provided by a legal representative.
[7]
The patient is 18 years or older if required by local law or regulations.
[8]
The patient has resolution to Grade ≤1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0, of all 
clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy 
(with the exception of alopecia).
[9]
The patient has an Eastern Cooperative Oncology Group performance status score 
of 0-1 (see Attachment 4).

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[10] Have the following laboratory values:

hematologic:  absolute neutrophil count 1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 9 g/dL.  Transfusion of blood products 
(including platelets or red blood cells) or administration of colony 
stimulating factors (including G-CSF, GM-CSF, or recombinant 
erythropoietin) within 4 weeks prior to Cycle 1 Day 1 are not allowed.

serum albumin ≥25 g/L

hepatic:  bilirubin 1.5 times the upper limit of normal (ULN), alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
transaminase (AST) 3.0 times ULN.  For patients with hepatic metastases, 
ALT and AST equaling ≤5.0 times ULN are acceptable.

renal:  serum creatinine 1.2 times ULN or calculated creatinine clearance 
>50 mL/min (per the Cockcroft-Gault formula as defined in Attachment 5)
for patients with creatinine >1.2 times ULN.
[11] Men who are sterile (including vasectomy confirmed by post-vasectomy semen 
analysis) or who agree to use a reliable method of birth control and to not donate 
sperm during the study (and for at least 12 weeks following the last dose of 
necitumumab and abemaciclib or country requirements, whichever is longer) OR
[12] Women who are either: (a) not of child-bearing potential due to surgical 
sterilization (at least 6 weeks following surgical bilateral oophorectomy with or 
without hysterectomy or tubal ligation) confirmed by medical history or 
menopause*; or (b) of child-bearing potential who have a negative serum 
pregnancy test within 14 days prior to study enrollment 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, antiestrogens, selective 
estrogen receptor modulators, or chemotherapy)
2. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone (FSH) level >40 mIU/mL

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† 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.
[13] Are able to swallow oral medications.
[14] Have an estimated life expectancy of at least 12 weeks.
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[15] The patient is currently enrolled in a clinical trial involving an investigational 
product (IP; hereon referred to as study treatment) or non-approved use of a drug 
or device (other than the study treatment used in this study), or concurrently 
enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study. Prior treatment with CDK4/6-targeting 
agents or necitumumab is not permitted.
[16] The patient has undergone major surgery or received any investigational therapy 
in the 30-days prior to study enrollment.
[17] The patient has undergone chest irradiation within 4 weeks prior to receiving 
study treatment (except focal palliative irradiation, which is allowed up to 
2 weeks prior to receiving study treatment).
[18] The patient has brain metastases that are symptomatic. (Patients who have 
completed radiotherapy for brain metastases at least 2 weeks prior to receiving 
study treatment, who are now non symptomatic or on stable dose of steroids or 
anticonvulsants during the 2 weeks prior to receiving study treatment, are 
eligible). Patients with asymptomatic brain metastases without need for treatment 
with steroids and who have not been treated with radiotherapy are eligible.  This 
exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.
[19] History of arterial or venous thromboembolism within 3 months prior to study 
enrollment.  Patients with a history of venous thromboembolism beyond 3 months 
prior to study enrollment can be enrolled if they are appropriately treated with low 
molecular weight heparin.
[20] History or evidence of current clinically relevant coronary artery disease 
≥Grade III by the Canadian Cardiovascular Society Angina Grading Scale or 
uncontrolled congestive heart failure of current > Class III as defined by the New 
York Heart Association.
[21] The patient has experienced myocardial infarction within 6 months prior to study 
enrollment.

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[22] The patient has active infection requiring systemic therapy, including active 
tuberculosis or known history of infection with the human immunodeficiency 
virus (HIV 1/2 antibodies), or hepatitis B (e.g., HBsAg reactive) and/or C virus 
(e.g., HCV RNA qualitative is detected).
[23] The patient has a history of significant neurological or psychiatric disorders, 
including dementia, seizures, or bipolar disorder, potentially precluding protocol 
compliance.
[24] The patient has a personal history of any of the following conditions: presyncope 
or syncope of either unexplained or cardiovascular etiology, ventricular 
arrhythmia (including but not limited to ventricular tachycardia and ventricular 
fibrillation), or sudden cardiac arrest.
[25] The patient has 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 informed consent document.
[26] The patient has a known allergy/history of hypersensitivity reaction to any of the 
treatment components, including any ingredient used in the formulation of 
necitumumab or abemaciclib, or any other contraindication to one of the 
administered treatments.
[27] The patient is pregnant or breastfeeding.
[28] The patient has a known history of drug abuse, that in the opinion of the 
investigator, may have an impact on the safety of the patient and/or limit the 
patient’s ability to complete the study or adhere to any protocol procedure.
[29] The patient has a concurrent active malignancy. Previous history of malignancy 
is permitted, provided that the patient has been free of disease for ≥3 years, with 
the exception of adequately treated basal or squamous cell carcinoma of the skin, 
preinvasive carcinoma of the cervix, or any cancers that in the judgment of the 
investigator and sponsor may not affect the interpretation of results (for example,
prostate, bladder).
[30] The patient is receiving concurrent treatment with other anticancer therapy, 
including other chemotherapy, immunotherapy, hormonal therapy, chemo-
embolization, targeted therapy, or an investigational agent.
[31] History of interstitial lung disease or an active non-infectious pneumonitis
[32] Recent (within 30 days before enrollment) or concurrent yellow fever vaccination
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.  
Exclusion Criteria [15] through [25] and [27] through [32] ensure that previous or currently 
required treatments or conditions do not complicate on-study treatment and/or analysis of data.  

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Exclusion Criterion [26] excludes patients who may be at elevated risk of toxicity based on the 
known safety profile of necitumumab and abemaciclib.
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 
treatment, will have procedures performed as shown in the Study Schedule (Attachment 1).
Patients who are discontinued from study treatment early 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 may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without study drug.  Inadvertently enrolled patients 
may be maintained in the study and on study treatment when the Lilly CRP agrees with the 
investigator that it is medically appropriate for that patient.  The patient may not continue in the 
study with or without study drug if the Lilly CRP does not agree with the investigator’s 
determination it is medically appropriate for the patient to continue.  The investigator must 
obtain documented approval from the Lilly CRP to allow the inadvertently enrolled patient to 
continue in the study with or without study drug. 
7.3.2. Discontinuation From Study Therapy
Patients will be discontinued from the study treatment in the following circumstances;

Enrollment in any other clinical trial involving a study drug 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 therapy occurs prior to introduction of the new agent.

Investigator/Physician Decision
o
The investigator/physician decides that the patient should be withdrawn from the 
study.
o
If the patient has progressive disease (PD).

Patient Decision
o
The patient or patient’s designee (for example, parents or legal guardian) requests 
to be withdrawn from the study or study treatment.

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
Sponsor Decision
o
The sponsor stops the study or stops the patient’s participation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practices (GCP).
o
The patient is significantly noncompliant with study procedures and/or treatment.
o
An unacceptable AE/toxicity (for example, a persistent moderate toxicity that is
intolerable to the patient).
o
A Grade 3 to 4 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.

The patient or the patient’s designee 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
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 
treatment within legal and ethical boundaries.  Site personnel, or an independent third party, may 
search public sources for vital status information. If the patient's vital status is determined, the 
vital status will be documented and the patient will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.
7.3.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.6. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.

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8.
Investigational Plan
8.1.
Summary of Study Design
Study I4X-MC-JFCU is a single-arm, multicenter, Phase 1b study with an expansion cohort to 
investigate necitumumab in combination with abemaciclib in approximately 70 patients with 
Stage IV NSCLC (AJCC Staging Manual, 7th edition).
The study consists of 2 parts:

Part A:  Dose-escalation part with increasing doses of abemaciclib (100, 150 or 200 mg 
Q12H on Days 1 to 21) to determine a recommended dose range for abemaciclib that 
may be safely administered in combination with a fixed regimen of necitumumab
800 mg Days 1 and 8 every 21 days in patients with Stage IV NSCLC.

Part B (Expansion Cohort):  Dose confirmation of abemaciclib in combination with a 
fixed regimen of necitumumab 800 mg on Days 1 and 8 every 21 days and exploration
of clinical antitumor activity.
In Part B, approximately 50 patients will be enrolled; approximately 25 patients with squamous 
and approximately 25 patients with nonsquamous histologies.
Figure JFCU.8.1 illustrates the study design.

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Abbreviations: D = day; DLT = dose-limiting toxicity; MTD = maximum tolerated dose; 
n = number of patients; Ph = Phase; Q12H = every 12 hours; Q21D = every 21 days.
Figure JFCU.8.1.
Illustration of study design.
Part A is a single-arm, dose-escalation study to determine the recommended dose for the 
expansion cohort (Part B).
Part A:
Cohort 1

Necitumumab, administered I.V. over 60 minutes at an absolute dose of 800 mg on 
Days 1 and 8, followed by

Abemaciclib at a dose of 100 mg orally Q12H on Days 1 to 21
Cohort 2

Necitumumab, administered I.V. over 60 minutes at an absolute dose of 800 mg on 
Days 1 and 8, followed by

Abemaciclib at a dose of 150 mg Q12H on Days 1 to 21
Cohort 3

Necitumumab, administered I.V. over 60 minutes at an absolute dose of 800 mg on
Days 1 and 8, followed by

Abemaciclib at a dose of 200 mg Q12H on Days 1 to 21
Cohort 1 (n 3-6)
Necitumumab 800 
mg D1 and 8 Q21D
Abemaciclib 100 mg 
Q12H
Cohort 2 (n 3-6)
Necitumumab 800 
mg D1 and 8 Q21D
Abemaciclib 150 mg 
Q12H
Cohort 3 (n 3-6)
Necitumumab 800 
mg D1 and 8 Q21D
Abemaciclib 200 mg 
Q12H
Add 3 patients
STUDY 
DISCONTINUATION
>2 DLT/6pts
1 DLT
Add 3 patients
MTD cohort 1 dose
>2 DLT/6pts
1 DLT
Add 3 patients
>2 DLT/6pts
1 DLT
1 DLT/6pts
0 DLT
0 DLT
MTD cohort 2 dose
Necitumumab 800 mg D1 and 8 Q21D
Abemaciclib Dose from Ph 1b Part A Q12H
Part B
(n = 50)
Part A (n = 3-18)
0 DLT
1 DLT/6pts
1 DLT/
6pts

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Note:  At the time of approval of the JFCU(b) protocol amendment, all patients who are still on 
the study will be administered necitumumab I.V. infusion over 60 minutes.
A maximum of 18 evaluable patients will be enrolled in Part A.  Any patient who is discontinued 
from the study before completing Cycle 1 will be excluded from the DLT population, unless a 
DLT was observed.  Patients who do not complete Cycle 1 for reason other than DLT will be 
replaced.
If 1 of 3 patients in each cohort experiences a DLT during Cycle 1, 3 additional patients will be 
enrolled in that cohort.  If 2 of 6 patients experience a DLT in Cohort 1, the study must be 
discontinued.
If 2 of 6 patients experience a DLT in Cohort 2 or 3, then the dose in Cohort 1 or 2 will be the 
MTD.
Dose escalation within a cohort will not be permitted. Patients assigned to a cohort dose level 
will remain at that level throughout the study.  However re-escalation will be permitted as 
specified in Section 9.3.2.2.1.
The individual recommended dose for necitumumab is 800 mg on Days 1 and 8 every 21 days 
and 200 mg Q12H for abemaciclib. For this reason, further dose escalation beyond Cohort 3 will 
not be tested.
Patients in whom DLT occurs in Cycle 1 may still continue study treatment according to the 
criteria for starting the next cycle or dose modification (specified in Section 9.3.2.2.1) if the 
patients are benefiting from study treatment in the opinion of the investigator.
Necitumumab plus abemaciclib may be continued at the assigned dose level until disease 
progression, the development of unacceptable toxicity or withdrawal of consent by the patient, or 
sponsor/investigator decision.
Part B is a single-arm study to evaluate efficacy and safety of necitumumab in combination 
with abemaciclib in patients with Stage IV squamous or nonsquamous NSCLC
(Figure JFCU.8.1).  Patients will be treated with necitumumab 800 mg on Days 1 and 8 every 
21 days and the dose of abemaciclib identified from Part A of the study Q12H on Days 1 to 
21.
Provided there is an acceptable safety profile in Part A of this study, Part B will be initiated,
which will include a safety interim analysis after the first 15 evaluable patients have completed 2
cycles of study treatment (or otherwise discontinued study treatment).  Patients with squamous 
and nonsquamous NSCLC who received the recommended abemaciclib dose for Part B in Part A
will be taken into account for the safety interim analysis.
The final analysis for all outcomes will be performed approximately 5 months after completing 
enrollment of the study population.

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A treatment cycle will be defined as 21 days.  Study therapy, consisting of necitumumab plus 
abemaciclib will continue until there is a radiographic documentation of PD, toxicity requiring 
cessation, protocol noncompliance, or withdrawal of consent.
Terms used to describe the periods during the study are defined below:

Baseline:  begins when the ICF is signed 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 case report form 
(CRF) as the Date of Discontinuation from study treatment.

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 approximately 
30 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.

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 approximately 30 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]) approximately 5 months after the last patient in the Part B of the study has been 
enrolled.  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 s tudy 
treatment and completed any applicable continued access follow-up (see Figure JFCU.8.2).

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Figure JFCU.8.2.
Study period and continued access diagram.
8.1.2. Continued Access Period
The continued access period will apply to this study only if at least 1 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 study drug exposure will be reported on 
the CRF.  Serious adverse events will also be reported to Lilly Global Patient Safety (see 
Section 10.2.1.1).  In the event that an SAE occurs, Lilly may request additional information 
(such as local laboratory results, concomitant medications, and hospitalizations) in order to 
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 (all outcomes)b
Last visit/
scheduled 
procedure for 
last patient
Patient 
Discontinues 
Study 
Treatment
b Approximately 5 months after enrollment completion

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evaluate the reported SAE. Blood samples for PK and immunogenicity analysis will be collected 
in the event of an infusion-related reaction and during the continued access follow-up.
During the continued access period, the sponsor will collect only the data shown in 
Attachment 1.  It is recommended that routine monitoring, using an assessment schedule similar 
to that outlined in Attachment 1 (including radiographic evaluation of disease), be continued as 
necessary to confirm patient eligibility to continue on treatment.  However, the results of all 
these assessments may not be routinely collected by the sponsor, and all nonmandatory 
assessments (that is, all assessments not explicitly described in Attachment 1) may be performed 
locally rather than centrally.
8.2.
Discussion of Design and Control
In this single-arm, Phase 1b study with an expansion cohort, the selected dose of necitumumab 
of 800 mg on Days 1 and 8 every 21 days is aligned with the MTD and the dosing schedule in 
the Phase 3 development program for necitumumab. The starting dose of abemaciclib will be at 
dose level -2 of the MTD (100 mg Q12H). This is aligned with the minimal dose applied in the 
dose adjustment schedule from clinical trials.
Patients with Stage IV NSCLC who have received no more than 2 lines of chemotherapy, of 
which at least one must be platinum-based, for advanced or metastatic disease will receive a 
combination of necitumumab and abemaciclib.  Prior treatment with EGFR-TKI, 
VEGF/VEGFR-targeting agents, and ALK inhibitors is permitted.
In Part B, approximately 50 patients will be enrolled with an even split between squamous and 
nonsquamous histology to enable a homogenous population in the study.
Provided there is an acceptable safety profile in Part A of this study, Part B will be initiated,
which will include a safety interim analysis after the first 15 evaluable patients have completed 2
cycles of study treatment (or otherwise discontinued study treatment).  Patients with squamous 
and nonsquamous NSCLC who received the recommended abemaciclib dose for Part B in Part A
will be taken into account for the safety interim analysis.
Based on the single-arm nature of the study, the outcome will be hypothesis generating only,
allowing for future consolidation of this regimen depending on the outcome.

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9.
Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study (Table JFCU.9.1):
In Part A, patients will receive oral abemaciclib 100 mg, 150 mg or 200 mg Q12H in 
combination with necitumumab 800 mg as an absolute dose on Day 1 and Day 8 every 21 days.
In Part B, the abemaciclib dose identified from Part A will be given Q12H in combination with 
necitumumab 800 mg as an absolute dose Day 1 and Day 8 every 21 days.
Necitumumab will be administered first followed by abemaciclib. Abemaciclib should be 
administered within 10 minutes of start of necitumumab infusion.
Table JFCU.9.1.
Treatment Regimens/Dosing Schedule
Part A
Cohort
Drug
Dose
Day
Infusion duration
Cohort 1
Necitumumab
800 mg absolute 
dose I.V. infusion
Days 1 and 8
over 60 minutesa
(5 minutes)
Abemaciclib
100 mg Q12H
Days 1 - 21
Cohort 2
Necitumumab
800 mg absolute 
dose I.V. infusion
Days 1 and 8
over 60 minutesa
(5 minutes)
Abemaciclib
150 mg Q12H
Days 1 - 21
Cohort 3
Necitumumab
800 mg absolute 
dose I.V. infusion
Days 1 and 8
over 60 minutesa
(5 minutes)
Abemaciclib
200 mg Q12H
Days 1 - 21
Part B
Drug
Dose
Day
Infusion duration
Necitumumab
800 mg absolute dose I.V. 
infusion
Days 1 and 8
over 60 minutesa
(5 minutes)
Abemaciclib
Dose from Part A Q12H
Days 1 - 21
Abbreviations: IV= intravenously; Q12H = every 12 hours.
a At the time of approval of the JFCU(b) protocol amendment, all patients who are still on the study will be
administered necitumumab I.V. infusion over 60 minutes (5 minutes).

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The individual recommended dose for necitumumab is 800 mg on Day 1 and Day 8 every
21 days and 200 mg Q12H for abemaciclib. For this reason, further dose escalation beyond 
Cohort 3 will not be tested.
Hypersensitivity/infusion-related reactions may occur during or following administration of 
necitumumab (see Section 9.3.2.2.3.1.1 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.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient,

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 so that the situation can be assessed.
9.2.
Materials and Supplies
All study treatment materials will be provided by Lilly.  Clinical trial materials will be labeled 
according to the country’s regulatory requirements.
Necitumumab is a sterile and preservative-free solution for I.V. infusion supplied in the 
following formulation:

Necitumumab at a final concentration of 16 mg/mL (800 mg/50 mL) 
contained in single-use vials, in a formulation of 10 mM citrate, 40 mM 
sodium chloride, 133 mM glycine, 50 mM mannitol, 0.01% polysorbate-80, 
pH 6.0.
All excipients used in the formulation of necitumumab are of pharmacopeial grade.  No 
animal-derived components are used in the manufacture of necitumumab excipients.  Refer to the 
IB for detailed information.
Abemaciclib will be supplied by Lilly as capsules for oral administration.  Abemaciclib capsules 
should be stored according to the temperature range listed on the product label, and should not be 
opened, crushed, or chewed.

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9.3.
Method of Assignment to Treatment
An interactive web response system will be used for treatment assignment in both Parts A and B 
of the study.
9.3.1. Selection and Timing of Doses
The first treatment will be administered within 7 days of enrollment.  Study treatment will be 
administered as described in Section 9.1.
A cycle is defined as an interval of 21 days.
Administration of necitumumab Day 1 dose will trigger the start of a new cycle. Infusions 
administered within 3 days before or after the planned infusion time point due to holidays, 
weekends, bad weather, or other unforeseen circumstances will be permitted and not counted as a 
protocol deviation. The necitumumab Day 8 dose can be delayed up to 5 days.  Beyond that, the 
Day 8 dose will have to be omitted in order to maintain the 21 day cycle. A minimum of 
7 days’ interval between any necitumumab dose must be maintained.
Abemaciclib will be taken orally every 12 (±2) hours on Days 1 through 21 of a 21-day cycle, 
for a total of 42 doses per cycle.  During all cycles, abemaciclib should be taken at 
approximately the same times each day.  If a patient misses or vomits abemaciclib, that dose 
should be omitted.
In the event of a cycle delay due to logistical reasons (for example, due to patient availability), 
the patient should continue on abemaciclib treatment. If abemaciclib is interrupted as a result of 
not having sufficient drug supply, the treatment may be delayed up to 5 days (and not be 
considered a protocol violation). In exceptional circumstances, a delay >5 days is permitted 
upon agreement between the investigator and the Lilly CRP.
A patient may continue to receive study treatment until he or she meets 1 or more of the 
specified reasons for discontinuation (as described in Section 7.3).
9.3.2. Special Treatment Considerations
9.3.2.1.
Dose-Limiting Toxicity (Part A)
A dose-limiting toxicity (DLT) is defined as one of the following AEs, occurring in Cycle 1 if 
considered to be definitely, probably, or possibly related to necitumumab and abemaciclib.  The 
following list will define DLT:

Grade 3 or 4 nonhematologic toxicity according to the NCI CTCAE Version 4.0 
except for nausea, vomiting, diarrhea, or electrolyte disturbance (see below)

Grade 3 or 4 nausea, vomiting, or diarrhea that persists more than 2 days despite 
maximal supportive intervention

Grade 3 thrombocytopenia with bleeding requiring transfusion

Grade 4 thrombocytopenia with or without bleeding

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
Grade 4 neutropenia  that persists more than 5 days

Grade 3 or 4 neutropenia with fever

Grade ≥3 skin toxicity despite best supportive care

If a total at least 75% of the planned dose for both agents cannot be administered 
in the first cycle due to toxicity
DLT is defined by sponsor and Principal Investigator.
The following toxicities will not be considered DLTs if they are transient <7 days) with full 
supportive therapy:

Grade 3 arthralgia or myalgia

Grade 3 asthenia or fatigue

Grade 3 constipation
The following toxicities will not be considered DLTs:

Grade 3 injection-site reaction

Grade 3 elevation of transaminases lasting <7 days

Grade 3 elevation of serum-bilirubin lasting <7 days

Transient Grade 3 elevation or decrease of electrolytes

Grade 3 or 4 hypersensitivity
If a Grade 3 or 4 infusion-related reaction (hypersensitivity) to necitumumab occurs, this event 
will not be considered a DLT; the patient will not receive any further study therapy and will be 
replaced in the study by a new patient.
9.3.2.2.
Dose Adjustments and Delays
9.3.2.2.1. Abemaciclib
Abemaciclib dose adjustments are allowed both within a cycle and between cycles. Abemaciclib
must be reduced sequentially by 1 dose level.
An abemaciclib dose level below 100 mg Q12H is not allowed.  For patients starting at 
abemaciclib 100 mg Q12H, no further dose reduction is permitted. For patients starting at dose
level 150 mg Q12H, only 1 dose reduction is allowed.
Abemaciclib may be held up to 14 days to permit sufficient time for recovery from the toxicity.  
If a dose suspension occurs, the investigator may resume abemaciclib dosing at the same dose 
level for the remainder of the study or at reduced dose (assuming resolution to at least Grade 1 
for nonhematologic and at least Grade 2 for hematologic toxicity).  If the patient experiences the 
same toxicity with the same or greater severity (CTCAE grade) requiring a dose suspension
within a cycle or at start of the next cycle, the patient must be dose reduced and not 
re-challenged a second time at the prior dose level.

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If a patient experiences CTCAE Grade 4 hematologic toxicity possibly related to abemaciclib, 
then dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 2) 
and the dose of abemaciclib must be reduced as outlined in Table JFCU.9.2.
If a patient experiences CTCAE Grade≥3 nonhematologic toxicity possibly related to 
abemaciclib, then dosing must be suspended (until the toxicity resolves to either baseline or at 
least Grade 1) and the dose of abemaciclib must be reduced as outlined in Table JFCU.9.2.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea) 
possibly related to abemaciclib that does not resolve with maximal supportive measures within 3
days (as outlined in Section 9.5.3) to either baseline or Grade 1, then dosing should be suspended 
(until the toxicity resolves to either baseline or at least Grade 1), and the dose of abemaciclib 
may be reduced as outlined in Table JFCU.9.2.
For patients requiring dose reduction(s), any re-escalation to a prior dose level is permitted only 
after consultation with the Lilly CRP.  After re-escalation, subsequent dose adjustments should 
be based on the dose of abemaciclib that the patient is currently receiving.
Table JFCU.9.2.
Dose Adjustments of Abemaciclib
Dose Adjustment Level
Oral Dose
Frequency
0
200 mg
Every 12 hours
1
150 mg
Every 12 hours
2
100 mg
Every 12 hours
Abemaciclib must be discontinued if further dose reduction is required beyond 100 mg every 
12 hours. The patient may continue to receive necitumumab as a single agent.
Patients not recovering from toxicity within 14 days should be considered for discontinuation
from abemaciclib treatment.
9.3.2.2.1.1.
Guidance for Monitoring of Renal Function in Patients on Abemaciclib
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C calculated glomerular filtration rate. 
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation. If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.  Dose alterations (omission, reduction, or 
discontinuation) should not solely be based on interpretation of serum creatinine values because 
these may not reflect renal function.
9.3.2.2.2. Necitumumab
Prior to each administration of necitumumab all toxicities associated with necitumumab must 
have resolved to Grade ≤2 (except for alopecia and skin toxicity) or baseline.  Pretreatment 
laboratory data may not be older than 72 hours (Day 1 of each cycle) or 24 hours (Day 8 of each 
cycle).

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If the criteria 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 9.3.2.2.3) or interrupted, but abemaciclib
will continue according to the planned schedule.

If administration of necitumumab is delayed for more than 6 weeks (2 cycles) 
after Day 1 of the most recent treatment cycle the patient should be discontinued 
from necitumumab treatment.
9.3.2.2.3. Necitumumab Dose Modifications
The following are general dose-modification guidelines for toxicity associated with 
necitumumab.  Please see Section 9.3.2.2.3.1 for specific information on the management of 
necitumumab-related hypersensitivity/infusion-related reactions, skin reactions, conjunctivitis, 
and hypomagnesemia.
Dose modifications are permitted for necitumumab following non-life threatening reversible 
CTCAE Grade ≥3 AEs that require delay of necitumumab treatment for up to 6 weeks following 
Day 1 of the most recent treatment cycle.  In this setting, necitumumab may be readministered at 
a reduced dose (600 mg) if necessary only if AE is resolved to Grade ≤2.  A second dose 
reduction (to 400 mg) is permitted for this level of event (Grade ≥3).
If a patient experiences CTCAE Grade ≥3 hematologic toxicity possibly related to necitumumab, 
then dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 2) 
and the dose of necitumumab must be reduced by 1 dose level (see below).
If a patient experiences ≥ CTCAE Grade 3 nonhematologic toxicity possibly related to 
necitumumab, then dosing must be suspended (until the toxicity resolves to either baseline or at 
least Grade 1) and the dose of necitumumab must be reduced by 1 dose level (see below).
Events that necessitate more than 2 dose reductions warrant discontinuation from necitumumab 
treatment.  Following a dose reduction, the dose of necitumumab may be re-escalated to the 
pre-reduction dose, provided that at least 2 administrations have elapsed following the first 
administration of the reduced dose, and only after consultation with the Lilly CRP.  For dose 
modifications in response to specific AEs related to necitumumab, please see Section 9.3.2.2.3.1.
Patients who enter the study with symptoms or laboratory values equivalent to NCI -CTCAE 
Version 4.0 Grade 1-2 AEs should not have dose reductions related to the persistence or mild 
worsening (for example, from Grade 1 to Grade 2) of those symptoms or laboratory values.  
Dose reductions (to 400 mg) are warranted in the setting of Grade 1-2 baseline symptoms or 
laboratory values that worsen to Grade ≥3 during treatment.
In the event of alterations of necitumumab therapy due to a necitumumab-related toxicity, 
abemaciclib need not be altered, and the planned abemaciclib schedule should be maintained.  
Similarly, necitumumab therapy should not be delayed for abemaciclib-related toxicities.

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9.3.2.2.3.1.
Treatment Guidelines and Dose Modifications for Specific Adverse Events 
of Necitumumab 
Adverse events of concern, which may or may not be associated with necitumumab therapy, 
include hypersensitivity/infusion-related reactions, skin reactions, conjunctivitis, electrolyte 
abnormalities, pneumonia and sepsis, and thromboembolic events.
9.3.2.2.3.1.1.
Hypersensitivity/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.
Hypersensitivity/IRRs are defined according to the NCI-CTCAE Version 4.0 definition of 
allergic reaction / hypersensitivity, as follows:

Grade 1:  transient flushing or rash, drug fever <38°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 may be utilized as 
detailed below.  Additional treatments, chosen according to clinical symptoms and local 
standards, may be utilized at investigator discretion.  Table JFCU.9.3 provides general treatment 
recommendations for hypersensitivity/IRRs to necitumumab.

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Table JFCU.9.3.
NCI-CTCAE 4.0 Infusion-Related Reactions
Grade 
of 
Reaction
Management Recommendations
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.
3-4

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.
N/A
Abbreviations:  I.V. = intravenously; N/A = not applicable; NCI-CTCAE = National Cancer Institute-Common 
Terminology Criteria for Adverse Events.
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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If a patient should have a hypersensitivity/IRR to necitumumab, all attempts should be made to 
obtain an anti-necitumumab antibody and necitumumab 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.
9.3.2.2.3.1.2.
Skin Reactions
9.3.2.2.3.1.2.1.
Reactive Treatment
Reactive treatment recommendations for skin reaction, based on the Canadian recommendations 
presented by Melosky et al. (2009), are summarized in Table JFCU.9.4.
Skin rash (any grade) should be treated, as per Table JFCU.9.4.  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 JFCU.9.4.
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 1 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.

Patients who experience Grade 3 skin induration / fibrosis will be immediately discontinued from 
necitumumab.
4

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion base twice daily to 
affected areas until resolution of reaction.

Administer oral minocycline or doxycycline 100 mg twice daily (or equivalent), for a minimum of
4 weeks and continuing for as long as rash is symptomatic.

Patients are advised to take appropriate protective measures prior to sun exposure to avoid 
exacerbation of rash severity.

Necitumumab administration must be immediately and permanently discontinued.
If necitumumab therapy is delayed due to acneiform rash, abemaciclib may be administered 
without interruption in the absence of disease progression.
A dermatology referral may be indicated for skin reactions that do not improve following 
1-2 weeks of treatment, reactions that are severely symptomatic (for example, necrosis, 
blistering, or petechial or purpuric lesions), reactions of NCI-CTCAE Grade ≥3, or reactions 
with an uncharacteristic appearance.

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As with all concomitant medications/procedures, any actions taken to ameliorate skin toxicity 
will be documented in the concomitant medication module of the electronic CRF (eCRF).
9.3.2.2.3.1.3.
Conjunctivitis
For patients with treatment-related conjunctivitis <Grade 3, the investigator is advised to initiate 
symptomatic treatment and follow up observation of the event.  If the severity increases to 
Grade ≥3, or symptoms persists for >10 days after symptomatic treatment, the investigator is 
advised to refer the patient to an ophthalmologist for further evaluation and treatment.
9.3.2.2.3.1.4.
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 necitumumab, until within normal limits.   
Prompt repletion is recommended, as appropriate.
9.3.2.2.3.1.5.
Pneumonia and Sepsis
During the conduct of Study JFCL (JFCL; Phase 2 study to investigate carboplatin and soluble 
paclitaxel 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. 
The early occurrence of a number of these cases may have indicated an issue regarding the 
enrollment of the appropriate 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 
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 (JFCC; SQUIRE) did not show any evidence of an increased risk of serious lung 
infections 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.
9.3.2.2.3.1.6.
Thromboembolic Events
In the Phase 3 study JFCC, there was an increase in venous thromboembolic events (VTEs) and 
arterial thromboembolic events (ATEs) in the investigational arm (necitumumab in combination 
with gemcitabine and cisplatin) compared to the active control arm (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.

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In the Phase 3 study JFCB, an increased rate of serious thromboembolic events, including fatal 
events, has been observed for the combination of necitumumab with pemetrexed and cisplatin as 
compared with treatment with pemetrexed and cisplatin alone in patients with nonsquamous 
NSCLC.  Administration of necitumumab in combination with pemetrexed and cisplatin is not 
recommended.
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 mFOLFOX-6 chemotherapy.
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.
9.3.2.2.3.1.7.
Cardiorespiratory Disorders
An increased frequency of cardiorespiratory arrest or sudden death was observed with 
necitumumab.  Cardiorespiratory arrest or sudden death was reported in the pivotal Study JFCC 
(SQUIRE) 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.
9.4.
Blinding
This is an open-label study.
9.5.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the CRF.  Concomitant medications and supportive 
care therapies must also be documented at the time of discontinuation and at the 30-day 
short-term follow-up visit.
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment. Palliative radiotherapy, unless required due to progressive disease, is permitted 
during the study.
The results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study 
indicate that oxidative metabolism of abemaciclib is primarily catalyzed by CYP3A4.  However, 
the extent of oxidative metabolism responsible for the systemic clearance of abemaciclib in 
humans is presently unknown.  Based on these in vitro findings, grapefruit juice as well as 
inducers (for example, phenytoin or carbamazepine) and strong inhibitors of CYP3A4 should be 

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substituted or avoided if possible (Attachment 8).  In addition, in vitro studies in primary cultures 
of human hepatocytes indicate that abemaciclib might inhibit the metabolism of CYP2B6 
substrate drugs in vivo in human.  Based on this finding, sensitive CYP2B6 substrates such as 
bupropion and efavirenz should be substituted or avoided if possible (Attachment 8).
Bisphosphonates or denosumab for bone metastasis are permitted.
9.5.1. 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.  Please see Section 9.3.2.2.3.1 for specific 
information on the management of necitumumab-related hypersensitivity/infusion-related 
reactions, skin reactions, conjunctivitis, electrolyte abnormalities, pneumonia and sepsis, and 
serious thromboembolic events.  Guidelines regarding the use of other specific supportive care 
agents are presented below.
9.5.2. Colony-Stimulating Factors and Erythropoiesis-Stimulating 
Agents
The use of colony-stimulating factors (CSF) or erythropoiesis-stimulating agents (ESAs) are 
permitted during investigational therapy at the discretion of the investigator.
Because recommendations on the use of CSFs/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, American Society of Clinical Oncology, American 
Society of Hematology, and/or Centers for Medicare and Medicaid Services Web sites) for the 
latest guidelines.
9.5.3. Therapy for Diarrhea
Diarrhea may influence tolerability of abemaciclib. During therapy with abemaciclib, early
treatment with antidiarrheal agents (for example, loperamide) is recommended immediately after
the first loose stool and should be continued until loose bowel movements cease for 12 hours.  If 
a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve within 24 
hours to either baseline or at least Grade 1, despite maximal treatment with antidiarrheal agents,
then dosing should be suspended (until the toxicity resolves to either baseline or at least 
Grade 1), and the dose of abemaciclib may be reduced by 1 dose level as outlined in
Table JFCU.9.2 at the discretion of the investigator.  If the same dose level was resumed and 
Grade 2 diarrhea recurs despite maximal treatment with antidiarrheal agents, the dose must be 
reduced by 1 dose level as outlined in Table JFCU.9.2.

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A patient experiencing diarrhea requiring hospitalization (irrespective of grade) or severe 
diarrhea (Grade 3 or 4) must have dosing suspended (until the toxicity resolves to either baseline 
or at least Grade 1) and must have the abemaciclib dose reduced by 1 dose level as outlined in
Table JFCU.9.2 and Section 9.3.2.2.1.
In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, loperamide,
octreotide, and other antidiarrheals. If diarrhea is severe (that is, requires intravenous hydration)
and/or associated with fever or severe (Grade 3 or 4) neutropenia, broad-spectrum antibiotics
must be prescribed. Patients with Grade ≥3 diarrhea or any diarrhea associated with Grade ≥3
nausea or vomiting should be considered for hospitalization for intravenous hydration and 
correction of electrolyte imbalance. Events that require a patient to be hospitalized are 
considered SAEs (see Section 10.2.1.1).
9.5.4. Antiemetic Therapy
The use of antiemetic agents is permitted during this study.
9.5.4.1.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.
9.5.5. Bisphosphonates and RANK-L Targeted Agents
Patients with bone metastases present on baseline imaging are allowed treatment with 
bisphosphonates or RANK-L targeted agents (for example, denosumab), per respective approved 
labels.  Initiation of treatment with bone-modifying agents must begin at least 7 days prior to 
enrolment.  Patients receiving bisphosphonates or RANK-L targeted agents should not switch 
treatments (for example, replace a bisphosphonate with denosumab) while on study treatment.  
However, exceptional cases without evidence of PD may be considered in consultation with the 
Lilly CRP.  These exceptional cases will not incur a protocol deviation.
9.5.6. Therapy for Febrile Neutropenia
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation of 
intravenous antibiotic therapy.  Events that require a patient to be hospitalized are considered 
SAEs (see Section 10.2.1.1).
9.6.
Treatment Compliance
Necitumumab will be administered intravenously at the investigational site, under the direction 
of the investigator. As a result, a patient’s compliance with study drug administration is ensured.  
Patients should attend scheduled clinic visits and must comply with study criteria under their
control.
Compliance with abemaciclib will be assessed at Day 1 and Day 8 of each cycle by evaluating
patient diaries and counting returned tablets.
Patients who are significantly noncompliant will be discontinued from the study.  A patient will 
be considered significantly noncompliant if he or she misses more than 5 consecutive days of 

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study medication, or more than 25% of the intended dose of study medication during any cycle 
(not applicable in case of omission or dose reduction of abemaciclib due to AE). Similarly, a 
patient will be considered significantly noncompliant if he or she is judged by the investigator to 
have intentionally or repeatedly taken ≥125% of the planned doses of study treatment in a cycle.
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP before any determination is made to discontinue the patient.
Patient Diaries
The study will include patient diaries to provide dosing instructions, help patients with treatment 
planning, and track actual doses of study treatment taken by the patient.  Information from the 
diaries may be used for documenting study treatment compliance as well as dosing time relative 
to PK blood draws.

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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 sections below and shown in the Study Schedule 
(Attachment 1).
10.1. Efficacy Measures
10.1.1. Efficacy Assessments at Baseline and during Study Treatment
Within 21 days before the first dose of study drug, baseline tumor measurement(s) will be 
performed on each patient.  Throughout the study, patients will be evaluated for response 
according to RECIST 1.1 (Eisenhauer et al. 2009).
A contrast computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain 
will be performed at pretreatment and thereafter approximately every 6 weeks ± 3 days, if a 
patient had brain metastases at study entry or if clinically indicated.
Computed tomography, including spiral CT, scans and MRI are the preferred methods of 
measurement.
The method of assessment used at baseline must be used consistently during the course of each 
patient’s evaluation during the study.
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. CT of the chest and CT or MRI 
of the abdomen is required at each time point; CT/MRI of the brain must be performed if 
baseline assessment identified any lesion in this area (or if clinically indicated).
Responses (CR or PR) must be confirmed no fewer than 28 days from the first evidence of 
response.  Thereafter, a responding patient will be followed approximately every 6 weeks
(± 3 days) until objective progression is observed.
For patients continuing treatment after study completion (continued access period), efficacy 
assessments (frequency and type of assessments) will be at the discretion of the investigator, 
based on the standard of care.
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).

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10.1.2. Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1).
For those patients who discontinue study treatment without objectively measured PD, the 
investigative sites will continue to monitor patients and periodically evaluate tumor response at 
the same frequency and by the same method used at baseline and throughout the study until the 
patient has objective disease progression, starts a new anticancer therapy, or until study 
completion, whichever occurs first. After the patient has objective disease progression or starts a 
new anticancer therapy, radiologic 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 comes first.
Response (CR or PR) should be confirmed before the initiation of additional anticancer therapy. 
However, initiation of new therapy should not be delayed solely to confirm response.
After patients have discontinued study treatment, they may receive additional anticancer therapy 
at the discretion of the investigator.  These postdiscontinuation therapies should be documented 
on the CRF.
10.1.3. Primary Efficacy Measure (Part B only)
The primary efficacy measure is Progression Free Survival Rate as defined by RECIST 1.1 
(Eisenhauer et al. 2009) provided in Attachment 6 at 3 months.
The PFS time is measured from the date of enrollment to the date of objective progression or the 
date of death due to any cause, whichever is earlier.  The censoring is taken in the following 
order:
-
if a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the enrollment date, regardless of whether or not objectively determined 
disease progression or death has been observed for the patient; otherwise,
-
if a patient is not known to have died or have objective progression as of the data 
inclusion cutoff date for the analysis, the PFS time will be censored at the last complete 
objective progression-free disease assessment date.
10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1).
Overall Survival (OS):  OS duration is measured from the date of enrollment to the date of 
death from any cause.  For each patient who is not known to have died as of the data-inclusion 
cutoff date for a particular analysis, OS will be censored for that analysis at the last known alive 
date.

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Objective Response Rate (ORR):  The objective response rate is the percentage of patients with 
a best response of CR or PR.
10.1.5. Disease Control Rate (DCR):  The proportion of patients 
achieving a best overall response of SD, PR, or CR.  Resource 
Utilization
Investigators will be asked to document the use of best supportive care measures, concomitant 
medications, transfusions, and treatment-related hospitalization days.  Such assessments are to be 
taken throughout the study through the [30]-day short-term postdiscontinuation follow-up visit.
10.2. 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 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 JFCU.10.1 presents a summary of AE and SAE reporting guidelines.  Table JFCU.10.1
also shows which database or system is used to store AE and SAE data.

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Table JFCU.10.1.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol procedures 
or study treatment
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment and 
no longer in follow-up)
All SAEs related to protocol procedures 
or study treatment that the investigator 
becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
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, vital sign 
measurements, or other procedures 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.  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.

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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.
In addition, all AEs occurring after the patient receives the first dose of study treatment must be 
reported to Lilly or its designee via eCRF.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure or study treatment via eCRF.
The investigator will decide whether he or she interprets the observed AEs as either reasonably 
possibly related to disease, to the study medication, study procedure, or other concomitant 
treatment or pathologies.  The investigator answers Yes/No to make this assessment in relation to 
study treatment and 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 and assessing severity grade based on the 
intensity of the event.
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA ™) dictionary.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.2.1.1. Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.

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Serious adverse event collection begins after the patient has signed informed consent and has 
received study treatment.  If a patient experiences an SAE after signing informed consent, but 
prior to receiving study treatment, the event will not be reported as serious unless the investigator 
feels the event may have been caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  If study site 
personnel contact Lilly or its designee by telephone regarding an SAE, study site personnel must 
also immediately provide official notification on study-specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
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 due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drugs.
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 Development Core Safety Information in the IB and that the investigator identifies as 
related to the study treatment or study procedure.  United States 21 CFR 312.32 and European 
Union Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national 
regulatory requirements in participating countries require the reporting of SUSARs.  Lilly has 
procedures that will be followed for the recording and expedited reporting of SUSARs that are 
consistent with global regulations and associated detailed guidances.

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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.  Patients must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT interval from 
baseline or other clinically significant quantitative or qualitative change from baseline is 
identified, the patient will be assessed by the investigator for symptoms (for example, 
palpitations, near syncope, syncope) and to determine whether 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 Global Patient Safety 
therapeutic area physician or clinical scientist, and review:

trends in safety data

laboratory analytes 

adverse events 

If a patient experiences elevated 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/weakness/asthenia, pain/chest pain, 
dyspnea, cough, nausea, anorexia/decreased appetite, disease progression, metastasis, 
hemoptysis, and 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 to facilitate process and product improvements.
Complaints related to concomitant drugs/drug delivery systems are reported directly to the 
manufacturers of those drugs/devices in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any 
associated AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to 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 schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.
Attachment 7 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
10.3.1. Samples for Study Qualification and Health Monitoring
Standard laboratory tests, including chemistry, hematology, coagulation, and pregnancy testing 
(if applicable in women of childbearing potential), will be performed and analyzed centrally. 
Urinalysis will be assayed by investigator-designated (local) laboratory. Attachment 2 lists the 
laboratory tests that will be performed for this study.  Central laboratory results 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.

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Blood and urine samples will be collected at the times specified in the Study Schedule
(Attachment 1).
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.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.3.2. Samples for Pharmacogenetics and Translational Research
Collection of samples for translational research is also part of this study.
Required samples for biomarker research to be collected from all patients in this study are the 
following:

Whole blood

Plasma

Archived tumor tissue (a minimum of 12 slides is required for study eligibility)
As part of an ongoing effort by Lilly to better understand how to predict which patients are 
more likely to respond to necitumumab and abemaciclib treatment, whole blood, plasma, and 
tissue samples will be collected to explore biomarkers including but not limited to, those related 
to the EGFR pathway, Rb pathway, CDK4/6, cell cycle, and/or the pathogenesis of lung cancer.  
Analyses may include, but are not limited to, potential nucleic acid and protein markers to better 
understand the disease process, and to develop predictive biomarkers and diagnostics.
10.3.2.1. Samples for Pharmacogenetic Evaluation
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 whole blood sample will be collected for pharmacogenetic 
analysis.  It is a 1-time collection, as noted in the Study Schedule (Attachment 1).
Samples will be stored and analysis may be performed on genetic variants thought to play a role 
in the EGFR-pathway, Rb pathway, CDK4/6, cell cycle, NSCLC pathogenesis, and the 
mechanism of action of necitumumab or abemaciclib to evaluate their association with observed 
clinical outcomes (OS, PFS, and ORR).
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 

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association with response to necitumumab or abemaciclib.  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 samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drugs.
Samples will be destroyed according to a process consistent with local regulation.
10.3.2.2. Archived Tumor Tissue Collection
To meet study eligibility criteria, and therefore mandatory for study participation, patients must 
have available formalin fixed-paraffin embedded (FFPE) tumor sample.  While the tissue can be 
from either initial diagnosis of Stage IV NSCLC or later (for example, at relapse), the most 
recent sample is preferred.  The sample can be either 12 serially cut unstained sections or a tissue 
block (preferred). Due diligence should be used to make sure that tumor specimens (not a 
normal adjacent or a tumor margin sample) are provided. Available FFPE primary and/or 
metastatic tumor tissue should be in a whole block, partial block, or unstained slides.  Archived 
tumor tissue must be made available for biomarker assessments.  If tumor tissue (primary or 
metastatic site, paraffin-embedded) is available from a recent biopsy performed as a part of 
routine clinical care prior to screening, this may be used if archived tissue is not available. If the 
required amount of tumor tissue is not available, the patient may still be eligible if willing to 
undergo a tumor biopsy and if the procedure is considered safe and feasible at the investigator´s 
discretion. Cytologic samples and fine-needle aspiration specimens are not 
acceptable. Pathology notes accompanying archival tissue may also be requested.
In tumor tissue samples, the CDK4/6 and EGFR pathway components and markers relevant to 
NSCLC pathogenesis may be evaluated to assess any potential correlation with response to 
therapy.  Tumor samples may be analyzed to explore potential tumor gene signature(s) 
associated with response or resistance to abemaciclib and/or necitumumab therapy.  These 
studies may be analyzed at a laboratory designated by the sponsor and may include, but are not 
limited to, immunohistochemistry of proteins, FISH for copy number amplifications, RNA gene-
expression profiling, and/or genetic analyses of the tumor specimen DNA.  Such analyses may 
employ targeted or high-throughput sequencing approaches.  For this purpose, the results of this 
analysis will be correlated with clinical efficacy data.
Samples will be identified by the patient number (coded) and stored for up to a maximum of 
15 years after the last patient visit for the study at a facility selected by the sponsor.  After testing 
has been completed, the paraffin-embedded whole blocks will be returned to the sites.  Whole 
blocks can be returned sooner, if requested by the sites.  Partial blocks and slides will not be 
returned.

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10.3.2.3. Plasma Sample Collection
At the visits and times specified in Attachment 7, EDTA-anticoagulated plasma will be collected
for exploratory biomarker analyses that may include, but are not limited to, exosomes, nucleic
acid and protein markers indicative of the pathobiology of the tumor, expected mechanisms of 
action of the therapy, responses to treatment, and molecular pathways.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drugs.
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 Section 9.3.2.2.3.1, 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 necitumumab 
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 (PK) samples (venous blood) will be collected as specified in the 
Pharmacokinetic, Immunogenicity, and Blood Based Markers Sampling Schedule 
(Attachment 7).  Blood samples will be collected to determine the serum concentrations of 
necitumumab using a validated enzyme-linked immunosorbent assay method at a laboratory 
approved by the sponsor.
Blood samples will also be collected to determine the plasma concentrations of abemaciclib and 
metabolites using a validated liquid chromatography–tandem mass spectrometry method.
Bioanalytical samples collected to measure necitumumab and abemaciclib (and metabolites)
concentrations will be retained for a maximum of 1 year following last patient visit for the study.

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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 CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect daily 
dosing schedule.
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
A total of approximately 68 patients evaluable for either the Part A or Part B portions of the 
study will be enrolled.  Part A requires up to 18 treated patients (3-6 per dosage cohort). Patients 
with squamous and nonsquamous NSCLC who received the recommended abemaciclib dose for 
Part B in Part A will also be part of the Part B portion of the trial.  These patients will also be 
included in the interim analyses as described in Section 12.2.10.
An evaluable patient for Part B will include any patient enrolled in Part A and treated at the 
recommended doses of necitumumab and abemaciclib.  In addition, patients will be entered 
strictly to Part B (with a total of 50 evaluable patients in Part B).  To be evaluable for Part B of 
the study, these additional patients entered must meet the following criteria:
(1)
The patient has received at least 1 dose each of necitumumab and abemaciclib.
(2)
The patient has a complete radiographic assessment at baseline.
The final analysis of the study will take place approximately 5 months after the last patient 
evaluable for Part B portion of the study has been enrolled. The primary Part B outcome 
variable in this study will be the 3-month PFS rate.  The Part B statistical null hypothesis states 
that the true 3-month PFS rate is 50%, whereas the research hypothesis states that the true 
3-month PFS rate is 65%.  Assuming the Part B portion of the study continues to a full 
enrollment of 50 evaluable patients, the null hypothesis will be rejected at the final analysis only 
if at least 60% of evaluable patients experience PFS ≥3 months.
If the research hypothesis is true, there is an 81% chance of reaching full Part B enrollment and 
rejecting the null hypothesis.  If the null hypothesis is true, then there is a 10% chance of
reaching full Part B enrollment and rejecting the null hypothesis. Therefore, the Part B portion 
of this study has a one-sided alpha level of 0.10, with statistical power of 81%.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
The primary analysis will be as described in Section 12.1.
All summary analyses, including efficacy and safety analyses, will be performed for all patients
enrolled in the study who receive any amount of study drug (necitumumab and abemaciclib).
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:

total number of patients enrolled; and

total number of patients treated (safety population).

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A detailed summary of reasons for patient discontinuation fro m treatment will be provided.  
A summary of all identified major protocol violations will be provided.
12.2.3. Patient Characteristics
A detailed description of patient characteristics at baseline will be provided, including:

patient demographics;

baseline disease characteristics; and

medical history.
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 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, and delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients.
Compliance information for abemaciclib will be collected through capsule counts at each 
cycle/visit.  The estimate of percent compliance will be given by:
Percent Compliance =
Actual cumulative dose taken
Expected cumulative dose to be taken × 100
The actual cumulative dose taken will be determined based on counting the number of capsules 
returned at each visit and subtracting that number from the number of capsules dispensed.  The 
expected cumulative dose to be taken will be determined based on the assigned dose and taking 
into account any dose reductions or suspensions.
12.2.6. Primary Outcome and Methodology
Please refer to Section 12.1 for details of the primary analysis.
12.2.6.1. Analyses of Efficacy
In addition to the analyses described in Section 12.1, this section provides additional details of
planned efficacy analyses.  For time-to-event variables, the Kaplan-Meier method will be used to
estimate parameters (for example, medians, quartiles, 1-year event rates).  See also the SAP for 
this study for additional details.
Table JFCU.12.1 provides definitions of key efficacy statistics used for this study. Exact 95% 
confidence intervals will be calculated for ORR and DCR.

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Table JFCU.12.1.
Definitions of Key Efficacy Statistics
Efficacy Statistic
Definition
Objective Response Rate 
(ORR) 
The denominator of ORR includes each patient enrolled who receives any amount of
study drug (necitumumab or abemaciclib), who has a complete radiographic assessment 
at baseline, and who has at least 1 complete radiographic assessment postbaseline. The 
numerator includes those patients counted in the denominator with a best overall tumor 
response of PR or CR.
Disease Control Rate 
(DCR)
Using the same denominator as for ORR, the numerator of the DCR includes those 
patients counted in the denominator with a best tumor response of SD, PR, or CR.
Median (OS, PFS)
Estimated using Kaplan-Meier method of estimation 
Abbreviations:  CR = complete response; DCR = disease control rate; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PR = partial response; SD = stable disease.
12.2.7. Pharmacokinetic and Immunogenicity Analyses
PK analyses will be conducted on patients who have received at least 1 dose of either study drug 
and have had samples collected.
PK parameter estimates will be computed for abemaciclib and its metabolites.  The abemaciclib 
PK parameters will be computed by standard noncompartmental methods of analysis using 
WinNonlin Professional Edition on a computer that meets or exceeds the minimum requirements 
for this program.
The primary parameters for analysis will be maximum concentration and area under the 
concentration-time curve (AUC0-tlast, AUC0-∞).  Other noncompartmental parameters, such as 
time of half-life, apparent clearance (CL/F), and apparent volume of distribution (V/F) may be 
reported.
Summary statistics of necitumumab PK data will be presented graphically as well as in tabulated 
form. Additional exploratory analyses will be performed if warranted by data, and other 
validated PK software programs (for example, NONMEM) may be used if appropriate and 
approved by Global Pharmacokinetic management.  The version of any software used for the 
analysis will be documented, and the program will meet the Lilly requirements of software 
validation.
Serum concentrations of necitumumab and plasma concentrations of abemaciclib and 
metabolites 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 or abemaciclib to facilitate 

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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.
12.2.8. Translational Research Analyses
Biomarker results will be summarized and correlated with clinical outcomes.
12.2.9. Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.2.
Overall exposure to study drugs, 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 entire 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 possibly 
related to study treatment, and repeated for events regardless of study drug 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 and related SAEs 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 
discontinued from the study therapy due to an AE will be summarized.
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 grade, including the total for maximum Grade 3 and above.  These summaries will be 
provided for events deemed by the investigator to be 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 System Organ Class (SOC) and by 
decreasing frequency of Preferred Term (PT) within SOC.
Reasons for death will be summarized separately for on-therapy and within 30 days of last dose 
of study drug.  Serious adverse events will be summarized by PT.
Hospitalizations and transfusions during the study treatment period or during the 30-day
short-term follow-up period will be summarized.

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12.2.10.
Interim Analyses
A safety interim analysis will be performed after the first 15 evaluable patients in the Part B
portion of the trial have completed 2 cycles of study treatment (or otherwise discontinued study 
treatment).
The safety interim analysis will be conducted to permit evaluation of safety data by Lilly.
The results from the safety interim analysis will be examined by an internal assessment 
committee, which will be established prior to enrollment of the first patient in the 
trial. The internal assessment committee will consist of a Lilly medical director, a Lilly 
CRP/clinical research scientist, a PK scientist, and a statistician and will make recommendations 
about the trial. Enrollment will continue while the safety interim analysis is being 
performed. The safety interim analysis results (including all tables, figures, and listings) will not 
be disseminated outside of the assessment committee, unless emerging safety outcomes warrant 
such a disclosure.  In case a disclosure is warranted, the outcome of the safety interim analysis 
will be documented and a written letter will be submitted to the ERB(s) and the investigators for 
documentation purposes.
Interim analyses for efficacy may be performed as needed to aid in the planning of future trials.  
There is no plan to stop the study for positive efficacy.  The type-1 error for final primary 
analysis will not be affected and hence is not adjusted.
Patients with squamous and nonsquamous NSCLC who received the recommended abemaciclib 
dose for Part B in Part A will be taken into account for the interim analyses.

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

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Some of the obligations of Lilly will be assigned to a third-party organization.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Physicians with a specialty in treating patients with lung cancer will participate as investigators 
in this clinical trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
The investigator chosen by Lilly 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
Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human 
Development Index (2008-2030): a population-based study. Lancet Oncol. 
2012;13(8):790-801.
Bunn PA. Worldwide overview of the current status of lung cancer diagnosis and treatment. Arch 
Pathol Lab Med. 2012;136(12):1478-1481.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
Edge, S, Byrd, DR, Compton, CC, Fritz, AG, Greene, FL, Trotti, A. AJCC Cancer Staging 
Manual. 7th Edition. 2009.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
RECIST (version 1.1). 2009.
Erbitux (cetuximab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.
Erbitux (cetuximab) [Summary of Product Characteristics]. Darmstadt, Germany: Merck KGaA; 
2014.
Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi H, Angeletti CA, Pingitore R, Pepe S, 
Basolo F, Bevilacqua G. 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.
Goldman JW, Gandhi L, Patnaik A, Rosen LS, Hilton JF, Papadopoulos KP, Tolaney SM, 
Beeram M, Rasco DW, Myrand SP, Beckmann RP, Kulanthaivel P, Frenzel M, Cronier D, 
Chan EM, Flaherty K, Wen PY, Tolcher AW, Shapiro G. Clinical activity of LY2835219, a 
novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung 
cancer. 2014 ASCO Annual Meeting [Abstract 8026].
Heigener DF, Reck M. Crizotinib. Recent Results Cancer Res. 2014;201:197-205.
Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, 
Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER 
Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, 
posted to the SEER web site, April 2014.
Melosky B, Burkes R, Rayson D, Alcindor T, Shear N, Lacouture M. Management of skin rash 
during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies: 
Canadian recommendations. Curr Oncol. 2009;16(1):16-26.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-655.
Ortega S, Malumbresa M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer.
Biochim Biophys Acta. 2002;1602(1):73-87.

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Paz-Ares L, Mezger J, Ciuleanu T, Fischer JR, Von Pawel J, Provencio M, et al. Randomized 
phase-3 trial (INSPIRE) of necitumumab plus cisplatin-pemetrexed versus cisplatin-
pemetrexed alone as first-line therapy in stage IV non-squamous NSCLC. J Thorac Oncol. 
2013;8(Suppl 2):O03.2.
Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, 
Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, 
Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in 
patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized 
phase III trial. Lancet. 2009;373(9674):1525-1531.
Pujol JL, Pirker R, Lynch TJ, Butts CA, Rosell R, Shepherd FA, Vansteenkiste J, O'Byrne KJ, de 
Blas B, Heighway J, von Heydebreck A, Thatcher N. Meta-analysis of individual patient data 
from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced 
non-small cell lung cancer. Lung Cancer. 2014;83(2):211-218.
Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and 
their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183-232.
Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672-1677.
Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK,
Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda
S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA, SQUIRE investigators. 
Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-
line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an 
open-label, randomized, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763-774.
Vectibix (panitumumab) [package insert]. Thousand Oaks, CA: Amgen Inc; 2014.
Vectibix (panitumumab) [Summary of Product Characteristics]. Breda, The Netherlands: Amgen 
Europe B.V.; 2014.

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Attachment 1.Protocol JFCU Study Schedule

I4X-MC-JFCU(b) Clinical Protocol 
 
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Study Schedule, Protocol I4X-MC-JFCU 
Perform procedure as indicated in the following schedules. 
Baseline Schedule, I4X-MC-JFCU 
 
 
 
Baseline 
 
 
 
Cycle 
BL 
 
 
 
Visit 
0
 
 
 
Relative day within a cycle 
≤21
≤14
≤7
 
Procedure 
Category 
Protocol 
Section 
Procedure 
 
Comments 
Study Entry/ 
Enrollment 
13.1 
Informed consent form signed 
 
 
 
ICF must be signed prior to performing any protocol-specific tests/procedures. 
7.1, 7.2 
Inclusion/exclusion evaluation 
X 
 
 
 
Medical History 
12.2.3 
Initial history/preexisting conditions 
 
X 
 
 
12.2.3 
Historical illnesses 
 
X 
 
 
 
Habits assessment 
 
X 
 
Smoking  
Physical 
Examination 
 
Height 
 
X 
 
 
 
Weight 
 
X 
 
 
 
Blood pressure/pulse/temperature 
 
X 
 
 
Att. 4 
ECOG performance status 
 
X 
 
 
Efficacy 
Assessment 
10.1.1 
Radiologic imaging/Tumor Assessment 
(according to RECIST v1.1)  
X 
 
 
A contrast CT scan or MRI of the brain will be performed if the patient is known to have CNS 
metastasis. 
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 
9.5 
Concomitant medication notation 
X 
 
 
 

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Baseline
Cycle
BL
Visit
0
Relative day within a cycle
≤21
≤14
≤7
Procedure 
Category
Protocol 
Section
Procedure
Comments
Laboratory/
Diagnostic Tests
Att. 2
Hematology (central)
X
Att. 2
Chemistry (central)
X
Att. 2
Coagulation (central)
X
Att. 2
Urinalysis (local)
X
Att. 2
Pregnancy test (central)
X
In women of childbearing potential
10.3.2.1
Whole blood for pharmacogenetic 
analysis
Refer to
Attachment 7
10.3.4
PK sampling (central)
Refer to
Attachment 7
10.3.3
Immunogenicity:  Anti-necitumumab 
antibodies
Refer to
Attachment 7
10.3.2.3
Plasma sample for Biomarker Analysis
Refer to
Attachment 7
10.3.2.2
Tumor tissue sample
X
To meet study eligibility criteria, and therefore mandatory for study participation, patients must 
have available FFPE tumor sample.  Previously archived Stage IV NSCLC tissue from the initial 
diagnosis may be used but the most recent sample is preferred (for example, at relapse).  The 
sample can be either 12 serially cut unstained sections or a tissue block (preferred). See 
Section 10.3.2.2 for further details.
10.2.2.1
ECG (local)
X
Abbreviations:  AE = adverse event; BL = baseline; CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formaldehyde fixed-paraffin embedded; ICF = informed consent form; MRI = magnetic resonance imaging; 
PK = pharmacokinetic; RECIST = Response Evaluation Criteria In Solid Tumors; SAEs = serious adverse events.

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Treatment Period Schedule, I4X-MC-JFCU
Comments
Repeat every 3 weeks
Cycle
(3-week cycle)
1-X
Visit
1-X
Relative day within a 
cycle
1
8
Except for the Cycle 1, Day 1 visit, allowable cycle windows are ±3 days, unless indicated 
otherwise (see Section 9.3.1)
Procedure 
Category
Protocol 
Section
Procedure
Physical 
Examination
Weight
X
Blood pressure/pulse
X
X
Att. 4
ECOG performance status
X
Tumor 
Assessment
10.1.1
Radiologic imaging (according 
to RECIST v1.1) and tumor 
measurement
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 the Response Evaluation 
Criteria In Solid Tumors (RECIST 1.1). A contrast CT scan or MRI of the brain will be performed 
if the patient is known to have CNS metastasis or if clinically indicated.
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.
Concomitant 
Medications
9.5
Concomitant medication 
notation
X
X
IP
9.2
Necitumumab
X
X
9.2
Abemaciclib
X
X
Every 12 hours (+2) D1-21. Oral administration of abemaciclib should take place within 10 minutes 
of start of necitumumab infusion.

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Comments
Repeat every 3 weeks
Cycle
(3-week cycle)
1-X
Visit
1-X
Relative day within a 
cycle
1
8
Except for the Cycle 1, Day 1 visit, allowable cycle windows are ±3 days, unless indicated 
otherwise (see Section 9.3.1)
Procedure 
Category
Protocol 
Section
Procedure
Laboratory/
Diagnostic 
Tests
Att. 2
Hematology (central)
X
X
Investigator-designated (local) laboratory can be used to perform additional tests for on-study 
dosing decisions. If so, the test must also still be performed by the central laboratory.
Pretreatment laboratory data may not be older than 72 hours (Day 1 of each cycle) or 24 hours 
(Day 8). Pretreatment laboratory tests at Day 1 Cycle 1 may not be repeated if the baseline data are 
not older than 72 hours from Day 1 Cycle 1.
Hepatic monitoring tests (per Attachment 3; assayed by central laboratory. Can be performed 
locally, if needed or per discretion of the investigator) to be done in the event of a treatment-
emergent hepatic abnormality.
In case of neutropenia, thrombocytopenia Grade 4 during Cycle 1 (dose finding part only), repeat 
every 2 days until recovery
Att. 2
Chemistry (central)
X
X
Investigator-designated (local) laboratory can be used to perform additional tests for on-study 
dosing decisions. If so, the test must also still be performed by the central laboratory.
Pretreatment laboratory data may not be older than 72 hours (Day 1 of each cycle) or 24 hours 
(Day 8). Pretreatment laboratory tests at Day 1 Cycle 1 may not be repeated if the baseline data are 
not older than 72 hours from Day 1 Cycle 1.
Hepatic monitoring tests (per Attachment 3; assayed by central laboratory. Can be performed 
locally, if needed or per discretion of the investigator) to be done in the event of a treatment-
emergent hepatic abnormality.
Grade 3 elevation of transaminases, bilirubin, change of electrolytes (see DLT criteria), repeat every 
2 days until recovery (Cycle 1, dose-finding part only).
Att. 2
Coagulation (central)
X*
* To be performed every second cycle starting from Cycle 2
Att. 2
Urinalysis (local)
X*
* To be performed every second cycle starting from Cycle 2
Att. 2
Pregnancy test  (central)
X*
* To be performed every cycle in women of childbearing potential
10.3.4
PK sampling (central)
Refer to Attachment 7
Note: If a patient experiences an IRR to necitumumab at any time during the study, blood samples for necitumumab 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
Immunogenicity:  Anti-
necitumumab antibodies
10.3.2.3
Plasma sample for Biomarker 
Analysis
Refer to Attachment 7
10.3.2.1
Whole blood for 
Pharmacogenetic evaluation
Refer to Attachment 7
10.2.2.1
ECG (local)
X*
* To be performed every second cycle starting from Cycle 2

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Abbreviations:  AE = adverse event; Att. = Attachment; CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; 
ECG = electrocardiogram; DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology Group; IP = investigational product; IRR = infusion-related reaction; MRI = magnetic resonance 
imaging; PD = progressive disease; PK = pharmacokinetic; RECIST = Response Evaluation Criteria In Solid Tumors; SAEs = serious adverse events.

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Postdiscontinuation Follow-up Schedule, I4X-MC-JFCU
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
Procedure
Comments
Physical 
Examination
Weight
X
Blood pressure/pulse
X
Att. 4
ECOG performance status
X
Tumor 
Assessment
10.1.2
Radiologic imaging 
(according to RECIST v1.1) 
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, the initiation of a new anticancer therapy
or overall study completion, whichever occurs first.
After the patient has objective disease progression, radiologic 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.
Survival 
information
10.1.4
Collection of survival 
information
X
Collection of survival data every 3 months (±7 days).  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
9.5
Concomitant medication 
notation
X
Laboratory/
Diagnostic 
Tests
Att. 2
Hematology (central)
X
Att. 2
Chemistry (central)
X
10.3.2.3
Plasma sample for 
Biomarker Analysis
X
When applicable, EDTA plasma should be collected as near as possible to the time of progression disease, 
during the study treatment period. If for any reason the post progression sample cannot be collected at the 
time of progression, this should be done at (or by) the short-term follow-up visit. The post progression 
sample should be collected before the initiation of any new anticancer therapy.
Att. 2
Pregnancy test (central)
X
In women of childbearing potential.
Att. 2
Urinalysis (local)
X
10.3.4
PK
Refer to Attachment 7
If a patient experiences an IRR to necitumumab at any time during the study, blood samples for 
necitumumab 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
Immunogenicity:  Anti-
necitumumab antibodies
10.2.2.1
ECG (local)
X

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Postdiscontinuation Follow-up Schedule, I4X-MC-JFCU (concluded)
Abbreviations:  AE = adverse event; CRF = case report form; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
IRR = infusion-related reaction; PD = progressive disease; PK = pharmacokinetic; RECIST= Response Evaluation Criteria In Solid Tumors; SAEs = serious adverse events.
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, the initiation of a new anticancer therapy 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-JFCU
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
Procedure
Comments
Physical 
Examination
Weight
X
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
PK
Refer to Attachment 7
If a patient experiences an IRR to necitumumab, blood samples 
for necitumumab 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
Immunogenicity:  Anti-necitumumab 
antibodies
Study 
Treatment
9.2
Necitumumab
X
X
9.2
Abemaciclib
X
X
Every 12 hours (+2) D1-21. Oral administration of abemaciclib 
should take place within 10 minutes of start of necitumumab 
infusion.
Abbreviations: AE = adverse event; CRF = case report form; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction; PK = pharmacokinetic; SAEs = serious 
adverse events.
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.
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 JFCU Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistrya:
Hemoglobin
Hematocrit
Erythrocyte count (RBC)
Mean cell volume (MCV)
Mean cell hemoglobin concentration (MCHC)
Leukocytes (WBC)
Neutrophils, segmented and bands
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Serum concentrations of:
Sodium
Magnesium
Potassium
Phosphate
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Blood urea nitrogen (BUN)
Creatinineb
Uric acid
Calcium
Glucose, nonfasting
Urinalysisc
Albumin
Color
Cholesterol
Specific gravity
Creatine kinase (CK)
pH
Protein
Glucose
Ketones
Blood
Urine leukocyte esterase
Pregnancy Test (females of childbearing 
potential only, serum required)d
Coagulation Testsd:
INR and PT
PTT
Fibrin D dimer
Protein C activity (baseline only)
Protein S activity (baseline only)
Abbreviations:  IDMS = isotope dilution mass spectrometry; INR = International Normalized Ratio; 
PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated (central) laboratory. Investigator-designated (local) laboratory can be used to 
perform additional tests for on-study dosing decisions. If so, the test must also still be performed by the central 
laboratory.
b
IDMS for United States sites.
c
Assayed by investigator-designated (local) laboratory.
d
Assayed by Lilly-designated (central) laboratory.

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Attachment 3.Protocol JFCU Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented and bands
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Anti-smooth muscle antibodya
CK
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = International Normalized Ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by central laboratory (can be performed locally, if needed or per discretion of the investigator).
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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

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

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

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

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

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

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

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

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

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Attachment 7.Protocol JFCU Pharmacokinetic, 
Immunogenicity, and Blood-Based Markers Sampling 
Schedule
It is essential that the exact infusion start and stop times (actual clock readings), as well as 
infusion parameters (such as 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 pharmacokinetic blood samples not be withdrawn from the same I.V. site as the 
drug infusion.
Oral administration of abemaciclib should take place within 10 minutes of start of necitumumab 
infusion.
Preinfusion samples should be taken as close as possible to the start of infusion, but can be 
drawn up to 1 hour (60 minutes) prior the infusion, and exact clock reading should be recorded.  
End-of-infusion samples should be drawn as soon as possible after the end of infusion, and no 
later than within 15 minutes, and exact clock reading should be recorded.
In addition, if a patient experiences an infusion-related reaction (IRR) to necitumumab, blood
samples for necitumumab 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.

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Part A:
Pharmacokinetic, Immunogenicity, and Blood-Based Markers Sampling Schedule
PK 
Sample 
Number
Cycle and Day
Time
Dosing of Study Drugs
Sampling Time 
for necitumumab 
PK a
Sampling time 
for necitumumab 
Immunogenicity a
Sampling for 
abemaciclib 
PK
Sampling 
for Plasma 
biomarkers
Whole blood Sampling for 
Pharmaco-genetic 
evaluation
C1D1
0-4 h pre-dose
X
X
X
X
X
C1D1
Dose event
Abemaciclib
Necitumumab
1
C1D1
Up to 15 min after end 
of necitumumab dose
X
X
2
C1D1
2 h ± 10 min after 
LY2835219 dose
X
X
3
C1D1
4 h ± 20 min after 
LY2835219 dose
X
X
4
C1D1
6 h ± 20 min after 
LY2835219 dose
X
5
C1D1
8 h± 20 min after 
LY2835219 dose
X
6
C1D1
10 h ± 20 min after 
LY2835219 doseb
X
X
7
C1D8
Predose (0-1 hour pre-
dose)
X
X
C1D8
Dose event
Abemaciclib
Necitumumab
8
C1D8
Up to 15 min after end 
of necitumumab dose
X
X
9
C2D1
Predose  (0-1 hour pre-
dose)
X
X
C2D1
Dose event
Abemaciclib
Necitumumab
10
C2D1
Up to 15 min after end 
of necitumumab dose
X
X

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PK 
Sample 
Number
Cycle and Day
Time
Dosing of Study Drugs
Sampling Time 
for necitumumab 
PK a
Sampling time 
for necitumumab 
Immunogenicity a
Sampling for 
abemaciclib 
PK
Sampling 
for Plasma 
biomarkers
Whole blood Sampling for 
Pharmaco-genetic 
evaluation
11
C2D1
2 h ± 10 min after 
LY2835219 dose
X
X
12
C2D1
4 h ± 20 min after 
LY2835219 dose
X
X
13
C2D1
6 h ± 20 min after 
LY2835219 dose
X
14
C2D1
8 h± 20 min after 
LY2835219 dose
X
15
C2D1
10 h ± 20 min after 
LY2835219 doseb
X
X
16->
Day 1 of Cycle 
3, 5, and 7
Predose (0-1 hour pre-
dose)
X
X
X
Xc
Day 1 of Cycle 
3, 5, and 7
Dose event
Abemaciclib
Necitumumab
17->
Day 1 of Cycle 
3, 5, and 7
Up to 15 min after end 
of necitumumab dose
X
30-day follow-
up
X
X
Xd
Abbreviations:  C = Cycle; D = Day; PK = pharmacokinetics.
a
In the event of a necitumumab infusion-related reaction, blood samples will be collected for analysis as close to the onset of the reaction as possible, at the 
resolution of the event, and 30 days following the event.
b
To omit the collection of the 10 hour “postdose” PK sample for that day does not constitute a protocol violation.
c
Cycle 3 only.
d
When applicable, EDTA plasma should be collected as near as possible to the time of progression disease, during the study treatment period. If for any 
reason the post progression sample cannot be collected at the time of progression, this should be done at (or by) the 30-day follow-up visit. The 
post-progression sample should be collected before the initiation of any new anticancer therapy.

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Part B:
Pharmacokinetic, Immunogenicity, and Blood-Based Markers Sampling Schedule
PK 
Sample 
Number
Cycle 
and 
Day
Time
Dosing of Study Drugs
Sampling Time 
for 
necitumumab 
PKa, c
Sampling time 
for necitumumab 
Immunogenicityc
Sampling for 
abemaciclib 
PKb, c
Sampling for 
Plasma 
biomarkers
Whole blood 
Sampling for 
Pharmaco-
genetic 
evaluation
1
C1D1
0-4 h pre-dose
X
X
X
X
X
C1D1
Dose event
Abemaciclib
Necitumumab
2
C1D1
Up to 15 min after end of 
necitumumab dose
X
X
3->
Day 1 of 
Cycle 3,
5, and 7
Predose  (0-1 hour pre-
dose)
X
X
X
Xd
30-day 
follow-
up
X
X
Xe
Abbreviations:  C = Cycle; D = Day; PK = pharmacokinetics.
a
Samples of approximately 2.5 mL of whole blood will be drawn into serum separator tubes for the measurement of necitumumab concentrations.
b
For the abemaciclib and metabolites assay, approximately 2 mL of whole blood will be drawn into tubes containing K2EDTA and processed to plasma.
c
In the event of a necitumumab infusion-related reaction, blood samples will be collected for analysis as close to the onset of the reaction as possible, at the 
resolution of the event, and 30 days following the event.
d
Cycle 3 only.
e
When applicable, EDTA plasma should be collected as near as possible to the time of progression disease, during the study treatment period. If for any 
reason the post progression sample cannot be collected at the time of progression, this should be done at (or by) the 30-day follow-up visit. The post 
progression sample should be collected before the initiation of any new anticancer therapy.

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Attachment 8.Protocol JFCU Inducers and Strong Inhibitors 
of CYP3A4 or Substrates of CYP2B
The information in this attachment is provided for guidance to investigators and 
does not preclude the use of these medications if clinically indicated.
Inducers of CYP3A4
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A4
All HIV protease inhibitors
Clarithromycin
Itraconazole
Ketoconazole
Nefazodone
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if 
clinically indicated.  A patient who develops brain metastases may receive acute or chronic therapy with 
dexamethasone, if clinically indicated.  Development of brain metastases is considered progressive disease and 
the patient should discontinue study treatment.
Substrates of CYP2B6
Alfentanil
Bupropion
cyclophosphamide
Efavirenz
Ifosfamide
methadone
Nevirapine
Propofol
Sertraline
sorafenib
tamoxifen
Valproic acid

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Attachment 9.Protocol JFCU Amendment (b) Summary 
Overview
Protocol I4X-MC-JFCU (A Single-Arm, Multicenter, Phase 1b Study with an Expansion Cohort 
to Evaluate Safety and Efficacy of Necitumumab in Combination with Abemaciclib in Treatment 
of Patients with Stage IV 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 overall changes and rationale for the changes made to this protocol are as follows:

Interim efficacy analyses (as needed) have been added to aid in the planning of future trials.

Specific AEs of necitumumab have been amended according to the new necitumumab IB.  

The infusion time for necitumumab has been updated to 60 minutes in accordance with the 
new necitumumab IB and Portrazza PI.  

Some changes in Section 5. Introduction have been made for updated approval and clinical 
trial information.  
Other change points are as follows:

A few additional minor changes were made for clarity.  

Minor editorial changes were made for clarity.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2. Synopsis 
Necitumumab (IMC-11F8; LY 3012211; Portrazza®) is a recombinant human monoclonal 
antibody (mAb) of the immunoglobulin G, subclass 1 (IgG1) that blocks the ligand-binding site 
of the epidermal growth factor receptor (EGFR).  EGFR is detectable in approximately 85% of 
patients with advanced, metastatic non-small cell lung cancer (NSCLC).  Necitumumab has 
shown signals of antitumor activity in 2 Phase 1 trials when administered as monotherapy in 
heavily pretreated patients including but not limited to patients with NSCLC. Two Phase 3 trials, 
the necitumumab SQUIRE trial and Portrazza has recently been approved in the United States 
(US) and European Union (EU) for the treatment of adult patients with metastatic squamous 
NSCLC in combination with gemcitabine and cisplatin.  the The cetuximab FLEX Phase 3 trial,
have has demonstrated a statistically significant improvement in survival for the combination of 
an EGFR mAb in combination with chemotherapy in the first-line treatment of patients with
metastatic squamous NSCLC and advanced metastatic NSCLC, respectively.

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Length of Study:  approximately 21 months
Planned first patient visit:  08 Sep 2015
Planned last patient visit:  19 Jun 2017
Planned interim analysisanalyses:  first 15 evaluable patients in Part B portion of the study who have completed 
2 cycles of study treatment (or otherwise discontinued study treatment) will be analyzed for safety.  Interim 
analyses for efficacy may be performed as needed to aid in the planning of future trials.  Patients with squamous 
and nonsquamous NSCLC who received the recommended abemaciclib dose for Part B in Part A will be taken into 
account for the safety interim analysisanalyses.
Objectives:
The secondary objectives of the study are:
Part A:

to investigate the safety profile as assessed by clinical and laboratory significant events of necitumumab in 
combination with abemaciclib

to determine the overall objective response rate (ORR)

to determine the pharmacokinetics (PK) of necitumumab and abemaciclib

to determine the immunogenicity of necitumumab
Test Product, Dosage, and Mode of Administration:

Necitumumab is a sterile, preservative-free, intravenous infusion supplied in 50-mL vials containing 
16 mg/mL (800 mg/50 mL) of product, and administered over 50 minutes at a dose of 800 mg on Days 1 and 8 
of each 21-day cycle.

Abemaciclib is administered orally as capsules (supplied for clinical trial use in strength of 50 mg/capsule) 
every 12 hours.  In Part A, abemaciclib will be administered at increasing doses of 100, 150, or 200 mg Q12H 
on Days 1 to 21.  In Part B, abemaciclib will be administered at a fixed dose determined in Part A of the study 
Q12H on Days 1 to 21.
Statistical Methods:
An safety interim safety analysis will be performed after the first 15 evaluable patients in the Part B portion of the 
trial have completed 2 cycles of study treatment (or otherwise discontinued study treatment).  Patients with 
squamous and nonsquamous NSCLC who received the recommended abemaciclib dose for Part B in Part A will be 
taken into account for the safety interim analysisanalyses.  The safety interim analysis will be conducted to permit 
evaluation of safety data by the sponsor.
Interim analyses for efficacy may be performed as needed to aid in the planning of future trials.  There is no plan to 
stop the study for positive efficacy.  The type-1 error for final primary analysis will not be affected and hence is 
not adjusted.
4. Abbreviations and Definitions
Term
Definition
ATE
arterial thromboembolic event
ORR
overall objective response rate
VTE
venous thromboembolic event
5.1.  Non-Small Cell Lung Cancer

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Current standard first-line chemotherapy for patients with advanced or metastatic NSCLC and a 
good performance status consists of a platinum-based doublet, using either cisplatin or 
carboplatin in combination with pemetrexed (only for nonsquamous NSCLC), taxanes, 
vinorelbine, or gemcitabine. The combination of a platinum-doublet with the anti-vascular 
endothelial growth factor (VEGF) antibody bevacizumab is a treatment option for nonsquamous 
patients only. Induction chemotherapy maybe followed by maintenance therapy, administered 
either as switch- or continuation maintenance. Second-line treatment options after failure of 
first-line chemotherapy with or without maintenance treatment consists of monotherapy with 
either docetaxel, erlotinib, or pemetrexed depending on type of prior treatment. Lately, an 
anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, ramucirumab, in 
combination with docetaxel was approved in the US and EU for the second-line treatment of 
metastatic NSCLC, including squamous and nonsquamous histologies (Cyramza Summary of 
Product Characteristics [SmPC]/US package insert [USPI]).  Recently, monoclonal antibodies 
(mAbs) directed against programmed death-1 (PD-1) T-cell co-receptor, nivolumab and 
pembrolizumab, have been approved in the US for the treatment of patients with metastatic 
NSCLC with progression on or after platinum-based chemotherapy, whereby pembrolizumab 
was approved for the treatment of those NSCLC patients whose tumors express PD-L1 as 
determined by an FDA-approved test (Opdivo USPI, Keytruda USPI).  In the EU nivolumab is 
available for the treatment of adult patients with locally advanced or metastatic NSCLC after 
prior chemotherapy (Opdivo SmPC).  For patients with tumors harboring epidermal growth 
factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-activating mutations, monotherapy with 
an EGFR TKI is used upfront, followed by osimertinib (Tagrisso PI) in patients with EGFR 
T790M mutation-positive cancer or a platinum-based doublet as second-line, or as second- or 
third-line treatment if not used previously. For patients with anaplastic lymphoma kinase 
(ALK)-gene arrangement, treatment should include monotherapy with an ALK inhibitor
(Heigener et al. 2014).
5.2.  Necitumumab 
Necitumumab (LY3012211) is a recombinant human monoclonal antibody (mAb) of the 
immunoglobulin (Ig) G1 class, which targets EGFR.  Necitumumab demonstrates a high affinity 
to its target and blocks ligand-induced receptor phosphorylation and downstream signaling.  In 
vitro studies further demonstrate that necitumumab inhibits EGFR-dependent tumor cell 
proliferation, and can exert cytotoxic effect in tumor cells through antibody-dependent cell 
cytotoxicity.
EGFR is expressed in a variety of tumors, including colorectal, head and neck, breast, and 
NSCLC (Salomon et al 1995).  In patients with advanced and metastatic NSCLC, EGFR is 
detectable in approximately 85% to 90% of patients (Fontanini et al 1995; Pirker et al 2009).  
Pharmacologic inhibition of EGFR signaling through competitive inhibition of ligand binding 
has been shown to play a role in the treatment of several cancers, leading to registration of 
necitumumab in squamous NSCLC and 2 other anti-EGFR mAbs in a number of other 
indications (Necitumumab/Portrazza SmPC, Cetuximab/Erbitux package insert [PI]/ Summary of 

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Product Characteristics [SmPC], Panitumumab/Vectibix PI/ SmPC). At present, no anti-EGFR 
mAb is approved for the use in patients with NSCLC; however, 2 Moreover, another randomized 
Phase 3 trials, one conducted with cetuximab another with necitumumab, showed evidence that 
the addition of an EGFR mAb to a platinum-based doublet can significantly increase survival in 
patients with advanced NSCLC (Pirker et al. 2009) and metastatic squamous NSCLC (Thatcher 
et al. 2014).
The necitumumab Phase 1 program included 2 single-agent dose-escalation Phase 1 trials in 
Western (I4XT-IE-JFCE [JFCE]) and Japanese (I4XT-IE-JFCA [JFCA]) patients with advanced 
solid tumors or for which whom no standard therapy was available.
The pivotal, randomized Phase 3 trial SQUIRE (I4XT-IE-JFCC) compared gemcitabine/cisplatin 
plus necitumumab (GC+N) versus gemcitabine/cisplatin (GC) as first-line therapy in 1093 
patients with Stage IV squamous NSCLC (Thatcher et al. 20154).  The study met its primary 
objective, demonstrating a statistically significant improvement in overall survival (OS) in the 
GC+N Arm compared with the GC Arm (hazard ratio [HR] = 0.84; p=0.012).  This was 
supported by a statistically significant improvement in progression-free survival (PFS; 
HR = 0.85; p=0.02). Several prespecified subgroup analyses for OS and PFS showed a 
consistent treatment effect in favor of GC+N.  Post-progression anticancer therapy was similar 
(47% vs. 45%).  The safety data obtained in SQUIRE overall were consistent with the safety 
profile expected for an anti-EGFR mAb, with skin reactions (any grade:  79% vs. 12%, including 
Grade ≥3:  8.2% vs. 0.6%) and hypomagnesemia (any grade:  31% vs. 16%, including 
Grade ≥39.3% vs. 1.1%) being the most frequently reported events (pooled terms) occurring at 
higher rates for patients receiving necitumumab.  The Grade ≥3 TEAEs with highest incidence 
for which incidence was higher in the necitumumab arm than in the control arm were 
hypomagnesemia (8.7% vs. 1.1%), rash (3.7% vs. 0.2%), pulmonary embolism (3.5% vs. 1.8%), 
hypokalemia (3.0% vs. 1.5%), and vomiting (2.8% vs. 0.9%).
In another randomized Phase 3 trial, INSPIRE (I4XT-IE-JFCB [JFCB]), 947 patients were 
planned to be randomly assigned to necitumumab plus pemetrexed - cisplatin (PC+N) versus 
pemetrexed - cisplatin (PC) as first-line therapy for Stage IV nonsquamous NSCLC (Paz-Ares et 
al. 2013).  Enrollment was halted, following an independent data monitoring committee (IDMC) 
recommendation, after 633 patients because of safety concerns related to thromboembolism as 
well as the overall number of deaths from all causes that were unbalanced against the 
experimental group; the trial continued for patients that had been enrolled.  Based on the final 
analysis, PC+N did not improve the efficacy outcome over PC alone in advanced nonsquamous
NSCLC (OS HR 1.01, p=0.96; PFS HR 0.96, p=0.66). The addition of necitumumab resulted in 
a higher frequency of Grade ≥3 TEAEs. Grade ≥3 TEAEs occurring more frequently in the 
necitumumab arm included skin or subcutaneous disorders (14.1 vs. 0.3%), thromboembolic 
events (9.5 vs. 6.4%), hypomagnesaemia (7.6 vs. 2.2%), asthenia (6.9 vs. 1.9%), vomiting (6.6 
vs. 3.2%), dyspnea (5.3 vs. 2.6%), and diarrhea (4.3 vs. 2.2%). The frequency of study drug 
related deaths was 4.9% and 2.9% for PC+N and PC, respectively.
Based on these data, the combination of necitumumab plus pemetrexed-cisplatin is not being 
considered for further development.  Of note, no safety signal with regard to thromboembolic or 

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potential thromboembolic events, including fatal events, has been identified for necitumumab in 
completed clinical trials when administered as monotherapy or in combination with mFOLFOX6 
chemotherapy.
Currently, 2The randomized Phase 2 trials, are ongoing (I4XT-IEMC-JFCL [(JFCL), ] and I4T-
JE-JFCM [JFCM]).  Study JFCL compares compared paclitaxel-carboplatin plus necitumumab 
versus paclitaxel-carboplatin in the first-line treatment of patients with Stage IV squamous 
NSCLC.  The overall efficacy and safety results were generally consistent with those of SQUIRE.  
Study I4X-JE-JFCM is a Phase 1b/2 study in Japanese patients with Stage IV squamous NSCLC 
that compares necitumumab plus gemcitabine-cisplatin versus gemcitabine -cisplatin alone.  
EachThe trial is monitored by an IDMC and continues as planned.
5.4.  Study Rationale 
Necitumumab (LY3012211) is a recombinant human mAb of IgG1 class, which targets EGFR.  
Necitumumab demonstrates a high affinity to its target and blocks ligand-induced receptor 
phosphorylation and downstream signaling.  EGFR is detectable in approximately 85% to 90% 
of patients with NSCLC (Fontanini et al 1995; Pirker et al 2009).  Pharmacologic inhibition of 
EGFR signaling through competitive inhibition of ligand binding has been shown to play a role 
in the treatment of several cancers, and EGFR mAbs are approved in various tumor indications 
(Erbitux PI/ SmPC, Vectibix PI/ SmPC). Portrazza has recently been approved in the United 
States (US) and European Union (EU) for the treatment of adult patients with metastatic 
squamous NSCLC in combination with gemcitabine and cisplatin (Portrazza USPI and SmPC).  
Two randomized Phase 3 trials show evidence that the addition of an EGFR mAb to a platinum-
based doublet can significantly increase survival in patients with advanced/ metastatic NSCLC 
(Pirker et al. 2009) and metastatic squamous NSCLC (Thatcher et al. 2014).  The necitumumab 
SQUIRE trial showed statistically significant improvements in OS and PFS, with an overall 
favorable benefit-risk profile.  In addition, a recent meta-analysis investigating the addition of an 
EGFR mAb to platinum-based first-line therapy demonstrated a significantly improved OS and 
PFS in patients with advanced NSCLC (Pujol et al. 2014).
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of necitumumab and abemaciclib may be found in the IBs and Portrazza SmPC.  Information on 
AEs expected to be related to the study drugs may be found in Section 7 (Development Core 
Safety Information) of the IB.  Information on serious adverse events (SAEs) expected in the 
study population independent of drug exposure and that will be assessed by the sponsor in 
aggregate, periodically during the course of the study, may be found in Section 6 (Effects in 
Humans) of the IB.
6.2.  Secondary Objectives
Part A:

to investigate the safety profile as assessed by clinical and laboratory significant events of 
necitumumab in combination with abemaciclib

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
to determine the overall objective response rate (ORR)

to determine pharmacokinetics (PK) of necitumumab and abemaciclib

to determine the immunogenicity of necitumumab
7.1.  Inclusion Criteria 
[10] Have the following laboratory values:

hematologic:  absolute neutrophil count 1.5 × 1099/L, platelets 
100 × 1099/L, and hemoglobin 9 g/dL.  Transfusion of blood products 
(including platelets or red blood cells) or administration of colony 
stimulating factors (including G-CSF, GM-CSF, or recombinant 
erythropoietin) within 4 weeks prior to Cycle 1 Day 1 are not allowed.  

Sserum albumin ≥25 g/L

hepatic:  bilirubin 1.5 ×times the upper limit of normal (ULN), alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
transaminase (AST) 3.0 times ULN.  For patients with hepatic metastases, 
ALT and AST equaling ≤5.0 times ULN are acceptable.

renal:  serum creatinine 1.2 xtimes ULN or calculated creatinine clearance 
>50 mL/min (per the Cockcroft-Gault formula as defined in Attachment 5) 
for patients with creatinine >1.2 times ULN.
[11] are mMen who are sterile (including vasectomy confirmed by post-vasectomy 
semen analysis) or who agree to use a reliable method of birth control and to not 
donate sperm during the study (and for at least 12 weeks following the last dose 
of necitumumab and abemaciclib or country requirements, whichever is longer)
OR
[12] are wWomen who are either: (a) not of child-bearing potential due to surgical 
sterilization (at least 6 weeks following surgical bilateral oophorectomy with or 
without hysterectomy or tubal ligation) confirmed by medical history or 
menopause*; or (b) of child-bearing potential who have a negative serum 
pregnancy test within 14 days prior to study enrollment 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).
7.2.  Exclusion Criteria 
[18] The patient has brain metastases that are symptomatic.  (Patients who have 
completed radiotherapy for brain metastases at least 2 weeks prior to receiving 
study treatment, who are now non symptomatic or on stable dose of steroids or 
anticonvulsants during the 2 weeks prior to receiving study treatment, are 
eligible).  Patients with asymptomatic brain metastases without need for treatment 
with steroids and who have not been treated with radiotherapy are eligible.  This 

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exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.  
[22] The patient has any ongoing or active infection requiring systemic therapy, 
including active tuberculosis or known history of infection with the human 
immunodeficiency virus (HIV 1/2 antibodies), or hepatitis B (e.g., HBsAg 
reactive) and/or C virus (e.g., HCV RNA qualitative is detected).
[31] History of interstitial lung disease or an active non-infectious pneumonitis
8.1.  Summary of Study Design  
Cohort 1

Necitumumab, administered I.V. over 50 60 minutes at an absolute dose of 800 mg on 
Days 1 and 8, followed by

Abemaciclib at a dose of 100 mg orally Q12H on Days 1 to 21
Cohort 2

Necitumumab, administered I.V. over 50 60 minutes at an absolute dose of 800 mg on 
Days 1 and 8, followed by

Abemaciclib at a dose of 150 mg Q12H on Days 1 to 21
Cohort 3

Necitumumab, administered I.V. over 50 60 minutes at an absolute dose of 800 mg on 
Days 1 and 8, followed by

Abemaciclib at a dose of 200 mg Q12H on Days 1 to 21
Note:  At the time of approval of the JFCU(b) protocol amendment, all patients who are still on 
the study will be administered necitumumab I.V. infusion over 60 minutes.
Provided there is an acceptable safety profile in Part A of this study, Part B will be initiated, 
which will include an safety interim safety analysis after the first 15 evaluable patients have 
completed 2 cycles of study treatment (or otherwise discontinued study treatment).  Patients with 
squamous and nonsquamous NSCLC who received the recommended abemaciclib dose for Part 
B in Part A will be taken into account for the safety interim analysis.
8.2.  Discussion of Design and Control  
Provided there is an acceptable safety profile in Part A of this study, Part B will be initiated, 
which will include an safety interim safety analysis after the first 15 evaluable patients have 
completed 2 cycles of study treatment (or otherwise discontinued study treatment).  Patients with 
squamous and nonsquamous NSCLC who received the recommended abemaciclib dose for Part 
B in Part A will be taken into account for the safety interim analysis.

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9.1.  Treatments Administered 
Table JFCU.9.1.
Treatment Regimens/Dosing Schedule
Part A 
Cohort
Drug
Dose
Day
Infusion duration
Cohort 1
Necitumumab
800 mg absolute 
dose I.V. infusion
Days 1 and 8
over 50 60 minutesa
(5 minutes)
Abemaciclib
100 mg Q12H
Days 1 - 21
Cohort 2
Necitumumab
800 mg absolute 
dose I.V. infusion
Days 1 and 8
over 50 60 minutesa
(5 minutes)
Abemaciclib
150 mg Q12H
Days 1 - 21
Cohort 3
Necitumumab
800 mg absolute 
dose I.V. infusion
Days 1 and 8
over 50 60 minutesa
(5 minutes)
Abemaciclib
200 mg Q12H
Days 1 - 21
Part B
Drug
Dose
Day
Infusion duration
Necitumumab
800 mg absolute dose I.V. 
infusion
Days 1 and 8
over 50 60 minutesa
(5 minutes)
Abemaciclib
Dose from Part A Q12H
Days 1 - 21
Abbreviations: IV= intravenously; Q12H = every 12 hours.
a At the time of approval of the JFCU(b) protocol amendment, all patients who are still on the study will be 
administered necitumumab I.V. infusion over 60 minutes (5 minutes).
9.2.  Materials and Supplies 
Necitumumab is a sterile, and preservative-free, solution for I.V. infusion supplied in the 
following formulation:

Necitumumab at a final concentration of 16 mg/mL (800 mg/50 mL) contained 
in single-use vials, in a formulation of 10 mM citrate, 40 mM sodium chloride, 
133 mM glycine, 50 mM mannitol, 0.01% polysorbate-(Tween®)-80, pH 6.0.

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All excipients used in the formulation of necitumumab are of pharmacopeial grade.  No 
animal-derived components are used in the manufacture of necitumumab excipients.  Refer to the 
IB for detailed storage information.
9.3.2.2.1.  Abemaciclib 
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (such asexcept
diarrhea) possibly related to abemaciclib that does not resolve with maximal supportive measures
within 3 days (as outlined in Section 9.5.3.) to either baseline or Grade 1, then dosing should be 
suspended (until the toxicity resolves to either baseline or at least Grade 1), and the dose of 
abemaciclib may be reduced as outlined in Table JFCU.9.2.
9.3.2.2.1.1.  Guidance for Monitoring of Renal Function in Patients on Abemaciclib 
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.  Dose alterations (omission, reduction, or 
discontinuation) should not solely be based on interpretation of serum creatinine values because 
these may not reflect renal function.
9.3.2.2.3.1.1.  Infusion ReactionsHypersensitivity/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.  
Hypersensitivity/infusion-related reactionsIRRs are defined according to the NCI-CTCAE 
Version 4.0 definition of allergic reaction / hypersensitivity, as follows:

Grade 1:  transient flushing or rash, drug fever <38°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)

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Consistent with usual medical practice, selected parenteral medications may be utilized as 
detailed below.  Additional treatments, chosen according to clinical symptoms and local 
standards, may be utilized at investigator discretion.  Table JFCU.9.3 provides general 
treatment recommendations for hypersensitivity/infusion-related reactionsIRRs to 
necitumumab.  
If a patient should have a hypersensitivity/infusion-related reactionIRR to necitumumab, all 
attempts should be made to obtain an anti-necitumumab antibody and necitumumab 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.
9.3.2.2.3.1.4.  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 necitumumab, until within normal limits.  
Prompt repletion is recommended, as appropriate.Hypomagnesemia occurred very commonly in 
patients receiving necitumumab.  Only individual cases led to discontinuation of necitumumab.  
Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia and 
replenish electrolytes as necessary.
9.3.2.2.3.1.5.  Cases of Pneumonia and Sepsis
In the ongoingDuring the conduct of Study JFCL (JFCL; Phase 2 study to investigate carboplatin 
and soluble paclitaxel 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.
The early occurrence of a number of these cases may have indicated an issue regarding the 
enrollment of the appropriate 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 
additional reports were received, notably of cases reporting pneumonia and septic complications 
with concurrent neutropenia.
an imbalance in the number of SAEs related to pneumonia and sepsis, including fatal cases, was 
observed.  After an unblinded review of all data by the IDMC assigned for this study, it was 
recommended to continue the study as planned.

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Serious infections are common complications of chemotherapy among oncology patients, due to 
the bone marrow suppressing effect of chemotherapy and associated in time with the occurrence 
of neutropenia.
It is of note that only some of the cases were associated with neutropenia and no imbalance was 
noted regarding events of neutropenia between the treatment arms.  Furthermore, a considerable 
number of cases observed in this study occurred very early after start of treatment, within 8 days 
after the first dose of the study drugs and before the administration of the second dose of 
necitumumab, which does not reflect the typical time pattern expected for a regimen including 
platinum-based chemotherapy and may indicate an underlying infection in these patients at time 
of enrollment into Study JFCL.
The review of the data from the Phase 3 study of necitumumab in combination with gemcitabine
and cisplatin (JFCC; SQUIRE) did not show any evidence of an increased risk of serious lung 
infections associated with necitumumab in this combination.
9.3.2.2.3.1.6.  Thromboembolic Events
In the Phase 3 study JFCC, there was an increase in venous thromboembolic events (VTEs) and 
arterial thromboembolic events (ATEs) in the investigational arm (necitumumab in combination 
with gemcitabine and cisplatin) compared to the active control arm (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.
In the Phase 3 study JFCB, an increased rate of serious thromboembolic events, including fatal 
events, has been observed for the combination of necitumumab with pemetrexed and cisplatin as 
compared with treatment with pemetrexed and cisplatin alone in patients with nonsquamous 
NSCLC.  Administration of necitumumab in combination with pemetrexed and cisplatin is not 
recommended.
In the Phase 3 study JFCC, a higher rate of thromboembolic events (for example, 
pulmonary embolism, venous thrombosis, cerebral ischemia, peripheral ischemia, and 
myocardial infarction) was observed in patients treated with the combination of 
necitumumab, gemcitabine, and cisplatin as compared to patients treated with 
gemcitabine and cisplatin alone.  No relevant imbalance was observed with regard to fatal 
thromboembolic events.
In cases of sudden death, investigators are requested to record on the SAE report form as much 
information as possible regarding the symptoms and signs immediately preceding death and any 
postmortem results so that an accurate cause of death may be established (specifically so that 
thromboembolism may be confirmed or denied).
9.3.2.2.3.1.7.  Cardiorespiratory Disorders

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An increased frequency of cardiorespiratory arrest or sudden death was observed with 
necitumumab.  Cardiorespiratory arrest or sudden death was reported in the pivotal Study JFCC 
(SQUIRE) 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.
12.1.  Determination of Sample Size 
A total of approximately 68 patients evaluable for either the Part A or Part B portions of the 
study will be enrolled.  Part A requires up to 18 treated patients (3-6 per dosage cohort).  Patients 
with squamous and nonsquamous NSCLC who received the recommended abemaciclib dose for 
Part B in Part A will also be part of the Part B portion of the trial.  These patients will also be 
included in the interim safety analysis analyses as described in Section 12.2.10.
The final analysis of the study will take place approximately 5 months after the last patient 
evaluable for Part B portion of the study has been enrolled.  The primary Part B outcome 
variable in this study will be the 3-month PFS rate.  The Part B statistical null hypothesis states 
that the true 3-month PFS rate is 50%, whereas the research hypothesis states that the true 
3-month PFS rate is 65%.  Assuming the Part B portion of the study continues to a full 
enrollment of 50 evaluable patients, the null hypothesis will be rejected at the final analysis only 
if at least 60% of evaluable patients expereinceexperience PFS ≥3 months.
12.2.10.  Interim Analyses 
An safety interim analysis will be performed after the first 15 evaluable patients in the Part B
portion of the trial have completed 2 cycles of study treatment (or otherwise discontinued study 
treatment).Patients with squamous and nonsquamous NSCLC who received the recommended 
abemaciclib dose for Part B in Part A will be taken into account for the safety interim analysis.
The safety interim analysis will be conducted to permit evaluation of safety data by Lilly.
The results from the safety interim analyses analysis will be examined by an internal assessment 
committee, which will be established prior to enrollment of the first patient in the 
trial. The internal assessment committee will consist of a Lilly medical director, a Lilly 
CRP/clinical research scientist, a PK scientist, and a statistician and will make recommendations 
about the trial. Enrollment will continue while the safety interim analysis is being 
performed. Interim The safety interim analysis results (including all tables, figures, and listings) 
will not be disseminated outside of the assessment committee, unless emerging safety outcomes 
warrant such a disclosure.  In case a disclosure is warranted, the outcome of the safety interim 

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analyses analysis will be documented, and a written letter will be submitted to the ERB(s) and 
the investigators for documentation purposes.
Interim analyses for efficacy may be performed as needed to aid in the planning of future trials.  
There is no plan to stop the study for positive efficacy.  The type-1 error for final primary 
analysis will not be affected and hence is not adjusted.
Patients with squamous and nonsquamous NSCLC who received the recommended abemaciclib 
dose for Part B in Part A will be taken into account for the interim analyses.
14.  References 
Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, Galiulin RK, 
Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Depenbrock H, Nanda 
S, Kruljac-Letunic A, Kurek R, Paz-Ares L, Socinski MA, SQUIRE investigators. 
Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-
line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an 
open-label, randomized, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763-774.
Thatcher N, Hirsch FR, Szczesna A, Ciuleanu T, Szafranski W, Dediu M, Ramlau R,  Galiulin R, 
Bálint B, Losonczy G, Kazarnowicz A, Park K, Schumann C, Reck M, Paz-Ares L, 
Depenbrock H, Nanda S, Kruljac-Letunic A, Socinski MA. 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). 2014 ASCO Annual Meeting [Abstract 
8008].  

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Attachment 2. Protocol JFCU Clinical Laboratory Tests
Hematologya:
Clinical Chemistrya:
Hemoglobin
Hematocrit
Erythrocyte count (RBC)
Mean cell volume (MCV)
Mean cell hemoglobin concentration (MCHC)
Leukocytes (WBC)
Neutrophils, segmented and bands
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Serum concentrations of:
Sodium
Magnesium
Potassium
Phosphate
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Blood urea nitrogen (BUN)
Creatinineb
Uric acid
Calcium
Glucose, nonfasting
Urinalysisc
Albumin
Color
Cholesterol
Specific gravity
Creatine kinase (CK)
pH
Protein
Glucose
Ketones
Blood
Urine leukocyte esterase
Pregnancy Test (females of childbearing 
potential only, serum required)d
Coagulation Testsd:
INR and PT
PTT
Fibrin D dimer
Protein C activity (baseline only)
Protein S activity (baseline only)

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Attachment 8. Protocol JFCU Inducers and Strong Inhibitors of CYP3A4 or Substrates of 
CYP2B
Substrates of CYP2B6
Alfentanil
Bupropion
cyclophosphamide
Efavirenz
Ifosfamide
methadone
Nevirapine
Propofol
Sertraline
sorafenib
tamoxifen
Valproic acid